Radiation and chemotherapy injury: pathophysiology, diagnosis, and treatment

Critical

ReviewIs in

ONCOLOGY/ HEMATOLOGY Critical

Reviews

in Oncology/Hematology

Radiation and chemotherapy

15 (1993) 49-89

injury: pathophysiology, treatment

diagnosis, and

David B. Busch

The text in general is not meant to represent the participants’

entire presentations. The lecture presenters in general are not responsible for the sum-

maries, and cannot necessarily be assumed to agree with all that is stated, but they deserve credit for providing the lecture and handout material on which the summaries are based, and in most cases have contributed far more to the summaries than 1 have.

Contents Introduction

2.

Basic concepts

3.

Basic concepts of radiation pathology; radiation tissues and organs (Philip Rubin. M.D.)

Busch,

of cellular

Ph.D..

M.D.)

and molecular

radiation

4.

Basic concepts

of chemotherapy

5.

Basic concepts

of chemotherapy-radiotherapy

6.

Radiographic

7.

Genetic

8.

Effects of radiation

9.

Respiratory

IO.

Pediatric

Il.

Bone and joint

radiation

pathology

12.

Cardiovascular

radiation

and chemotherapy

13.

Oral radiation

14.

Dermatologic ionizing radiation. Morgan. COL, USAF. MC)

changes

Gastrointestinal

16.

Pancreatic

17.

Hepatic

1040-8428(93)00078-T

injury

and chemotherapy

radiation

and salivary radiation

(Theodore

to radiation

and chemotherapy

(James

pathology

(Louis

injury

injury

volumes

of specific

54

(Herman

M.D.)

I. Libshitz.

54 M.D.)

55

Ph.D.)

56

(Louis Constine.

(Theodore

Phillips,

Constine,

M.D.)

M.D.)

59

M.D.)

59 60 61

(Luis Fajardo,

(Sol Silverman. radiation,

M.D.)

Jr., M.A..

62 63

D.D.S.)

and chemotherapy

pathology

(Andrew

M. 61

and chemotherapy

and chemotherapy

51

E. Sweet. M.D.)

non-ionizing

radiation

D.Ph.)

M.D.)

(Louis Constine,

E. Cleaver.

pathology

(Donald

doses and tolerance

L. Phillips.

on bone marrow

injury

Brown.

52

interactions

and chemotherapy

(J. Martin

tolerance

and chemotherapy

and chemotherapy

radiation radiation

pathology

biology

in radiation

predisposition

15.

1040-84281931$24.00 SSDI

(David

SO

.

I.

pathology

pathology (Kay

pathology

(Barbara

Woodruff.

(Luis Fajardo.

Egbert.

M.D.) M.D.)

M.D.)

68 71 71

D. B. Busch / Crit. Rev. Oncol. Hemarol. IS (1993) 49-89

50

......................................

18.

Endocrine

19.

Urinary

20.

Male reproductive

21.

Female

22.

Ophthalmic

23.

Central

24.

Radiation

and chemotherapy

cytopathology

(Kent

25.

Pathology

of acute

injury

Busch. Ph.D .. M.D.)

26.

Therapy

21.

Pathology

28.

Late effects consensus

29.

Additional special subjects not discussed at course (David Busch, Ph.D .. M.D.) ................ 29. I. Atypical cells in irradiated tissue .................................................... 29.2. General summary of radiation’s pathologic effects ..................................... ............................... 29.3. Information sources and resources in radiation pathology ..................................................................... 29.4.Hyperthermia .............................................................. 29.5.Cannabis controversy 29.6. Chronobiological and cell cycle effects in radiation and chemotherapy

30.

Military

31.

Biography

32.

Reviewer

33.

References

radiation radiation

pathology

and chemotherapy radiation

reproductive

radiation

of chemical

disclaimer.

(Devron

radiation

of acute radiation

pathology

(Theodore

L. Phillips,

pathology

(Luis F. Fajardo,

and chemotherapy

pathology

system

M.D.)

and chemotherapy

radiation

radiation

nervous

(Kay Woodruff,

(David (Daniel

agents

conference

(Theodore

acknowledgements

pathology Nowels,

F. Flynn,

(David

M.D.)

Busch,

and dedication

.............................................................................. ............................................................................

1. Introduction (David Busch, Ph.D., M.D. ) This article is based on presentations made at a threeday (approximately 20.25 CME credits) course on radiation and chemotherapy injury held August 29-31, 1992 at Laurel Heights Conference Center, University of California, San Francisco, with some additional material provided on subjects not addressed in detail at the course. This was the fourth course organized by me on this subject under the auspices of the Armed Forces Institute of Pathology (AFIP) and the American Registry of Pathology (ARP), which together sponsor about 50 short courses each year on different aspects of pathology. This course had previously been conducted three times in Bethesda, MD (intended site for the next such course in 1994). The course was originally intended for pathologists and military physicians concerned about diagnosis of radiotherapy injury or acute radiation injury. However,

.............

M.D)

Busch, Ph.D.,

(Richard

M.D.)

M.D.)

.......

Davis. M.D.)

M.D.)

72 73 74 75

..........

76

............................

77

.............................

79

..................................

Ph.D .. M.D.)

L. Phillips,

.............................................................................

(David

..................

......................................

M.D.)

and chemotherapy

injury

warfare

Char,

pathology

M.D.)

71

...........................

..............................

......................................

79 80 80 81 81 81 82 83 83 84 85 85 86 86

at the first session of the course it became clear that the principal group of people in the audience were cancer therapists and not pathologists; and since then the course has particularly emphasized cancer therapy effects. My belief is that military physicians generally are more concerned with therapy of acute radiation injury than with learning how to diagnose it. and that pathologists generally regard cancer therapy injuries as representing consultation cases that they encounter relatively infrequently, so that they are more likely to be attracted to courses discussing more commonly seen pathologic entities such as courses on cytopathology, skin or lymph node pathology. In contrast to pathologists, cancer therapists (especially radiation oncologists) are relatively likely to attend this course because of their concern with being able to recognize, monitor, and prevent the undesired harmful effects of their therapy. Thus, this is really a pathology-oriented course primarily for non-pathologists. In recognition of this

D. B. Busch / Crit. Rev. Oncol. Hemotol.

51

15 / 1993) 49-89

reality, the course has gradually evolved to emphasize histopathology somewhat less and other methods of diagnosis somewhat more, despite the extremely important continuing role of pathology in the course. An inherent problem with a heterogeneous audience with mostly clinicians but partly pathologists is that the nonpathologists may prefer less emphasis on pathology and more on other aspects of therapeutic injury, while pathologists may be primarily interested in tissue diagnosis. Providing sufficient material to satisfy both groups represents an important challenge for the course faculty. Because of the diabetic-like poor healing characteristics of many irradiated tissues, cancer therapists are often reluctant to have their patients biopsied in order to confirm a suspected diagnosis of radiation injury. This means that patients with mild to moderate radiation changes tend to not be biopsied, so that teaching files as well as surgical and autopsy pathology files have a relatively high proportion of cases from severely injured patients with cancer therapy complications, including end stage organ degeneration and ‘disaster cases.’ With their limitations on sampling irradiated tissues, clinicians rely heavily on other sources of information for the diagnosis, resulting in a decreased likelihood of the surgical pathologist having material to review. These other sources of information may include radiographic and imaging studies, visual appearance of site of irradiation, exfoliative cytology, and diverse tests of organ function, including clinical chemistry: and such studies are receiving increasing emphasis in the course. The course ideally provides at least a good introduction to basic principles and organ specific effects for histopathologic changes and other important aspects of the injuries, but the registrant may wish to spend some time in independent study following the course in order to review in more detail areas of particular interest. This may be helped by review of study sets on radiation injury available from ARP and AFIP. Ideally, the pertinent lecture and handout material will provide a good basis for further independent study of this type. In addition, personal contact with the faculty at the course may provide an introduction for further consultation after the course is over. Registrants have an opportunity to address their concerns about the course in written course evaluation forms provided by the AFIP, which have been helpful in deciding on areas of emphasis as well as in selection of faculty. The following sections of this article are based on my notes on other participants’ lectures, on theirs’ and my handouts, and on additional literature cited in the reference section. First person references refer to me (David Busch). An effort has been made to give participants an opportunity to review this text for errors and inclusion of particularly important points, and such review has been performed by most lecturers. During this review,

the sections by Dr. Sol Silverman, Jr. and Dr. Daniel F. Flynn were completely rewritten by them and thus are the only sections not written by me. Because this article is primarily intended for cancer therapists, a section of the course addressing injury by chemical warfare agents has been omitted aside from a mention of its occurrence and inclusion of pertinent references; and material on acute radiation injury and its therapy have been abridged and reworded in order to emphasize aspects relevant to therapeutic total body radiation and de-emphasize military medicine aspects. The references were in most cases provided by the lecturers. For those sections without cited references, a review of the subject is usually available in the texts by Berdjis [I], Fajardo [2], Rubin and Casarett [3], and White [4]. with extensive more recent material usually available in the medical literature.

2. Basic concepts of cellular and molecular biology (J. Martin Brown, D. Ph. i

radiation

The electromagnetic spectrum includes ionizing radiaseen in tion. For photons of 1-20 MeV, commonly radiotherapy, Compton electrons cause most of the associated radiation tissue damage. The occurrence of the effect is relatively independent of atomic number, with similar doses received by bone and by soft tissue. For diagnostic radiography. lower energy photons are employed. Here the photoelectric effect is relatively important, particularly below about 100 keV. The effect occurs at a rate proportional to the cube of the atomic number of the target material, so that bone absorption is much greater than soft tissue absorption. High energy photons can produce characteristic X-rays from the target material due to quantum changes in its electrons such as refilling of a shell vacancy following photoelectric effect. Ionizing radiation causes direct and indirect effects on the cell. Direct effects refer to absorption of radiation by DNA, producing lesions such as base changes. and also damage to the sugar-phosphate backbone. which may result in single and double strand breaks. Indirect effects, in which radiation generated reactive chemicals such as hydroxyl radical react with cellular DNA to cause base lesions and other damage. are thought to cause about 70% of mammalian cell killing by X-rays. Double strand breaks are the most toxic of radiation lesions. A gray (I Gy) (100 rad) of radiation produces about a thousand ionization tracks within a mammalian cell, resulting in about a thousand single strand breaks and about 40 double strand breaks. Double strand break repair is critical for cell survival. Yeast cells that are deficient in double strand break repair are killed by one double strand break. SCID mice, which have been likened to human ataxia telangiectasia patients. have a

D. B. Busch / Crir. Rev. Oncol. Hm~ulol. I5 ( 1993) 49-X9

52

double strand break repair deficiency and are radiation sensitive. Premature chromosome condensation is a method used to study the initial amount of chromosome breakage. Approximately ten per cent of double strand breaks manifest themselves as chromosome breaks immediately after irradiation. The other ninety percent of the double strand breaks cannot be visualized by this technique, and might be stabilized in nucleosomes and by protein binding that prevents the chromosome from flying apart. About a twelfth of chromosome breaks are not repaired, resulting in a chromosomal aberration such as a break or a dicentric. G2 block allows more time to repair the DNA before division; a block at the G,/S transition allows repair to occur before S phase. The cell will die or grow poorly if it generates an acentric fragment of an unrepaired or misrepaired chromosome. This fragment is seen during mitosis as a micronucleus. For both wild type cells and fibroblasts from ataxia telangiectasia patients, there is a close correlation between number of chromosome breaks per cell and level of cell survival. There are different preferred mathematical models for characterizing cell survival curves. The simple multitarget model is in disfavor because it fails to predict the slight degree of killing (non-zero lethality) seen at low doses. The linear quadratic model is now popular, surviving

fraction

= exp -(crD + PD’)

where a! reflects killing from a single hit and is independent of dose, while /3 reflects killing from two hits and is dose dependent. Recombination can influence cell survival. Two adjacent damaged chromosomes may have a symmetrical exchange of their arms, a non-lethal event; or an asymmetrical exchange resulting in a dicentric plus acentric fragment, which is lethal. Repair of potentially lethal damage is seen when one compares survival of cells plated right after irradiation with survival of cells of those where plating is delayed in order to allow additional repair to occur before cell division. Repair that results from changes in postirradiation conditions is generally referred to as repair of potentially lethal damage. Repair of sublethal damage (Elkind repair) is different; it is the repair that is seen when the dose is split. There are cell cycle effects that result in a complicated curve of survival fraction as a function of hours between the two doses of a split fraction unless there is liquid holding at room temperature, with nadirs in survival at approximately 0 or 6 h between fractions. This dependence of survival on interval between fractions is important to consider if radiotherapy is to be given more than once in the course of a day. Repair of both potentially lethal damage and sublethal damage may incorporate different aspects of an identical repair process involving strand break repair.

Oxygen is the most important chemical modifier of radiation damage both in vivo and in vitro. Oxygen enhancement ratios (OERs) of up to three are seen with radiation injury, even at low doses. A molecule RH is lysed by radiation to form a free radical, R’ , which reacts with oxygen to produce the peroxy radical ROO ’ ; this damage has been fixed by the oxygen before RH could be regenerated by donation of a hydrogen atom by another cellular molecule. Use of radioprotective agents such as those with the formula R’SH will help prevent this oxygen reaction by regenerating RH in the reaction R’

+R’SH

-

RH + R’S’

The best of the radioprotective agents in an aerobic environment is the sulfhydryl compound WR2721. There also are radiosensitizers that, like oxygen, react with organic free radicals; these can increase killing in hypoxic environments such as the interior of a large tumor. Hyperbaric oxygen also enhances the lethal effects of radiation. A correlation between oxygen tension and tumor response to radiotherapy has been reported. For cervical carcinomas, and probably head and neck tumors as well, free survival recurrence greatly improved as the oxygen tension within the treated tumor increased. A more detailed discussion of principles covered in this paper is provided by Hill [5]. 3. Basic concepts of radiation pathology; radiation tolerance doses and tolerance volumes of specific tissues and organs (Philip Ruhin. M.D.) Radiotherapists wish to maximize the difference in radiosensitivity between the tumor and the normal tissue, in order to minimize complications from irradiation of healthy tissue. Both normal tissues and their tumor counterparts have families of dose response curves. In general, the radiosensitivity of a tumor reflects the radiosensitivity of its tissue of origin e.g., lymphomas and seminomas are very radiosensitive, while rhabdomyosarcomas and leiomyosarcomas are highly resistant [6-91. For class I organs whose loss of function will be fatal, such as heart, lung, and bone marrow, TD,,,, levels have been determined by experience for both single and fractionated radiation. Marrow and gastrointestinal stem cells are far less radiation sensitive if the same dose is fractionated instead of being given in a single dose. Testis is unusual in showing increased sensitivity with fractionation. There are a number of variables that can affect an organ’s response to radiation, including dose, time, volume, expression time, age, host factors such as diabetes and hypertension, surgery, trauma, chemotherapy, hyperthermia, and biological response modifiers.

D.B. Busch/Grit.

Rev. Oncol. Hemarol. I5 (1993) 49-89

Mathematical modeling has been done to characterize organ response to radiation. This has resulted in Strandqvist lines, NSD, TDF, CRE, computerized guidelines, al/3 ratios, etc. The Strandqvist line represents an isoeffect line for tumor recurrence versus skin irritation or necrosis, used to help seek the best balance between inadequate and excessive radiotherapy. Modeling can allow one to study changes in radiosensitivity with changes in dose per fraction. Some organs show a rapid change in radiosensitivity with change in dose per fraction, while others do not, reflecting rapid versus slow renewal of cells. Volume effects are important in radiotherapy, with the whole organ versus a portion of the organ being irradiated and with large versus small tumors being irradiated. It is easier to sterilize a small tumor than a large tumor, and there is less likelihood of significant morbidity such as skin breakdown with a dose regarded as adequate to sterilize a small tumor than with a sterilizing dose for a large tumor. It may be important to consider how much of the organ can be lost without killing the patient; 5-25X destruction of the organ may be lethal for organs such as brain, cord, and GI tract, while marrow, heart, lung, liver. and kidney may continue to function at a clinically acceptable level with 50-90% destruction. Radiotherapists need good methods for measuring doses delivered to partial volumes. As the volume changes, the dose required to cause functionally serious organ damage changes. If the fraction of the organ that is irradiated increases, the dose must be decreased in order to keep toxicity at an acceptable level. Imaging techniques will assist in the understanding of dosevolume relationships in the future. The larger the tumor, the larger the dose required to control it. A large tumor has both more cells and a larger proportion of radiation-resistant hypoxic cells. It is easier to kill 99.9% of the cells in a tumor than to kill all of the cells, but all of the cells must be killed in order to eradicate the tumor, including the hypoxic cells. Methods to increase the radiation response of the hypoxic cells are needed; these include reoxygenation and fractionation. Cell synchronization may sometimes be helpful in optimizing radiotherapy due to differences in cellular radiosensitivity for G,, G2, M, early S, and late S cells. Hydroxyurea can be used to synchronize cancer cells in vivo in order to take advantage of this. There is about a fivefold to tenfold range in radiosensitivity of organs depending on volume and dose-time factors. The tolerance doses such as TD5,S and TD50,5 represent guidelines, not safe doses; and it iS important to consider medications and other factors which may affect the response to radiotherapy and make tolerance dose ligures unreliable in specific circumstances. There is a need to develop uniform methods for studying radiation tolerance. for both early and late effects. The

53

radiotherapy literature mainly discusses late effects. The relationship between occurrence of an early effect and the likelihood of developing a late effect is not well understood. Chemotherapy can cause a ‘recall phenomenon’ in radiation injury. In some cases. this is a combined modality late effect. Cycling cells generally are more radiosensitive than non-cycling cells. Thus, organs with non-cycling parenchymal cells, such as brain and heart. are generally more radiation-resistant than organs with cycling parenchymal cells, such as marrow and GI tract. Both radiation and chemotherapy may injure parenchymal ceils. However, vascular injury and edema are far more characteristic of radiation injury than chemotherapy injury [6-IO]. It is possible to plot curves showing the time to expression of injury following different methods of treatment, dividing the curves into acute, subacute, chronic, and late periods. There may be subclinical damage, clinically apparent damage (damage above a threshold for clinical detection), organ loss or death. Both chemotherapy and radiotherapy cause stem cell depletion or senescence and parenchymal cell hypoplasia; but chemotherapy is particularly effective at damaging non-cycling cells, and radiotherapy is particularly effective at damaging the microcirculation to cause spotty damage along the course of vessels. Confocal microscopy or microangiography allow visualization in three dimensions of these irregularly radiation injured vessels. Von Willebrand factor is released by damaged endothelium; it is difficult to assay, but is of interest because it may contribute to thrombosis of radiation injured vessels. Von Willebrand protein, which mediates platelet agglutination. is stored in endothelial cells’ Weibel-Pallade bodies. Risk of radiation-associated mental deterioration, seizures, learning disabilities. and other changes in brain function is correlated with presence of changes in the brain detectable on MRI study. An earlier marker of CNS radiation injury is myelin basic protein. In irradiated rat brain, vascular changes are evident six months after a dose of 60 Gy, followed in another six months by decreased cortical thickness. Heart injury by cancer therapy may include pericarditis from interstitial damage, and cardiomyopathy from microvascular damage. Myocyte damage is seen after high doses of adriamycin. and microvascular damage is seen after high radiation doses; while combined radiotherapy and adriamycin therapy may result in damage with low doses of each. Late gastrointestinal injury from radiotherapy may include bleeding, obstruction, necrosis, fistulization, subcutaneous fibrosis, and other effects associated with damage to crypt cells and endothelial cells. There are also acute GI effects such as esophagitis and enteritis. The risk of radiation-induced GI lesions is increased

D. B. Busch / Crii.

54

with concurrent chemotherapy, so that lesions may be seen at doses that do not normally cause the same lesions without chemotherapy. There may be combined effects of microvascular injury from radiation and crypt stem cell injury from chemotherapy that cause these problems. In liver, venous congestion injures hepatocytes after irradiation while, in kidney, radiation injures capillaries and arterioles, in contrast to the predominately tubular injury seen with chemotherapy. In marrow, hypoplasia or aplasia may be seen as a late effect. Good blood counts may be seen without concurrent good marrow regeneration in irradiated areas. Granulocyte colony-stimulating factor may stimulate marrow regeneration. It is likely that there are intercellular communication effects which occur in both marrow and organs immediately following irradiation that will modulate radiation effects. Organ transplantation and use of growth factors may reduce the late effect of radiation in marrow and possibly in some other organs, Irradiation of rabbit lung results in an increase of surfactant apoprotein in the serum. Radiation pneumonitis is thought to be secondary to release of stimulatory and inhibitory growth factors which may allow ‘conversations’ about the response to the radiation among endothelial cells, macrophages, libroblasts, etc. in the lung. Blockage of these growth factors could reduce the severity of radiation pneumonitis. Macrophage-conditioned medium stimulates proliferation of lung libroblasts, and this stimulation increases with increasing dose to the lung. Type II pneumocyte irradiation stimulates fibroblast proliferation. Messages from growth factors could be used to monitor and predict radiation effects, and could be modulated in order to decrease late effects. Radiation pneumonitis and lung fibrosis are different stages of the same multicellular process. 4. Basic concepts of chemotherapy L. Phillips, M. 0.)

pathology

(Theodore

Enhancement of radiation toxicity is seen with many chemotherapy drugs, including cisplatin, 5-FU, mitomytin C, bleomycin, hydroxyurea, and BCNU. Cisplatin causes intrastrand and interstrand crosslinks and free radical formation. It sensitizes hypoxic cells, inhibits DNA synthesis, and inhibits repair of potentially lethal and sublethal damage. FU is metabolized to form FdUTP, which is incorporated into DNA and causes chromosomal breaks resulting from DNA strand breakage. Mitomycin C causes interstrand crosslinks and chromosome breaks. It requires metabolic activation, which is efficiently performed by hypoxic cells. Bleomycin is a generator of superoxide and hydroxyl radicals, and causes strand breaks. Hydroxyurea, an inhibitor of ribonucleotide reductase.

Rur. Oncol.

Hentutol.

15 ( 19931 49-W

is toxic to S phase cells. It may inhibit repair of potentially lethal damage. BCNU, which carbamoylates DNA, causes crosslinks. Intestinal crypts are shortened due to radiotherapy induced loss of stem cells, with regrowth of stem cells followed by crypt elongation. Radiation killing of crypt cells is potentiated by BCNU, bleomycin, cisplatin, and 5-FU. There is an optimum time for administering the chemotherapy in the irradiated patient in order to maximize tumor kill while minimizing the killing of crypt cells and other normal cells. Many other organs show chemotherapy-radiotherapy interactions. For example, radiation esophagitis is enhanced by use of BCNU or cis-platinum. Clinical findings in radiotherapy-chemotherapy interactions may include acute skin, mucosal, and GI reactions which are increased by chemotherapy. These reactions may not be dose limiting, but they may increase both the need for supportive care and the rate of complications. There is a modestly increased incidence of late complications of radiotherapy in cisplatin and 5-FU therapy. Sensitization by drugs to radiation injury is tissue and drug specific. In general, acute effects are enhanced more than late effects. Chemotherapy drugs may increase the therapeutic index of radiotherapy, allowing more effective treatment without increasing the rate of late effects. 5. Basic concepts of chemotherapy-radiotherapy tions (Louis Constine, M.D.)

interac-

Normal tissue damage due to radiation therapy injury can be enhanced by chemotherapy. Conversely, use of radiotherapy can increase injury from chemotherapy. Both may cause toxicity to the same organ by different mechanisms. Combined use of chemotherapy and radiotherapy in a patient may cause a degree of injury that would not be clinically toxic following radiotherapy alone or chemotherapy alone. One may see acute effects without late effects, or late effects without acute effects. In ‘recall phenomenon,’ with radiation followed by chemotherapy, eruption of a radiation-like injury may follow the chemotherapy. For a drug, the dose effect factor (DEF) is defined as: ‘the radiotherapeutic dose required for biological effect without drugiradiotherapeutic dose required for biological effect with drug’. It is desirable to have a DEF value > 1 for tumors and a DEF value < 1 for normal tissue. There is a therapeutic gain if the relative effect of combined radiation and chemotherapy on the tumor exceeds that of important normal tissues. There are several ways to sequence radiation therapy and chemotherapy: (i) simultaneous: both given at the same time; (ii) adjuvant: chemotherapy follows radio-

D.B. Busch/Cd.

5s

Rev. Oncol. Hematol. 15 (1993) 49-89

therapy; (iii) neoadjuvant: chemotherapy precedes radiotherapy; and (iv) alternating: chemotherapy alternates with radiotherapy. Different magnitudes of radiotherapy/chemotherapy interactions may occur. These include: (i) independent activity. (ii) increased activity; (a) subadditive, (b) additive, and (c) enhanced (synergistic). (iii) Decreased activity (as in antagonism or inhibition). Some mechanisms for chemotherapy-radiotherapy interactions: ( 1) Physiological mechanisms, some speculative e.g., increased blood flow. increased uptake of agent, reoxygenation, increased cell-cell interactions increasing sensitivity. (2) Cell kinetics: recruitment of G, cells into the cell cycle, in which sensitivity is greater; redistribution of cycling cells to a more sensitive phase within the cell cycle e.g., hydroxyurea synchronization at the G,/S junction. (3) Cell survival or repair: inhibition of repair; increased accumulation of sublethal damage; decreased recovery from potentially lethal damage; change in slope of dose response curve. Diverse agents, such as caffeine and chemotherapy drugs, decrease recovery from radiation damage. There also are patient factors determining chemotherapy and radiotherapy effects. These include: (1) Genetic predisposition e.g., nevoid basal cell syndrome. (2) Structural changes e.g., one kidney absent. (3) Illness e.g., diabetes. (4) Age. (5) Inherent normal tissue sensitivities and repair capacities. There also are therapeutic factors affecting response to radiotherapy and chemotherapy, including: (1) Agent type, dose, and schedule. (2) Radiotherapy dose, fractionation rate, treatment time, treatment volume, dose distribution. and machine energy. (3) Time between radiotherapy and chemotherapy. (4) Chemical and biological dose response modifiers e.g., sensitizers, protectors, and immunotherapy. Combined adriamycin and radiation therapy inhibits wound healing more severely than either by itself. Tumor factors affecting chemotherapeutic response include sensitivity, repair capacity, direct effects on normal tissue dependent on extent of invasion, and indirect effects on tissues. Therapeutic implication of chemotherapy-radiotherapy interactions: try to select agents that increase tumor kill but affect a different normal tissue cell population than that affected by irradiation. Chemotherapy can be most useful in sterilizing micrometastases and improving local control. 6. Radiographic changes in radiation and chemotherapy injury (Herman I. Libshit:. M.D. ) Treatment volume, shape of field, dose, time since completion of radiotherapy, and use of other medications all may affect radiographic changes following radiation [I I]. The radiation field defines the limits of these

changes. It is important to give an adequate radiation history to the consulting diagnostic radiologist; knowing the portal can allow the identification of a lesion as caused or not caused by irradiation. Some of the important changes are listed below. 6.1. Lungs [12-141 After about 8 weeks with doses of 35-40 Gy, radiation pneumonitis is seen. This eventuates in radiation fibrosis. After about 9-12 months, changes of radiation fibrosis become stable. A later change in this pattern can indicate a complication such as tumor recurrence. Patients with radiation-induced pulmonary changes are more often than not symptomatic. In addition to local recurrence, the differential diagnosis may include lymphangitic spread, infection, and a second primary. Pleural effusions may be seen within 6 months of radiotherapy, occurring concurrently with pneumonitis. There are different stages in the evolution of radiation change in the lung seen at CT. It begins with homogeneous consolidation that progresses to a more discrete consolidation. The radiation change may be patchy within the treated volume. At higher doses ( >45 Gy) a solid consolidation is seen in which only dilated bronchi are present. 6.2. Heart [15-171 About 5% of patients develop symptomatic heart disease at doses of approximately 40 Gy. Sixty percent of radiation pericarditis cases are seen 4-12 months after radiotherapy. The remainder develop later. Radiographic (CXR or CT) changes following radiation injury of the heart include pericardial effusion and congestive heart failure changes. 6.3. Esophagus [IS] Abnormal motility may occur 4- 12 weeks after therapy but occasionally after 1 week if chemotherapy has also been given. Strictures are seen after 4-8 months. In addition, ulcerations, pseudodiverticuli. and tistulae may develop. This is more common with combined radiotherapy and chemotherapy than after radiotherapy alone. 6.4. Stomach There may be ulceration. Radiation-induced ulcers are radiographically indistinguishable from benign peptic ulcers. 6.5. Duodenum There may be mucosal

thickening

or ulceration.

6.6. Small bowel [ 191 There may be mucosal thickening. stricture, distensibility, fixation, or ulceration.

decreased

D. B. Busch / Crit.

56

6.7. Large bowel [20-2 1I Similar changes are seen as in the small bowel. In radiation colitis, there is often smooth, elongated narrowing. Endoscopy is better for studying mucosal changes, and barium enema better for evaluation of stenosis and strictures. The studies are complementary. In general, CT and MRI are less valuable than barium studies in evaluating radiation injury of the bowel. 6.8. Urinary [2 l-241 Acutely there may be a swollen, non-functioning kidney. There may aiso be later chronic effects, with a small and contracted kidney. Radiation nephritis may have associated benign hypertension, late malignant hypertension, or asymptomatic proteinuria. There may also be extensive perivesical adipose tissue, marked bladder wall thickening and decreased bladder volume. Ureteral strictures are uncommon, and usually result from cancer and not from therapy. There may be tistulas from the bladder to the bowels, vagina. rectum, skin, or peritoneal cavity. 6.9. Brain [25-261 There may be subclinical changes evident only on MRI; leukoencephalopathy is seen in almost all treated patients. CT or MRI may also show asymptomatic edema. There may be focal necrosis which is difficult to distinguish from cancer. 7. Genetic predisposition Cleaver, Ph.D.)

to radiation injury (James E.

There are genetic diseases causing sensitivity to UV, X-rays, or chemotherapy [27-321, some of which are listed below. 7.1. Ataxia telangiectasia These patients have impaired motor function, impaired intellectual function, impaired immune response, and characteristic chromosomal exchanges at loci important in the immune system. The disease is seen in l/40 000 live births, with 0.5-l%, of the population being carriers of this autosomal recessive disease. Fibroblasts of carriers have intermediate radiation sensitivity. In contrast to the observed variations in radiation sensitivity seen in normal patients, which may reflect factors such as the redox state of the cell and glutathione levels, AT patients have abnormal sensitivity to radiation associated with their absence of G2 block and S phase block, a regulatory deficiency preventing adequate repair of radiation damage before mitosis. Carriers are at increased risk of cancer [33], but the risk for patients is much higher. In irradiating AT patients, one must greatly decrease the dose in order to avoid disasters such as were seen in early radiotherapy experiences with AT patients who were given normal radiotherapy [34-361.

Rev. Oncol.

Hematol.

15 (1993)

49-89

There is a wide distribution curve for in vitro radiosensitivity of fibroblasts from AT and normal patients, with the two curves not quite overlapping [27,37] and the AT fibroblasts showing generally abnormally high radiosensitivity, reflecting the in vivo radiation responses. Cells of AT heterozygotes are at the low end of the normal distribution curve. In a similar mouse disease, SCID mice have defective strand break rejoining after Xirradiation. They lack B and T lymphocytes and have a defective JDCJJ rearrangement system with abnormal rearrangements of immunoglobulin and T cell receptor genes. AT patients are sensitive to bleomycin and neocarcinostatin, which cause chromosomal deletions and breaks. These patients also are vulnerable to sinopulmonary infections, and have oculocutaneous telangiectasias. There are four or live AT genes, including A, C, D, Vl, and V2, which are on chromosome 11, different from the SCID gene on chromosome 8. 7.2. Xeroderma pigmentosum [38] These are among the patients most susceptible to damage from sunlight, which includes UVC ( c 290 nm), UVB (290-320 nm), and UVA (320-400 nm). XP patients have a massive incidence of skin cancers in sun exposed areas. Neurological changes, including cortical atrophy, hyporeflexia, and neuronal degeneration, are seen in some patients. 7.3. Cockayne’s syndrome These sunlight sensitive patients have erythema, developmental delay, premature aging, skeletal changes, demyelination, and retinal degeneration but no increased cancer risk. 7.4. Trichothiodystrophy These patients have photosensitivity, ichthyosis, sulfur deficiency, brittle hair with alternating light and dark areas, and mental and growth retardation. XP patients have unrepaired UV photoproducts in their DNA, including pyrimidine dimers and 6-4 photoproducts. Except for occasionally seen ‘XP variants,’ XP patients’ cultured skin Iibroblasts show reduced or absent unscheduled DNA synthesis in vitro compared to wild type cells (Fig. 1), reflecting their reduced ability to excise and replace UV damaged segments of DNA. XP and ERCC proteins bind to the photoproduct, then cause excision from 6 bases to one side of the lesion to 22 bases to the other side. Human single strand binding protein occupies the remaining strand until DNA polymerase and DNA ligase fill in and seal the gap. Normally, actively transcribed genes are repaired more rapidly than inactive genes. In XP, dimers are removed very slowly. An intensively studied gene is the gene for XP group A, which codes for 273 amino acids; has a zinc finger area for making loops to bind to the DNA helix; and has six exons.

57

D. B. Busch / Crit. Rev. Oncol. Hematol. 15 (I 993) 49-89

B

A

.

D

:.

.2?

*” . ,

-.

. .

t c *

. 1 f

:.

*

. Fig. I Autoradiography of UV-treated and unirradiated wild type and xeroderma pigmentosum group A (XP A) human diploid fibroblast strains. 750 x Normal non-S phase fibroblasts produce several dozen grains per nucleus when irradiated with UV and incubated with tritiated thymidine. reflecting UV excision repair that removes and replaces UV-damaged DNA segments. S phase cells. which are not scored, have variable but generally distinctly higher levels of grain production (tritiated thymidine incorporation) due to the particularly high level of DNA synthesis seen during S phase. Irradiated XP cells usually have subnormal unscheduled DNA synthesis (LIDS) levels. (A). Four unirradiated wild type nuclei with no gram production (no damage to repair). (B), Two irradiated wild type cells. showing UDS in one nucleus represented by production of several dozen grains. and much more heavy labeling from normal S phase replication in an adjacent nucleus. (C), Two unirradiated XP A nuclei with no grain production (no damage to repair). (D). irradiated XP A nuclei. two showing no UDS (no observable UV excision repair system to handle damage. due to‘genetics) and one showing heavy S phase DNA synthesis.

58

D. B. Busch / Crif. Rev. Oncol. Hemarol. 15 (1993) 49-89

Fig. 2. Hypocellular bone marrow, 300 x (A). Chemotherapy injury, marrow from malignant lymphoma patient with disseminated aspergillosis following administration of Cytoxan. Oncovin, prednisone. bleomycin. adriamycin. vincristine. Decadron. cisplatin. VPl6. and high dose ara-C (no lymphoma seen at autopsy). The marrow is hemorrhagic. (B), Fanconi’s anemia (hereditary pancytopenia) patient with no history of cancer therapy. These cancer prone patients have congenitally hypocellular marrow resembling irradiated or chemotherapy treated marrow, and also have an inherited susceptibility to mitomycin C damage.

D.B. Busch/ Cd.

59

Rev. Oncol. Hemarol. 15 (1993) 49-89

XP patients must avoid sunlight! They are sensitive in vitro to cisplatin, psoralens, and other mutagens, mandating caution in chemotherapy. In addition to the information provided by Dr. Cleaver, Dr. Busch [29] proposed that many patients showing injury from radiotherapy and chemotherapy might be carriers for diseases such as XP and AT. This was prompted by case reports of radiation sensitive patients with radiation sensitive cells [39-411, and by publications noting heterogeneity in patient radiosensitivity and proposing procedures for individualizing treatment to allow for genetic susceptibility to radiation injury [34,42-451. Dr. Busch proposed that AT carriers. who have relatively radiation sensitive fibroblasts, represent about 1%) of the population, and are overrepresented among cancer patients [33], might represent a high percentage of injured cancer therapy patients, as might Fanconi’s anemia (FA) patients (Fig. 2). Genetic screening methods might be developed to identify these individuals as high risk patients requiring particularly therapy careful monitoring and individualized [39,43-451. Their therapy might be assisted by quantitatively comparing the in vitro sensitivity of their cells to radiation or chemotherapy drugs to the sensitivity of normal cells, as was done in a published case of radiotherapy of a child with medulloblastoma and AT [42]. Cloned human DNA repair genes might be useful in developing these genetic screening methods, and also could lead to insights into methods for stimulating patients’ normal cells’ DNA repair levels in vivo. Norman et al. [46] have recently published a study suggesting that AT carriers are overrepresented among injured breast cancer patients, raising additional concern about this problem. 8. Effects of marrow (Louis

radiation and chemotherapy Constine, M.D. )

on bone

Bone marrow is often the dose-limiting organ in patients given radiotherapy or chemotherapy [47]. Bone marrow damage can result from: (i) stem cell injury; (ii) stromal or microcirculatory damage; (iii) perturbation in bone marrow function from underlying disease; and (iv) inherent stem cell defect from underlying disease. Acute peripheral blood changes may include thrombocytopenia, granulocytopenia, and anemia, reflecting underlying marrow changes (Fig. 2). Chronic changes may include decreased tolerance for additional cancer therapy; early marrow failure, possibly representing accelerated aging; cell and hypoplastic and myelodysplastic syndromes. Recovery may be rapid following some chemotherapy drugs. With other cytotoxic agents, such as gamma irradiation, busulfan, carmustine, and melphalan, there may be delayed recovery. Myelosuppression may be immediate, early or late following therapy. The time course

of the myelosuppression is a function of drug mechanism of action, dose, schedule, route of administration, use of combined therapies, and other factors. Chronic toxicity may reflect decreased numbers of stem cells or decreased stem cell proliferative potential (stem cell compartment problem), or microenvironment changes affecting tibroreticular precursors, or inhibition of sustained marrow support. Radiotherapy causes hematopoietic cells to diminish in days, possibly slowly returning to normal levels within weeks to years, depending on the radiation dose and volume. In chronic marrow injury, one may see regeneration in the irradiated area with hyperplasia elsewhere; marrow production in new areas of bone; or extramedullary hematopoiesis. Following a very large dose. there is collagenization of the marrow cavity without replacement of marrow. Damage to stroma causes most of the chronic injury in irradiated areas of marrow. Marrow shows a greater capacity for repair in vivo than in vitro. Marrow toxicity may be less with use of chemotherapy followed by radiation than in the opposite sequence. Tolerance of marrow for radiation may be increased by chemical protective agents such as WR-272 1: biological protective agents such as ILl; growth factors that increase stem cell reserve and increase the number of cycling cells; and by bone marrow transplantation. 9. Respiratory radiation and chemotherapy ( Theodore Phillips, M.D. )

pathology

Irradiated lung may show acute, intermediate, and late effects. Acutely, about l-3 months after the midpoint of the radiotherapy course, the patient may be asymptomatic while microscopically having decreased type II pneumocytes, type 11 pneumocyte degranulation, collagenization, plasma cell and mast cell infiltration, and blebbing and loss of endothelial cells. Intermediate effects, seen 4- 18 months after the midpoint of radiotherapy, are progressive with symptoms depending on the dose and volume of treatment. Capillary lumina are collagenized or show ingrowth of new capillaries, patent capillaries are decreased, basement membrane is thickened, and alveoli are decreased. Subsequently (after the first 18 months), late effects are seen, with chronic and progressive fibrosis seen in a patient who may have been initially asymptomatic. Late effects may be graded using such endpoints as cough, radiographic changes, and dyspnea or oxygen requirement. Pulmonary function tests and quantitative V-Q scans are helpful in evaluating these patients. Chemotherapy drugs, including alkylating agents. antimetabolites, antimitotic drugs, and cytotoxic drugs all can profoundly affect the lungs (Fig. 3). Cyclophosphamide interacts with radiation to increase radiation toxicity. Melphalan can cause irreversible lung damage.

D. B. Busch / Crit. Rev. Oncol. Hematol. 15 (1993) 49-89

60

Fig. 3. Lung, 150

x

Diffuse alveolar damage following chemotherapy

ate. There is hyaline membrane

formation.

in addition

with bleomycin. Adriamycin.

Busulfan has cumulative respiratory effects. BCNU also has cumulative effects, above 1200 mg/m*. Methotrexate causes reversible lung changes. Among the many other lung-injuring drugs include araC, cyclosporin A, vinblastine, vincristine, bleomycin (high risk of lung injury above 400 units), mitomycin C (may be more dangerous with concurrent bleomycin therapy), and actinomycin D and adriamycin (more dangerous with radiotherapy). In summary, different lung cells have different roles in acute versus late effects. Time, dose, and fractionation effects are important determinants of risk for lung toxicity. There are many quantitative endpoints for assessing the level of these common radiation and chemotherapy induced lung effects. 10. Pediatric radiation and chemotherapy

cyclophosphamide,

to edema. atypia, desquamated

injury (Louis

Constine, M.D. ) It is at times difficult to evaluate late normal tissue effects in pediatric patients due to the paucity of systematic data, long latent periods from therapy to toxicity, death of many of those treated, and poorly defined treatment populations. The age of the patient will affect the vulnerability of different organs e.g., the brain is largely developed at about 3 years but not fully myelinated until 12 years, yet the skeleton may grow until the third decade. Sexual organs develop primarily in puberty. Here are effects of some therapies [48].

pneumocytes.

vincristine, and methotrex-

and hemorrhage.

In leukemia therapy, there may be brain and hypothalamic/pituitary injury from prophylactic irradiation. Cognitive deficits are seen, with deficits of 5-20 IQ points after radiotherapy and chemotherapy. Leukoencephalopathy and mineralizing microangiopathy can also infrequently occur. In 65% of patients receiving over 20-30 Gy, there is a deficiency in growth hormone, probably due to hypothalamic injury. There are secondary malignancies, including astrocytomas and AML. In radiation therapy for Hodgkin’s disease, many organs can be affected. These may include: (I) Cardiac changes - more common previously than with current therapy. (2) Dental and salivary gland injuries. (3) Bone injuries, such as decreased epiphyseal chondrogenesis, defective metaphyseal absorptive processes, and altered diaphyseal periosteal activity and remodeling which can result in (a) decreased height, especially for irradiation before 6 years or following over 35 Gy, (b) slipped capital femoral epiphysis, (c) avascular necrosis of the femoral or humeral head and (d) shortening of the clavicle. (4) Lung injury in 5% of patients after 35-40 Gy; there can be late fibrosis without early pneumonitis. (5) Reproductive system. (a) Ovarian injury with decreased sexual development, decreased menstruation, and decreased fertility. Sterility is reduced if oophoropexy is performed. 15% of girls are sterilized by

D. B. Busch / Crit. Rev. Oncol. Hematol. I5 (19931 49-89

10 Gy; while women, who have fewer ova left to kill, are sterilized by 6 Gy. (b) Testicular injury with decreased sexual development, decreased libido after >25 Gy (Leydig cell injury) and decreased fertility with oligospermia after l-5 Gy. Recovery can occur over several years e.g., after 5 years following 4-6 Gy. (6) Radiotherapy also causes thyroid insufficiency. After 26 Gy, there may be decreased or normal T4 and elevated TSH. Children may spontaneously recover thyroid function. Wilms tumor patients now have 70% overall survival; and over 90%) survival for early stage disease. Radiotherapy may result in renal dysfunction, with decreased creatinine clearance; liver injury evident with LFTs or scans; restrictive lung disease resulting from impaired development of the ribcage causing decreased lung expansion; and scoliosis. Treatment of Ewing’s sarcoma may cause pathologic fracture (if the bone has been surgically manipulated); or limb shortening, atrophy, fibrosis, or lymphedema; however. improved therapy is decreasing the complication rate. Orbital radiotherapy of rhabdomyosarcoma may result in cataracts, orbital hypoplasia, facial asymmetry, cornea1 changes, enophthalmus, lacrimal duct stenosis, retinal changes, impaired vision, photophobia, conjunctivitis, and ptosis. Therapy of brain cancer may result in cognitive changes, neuroendocrine changes such as hypothyroidism and alopecia. Secondary neoplasia may occur in children, which may be enhanced by cytotoxic therapy. Children with one tumor have an increased risk of a second tumor, including a fourfold risk after surgery, a sixfold risk after chemotherapy, and a ninefold risk after combined radiotherapy and chemotherapy. 11. Bone and joint radiation pathology (Donald E. Sweet, M.D.1 Radiation effects on bone may include changes in bone growth, radiation osteitis, radiation necrosis, and neoplasia. These complications are a function of time, place, and amount of radiation. In considering these complications, one must consider both growing bone, and bone in the skeletally mature patient. Bone is shaped by osteoblasts and osteoclasts. Bone and joint growth, development, and remodeling depend on metabolism. stress, and circulation. Bone may be formed from a cartilaginous model, or by intramembranous bone formation, or by remodeling of existing bone. Cell hypertrophy, cell proliferation, and matrix elaboration all lengthen bone in a cartilage model. The TD,,, for radiation injury is approximately 1000 R for children’s cartilage, 2000 R for children’s bone, and 6000 R for the more resistant, mature bone of

hl

adults. Radiation-induced growth changes may involve widening of the epiphyseal growth plate and decreased mineralization. There may be changes in the mechanics of the diaphysis. The area of injury may migrate away from the growth plate as the bone continues to grow, with the injured area eventually remodeled out of existence in some cases. The injured area, with relatively weak bone, may be the site of a pathologic fracture [49]. In perichondral injury, there may be an osteochondroma resulting from displacement of the cartilage cap. Spinal injury may result in osteoporosis with spinal collapse. Thorotrast accumulates in RE cells and in marrow. In the process of creating necrotic bone that fails to remodel, it can leave a radiopaque zone in the bone that has the size and shape of the bone at the time of its absorption of the thorotrast, giving a ‘bone within a bone’ radiographic image. Another complication of bone irradiation is radiation osteitis, in which marrow has fibroblast and capillary proliferation and dystrophic mineralization. with avascular necrosis from the damage and reaction to the damage causing increased pressure in the marrow cavity. Osteoradionecrosis and radiation osteitis have similar radiographic presentations. Microscopically. there are dead bony trabeculae. dystrophic mineralization, ischemic ossification (an abnormal ossification pattern with poor quality osteoid resulting from ischemia), and dead adipocytes, the latter resulting from 4-5 days of anoxia. Neoplasia may occur in different situations in irradiated bone [50-511. These include normal bone becoming sarcomatous; a benign lesion such as a giant cell tumor becoming sarcomatous; and one malignancy such as Ewing’s sarcoma being followed by a histologically distinct malignancy. It is reasonable to suspect a radiation etiology in a new tumor when it occurs in an irradiated area of previously normal bone with a latency of about 4 years or more, with histologic examination required for the diagnosis of the cancer. Radiation-induced bone sarcomas may occur from about 3.5-20 or more years after irradiation. Histological types found include malignant fibrous histiocytoma (pleomorphic spindle cell tumor), fibrosarcoma, chondroosseous tumors (osteosarcomas and chondrosarcomas), and angiosarcomas. The secretory product, or matrix, of bone sarcoma is not very useful in predicting tumor behavior. Different histology may be seen in different areas of a bone tumor reflecting both the cell of origin and the development of the bone. Matrix made by a tumor may depend on where it is e.g.. an osteosarcoma may appear cartilaginous when invading cartilage. but may make osteoid when invading bone. An X-ray of an osteosarcoma may show bone infarction. One unusual case of radiation-induced bone sarcoma was seen in an irradiated Ewing’s sarcoma

62

(femoral head) patient with subsequent patellar chondrosarcoma. Relatively little is known about chemotherapy effects on bone. However, it is noted that steroids can cause osteonecrosis (avascular necrosis) by increasing adipocyte mass within the marrow and thus increasing intramedullary pressure. Chemotherapy also is toxic to bone marrow as well as to tumors occupying the marrow; the extent of chemotherapy-induced marrow tumor lysis may be evaluated with a whole mount section of the

bone. 12. Cardiovascular radiation and chemotherapy pathology (Luis Fajardo, M, D. ) Changes in the heart following irradiation may include acute pericarditis, delayed pericarditis, chronic pericardial effusion, pancarditis, and coronary artery disease [52]. Acute pericarditis is rarely seen acutely during irradiation, usually as a response to tumor necrosis and not to the radiation by itself. More often, there is delayed pericarditis occurring at least 6 months after irradiation, which may require several pericardiocenteses. Radiation pericarditis includes deposition of fibrinous material on parietal and visceral pericardium in addition to a serous effusion. It is necessary to exclude recurrent malignancy in such cases. Irradiation of the myocardium may result in patches of diffuse fibrosis, particularly involving the anterior left ventricular wall, but also occasionally affecting the anterior right ventricular wall. Occasional calcified myocytes may be seen. Irradiated coronary arteries may have changes indistinguishable from those of ‘spontaneous’ atherosclerosis. The New Zealand white rabbit represents a good laboratory model for radiation injury of the heart. The following observations refer to animals receiving a single dose of 20 Gy in the heart. During the first 48 h after irradiation, they show a diffuse neutrophilic infiltrate of the heart, which is speculated but not proven to occur early in radiotherapy of humans. After about 70 days, the animals show fibrinous and fibrous pericarditis and also myocardial fibrosis. The irradiated rabbit myocardium has microcirculatory failure and thus ischemia. Five days after irradiation, the rabbit myocardial endothelial cells have thickened cytoplasm with projections in the capillary lumina and narrowing of lumina. The swelling eventually increases to block the capillaries, and then thrombi are seen by 40 days. The reto injury also includes endothelial cell sponse proliferation, peaking at 50 days, and detectable using autoradiography with tritiated thymidine. The mechanism of rabbit myocardial fibrosis is endothelial damage with inadequate proliferation of endothelial cells,

D.B. Busch/Grit.

Rev. Oncol. Hemarol. IS (1993) 49-89

leading to ischemia and fibrosis. This occurs after a single dose of 2000 rad, but similar changes are seen with fractionated radiation. Capillary injury of this type probably represents the basis for radiation changes in many other organs as well. In the pericardium, there are probably leaky capillaries with fibrin exudate. Fibrin resorption may be impaired by tumor induced changes in the level of plasminogen activator. Both the ischemia and the fibrin may be important in the pathogenesis of the radiation pericarditis. Chemotherapy also can injure the heart. Adriamycin mainly causes myocyte and not vessel injury, in contrast to radiation, which causes little cardiocyte injury directly. Adriamycin use is followed by myocyte vacuolization (Fig. 4) representing dilated sarcoplasmic reticulum. Also seen are characteristic but not pathognomonic ‘adria cells’ with homogeneous basophilic material in place of myolibrils. These ultrastructurally show partial or complete loss of contractile elements with only remnants of filaments. Fibrin and increased collagen are seen around the cardiocytes, and these adriamycin induced deposits may evolve to generate a diffuse myocardial fibrosis as dead or dying cardiocytes are replaced by scar tissue. Billingham has offered a grading system for anthracycline cardiotoxicity going from 0 to 3, which is used for determining if the chemotherapy may be continued. In rabbits given levels of adriamycin and radiation that by themselves would not cause severe cardiac injury, additive but not synergistic damage may be seen in which there is combined myocyte damage, capillary damage, and pericarditis. In humans a cumulative adriamycin dose of 550 mgim’ causes a 5% incidence of heart failure. This complication is more frequent following irradiation; use of some other chemotherapy drugs such as cyclophosphamide; previous disease of myocardium, valve, or coronary arteries; hypertension; and diabetes. Heart radiation injury is irreversible, since overall the lesions are not repaired. The risk of cardiac injury is greatly reduced if the irradiation includes less than 60% of the cardiac silhouette. In general, vascular radiation injury particularly involves injury of capillary endothelial cells [53]. Injury of endothelium in large vessels may have relatively little impact because it does not result in acute obstruction. In general, arterioles, capillaries, and sinusoids are most vulnerable to radiation injury. Macrophages forming collections of intimal foam cells in small arteries are almost pathognomonic of radiation injury, although they also are seen in metabolic lipid disease. Most large arteries are rarely affected by irradiation (except possibly for coronary arteries). There are occasional cases of carotid artery rupture following irradiation. However, these are generally associated with surgery, probably from vasa vasorum injury from desiccation (vessel drying due to exposure to air), or from exposure

D. B. Busch / Cd.

Rev. Oncol. Hematol.

Fig. 4. Heart. 300

x Adriamycin

63

IS (1993) 49-89

cardiomyopathy

with edema,

vacuolization tolysis.

to digestive enzymes. Thus, these are not truly radiationinduced. It may be difficult to save a patient with a ruptured carotid artery, although gradual rather than abrupt rupture improves the odds. Irradiated vessels generally do not show acute inflammation except very early, before symptoms occur. An exception is acute radiation vasculitis seen in some patients, with lymphocyte infiltration and fibrin deposition, resembling the spontaneous vasculitis of polyarteritis nodosa and in Churg-Strauss but confined to the radiation field. This is a delayed, local phenomenon due to local radiation effects, and is not an ominous sign of a systemic disease. It may particularly affect the breast and mesenteric vessels. 13. Oral radiation and chemotherapy Silverman, Jr., M. A., D. D. S. )

pathology

(Sol

This text was written by Dr. Silverman. Ionizing radiation delivered in doses that will kill cancer cells induces unavoidable changes in normal tissue, causing compromises in function and host defenses and severe complications. The degree of these changes is directly proportional to the volume of tissue irradiated and the total dose given, and is inversely proportional to the number of fractions and total time in which this dose is delivered. The radiation changes associated with treatment of the oral cavity include acute skin reactions, or radiation dermatitis, and delayed skin and subcutaneous damage,

of cardiocytes.

fiber atrophy.

loss of cross striations.

and myocy-

including telangiectasia, fibrosis, and edema. Intraoral changes include acute mucositis (erythema, pseudomembrane-covered ulcerations, and hyperkeratosis) and delayed soft tissue necrosis [54-551. Damage to the bone can result in osteonecrosis and sequestration or progressive osteonecrosis. Radiation changes in the salivary glands result in abnormal saliva and secondarily increased caries and other dental defects. Radiation also directly damages the taste buds in the tongue and results in transient, or sometimes permanent, loss or alteration of taste. 13.1. Mucocutaneous changes Unless intraoral or interstitial treatment is used, most patients will develop some erythema and moderate tanning of the skin in the treatment portal. Hair follicles are quite radiosensitive, therefore if hair is in the treatment beam it will cease to grow and will fall out. This is often transient. The acute oral mucosal reaction (mucositis) is secondary to radiation-induced mitotic death of the basal cells in the oral mucosa. Because these cells require approximately two weeks to mature, there is a delay of about this time between the onset of radiation therapy and the appearance of mucositis. If the radiation is delivered at a rate equivalent to the ability of the oral mucosa to regenerate, then only mild mucositis will be seen. When the weekly or daily dose is increased just slightly, destruction will outpace proliferation and a rather marked mucositis will develop. This occurs with doses of be-

64

tween 180 and 220 cGy (1 cGy = 1 rad) per day, five days per week. Thus, patients receiving 170 cGy per day will rarely develop mucositis, and those receiving 220 cGy per day will always develop a rather marked confluent mucositis. The reason for a higher daily dose is the possibility of a greater killing effect on cancer cells. Acute mucositis is not related to late radiation-induced atrophy and telangiectasia of the mucosa. However, this late change often increases the risk for pain and/or necrosis. Management may sometimes require a one-week interruption of therapy. Topical anesthetics (viscous xyloCaine) may be of some value, but the pain usually requires systemic analgetic drugs. Since infections may be associated, appropriate diagnoses and antimicrobial agents must be considered. When chemotherapeutic agents are added to therapy, the adverse side effects are increased primarily due to leukopenia. 13.2. Loss of taste Because of the irradiation of the taste buds, patients will develop a partial (hypogeusia) or complete (ageusia) loss of taste during treatment. The alterations in taste for sweet, sour, butter, and salt are variable and are caused by damage to the cells in the taste buds and/or their innervating nerve fibers. These cells will regenerate within four months after treatment in most cases, although permanent impairment may result. Dietary consultations regarding recipes with pleasing texture and perceptible and pleasing taste are essential to improve intake of food. Failure to eat is often associated with the loss of pleasure in eating and lack of imagination in food preparation. This is further complicated when surgery, often presenting problems in mastication and swallowing, has been required as part of the treatment. Trials with zinc supplements far exceeding recommended daily doses appear to be promising (zinc sulfate capsules, 220 mg twice daily with meals; approximately 100 mg elemental zinc). In addition to improving taste perception in some patients, zinc has occasionally improved saliva production. 13.3. Dental caries Patients who have not shown any degree of caries activity for years may develop dental decay and various degrees of disintegration after irradiation. The cervical areas are most typically affected. This condition appears to be due to the lack of saliva as well as to changes in its chemical composition. One result of radiation xerostomia is a pronounced shift towards a highly acidogenic, highly cariogenic oral microflora. The protective influence of saliva has been demonstrated by the extensive dental destruction found in animals subjected to salivary gland ligation or removal and in patients with xerostomia caused by drugs (e.g., diuretics, antidepressants) or disease (e.g., Sjogren’s syndrome).

D. B. Busch /Ct.

Rev. Oncoi. Hematol. 15 (1’9%) 49-89

Radiation-induced dental effects depend upon salivary changes and occur when the glands are included in the field of treatment, not upon direct irradiation of the teeth themselves. Whether direct irradiation of teeth alters the organic or inorganic components in some manner, making them more susceptible to decalcitication, has not been shown clearly. Remineralization of enamel by a salivary substitute has been reported. There do not appear to be any clinical or histological pulpal differences in non-carious human adult teeth, whether they have been in or out of the field of radiation. Studies in monkeys have also found no dental pulp damage. To prevent or at least minimize radiation caries, oral hygiene must be maximal, including intensive home care and frequent office visits for examination and prophylaxis. Mouth rinsing is essential; hydrogen peroxide rinses (3% Ht02 and equal parts water) and/or antiseptic mouth rinses, if tolerated are helpful in eliminating debris and controlling microbial flora. Daily topical fluoride applications, either as a solution for mouth rinsing or a gel delivered by means of a tray are extremely effective. Attempts should be made to increase salivary flow either by local or systemic means. Foods and beverages containing sucrose should be avoided as much as possible. If carious lesions develop, removal and restoration should take place immediately. Appropriate use of dental X-ray imaging is in order when indicated to monitor caries activity. When teeth during development are exposed to radiation (before age 10) significant dental anomalies can occur. These include tooth agenesis, arrested root development, microdontia, and enamel dysplasias. 13.4. Salivary function Exposure of the salivary glands to the field of ionizing radiation (Fig. 5) induces fibrosis, fatty degeneration, acinar atrophy, and cellular necrosis within glands. A critical dose level has not been identified. The serous acini appear to be more sensitive than the mutinous. During irradiation, the glandular secretions are usually diminished, thick, sticky, and very bothersome to the patient. Some patients are unable to produce more than 1 ml of pooled saliva in 10 min. The duration of this depressed salivary function varies from patient to patient. In most patients, there is usually regeneration several months after treatment, and the undesirable signs and symptoms of xerostomia (discomfort, difficulty in speech and swallowing) are at least partially reversed. In some patients, recovery of adequate saliva for oral comfort and function may take from 6 to 12 months; in others, the saliva remains inadequate indefinitely and is the source of major posttreatment complaints. When both of the parotid glands are exposed to the treatment beam, saliva diminution is most marked, and the prognosis for recovery is the worst. Frequent sips of water and water rinses are essential

D.B. Busch/Cd.

Rev. Oncol. Hematol.

Fig. 5. Submandibular

15 (1993) 49-89

gland, 150 X. Radiation

65

sialoadenitis with duct ectasia, acinar atrophy with minimal residual mucous secretory cells; stl fibrosis, edema, and round cell infiltrate;

for partial control of radiation-induced xerostomia. Sugarless chewing gum and tart candy may be helpful. In some patients, pilocarpine hydrochloride (solution or tablets) has been effective in stimulating saliva production. Approximately 5 mg four times daily has been an optimal dosage for most patients. Side effects can include sweating and stomach discomfort, but this usually occurs only at higher dosages. Another salivary gland stimulant, bethanechol (Urecholine@ administered as tablets in divided doses varying from 25 to 200 mg daily) has been helpful in many xerostomic patients. Synthetic saliva solutions and saliva substitute lubricants have been of limited help in the majority of patients with dry mouths, although some favorable reports have been published. 13.5. Candidiasis Infections of the mouth by Candida albicans are commonly seen in irradiated patients and are related to alterations in saliva. Clinically the signs may be confused with radiation mucositis or other sources of infection. Candidiasis is usually painful. Management is primarily with the use of antifungal drugs. Systemic administration (200 mg ketoconazole daily with food) is usually more effective for both response and compliance. Topical administration entails the use of nystatin or clotrimazole tablets dissolved orally. Because of pain from mucositis and dryness, patients may experience difficulty in dissolving tablets topically. Suspensions are

and atypia.

another alternative form of treatment, but often this treatment is not as effective as the tablets (possibly because of limited contact time between drugs and fungus). These fungal-control approaches are often used in combination. Antiseptic mouth rinses similar to those used for caries control may be helpful if tolerated. In addition, topical (viscous xylocaine) or systemic analgetics may be required.

13.6. Osteoradionecrosis Osteoradionecrosis is one of the more serious complications of head and neck irradiation for cancer. Bone cells and vascularity may be irreversibly injured. Fortunately, in many cases devitalized bone fragments will sequestrate and lesions will spontaneously heal. However, when radiation osteonecrosis is progressive, it can lead to intolerable pain or fracture and may necessitate jaw resection. The preventive and therapeutic use of antibiotics and hyperbaric oxygen can be effective, but reproducible beneficial results remain uncertain. The incidence of osteoradionecrosis varies depending on the reporting institution, aggressiveness of radiotherapy, and follow-up time. The risk for developing a spontaneous osteoradionecrosis is somewhat unpredictable, but it is related to the dose of radiation delivered and bone volume. The risk is increased in dentulous patients, even more if teeth within the treatment field are removed after therapy. Spontaneous bone

66

exposure usually occurs more than one year after radiation is completed. Animal models to study the effects of ionizing radiation on jaw bones have demonstrated changes similar to those observed in human specimens: marrow avascularity and fatty degeneration; reduction of osteocytes, osteoblasts, and osteoclasts; enlarged lacunae; and microfractures. 13.7. Soft tissue necrosis Soft tissue necrosis may be defined as the occurrence of a mucosal ulcer in irradiated tissue that has no residual cancer. The incidence of soft tissue necrosis is related to dose, time, and volume irradiated. The risk is far greater with interstitial implantation and intraoral techniques because of the higher irradiation doses used. In a University of California, San Francisco, study of 278 patients, soft tissue necrosis occurred in 18 cases (6.5%). Eleven of these patients were treated by needle implantation or intraoral cone techniques. The average time of onset was within a year of therapy. Fifteen cases were self-limiting in time periods ranging from one to ten months (average three months), but three cases required surgical intervention. Soft tissue necrosis is usually quite painful. Optimal hygiene is required and analgetics are usually helpful, but antibiotics are generally of little help in relieving pain and promoting healing. Since these ulcerations are often at the site of the primary tumor, periodic assessment for recurrence is essential until the necrosis heals. 13.8. Management In view of the risk that accompanies high-dose irradiation, special attention to preradiation dental planning appears critical. Factors important in the dental management of these patients include the following: (1) anticipated bone dose, (2) pretreatment dental status, dental hygiene and retention of teeth that will be exposed to high-dose irradiation, (3) extraction techniques, (4) allowance of adequate healing time for teeth extracted before radiotherapy, and (5) patient motivation and capability of compliance to preventive measures. Since many infections occur months or years after treatment, it is evident that the tissue changes induced by radiation persist for long periods of time and may be irreversible. Therefore, extreme care must be taken in evaluating the status of the teeth and periodontium before, during, and after treatment, and optimal oral and periodontal hygiene must be maintained because of the lowered biological potential for healing in response to physical irritation, chemical agents, and microbial organisms. Such attention is critical because of the potentially progressive nature of radiation osteonecrosis, which may involve large segments of bone and present a major therapeutic problem, possibly requiring extensive resection.

D.B. Bus&/Crit.

Rev. Und.

Hemafol.

I5 ( 1993) 49-89

It is impossible to establish precise formulae for managing preradiation and postradiation dental problems. Extractions are considered primarily for teeth with a poor prognosis due to such conditions as advanced periodontal disease, extensive caries activity, and periapical lesions. Other considerations are sources of chronic soft-tissue irritation (trauma), and the degree of patient cooperation in preventive home care and dental office programs. The decision is modified further for each patient on the basis of the individual’s prognosis, age, desires, economic aspects, and radiation delivery. Reported studies and personal experience do not substantiate the advisability of extracting all teeth before treatment as a good preventive measure. When teeth are extracted before or after radiation, the alveolar bone must be evenly trimmed and carefully smoothed so that a primary tissue closure is possible. This is necessary because suppression of bone cell viability diminishes remodeling, and if a suitable alveolectomy is not performed, the resulting alveolar ridge will be irregular and may increase the risk of subsequent bone exposure and discomfort. A minimum of one week to ten days is arbitrarily allowed for initial healing before radiation is instituted. However, if the situation permits, more time is preferable, up to 14 or even 21 days. Since dosages are fractionated, healing can usually continue before damaging levels of radiation are delivered to a surgical area. Obviously, teeth completely out of the treatment field are not affected similarly. There is no evidence as to how many teeth should be extracted at one time. Therefore, whether before or after irradiation, all of the teeth indicated for removal are extracted as suits the needs of the surgeon and patient. The use of antibiotics during the healing period is important to minimize infection. Whenever possible, an attempt is made to retain teeth to support tooth-borne appliances for the tentatively planned rehabilitation of these patients. It must be recalled that many teeth, either primarily or secondarily exposed to radiation, remain relatively free of disease and functional for long periods of time. This significantly facilitates rehabilitation. However, tissue-borne prostheses are not contraindicated. In general, mucosa that appears to be fibrosed, telangiectatic, and atrophic is a greater risk. The periodontium is maintained in optimal condition by periodic routine periodontal procedures. When areas exposed to radiation are treated, extreme care is exercised and antibiotics may be selectively administered. Fluoride applications (daily, in the form of mouth rinses or gels) appear to aid in minimizing tooth decalcitication and caries in these patients. There are no unusual contraindications for endodontic procedures. In conclusion, review of the literature and our own experience indicate that carefully controlled studies are necessary before more definitive guidelines can be for-

67

D. B. Busch / Crit. Rev. Oncol. Hematol. I5 (1993) 49-89

mulated for managing dental structures which have been or are to be radiated. Until such information is available, each case must be managed individually, based on the patient’s needs, the status of the tumor, and the risks known to exist for dental health in irradiated tissues. An overall ‘one-type’ empirical approach for all patients is contraindicated. 13.9. Chemotherapy When using cytotoxic chemotherapeutic drugs, it is extremely important to keep patients free from oral foci of infection and pain in order to minimize local infections and bacteremia, and to enable them maintain a nutritious diet. The chemotherapeutic agents utilized to eradicate tumor production also adversely affect normal cells, particularly those that have relatively high turnover rates, such as oral epithelial tissues. The depressant effect of therapy on oral epithelial mitoses can result in thinning and ulcerations of the tissues as well as salivary gland and taste dysfunction. The oral ulcerations may be due to direct cellular cytotoxicity from the chemotherapeutic agents, to increased susceptibility to microorganisms owing to neutropenia, to trauma, or to a combination of these factors. It is important to realize that the ability of oral tissues to resist trauma and to repair themselves is significantly compromised, and even irritation from eating and talking can lead to mucosal breakdown. Since continued therapy will further induce myelosuppression, leukopenia and thrombocytopenia, patients will become even more susceptible to infection and bleeding. The increased risk of infection is particularly important: not only can periodontal and dental infections have serious consequences, but the oral cavity can be the site of infections caused by viruses, fungi and acquired bacterial pathogens. The reactivation of herpes-family viruses such as herpes simplex I and Varicella roster, can cause significant mucosal breakdown, pain, hemorrhage, and increase in the risk of secondary infection. Fungal infection, caused by Candida and Aspergillus to producing local disease, can species, in addition spread systematically and cause serious infections. Bacterial infections can be caused by organisms normally found in the oral cavity, as well as by a number of opportunistic pathogens such as Pseudomonas, Klebsiella, Serratia, Escherichia, and other gram-negative bacteria. Identification of the source of infection and appropriate selection of antimicrobial agent(s) are critical to effective management. Marrow transplantation is associated with frequent and significant oral and head and neck complications. High doses of chemotherapeutic agents, with or without total body irradiation, can result in severe oral and pharyngeal mucositis, pain. infections, and hemorrhage. An additional complication of marrow transplantation is graft-versus-host disease (GVHD) which results from

the reaction of donor T-lymphocytes against host antigens. The oral cavity can be the site of both acute and chronic GVHD. Children who receive chemotherapy and/or radiation therapy to the jaws when permanent teeth are developing may suffer a number of abnormalities involving teeth and jaws: complete or partial dental agenesis, root malformation, and maldevelopment of jaws. 14. Dermatologic ionizing radiation, non-ionizing radiation, and chemotherapy pathology (Andrew M. Morgan, COL,

USAF.

MC)

Ionizing radiation from therapy, accidents, or atomic weapons may damage skin, with sequelae including chronic radiation dermatitis (Fig. 6). which resembles accelerated aging of the skin; basal and squamous cell carcinomas; alopecia; erosion; ulceration; and contractures [56-591. Radiotherapy is used more carefully on skin now than previously, with applications in treatment of malignancy, especially in older patients or in patients who cannot tolerate surgery. Cancers of the tip of the nose and also large, ulcerating lip cancers are situations in which radiotherapy also is useful. Radiotherapy has about the same cure rate as surgical excision for basal cell carcinoma. with better results than curettage and electrodesiccation. Grenz rays are used for some dermatoses. Disadvantages of skin radiotherapy may include worsening of scars; sensitivity to sun, wind, and cold: alopecia; requirement of multiple office visits; and damage to underlying tissue. Skin radiotherapy is with X-rays of < 100 kV and usually < 50 kV, with exposures of 90- 110 R/minute, using minimal filtration with a beryllium window. Ultrasoft radiation of < 20 kV (Grenz ray), used for some superficial dermatoses, only penetrates 2-3 mm of skin and gives incomplete depilation. Soft X-rays of 20-60 kV are useful for superficial facial cancers. while X-rays of 60- 100 kV are useful for less superficial cancers. Indications for radiotherapy may include the following: (1) Previous radiotherapy making surgical treatment hazardous. (2) Location susceptible to surgical deformity or clinically important altered function, including nasolabial fold, eyelid (reduced risk of distortion), canthi, lips, cheeks, preauricular area. ear. and forehead. (3) Tumor size; large tumors may be surgically difficult to approach without complications or mutilation. (4) Histology; radiation sensitivity follows the order lymphoma > basal cell carcinoma > squamous cell carcinoma > endothelioma > adenocarcinoma > sarcoma > melanoma. Radiotherapy also is used for Kaposi’s sarcoma, mycosis fungoides. lentigo maligna, Bowen’s disease, lymphocytoma cutis, and lymphoma cutis.

68

Fig. 6. Skin, 75 X

D.B. Busch / Crit.

Rev. Oncol.

Hemarol.

Radiodermatitis. Dermal hbrosis telangiectasia. basophilic change (not shown), and mild round cell infiltrate maI appendages: flattening of rete ridges; epidermis with variable thickness and with hyperkeratosis.

(5). Age. Radiation fibroblasts are encountered in irradiated dermis. They have abnormally enlarged nucleus and cytoplasm; nuclear atypia including pleomorphism, enlargement, irregularity, and hyperchromasia; multinucleation; and stellate shape. Irradiated skin also has vascular injury, with reduced number of vessels, hyalinized and thick walled vessels, thrombosed vessels, obliterated arteries, and telangiectasia. Irradiated skin with a chronic, non-healing ulcer showing peripheral keratosis should raise concern about squamous cell carcinoma; the periphery of the ulcer will hopefully show pseudoepitheliomatous hyperplasia, but there may instead be cancer. Although squamous cell carcinoma is the malignancy most commonly encountered next to radiation induced skin ulcers, basal cell carcinoma is the most common postradiation skin cancer. There are also occasional cases of radiation induced skin sarcomas. Postradiation skin squamous cell carcinomas, in contrast to the same cancers in unirradiated patients, metastasize readily (l/5- l/4 of cases). Cancer chemotherapy may cause a variety of skin changes [60-631, particularly alopecia and hyperpigmentation. The alopecia occurs with l-2 weeks delay. There are proliferating follicles with anagen effluvium (shedding). Hyperpigmentation is induced by alkylating agents and by antibiotics, with variable distribution including a tendency to involve nails, pressure areas, and scratch lines; there is increased melanin with incontinent pigment. Less common skin complications

15 (1993)

49-89

with loss of epider-

of chemotherapy include photosensitivity and hypersensitivity reactions; radiation enhancement; UV recall phenomenon; phlebitis; and chemical cellulitis. Rare complications include acral sclerosis, Raynaud’s phenomenon, sterile folliculitis, skin or nail atrophy, and dystrophy and lysis of nails. There also may be palmar and plantar erythema and tenderness. COL Morgan also discussed in detail the pathology of skin injury by non-ionizing radiation such as visible light and ultraviolet [56,64-681. This is generally of little relevance to cancer therapy except for treatment of mycosis fungoides by PUVA (psoralen plus UVA), but represents a large fraction of clinically observed skin lesions. 15. Gastrointestinal radiation and pathology (Barbara Egbert, h4. D. )

chemotherapy

Both acute and late radiation changes have been described in the irradiated GI tract distal to the oral cavity [69-731. Acute changes in the esophagus include cellular swelling, vacuolation, and atypia; ulceration with inflammation; and degeneration of submucosal glands. Chronic esophageal radiation changes include thickening of the regenerated epithelium; parakeratosis; basal cell atypia; telangiectasia; arterial thickening; mucous gland fibrosis and squamous metaplasia; homogenization of collagen; atypical fibroblast appearance; and stricture. The squamous metaplasia may be confused with malignancy.

69

D. B. Busch / Crit. Rev. Oncol. Hematol. IS (1993) 49-89

The stomach acutely shows decreased chief and parietal cell granules; pyknosis; necrosis; round cell inflammatory infiltrate; and regeneration. Chronic radiation changes in stomach include ulceration and chronic radiation gastritis. The ulcer is likely to be solitary and antral, with the risk of perforation, and with microscopic findings of fibrin, telangiectasia, radiation fibroblasts, and prominent vessels. Chronic radiation gastritis microscopically shows in the irradiated area the presence of lymphoid aggregates, atypical glandular nuclei, fewer glands, perivascular lymphocytes and fibrosis, submucosal fibrosis interrupting muscle bundles, cyst formation, and intestinal metaplasia. The irradiated small bowel is more likely to be injured if adhesions are present, since these reduce the mobility of the affected area and can increase its dose by preventing it from migrating into and out of the radiation port during successive fractions. Similarly, the terminal ileum, which is normally in a tixed position, is a commonly injured area of irradiated intestine. Acutely, irradiated intestine has crypt cell pyknosis, karyorrhexis, erosions, fluid and electrolyte changes, and villous shortening. The villi are denuded of their epithelium, despite efforts by the relatively few residual epithelial cells to cover the exposed villi. Chronic radiation changes in small bowel include ulceration, perforation, blunting of villi, lymphoid atrophy, submucosal fibrosis, presence of radiation libroblasts, vascular radiation

Fig. 7. Colon,

15

x

Colitis cystica profundis

after irradiation.

changes, fibrinoid change, fibrosis of the muscular layer with nerve entrapment, stricture, and perforation. Appendix and colon both show chronic changes consisting of fibrosis, decreased lymphocytes, radiation injury of vessels, and presence of radiation tibroblasts. The large bowel is more resistant to radiation than the small bowel, although the rectosigmoid is more vulnerable than the rest of the large bowel due to its fixation. Acutely, large bowel shows atypical cells, pyknotic nuclei, decreased crypt content of mucin, and crypt abscesses with both neutrophils and eosinophils. Chronic large bowel changes also include ulceration, atrophy, pseudopolypoid hyperplasia, colitis or proctitis cystica profundis, and vascular changes. Colitis cystica profundis (Fig. 7) is seen with polyps, ulcerative colitis, surgery, salmonellosis, amoebic dysentery, chronic ulcers, diverticulosis, radiation, and without explanation. It can result in rectal bleeding, mucous discharge, diarrhea, rectal prolapse, and sacral pain. A radiation etiology is not excluded if the lesion is in the radiation field; one sees stromal and vascular radiation changes with glands in the submucosa and muscular layer. With a non-radiation etiology, the glands are submucosal, are particularly likely to be seen in the rectosigmoid, and are unaccompanied by other vascular and stromal stigmata of irradiation. Neoplasia may occur in the GI tract due to irradiation. The atomic bombs used in Japan are blamed for

with erosion and fissuring of mucosa and apparent

dular structures. and degeneration

of this trapped epithelium.

ingrowth.

entrapment

as glan-

70

D.B. Busch/Cd.

Fig. 8. Autoradiography of tissue, a ‘special stain’ for tissue radioactivity. Alpha emitters Thorotrast liver, 300 x Linear tracks representing alpha particles released by thorium decay. alpha tracks radiating from particles of plutonium inhaled in experimental study with dogs. far more numerous tracks than in the thorotrast

Rev. Oncol. Hemaiol. I5 (1993) 49-89

produce straight tracks a few microns in length. (A). (B). lung, 150 x Starburst like patterns of numerous The far shorter half life of plutonium has resulted in liver case.

D.B. Busch / Crit. Rev. Oncol. Hematol. 15 (1993) 49-89

increased esophageal cancer in the survivors [74-751. Radiation may increase the incidence of GI angiosarcomas and gastric stromal tumors as well. 16. Pancreatic

and salivary radiation pathology (Ku?

WoodrufJ: M.D. )

The pancreas and salivary glands all have mucous, serous, and mixed glands with ducts and a supporting stroma. Rodent salivary gland, which is under endocrine control, is not an ideal model for the human. The golden Syrian hamster pancreas is a reasonable model for the human pancreas due to the similarity of its tumors. The pancreas, a 80% exocrine and 20% endocrine organ, secretes 1.5-3 liters of digestive fluid per day, with fluid production stimulated by secretin and with cholecystokinin stimulating production of enzyme rich fluid. Like most organs, it has a reserve capacity of about 90%. Release of pancreatic digestive enzymes can cause injury to the organ. Irradiation of the pancreas will also affect the stomach, duodenum, gall bladder. bowel, liver, ducts, vessels, etc. About a month after irradiation, the pancreas shows vascular dilatation. At 4 months, there is early fibrosis, vascular lipid deposition and myointimal hyperplasia, radiation fibrosis, and a chronic inflammatory infiltrate that is not abundant. Thereafter, there is progressive fibrosis and on rare occasions development of squamous metaplasia [76,77]. There are also rare examples of vascular thrombosis in the irradiated area; however, this is likely to be an effect of the cancer and not of the irradiation, since pancreatic cancers are prone to induce thrombosis. Progressive radiation fibrosis of the pancreas impairs the organ’s exocrine function more than the endocrine, and it is unusual to see clinical changes from radiation injury of the endocrine pancreas. It also is possible to see concurrent late radiation changes of the pancreas and chronic duodenitis. The salivary glands are also injured by irradiation 1781. Exposure of l-4 Gy to the parotid causes transiently increased serum amylase, with more severe elevation seen with more radiation and with xerostomia following very large doses, as discussed by Dr. Silverman. 17. Hepatic radiation and chemotherapy pathology (Luis Fajardo, M.D. )

Severe hepatic injury is seen after doses exceeding 35 Gy administered over a 3-4 week period [79]. The regenerating liver is more radiation sensitive. The presentation is sub-acute: within about 3 months of radiotherapy there is rapidly increasing weight, increased abdominal girth, hepatic enlargement, ascites, jaundice, elevation of liver enzymes (particularly alkaline phosphatase), and decreased blood platelets (usual-

71

ly not below 25 OOO/mm’). The characteristic venoocclusive lesions develop 1.5-5 months after irradiation. Delayed effects (occurring in 6 months-6 years) include minimal to moderate scarring. In Thorotrast deposition (Fig. 8) there is initial fibrosis and then neoplasia up to 40 years after initial exposure. Chemotherapy (pre-marrow transplantation) and radiotherapy acutely cause similar liver changes, including veno-occlusive disease. Irradiation of the whole liver gives mottling with bilirubin staining of the lobules except for a dark dot representing the congested central vein. If only part of the liver is irradiated, this may result in a sharp boundary between irradiated and unirradiated tissue. Combined radiation and chemotherapy usually results in more severe injury than irradiation alone. Venoocclusive disease is characterized by obstruction of central and sublobular veins by fine collagen librils causing stasis, in these veins and the surrounding sinusoids and necrosis of the central liver cell plates. A collagen stain is useful in this situation to identify the central vein, since the veins and sinusoids are severely congested. Veno-occlusive disease may result from several causes. However, in the United States today the vast majority of cases result from chemo-radiotherapy, or chemotherapy alone. 18. Endocrine

radiation

pathology

I Kay

WoodrujJ

M.D.)

Endocrine glands may be injured by radiation, but the damage may not be expressed for decades. There is very little information about acute effects of radiation on endocrine glands. Pituitary irradiation [80-821 is performed for pituitary adenoma and in treatment of diabetic retinopathy. The Bragg peak resulting from therapy with particle beam (high LET) therapy combined with the vascular architecture of peripheral pituitary vessels running towards the center result in central cystic change. Also seen are decreased parenchymal cells, fibrosis with fibrous septae, atypical pituicytes, and radiation vascular changes. TSH cells are greatly diminished by irradiation; GH and ACTH producing cells are more resistant. although pituitary irradiation is followed by adrenal atrophy in some cases. The irradiated thyroid [83, 841 might have a moderate decrease in follicular size early after irradiation. I-131 causes follicular necrosis, edema, and vascular injury. Late thyroid changes include severe atrophy (Fig. 9) and vascular degeneration. In a patient with thyroid cancer metastasizing to the lung, I- 131 therapy may cause lung parenchymal injury in the area of the metastases. The parathyroid [85] is rarely made necrotic by irradiation, since it is a radiation resistant organ. Irradiated adrenals have been studied very little,

D.B. Busch/Grit.

12

_ Fig. 9. Thyroid,

300 x.

Hyperthyroid

-

patient treated with radioiodine.

although there is a case report of marked adrenal fibrosis in an irradiated patient. The irradiated endocrine pancreas has been studied in humans and dogs Little is known about radiation changes in the human pancreas. 19. Urinary radiation and chemotherapy ( Theodore 15. PhilIips. M.D. )

pathology

The kidney is relatively radiation-sensitive. Radiation changes are seen beginning 4- 12 months after exposure to therapeutic levels of radiation. Capillary lumina are increasingly blocked with collagen, and there is progressive damage to small arteries. Glomerular changes include foot process flattening and thickening, mesangial thickening, basement membrane thickening, and hyalinization. There is a gradual decrease in the number of tubules and glomeruli. Many tubules are nonfunctional due to replacement of normal cuboidal cells by a flat epithelium. Renal radiation syndromes include acute radiation nephropathy, chronic radiation nephropathy, benign hypertension, malignant hypertension, and proteinuria; which may regarded as separate entities or as representing parts of a continuum of changes. Signs, symptoms, and laboratory findings of acute radiation nephropathy may include headache, pallor, edema, dyspnea, congestive heart failure, hypertension, proteinuria, uremia, narrow arterioles in fundus, and low urine specific gravity.

Rev. Oncol. Hematol. 15 (1993) 49-89

with fibrosis and follicular

atrophy

with atypia.

The delayed effects of chronic radiation nephropathy may occur as a primary condition without pre-existing acute renal changes; or secondary to acute radiation nephropathy. If severe, chronic radiation nephropathy may result in azotemia, decreased serum globulins, malignant hypertension, elevated renin, and anemia from decreased erythropoietin. It is important to monitor these patients’ blood pressure. Pathologic changes include narrowing of arterioles, arterial nephrosclerosis, glomerular wall thickening, glomerular wall proteinaceous deposits, and hyalinized glomeruli. Tubules are decreased, with thickened basement membranes and thinning of the epithelium. Radiation nephropathy generally may be avoided if there is a total dose of up to 1500 cGy in 10 fractions; the risk is 5% after 2000 cGy, with a 50% risk after 2500 cGy. There are substantial dose modifying effects from fractionation and from varying the fraction size. The kidney has very little time dependent repair and little recovery with time, but there is some tubular regeneration. Among the methods for evaluating the function of the irradiated kidney are: Tc 99m-DTPA renal scintigram, serum p-2 microglobulin, and creatine clearance for glomerular function; and Tc~~~-DMSA renal scintigraphy, urine N-acetyl glucosaminidase, alanine aminopeptidase, urine concentration test, and urine P-2 microglobulin for tubular function. Chemotherapy can damage the kidneys as well. Cisplatin causes severe tubule damage that is cumulative

D.B. Busch/ Crir. Rev. Oncol. Hemarol.

73

I5 (1993) 49-89

with dose, although good hydration during therapy prevents much of the damage. Cisplatin also may enhance ifosamide toxicity. The nitrosoureas streptozotocin, CCNU, BCNU, and meCCNU have a cumulative effect on the glomeruli and tubules. High dose methotrexate causes tubular injury in the inadequately hydrated patient with acidic urine, as the drug precipitates out of solution and forms crystals. Mitomytin C causes microangiopathic hemolytic anemia, and its use may result in hemolytic uremic syndrome. Cyclophosphamide causes a moderate incidence of tubular damage and can increase sensitivity to radiation injury. It induces hemorrhagic cystitis. Moderate risk of nephrotoxicity also is associated with use of low dose methotrexate. 5azacytidine, and high dose IV 6-thioguanine. There is a low risk of nephrotoxicity with use of the anthracyclines doxorubicin and daunomycin, low dose mithramycin, tenoposide. 5fluorouraci1, vincristine, and &mercaptopurine. Doxorubicin also is a radiosensitizing agent, with dose effect factor of 1.9. 20. Male reproductive radiation pathology (Luis F. Fajardo. hf. D)

and

chemotherapy

Oligospermia in men is seen after 25 fractions totaling 500 rad, or by a single dose of 150-450 rad. There is a 50% chance of permanent sterility after a single dose of 500-600 rad. Testicular irradiation occurs from scattering effects during pelvic node irradiation; but one study found 34 of 74 men with pelvic node radiotherapy to have subsequently fathered children. A single dose of

Fig. IO. Testis.

150

x

Degeneration

of germinal

epithelium

1200 rad gives massive germ cell necrosis observed after 3.5-48 h and peaking at 5 days (Fig. IO); the necrotic cells persist for 10 days. Syncytial masses of pyknotic spermatocyte nuclei may persist in tubule lumina for weeks. Abnormal mitoses and meioses also are seen. Oligospermia or azoospermia occur weeks later since 64 days are required for human spermatogenesis. The irradiated testis develops progressive thickening of basement membrane, lamina propria, and vessels. Sertoli cells decrease, but Leydig cell numbers are generally unchanged. The irradiated testis may progress to total atrophy over several years, with loss of Sertoli cells and only a fibrous remnant of the testis. With non-sterilizing doses, spermatogonia may regenerate in 2-8 weeks; but spermatozoa may not appear for months or even years. The irradiated testis should be differentiated histologically from that of ‘Sertoli-cell-only-syndrome.’ which differs in having only increased Sertoli cells and no germ cells. The irradiated prostate may show atrophy, squamous metaplasia, atypia of benign glands. fibrosis. rare radiation fibroblasts, radiation vascular changes, and stromal atrophy. The seminal vesicles may become fibrotic, and the urethra may undergo squamous metaplasia or show cellular atypia. Irradiated prostate tumors may disappear after therapy, or else may leave rare glands. Irradiated prostate may also have corpora amylaceae released free in the stroma, with giant cell reaction. It is often difficult to rule out cancer when one sees atypical glands and atypical cells in needle biopsies of irradiated prostate: but these cells and glands may be

2 days after fatal total body irradiation

in reactor

fuel processing

accident

14

assumed to be reproductively dead if the cells are extremely large with excessive chromatin. It is not always possible to diagnose such cases as benign versus malignant; but an unequivocal biopsy diagnosis of malignancy greatly increases the risk of clinical recurrence of prostate cancer, while an equivocal postradiation biopsy diagnosis often is followed by finding no cancer on subsequent followup. It is important to review the earlier biopsies in assessing the malignant potential of a postradiation biopsy.

21. Female reproductive radiation and chemotherapy pathology (David Busch, Ph.D., M.D. ) Radiation and chemotherapy cause diverse effects in the female reproductive system, including parenchymal loss, tissue necrosis, altered menses, cellular atypia, and secondary malignancy. The effect of radiation and chemotherapy on the ovary may largely be regarded as a premature aging. Radiation, and also some cytotoxic drugs such as cyclophosphamide, destroys ovarian follicles; with radiation also killing ovarian stromal cells and vessels. This results in altered hormonal production, and disruption of the menstrual cycle, including ovulation [86-941. Depending on the level of exposure and the ovary’s pretherapeutic content of ova, this may result either in an earlier age of menopause as a result of there being fewer ova left to deplete before menopause, or else sterility due to destruction of all ova. In general, a woman whose ovaries have received over about 600 rad is likely to be sterile, although this is much less likely in young women or particularly teenagers and girls with many more ova. The irradiated patient may have months of amenorrhea followed by resumption of normal menses, so that cessation of menses does not guarantee permanent sterility. In general, a cancer patient with regular menses should be assumed to be fertile unless there is another reason to assume or suspect sterility. The uterus and cervix receive particularly high doses of radiation, possibly in excess of 10 000 rad, in areas in close proximity to intracavitary (uterine cavity, cervical OS, or upper vagina) pellets of radium and other isotopes used in treatment of endometrial and cervical cancer. This causes coagulation necrosis within a few mm of the source, rapidly falling off away from the source due to inverse square law effects in the case of emitted photons and probably more importantly, particle attenuation in the case of emitted alpha or beta particles and secondary electrons. The AFIP has a case report in its tiles in which necrosis of a uterine vessel resulted in protracted, eventually fatal bleeding following intracavitary radiotherapy. In addition, the necrotic, hemorrhagic tissue is a potential site of infection. Scarring, atrophy, and contracture are potential pro-

D B. Busch/Grit.

Rev. Oncol. Hemutol. IS (1993) 49-N

blems in the irradiated vagina, in addition to mucositis acutely following irradiation. Irradiated vulva have changes essentially identical to those of irradiated skin, including depilation. Irradiated breast may undergo fibrosis, possibly indistinguishable from fibrous change in unirradiated breasts. Breast epithelium may degenerate, with relative sparing of myoepithelial cells, or may show marked atypia, with cellular and nuclear enlargement, nuclear pleomorphism and hyperchromasia, and vacuolization but no invasion. The lobular basement membrane may be thickened. Fat necrosis may occur in heavily irradiated breasts, leading to contractures and mineralization that could be confused with malignancy. Irradiation is associated with development of breast cancer and of uterine sarcomas [74,75,95,96]. Thus, development of a second malignancy is a potential complication following radiotherapy of these organs. Diagnosis of radiation-induced malignancy ideally requires that the area have a history of radiation associated with this type of secondary malignancy, with reasonable time period for tumor latency and distinct histology from originally treated primary tumor. Irradiation of female reproductive organs can damage nearby organs. Examples include heart and lung injury in therapy of breast cancer; and renal, ureteral, bladder, and bowel injury during therapy of pelvic reproductive organs. Fetuses occupying irradiated women also are susceptible to radiation injury. Fetal irradiation may result in growth retardation, microcephaly, mental retardation, microphthalmus, cataracts, and mutation [97,98]. The fetal nervous system, and not the placenta, appears to be the critical target for radiation induced fetal demise [99]. Fetal doses may be kept very low during radiotherapy, as in a case of a breast cancer patient who died from metastatic disease after radiotherapy that delivered 4000 rad to the chest and 13 rad to the fetus, who survived [lOO]. Diagnostic radiographic studies giving a total fetal dose below 5- 10 rad, representing the great majority of such studies, are expected to result in significant injury or disease (including expressed harmful effects of somatic or germ line mutation) only in rare cases, so that fetal or later injury or disease from other causes such as infection, Rh disease, smoking, or alcohol is far more likely. However, this does negate the value of minimizing use and dosage of radiographic and radioimaging studies during pregnancy [ 101,102]. Fetuses can survive surprisingly high levels of radiation, as in a case of a fetus exposed to an estimated 680 rad from his mother’s radiotherapy, beginning at the 19th week of pregnancy. There was no apparent injury to the delivered infant, who eventually became the father of a healthy son [97]. The AFIP has a case of an infant who survived for 17 days after being delivered from a mother who had received radiotherapy for cervical carcinoma.

D. B. Busch / Cd.

Rev. Oncol. Hematol. IS (1993) 49-89

The infant had markedly phoid tissue.

hypoplastic

22. Ophthalmic radiation pathology M.D.)

marrow

15

and lym-

(Devron

Char,

Satisfactory lecture notes were not available for this lecture, so I have independently prepared the following text on this subject, relying on a combination of incomplete lecture notes, an old handout prepared by COL Ian McLean (Chairman, AFIP Dept of Ophthalmic Pathology), AFIP study set tiles, and several published articles. Radiation injury of the eye includes ionizing radiation injury, of particular importance in this text; and nonionizing radiation injury, which is important in both etiology and therapy of orbital lesions requiring irradiation. Non-ionizing radiation eye injuries are several, resulting from both artificial and natural sources of radiation. There are strongly contested claims of cataracts induced by chronic exposure to intense radio waves. There also are disputed claims of acute cornea1 and lid burns by infrared radiation, in addition to chronic exposure that results in lens injury; one source questions whether molten glass or metal can produce effects beyond ‘dry eye’ [103]. Solar retinitis results from staring directly at the sun, with resulting fovea1 burn that gives acute visual loss followed by recovery. Laser burns follow absorption of the light by the pigmented epithelium. with particularly severe injury following in the outer retinal layers. The injury is repaired if restricted to the outer segment. Lasers give extremely sharply demarcated areas of coagulation necrosis. Ultraviolet light damage has actinic effects on the eye, particularly the conjunctiva, whose melanin content is low. Squamous cell carcinomas of the eye result from this irradiation [ 1041. These malignancies are seen more frequently, and in younger patients, in areas with relatively high levels of UV. Xeroderma pigmentosum patients have a markedly elevated incidence of these cancers, concurrent with their increased incidence of sunlight induced skin cancers. The AFIP has a case of a teenage woman with XP with squamous cell carcinoma occurring in both eyes. Cataracts also result from UV exposure. This involves both photooxidation of lens crystal crystallin protein, with oxygen free radicals inducing cross linking; and brunescence, in which aromatic amino acids oxidize and form pigments. The ionizing radiation that the eye encounters may result from therapy for UV-induced malignancy. However, it also may be for other orbital, head, or neck malignancies, and on occasion for non-malignant indications such as attempts to inhibit vascularization in

a cornea1 graft. In addition, there are regional malignancies associated with radiotherapy. Radiotherapy has diverse effects on the entire eye, including both the radiosensitive lens and the radioresistant mature neural elements. The exterior of the eyelid and the orbital skin have essentially the same histopathologic changes acutely and chronically as irradiated skin elsewhere. Irradiated conjunctiva may develop telangiectasia, fibrosis, and elastosis. The upper palpebral conjunctiva may keratinize on occasion to give a roughened surface perceived by the patient as a foreign body in the eye, and capable of rubbing the cornea to result in a punctate keratitis. photophobia, and irritation. Once identified by lid eversion, this persistent lesion may be treated with a mucosal membrane graft. The irradiated limbus may react acutely to radiotherapy to give pericorneal congestion, which may be followed by generalized conjunctival congestion. Rarely, there is cornea1 edema. Limbus neovascularization is an extremely rarely seen late effect of irradiation following particularly high doses. Ulcers in irradiated corneas in most cases result from causes other than direct radiation damage. These may include eyeshield, tumor, and exposure injuries. Scleral irradiation in utero may result in microphthalmia. Iridocyclitis may be seen acutely after irradiation. There is pupillary constriction, with congestion, inability to focus, and blurred vision. The uveal tract may develop anterior or posterior synechiae as a late effect of radiation. These may result in severe glaucoma and eventual blindness. The irradiated iris may lose pigment, or develop ciliary artery narrowing with myointimal proliferation [105], or rubeosis [106] with hemorrhage. Irradiated fetuses may develop heterochromatic segments of iris, with the incidence increasing with decreasing gestational age in the range of five to nine months. Radiation may have little effect on uveal melanomas, which may require 10 000 rad to regress; rapidly regressing tumors metastasize more readily. Radiation acutely inhibits tumor mitotic activity, with subsequent occurrence of necrosis and fibrosis. The irradiated lens has received much attention because of its radiosensitivity [ 107- 1091. The adult lens may develop clinically important cataracts, initially posterior subcapsular, after an acute dose above 450 rad of X-rays, or fractionated doses of radiotherapy exceeding about 1100 rad. Cataracts are seen at lower doses with neutrons. The irradiated fetal lens also develops cataracts [l lo]. The clinical progression of the cataract consists of an initial small posterior pole dot that enlarges and develops peripheral granules and vacuoles. The opacity enlarges to 3-4 mm as it develops central clearing. The opacification may arrest at any time during its development. There may be a final progression to a non-specific cataract with cornea1

16

opacification. The earliest detectable slip lamp change is a golden yellow reflex, followed by the development of granular, usually yellow opacities. The opacities eventually split parallel to the plane of the capsule to give a bivalve appearance. There are late developing flocculent cortical opacities occurring anterior to the posterior capsule, that are white with jagged edges. The retina is more radioresistant, with vascular injury seen at 3000 rad. Retinal vessels may develop deposits of librillary material or fibrin [ 1051. There may be retinal neovascularization with vitreous hemorrhages that can lead to blindness [ 1061. Intrauterine irradiation can cause retinal pigmentary degeneration [ 1lo]. Other retinal changes include an early retinal edema that may persist for months and give the retina a greyish white appearance; and tumor area hemorrhages that may give macular cherry red spots. Both residual tumor stroma vessels, and vessels from neovascularization, may cause vitreous hemorrhage approximately l-3 years after irradiation [lll]. The optic nerve may undergo necrosis with neuronal atrophy above 6000 rad and occasionally at lower doses, with associated librinoid degeneration of vessels similar to that in irradiated brain, telangiectasia, gliosis, and hyaline change. Similar damage may be seen at doses as low as 2400 rad with concurrent intrathecal neurotoxic chemotherapy [112]. The AFIP has a case of severe stenosis of the central artery of the retina due to myointimal proliferation, with associated optic nerve necrosis. Extremely rare cases of radiation panophthalmitis requiring enucleation have followed doses of approximately double normal therapeutic levels. Retinoblastoma is of interest as a primary tumor, a potentially multifocal tumor, a tumor associated with the development of other spontaneous tumors, and a tumor whose irradiation may cause secondary malignancies. It also is of interest as a disease providing insight into mechanisms of human carcinogenesis. Retinoblastoma may result from germ line mutation (hereditary form) giving a heterozygous state for the RB tumor suppressor gene [113], with a high probability of a second mutation developing in the second copy of the same gene within at least one orbital retinal cell to give a malignancy. The child may develop several such mutant retinal cells in either eye, with resulting multiple foci of primary retinoblastoma in either or both eyes. Retinoblastoma gene carriers have a 50% chance of developing retinoblastoma, and a 25”X chance of developing bilateral retinoblastoma. It also is possible to have two independently occurring mutations in a retinal cell that was initially genetically normal; retinoblastoma arising by this non-hereditary mechanism is always unifocal. Retinoblastomas are radiosensitive, with regression occurring after 5000 rad and with a 95% cure rate for tumors confined to the interior of the eye. Patients with the hereditary form of retinoblastoma are at

D.B. Busch / Crit. Rev. Oncol. Hematol. 1.5 (1993) 49-89

risk for subsequent development of Ewing’s sarcoma [ 114,115], pineal tumors, and radiation-induced osteosarcomas and other sarcomas. However, the occurrence of radiation-induced osteosarcomas in these patients may have been overestimated, since similar tumors can develop without irradiation [116]. Retinoblastoma may be treated with chemotherapy as well as with radiation [ 1171. Other orbital tumors, such as nonHodgkins lymphoma, may also be treated with irradiation [I 181.

23. Central nervous system radiation and chemotherapy pathology (Richard Davis, M.D.)

Children and the elderly are particularly vulnerable to radiation injury of the brain. Cerebral irradiation can greatly impair children’s development, while the elderly may have more radiation-sensitive brains than expected for adults. Children years ago were treated with radiotherapy for their tinea capitis. They developed a syndrome of transient lethargy, inattentiveness, and poor learning ability after 7-10 days, probably from transient brain edema. This is probably the clinical manifestation of the ‘early’ response to radiation. An ‘early delayed radiation response’ is rarely seen approximately 10 weeks aft& radiotherapy, especially with nasopharyngeal carcinoma and ear cancer cases. There is development of demyelinated plaques with an intense marginal microglial and astrocytic reaction and perivascular lymphocyte and plasma cell reaction but few obvious degenerative vascular changes [ 119- 1211. Some have interpreted these cases as radiation exacerbated multiple sclerosis. Later developing ‘late delayed effects’ ] 119,122- 1261 may include diffuse demyelination and necrosis with relative sparing of the cortex; variable glial reaction with few microglial cells; perivascular hyaline deposits; and severe degenerative vascular changes. Diffuse mineralization may be present in necrotic areas. There is hyalinization around small vessels, vessel wall proliferation, and vascular ectasia with occasional thrombosis. Symptoms can occur years later due to problems with irradiated vessels eventually resulting in vascular malformations or as a result of radiation-induced atherosclerosis. Very late after irradiation, large cavitary areas may develop that generally spare the grey matter, with minor peripheral gliosis. A very rarely observed late change is hypertrophy of grey matter neurons, which is of unknown clinical importance. Intrathecal chemotherapy may result in meningitic, myelopathic, and encephalopathic changes [ 1271. Human material for study of these cases generally comes from therapeutic disasters representing an inadequate sample for study of these changes.

Fig. I I. Brain. 7‘5 x. Mineralizing

radiation

and methotrexate

with leukemic infiltrate,

(intrathecal.

demyelination.

Chemotherapy-induced myelopathic changes have been inadequately studied pathologically. Brain chemotherapy injury is seen with methotrexate, which causes periventricular white matter necrosis and astrogliosis [ 128- 1341 (Fig. 11). Intrathecal methotrexate must not be given to patients with blocked ventricles. Methotrexate can also induce massive brain edema following induction of tumor necrosis; steroids decrease this edema. Intraneuronal crystalloid structures are seen in accidents with intrathecal injection of vincristine and a rat model suggests that these human patients have crystallization of their neurofilaments [135]. A combined radiotherapy and chemotherapy leukoencephaloand pathy is seen with methotrexate, araC, hydrocortisone. It consists of an axonopathy with marked axis cylinder swelling in a bland background with some mineralization, which also may be seen with irradiation alone, with histology similar to that of radiation retinopathy. 24. Radiation and chemotherapy cytopathology Newels,

(Kent

M.D.)

Cytologic changes induced by irradiation depend on the dosage and the degree of cell differentiation. Radiation may destroy the cells, or cause genotypic changes with associated phenotypic consequences. It is important to know these changes in order to avoid a false positive diagnosis of malignancy. The radiation response

with cytosine arabinoside) necrosis, and dystrophic

leukoencephalopathy

in leukemic cerebl

calcification.

(‘RR’), defined as the percentage of benign squamous cells showing radiation changes, is not a useful prognostic indicator. Ultrastructurally, irradiation causes abnormal clearing of chromatin, increased numbers of lysosomes and lipid droplets, dilatation of endoplasmic reticulum, and disruption of mitochondrial cristae. The cervix shows acute radiation cytologic changes of concurrently increased cellular and nuclear size, with approximately normal N:C ratio in contrast to the increased N:C ratio of cervical carcinoma cells; bizarre cell shapes; multinucleation; degeneration including nuclear fragmentation; cytoplasmic vacuoles; and altered cytoplasmic staining. There also may be an inflammatory exudate, histiocytes including multinucleated giant cells, necrotic debris, phagocytosis of neutrophils and other cells, reparative changes, and nuclear ‘vacuoles’ that represent cytoplasmic invaginations. These changes are not specific for radiation. The repair changes include monolayered sheets of cells with macronucleoli, normal N:C ratio, and fine, evenly distributed chromatin unlike that seen in malignancy. There may be persistence for years of bizarre cell shapes, concurrent cellular and nuclear enlargement, nuclear hyperchromasia, multinucleation, and cytoplasmic polychromasia [ 136- 1411. Malignant cells in the Pap smear have changes similar to those in benign cells on the same slide, including concurrent nuclear and cellular enlargement, but in this case with elevated N:C ratio because the N:C ratio already was elevated before irradiation; and alteration of the

malignant cell’s initial chromatin pattern. Malignant cells should vanish from the Pap smear within about a month of therapy; persistence beyond a month generally means a poor prognosis. Postradiation dysplasia represents nuclear abnormalities in benign epithelial cells after radiation. It is seen in up to 20% of irradiated cervical cancer patients, with a latency of months to years. It differs from usual cervical dysplasia in having abnormal cytoplasmic staining and occurrence of cells in groups or in sheets. Its significance is controversial, with some believing that it worsens prognosis and is likely to be a precursor of recurrent cancer [142,143]. The irradiated respiratory tract acutely shows cytologic changes of multinucleation, concurrent nuenlargement, cytoplasmic clear and cytoplasmic vacuolization, necrosis, and inflammation. Late changes include nuclear atypia, cytoplasmic polychromasia, and nuclear pyknosis. Cells with cilia are unequivocally benign. Irradiated urothelium may show nuclear and cytoplasmic enlargement, nuclear hyperchromasia with even chromatin distribution, cytoplasmic vacuoles, cytoplasmic polychromasia, phagocytosis, nuclear pyknosis, and bizarrely shaped cells [ 1441. Effusion specimens may show radiation changes of cytoplasmic and nuclear enlargement, multinucleation, and cytoplasmic vacuoles, which also are seen with chemotherapy or inflammation. Thyroid may show radiation changes of nuclear en-

Fig. 12. Urinary

bladder,300

x Urothelial

atypia

after chemotherapy

largement, intranuclear inclusions, clumped chromatin, and abnormal nuclear shape. Fine needle aspiration of irradiated breast generally yields few cells, with changes including abnormal nuclei with at times severe atypia, including hyperchromasia, enlargement, pleomorphism, and irregular nuclear membranes [145]. There is dyscohesion, and necrotic debris may be present. There is a risk of a false positive diagnosis of cancer, so that nuclear atypia by itself is not diagnostic of cancer in an irradiated breast; it is necessary to fulfill all criteria for a cancer diagnosis. Chemotherapy induces systemic radiation-like changes, while radiation changes are confined to the irradiated area [ 146-1481. Busulfan affects many organs. Respiratory epithelium reacts with nuclear and cytoplasmic enlargement, nucleolar enlargement, retention of cilia, and retention of normal appearance for most bronchial cells in the specimen. Urine cytology specimens show busulfan changes that include cellular and nuclear enlargement; nuclear hyperchromasia, size variation, and irregularity; and cytoplasmic vacuoles. Busulfan also affects the cytology of cervical, esophageal, hepatic, and other cells. Bleomycin changes are similar to those of busulfan, but are generally less severe; the drug also induces squamous metaplasia of the bronchial mucosa. Cyclophosphamide is metabolized by the liver to induce formation of phosphoramide mustard; the byproduct acrolein causes hemorrhagic cystitis. Cyclophosphamide changes seen in urine cytology due to

with cytoxan,

prednisone.

methotrexate.

and Sfluorouracil.

bladder injury (Fig. 12) include cytoplasmic vacuoles, frayed and irregular cytoplasmic borders, cytoplasmic and nuclear enlargement, and nuclear hyperchromasia. The cells are easy to mistake for malignant cells, so it is important for the cytopathologist to be aware of the chemotherapy. Thiotepa induces urothelial nuclear enlargement with smooth nuclear outlines, multinucleation, and cytoplasmic vacuoles, in general resembling both benign reactive changes and mitomycin C changes. 25. Pathology Ph.D.. M.D.)

of acute radiation injury (David Busch,

This subject was covered both for the benefit of military physicians concerned about preparedness for atomic weapon injury, and for the benefit of cancer therapists using total body irradiation. The covered material, and also the subsequent lecture by Dr. Flynn, has been edited to delete material primarily of interest to military physicians that is not regarded as relevant to this cancer therapy related article. Minor changes in emphasis have been made in the text for Dr. Flynn’s lecture, in order to illustrate applicability of military medicine principles covered to therapeutic total body irradiation (TBI). Exposure within a very brief time to large doses of radiation may result in different ‘acute radiation syndromes,’ depending on the dose 1149-1531. At doses exceeding approximately 200 rad (2 Gy, 200 cGy) of photons, the hematologic (or hematopoietic, or bone marrow) syndrome is seen. Here, the highly radiationsensitive lymphocytes and bone marrow stem cells are severely depopulated, resulting in lymphopenia occurring within hours in addition to thrombocytopenia and granulocytopenia occurring over the next few days as the mature formed elements turn over and fail to be replaced. Nausea and vomiting (which also may be induced by anxiety) and prostration (early transient incapacitation) also soon follow total body irradiation. The more slow decline of platelets and granulocytes allows a grace period of many hours during which surgery may be performed with less risk of hemorrhage or infection. Depending on the dose and the quality of care, the blood profile may return to normal over a period of weeks to months, or the patient may expire from hemorrhage or infection. Care includes blood and platelet transfusions, with antibiotics for infections. Bone marrow transplantation has been attempted in both accidental and therapeutic TBI cases, with mixed results due to infection or graft versus host disease [ 1541. ‘Gastrointestinal syndrome’ has been used by some to describe rare cases in which the patients have been exposed to usually lethal doses of radiation falling within a narrow range (near 1000 rad, or 10 Gy) that severely depopulates the GI tract stem cells without causing

massive vascular injury. This results in progressive denudation of the GI tract mucosa over a period of several days as the epithelium undergoes normal physiological turnover and fails to be replaced. The result is malabsorption, diarrhea, and GI bleeding complicated by the extremely severe thrombocytopenia and leukopenia resulting from sterilization of bone marrow stem cells and destruction of lymphocytes. Patients are likely to die within about a week. Treatment may include blood products, bone marrow transplantation, intravenous fluids, selective antimicrobial decontamination of bowel to eliminate gram negative aerobes, and additional antibiotics for appropriate treatment of infections [ 149,152,155- 1581. Similar, generally less severe GI effects may be seen in therapeutic TBI. Cardiovascular, cerebrovascular, neurovascular, cerebral, or neurologic syndrome is used to describe rare, rapidly fatal cases of acute radiation injury in which doses of several thousand rad cause prompt generalized endothelial injury with resulting vascular leakage and progressive cardiovascular collapse accompanied by neurologic symptoms such as ataxia, somnolence, coma, and visual changes. The prognosis is hopeless. Care is supportive. Such cases are not expected in normal radiation therapy situations, but could occur in rare accidents with extreme overexposure during a fraction. What might be considered a subtype of this syndrome, with only partial body (temporal) irradiation, was seen in a Therac 25 incident, in which a patient received approximately 100 times the expected dose in a fraction of radiation used for treatment of a preauricular tumor and expired three weeks later. Pathologic changes in the most heavily irradiated brain tissue included necrosis, parenchymal edema, demyelination, and subacute inflammation; and vascular fibrinoid degeneration, necrosis, and thrombosis. There was fibrinoid material and flame or cuff hemorrhages around small necrotic vessels. Other injuries, including surgical, may heal slowly in heavily irradiated persons, and may be complicated by infections encouraged by bone marrow and lymphoid tissue injury. Radiation injury and surgical injury may act synergistically to increase fatalities. 26. Therapy of acute radiation injury (Daniel F. Flynn, A4.D.i

Treatment of acute whole body exposure following doses exceeding about 1500 rem is futile because vital organs, particularly lung, but also kidney and liver are severely damaged and marrow regeneration by itself will not permit survival. The degree of depression in peripheral blood lymphocytes, granulocytes, and platelets reflect the size of the acute whole body dose and may be utilized, together with clinical symptoms, such as vomiting, to triage patients. Conventional trau-

D.B. Busch / Crit. Rev. Oncol. Hematol. 15 (19931 49-89

80

ma management and decontamination have therapeutic priority during the first day following any whole body exposure. The definitive care of hematopoetic injury involves maintaining the platelet count at an appropriate level approximately 50 000 per mm’. Hematopoetic growth factors such as G-CSF (granulocyte colony-stimulating factor) and GM-CSF (granulocyte-macrophage colonystimulating factor) appear to have a role in stimulating the bone marrow for certain circumstances. Absorbed doses of 800-900 rem may not completely ablate the marrow in some cases as seen in several Chernobyl patients who regenerated their own marrow without bone marrow transplant. Bone marrow transplant does not have a clear role in the acute whole body exposure as seen in the Chernobyl experience [ 1541. In matched subgroups for whole body exposure between 4 Gy-9 Gy, only 217 transplanted Chernobyl patients survived. Both had transient engraftment followed by recovery of autologous hematopoeisis. For non-transplanted patients 6/8 survived. The definitive care of infectious complication involves selective gut decontamination in the afebrile neutropenic patient by selectively eradicating the aerobic gram-negative bacilli with a quinolone antibiotic. Germ-free mice have a much higher mortality than conventional mice that have retained anaerobic flora. Non-febrile patients are treated with combination systemic antimicrobial therapy, i.e., penicillin or cephalosporin plus and aminoglycoside f vancomycin if there is evidence of resistant gram-positive infection. Amphotericin B should be added for patients persistently febrile for days. Acyclovir is added to combat viral infection. 27. Pathology of chemical warfare agents (David Busch, Ph.D., M.D.) This is the only course subject not covered in this cancer therapy oriented course summary, because the subject is irrelevant to cancer therapy. Pertinent references for interested readers are provided in the following references [ 159- 1641. 28. Late effects Phillips, M.D. )

consensus

conference

(Theodore

L.

A summary of the Late Effects Consensus Conference (LECC) on radiation injury, which immediately preceded (August 26-28, 1992) this course at the same location, was provided by Dr. Phillips. A detailed summary of the LECC would be beyond the scope of this course summary, but Dr. Phillips reviewed the key issues during his presentation of the LECC during the course, with his remarks summarized here.

The LECC represented an attempt to design a new grading system for late effects of radiation in clinical trials and for general use in radiation oncology. There are currently subjective, spottily applied grading systems for assessing patient radiation injury. The LECC led to the proposal of a two tier scale; one scale that is a simple clinical system for routine clinical use, and a second scale that reviews quantitatively and in detail patient injuries for research purposes. Proposals included protocols for intervention; an atlas for grading of clinical scores; and an atlas of radiation pathology. Patient evaluations could be subjective, with covering of symptoms that would preferably be quantified; and objective, with requirement for a consulting specialist such as a pulmonologist or nephrologist. The objective evaluations could include clinical signs and measurements; blood tests; radiographic studies; nuclear medicine studies; function tests for specific organs; and stress tests for specific organs. For the two tier systems, the clinical system would use a O-5 scale for quantifying variables, while the objective, quantitative systems would quote continuously variable values. There are different ways that endpoints could be combined in assessing patient response to irradiation. The options for this include: (1) record all data in a parallel manner on a flow chart. (2) Add variables like in the Glisson scoring system for prostate cancer, with a system to equate different grades with different ranges for the sums of the variables. (3) Use a weighted combination of variables with 3 dimensional modeling and with grading of the combined effects of continuous variables. (4) The old system. in which each grade is a ‘hodgepodge.’ The new ‘LENT system’ would review on a 0-Cscale the patient’s symptoms (TO-T4), signs (NO-N4), management difficulty (MO-M4), and results of quantitative assays (QO-Q4) to give a total grade of O-16 by summing the grade O-4 found with each endpoint. These endpoints also could be combined to give stages or cumulative grades of I-IV. For example, a way to evaluate the severity of lung damage might include symptoms such as cough, hemoptysis, sputum, and fever; signs such as respiratory rate, pulse, and dyspnea score; radiographic changes such as CXR and quantitative CT; and additional quantitative special studies such as PFTs, V-Q scans, and ABGs. Salivary injury could be reviewed by evaluating xerostomia, fraction of pretreatment salivary flow attained, and requirement for interventions such as artificial saliva. Mucosal injury could be evaluated using level of pain, dysphagia, ulceration, pallor, thinning, telangiectasia, fibrosis, need for analgesia, and dietary constraints. Laryngeal injury could be evaluated on the basis of hoarseness, dyspnea, pain, edema, need for surgery, and need for analgesia.

D. B. Busch / Crit. Rev. Oncol. Hematol.

15 (1993) 49-89

29. Additional special subjects not discussed at course These include: atypical cells in irradiated tissue; general summary of radiation’s pathologic effects; information sources and resources in radiation pathology; hyperthermia; cannabis controversy; and chronobiological and cell cycle effects in radiation and chemotherapy (text prepared by David Busch, Ph.D., M.D.) 29. I. Atypical cells in irradiated tissue This lecture for the course was cancelled due to Dr. Fajardo’s unfortunate illness near the end of the course. For the sake of completeness, here follows a brief discussion of the issue that relies in part on the information provided in Dr. Fajardo’s text [2] in the chapter on ‘Morphologic changes in irradiated tumors.’ Additional material on distinguishing benign cells reacting to radiation from malignant cells is provided in several sections of this article, particularly in Dr. Nowels’ discussion of cytopathology. It hardly needs to be emphasized that distinguishing benign from malignant and live from malignant and dead is critically important to the pathologist reviewing irradiated tissue, but at times this task is difficult. Irradiated tumors may undergo necrosis either spontaneously or due to therapy. Some tumors, such as adenocarcinomas and squamous cell carcinomas, may degenerate over a period of weeks to months so that there may be sterilized cancer cells on follow-up biopsy. These must be distinguished from both residual live cancer cells and reactive normal cells such as radiation libroblasts. Cancer cells that have undergone remarkable enlargement, have extremely large nuclei (often multinucleated) with marked hyperchromasia, and no mitoses, may generally be presumed to be sterilized. As tumor cells disappear, they may leave behind considerable collagen representing residual stroma, reaction to the therapy, or both. Keratinizing tumors’ necrotic debris may result in a foreign body giant cell reaction. Serial biopsies may be helpful in documenting either the abrupt or gradual disappearance of cancer cells, or their persistence and increase in numbers that indicates treatment failure. Isolated, widely scattered cells are seen in the form of innocuous radiation fibroblasts, which usually are not closely opposed to each other, unlike regenerating clones of cancer cells. Reactive normal cells found in close proximity, such as in epithelium, may be difficult to distinguish from carcinoma, but criteria such as N:C ratio, persistence of differentiated features such as cilia, and presence or absence of invasion may be helpful in making the diagnosis. In some situations, such as irradiated prostate, even experienced

81

pathologists may find it impossible to make a diagnosis, in which case close follow-up and repeat biopsy may be the only reasonable option. However, an experienced pathologist who is having difficulty diagnosing malignancy in a doubtful case is likely to be seeing radiation reaction, Both comparison of the suspicious cells with cancer cells in earlier slides from the case, and any identification of a continuum of cellular changes on the slide ranging from obviously normal to less clearly benign may be helpful in making the diagnosis. As with all difficult cases, review in consultation with other pathologists is very important for both therapeutic and medical legal purposes. 29.2. A general summary of radiation’s pathologic effects

This was based on course handout without accompanying lecture. 29.2.1. Cellular changes Some of the main cellular changes are listed below. Abnormal mitotic figures. Altered cytoplasmic staining. Cellular enlargement - ratio of nucleus to cytoplasm remaining relatively constant unlike in many cancers, which involve greater enlargement of nucleus than of cytoplasm. Clumping of chromatin. Cytolysis and presence of cellular debris. Cytoplasmic ‘vacuoles’ from enlarged mitochondria; dilated endegenerating, doplasmic reticulum; metabolite accumulation; or phagocytosis. Degeneration . Giant cell formation, including multinucleated. Increased variation in cell size. Increased variation in nuclear size. Karyolysis. Karyorrhexis. Metaplasia. Micronucleus formation. Nuclear hyperchromasia. Nuclear irregularity and varied nuclear shape e.g., elongated, elliptical, clefted, or with projections. Nuclear ‘vacuoles’ (cytoplasmic invaginations). Prominent, enlarged, or irregular nucleoli. Pyknotic nuclei. In addition, cytology specimens may contain erythrocytes, leukocytes, necrotic debris. sloughed tumor cells etc. 29.2.2. Tissue changes At the tissue level, early effects (generally seen hours to a few weeks after irradiation) may include the following: direct killing of radiosensitive parenchymal cells, e.g., germ cells, marrow stem cells, lymphoid cells (note relative sparing of plasma cells and macrophages). Edema; may persist. Fibrosis/scarring, early. Hemorrhage. Inflammation; may persist as round cell infiltrate. Ulceration or erosion from combined effects of stem cell sterilization and physiologic turnover of maturing epithelial cells. Vascular, especially endothelial, injury at high doses with plasma leakage into extravascular space.

82

D.B. Busch /Cd.

In addition, these late (typically many weeks to years) effects of radiation may be seen at the tissue level: atrophy due to ischemia or parenchymal cell direct injury. Basement membrane thickening. Edema. Hemorrhage. Hyperplasia. Hypoplasia (may be seen next to hyperplasia). Infarction. Inflammation, both persistent round cell infiltrate, and reaction to tissue breakdown resulting from radiation vasculopathies. Microvascular injury, with diabetic like effects of tissue degeneration, gradually progressive ischemia, and poor healing after surgery. Necrosis, generally ischemic. Neoplasia (important to distinguish radiation-induced from preexisting or coincidental). ‘Radiation fibroblasts’ - large, reactive, pleomorphic, atypical libroblasts present in areas of edema and inflammation. Scarring - fibrosis with secondary tissue disruption (e.g., separation and disorganization of muscle fibers) and atrophy; in central nervous system and optic nerve, gliosis occurs. Telangiectasia. Ulceration and erosion, ischemic. Vascular stenosis due to mural fibrinoid material, intimal foam cell accumulation (almost pathognomonic of radiation in small arteries), collagenization, and thrombosis with resulting ischemia, atrophy, and infarction. 29.2.3. Organ level consequences The following may result from the above cellular and tissue changes: cancer. Fistulization, often secondary to breakdown of cancer invading adjacent organs. Hemorrhage. Infection. Loss of function. Perforation. Secondary disturbance of unirradiated organs by humoral, vascular, secretory, or mechanical mechanisms. Stenosis or obstruction. 29.3. information sources and resources pathology

Rev. Oncol. Hematol.

IS (1993) 49-89

nature of the injuries (emphasizing acute problems), and treatment of casualties. Intended for health care workers, especially but not exclusively military personnel and US Department of Defense employees. Teaching materials are distributed. (3) REACTS. Frequent courses on radiation incidents and their management. 29.3.2. Study sets. (1) 35 mm (2 N x 2 n ) color projection slide study sets available from American Registry of Pathology: (a) Pathological Effects of Radiation ( 1989, 200 slides, currently $130.00). (b) Histopathology of Cancer Chemotherapy Drugs and Chemical Warfare Agents ( 1991, 100 slides, currently $70.00). Includes some cases with combined radiation and chemotherapy injury. (2) Glass microscope slides available on a loan basis from Education Division, AFIP (may use to prepare photomicrographs during loan period). (a) Ml2464 ‘Plutonium inhalation studies VI. Pathologic effects of inhaled plutonium particles in dogs.’ 24 slides. (b) M89002 - ‘Radiation Pathology.’ 76 slides. (c) M89010 - ‘Radiation Pathology Part 11.’ 90 slides. (d) M91003 - ‘Histopathology of Cancer Chemotherapy Drugs and Chemical Warfare Agents.’ 54 slides. Includes some cases of combined radiation and chemotherapy injury. (3) Projection slide study sets available on a loan basis from Education Division, AFIP. (a) LOO003- ‘Clinical reactions following exposure to ionizing radiation.’ 83 slides. (b) LOO004- ‘Pathology of radiation injury.’ 74 slides. (c) LOO053- ‘The gross pathology of total body irradiation in swine.’ 59 slides. (d) L 15172 - ‘Pathologic changes induced by Thorotrast.’ 90 slides.

in radiation

This was based on course handout material without accompanying lecture. Note: this information is not an endorsement of any of these references, organizations, or individuals. The Department of the Army and the AFIP maintain strict neutrality in these matters. This section reviews: (A) courses on radiation injury, (B) study sets and (C) pertinent address and telephone numbers. 29.3.1. Courses on radiation injury (1) AFIP/ARP short course on radiation and chemotherapy injury (this course). Expected to be held every l-2 years. Next course is planned for 1994 in Bethesda, MD. (2) Medical Effects of Nuclear Weapons (MENW), taught by the Armed Forces Radiobiology Research Institute (AFRRI) of Bethesda, Maryland. Taught in Washington, D.C. area three times per year (typically January, May, and late summer), and lasting four days. Discusses how nuclear weapon injuries could occur, the

29.3.3. Addresses and telephone numbers (1) American Registry of Pathology, Armed Forces Institute of Pathology, Washington, D.C. 20306-6000. (301) 427-5231 (courses) (202) 576-2940 (bookstore). (2) William C. Black, M.D., Dept. of Pathology, University of New Mexico Cancer Center, 900 Camino de Salud, NE Albuquerque, NM 87131 (505) 277-6308. (Accepts radiation consult cases; expert witness). (3) LTC Doris Browne, Defense Nuclear Agency, Armed Forces Radiobiology Research Institute, Bethesda, MD 20814-5145. (301) 295-0316/295-3909 (MENW course director; information on Medical Radiobiology Advisory Team for radiation injury incidents, especially involving US Dept. of Defense or continued treatment of radiation accident victims). (4) David Busch, Ph.D., M.D. Dept. of Environmental and Toxicologic Pathology, Armed Forces Institute of Pathology, Washington, D.C. 20306-6000 (202) 576-0265; FAX (202) 576-2164. (Director of AFIP/ARP course on radiation and chemotherapy pathology; accepts consult cases involving radiation injury but cannot return case materials

D. B. Busch / Cd.

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accessioned by AFIP; lectures and prepares study materials on radiation pathology and related subjects; not available as an expert witness; most of time devoted to laboratory identification of radiation sensitive cells, including diagnosis of xeroderma pigrnentosum patients). (5) Education Division, AFIP. The Armed Forces Institute of Pathology, AFIP-EDL-L, Room G124, Building 54, Washington, D.C. 20306-6000. (202) 576-2979. (Source of AFIP study sets available by interlibrary loan). (6) Luis F. Fajardo, M.D., Pathology Service (113), Veterans Administration Medical Center, 3801 Miranda Avenue, Palo Alto, CA 94304. (415) 858-3947 (Accepts radiation consult cases; lectures on radiation injury; interested in hyperthermia; available as an expert witness, but prefers giving depositions or written opinions to appearing at trials. Author of ‘Pathology of Radiation Injury’ [2]). (7) Medical Radiobiology Advisory Team (MRAT) - see LTC Browne. (8) Radiation Effects Research Foundation, 5-2 Hijiyama Park, Minami-Ku, Hiroshima City 732, Japan. (082) 261-3131 (Ongoing studies of medical and genetic effects of Hiroshima and Nagasaki detonations on survivors and their children, with numerous publications). (9). REAC/TS, Oak Ridge Institute for Science and Education, Medical Sciences Division, P.O. Box 117, Oak Ridge, TN 37831-0117. (615) 576-3131, FAX = 576-9522, emergencies (24 h) = (615) 48 l- 1000 (ask for REAC/TS). (REAC/TS is available for consultation in radiation emergencies, especially involving US Dept. of Energy facilities or triage and early management of radiation casualties. Group members may travel internationally, as in the Goiania, Brazil radiocesium incident, and have ties with the World Health Organization). (10) David C. White, M.D., Chief, Laboratory Service, VA Medical Center, Tucson, Arizona 85723. (602) 792-1450 ext. 6756. (May be available for lectures, but does not accept consult cases. Author of ‘An Atlas of Radiation Histopathology’ [4]). 29.4. H_vperthermia

This subject was not covered as planned, due to the illness of the intended presenter, Dr. Mullick. Here follows a cursory presentation by Dr. Busch of the issue as it relates to cancer therapy. Recent experimental and clinical studies have shown that treatment of cancers with combined radiotherapy or chemotherapy and hyperthermia therapy may give better killing of tumors than therapy without hyperther-

mia [ 165- 1741. This artificial heating of the tumor is accomplished with several devices, including microwave applicators, ultrasound transducers, inductive coils, capacitive heating systems, and annular phased arrays. The elevated temperature in the tumor may have several advantageous effects therapeutically, including inhibition of tumor cell DNA repair to increase radiosensitivity and sensitivity to cytotoxic agents; increased cytotoxic agent activation, uptake. and DNA binding; and preferential killing of hypoxic and acid exposed cells, such as those inside a solid tumor. Hyperthermia has the advantage of lack of DNA damaging effects on normal tissue and lack of interaction with accumulated radiation and chemotherapy damage in normal tissue, so that it is well tolerated even in heavily irradiated patients. Response to’therapy is affected by tumor size, histology, and location. Tumors of < 3 cm were more effectively treated in one study than larger tumors. possibly because of the relative difficulty of adequately heating large tumors. Chest wall tumors may respond better to therapy than head and neck tumors; and adenocarcinomas, sarcomas, and melanomas may respond better than squamous cell carcinomas. Normal as well as cancerous tissue has only limited ability to withstand excessive heating without significant damage. Thus, hyperthermia must be carried out with care in order to maximize tumor injury without causing significant injury to normal tissue from overheating. Among the adverse effects observed with hyperthermia are skin burns with blistering, wet desquamation, ulceration, or infarction; subcutaneous necrosis including fat necrosis: osteomyonecrosis; neuropathy associated with heating a tumor mass close to the affected nerve; tachycardia; systemic temperature elevation; burn injuries associated with incidental overheating of leaked urine or passed stool; local discomfort (sensation of pain or burning); and infection from associated invasive instrumentation. A scoring system exists for quantifying skin damage on a scale of 1 (no visible reaction) to 10 (ulceration). The risk of these effects depends on the degree and duration of induced heating of the tumor and on the number of treatments. One study found a maximum measured tumor temperature of 44.6% in patients without complications, versus 45.9”C in patients with complications. The study also reported 7.5% complications in fields receiving l-2 treatments, versus 18.6% complications in fields receiving over two treatments. 29.5. Cannabis controvers? This issue has attracted recent attention due to the passage of a voter initiative called ‘Proposition P‘ at the conference location, San Francisco, that expressed voters’ wishes that police not arrest patients whose cannabis (marijuana) use was regarded as medicinal in

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nature rather than for use solely as an intoxicant. Benefits from cannabis use claimed by cancer and AIDS patients and their supporters have included reduction of chemotherapy associated nausea, emesis, and dysphoria; improved appetite (‘food tripping’ or ‘marijuana munchies’); and weight stabilization or gain, with potential immune system benefits [ 17% 1791. Specialists following other patients have claimed benefits in some other situations, such as reduction of ocular tension in glaucoma, and reduction of spasms, seizures, and chronic pain in neurological patients. The initiative is regarded by government officials as being without actual legal authority and as only a representation of voters’ personal sentiments, because state and federal laws supersede local law. However, proponents of medical use of cannabis have voiced arguments that its therapeutic use might be protected under the 5th, 9th, and 14th Amendments of the US Constitution [ 1SO],and also that jury use of its power to acquit the obviously guilty [ 181,182] could protect cannabis-using patients and their suppliers. However, it is not widely believed that the US Supreme Court would recognize cannabis use with therapeutic intent as constitutionally protected for the foreseeable future; and courtroom instructions in general have discouraged the practice of ‘jury nullification’ since the mid-19th century. Some courts have recognized a ‘medical necessity’ defense in cases in which physicians defend their patients’ cannabis use on therapeutic grounds, although this rarely is successful. Most states have passed legislation allowing the therapeutic use of cannabis, but this has little impact on the patients using the drug because of continued enforcement of state and federal drug laws that do not offer medical exemptions from penalties. At present cannabis is a Schedule I drug, like heroin i.e., not available as a prescription drug. In contrast, dronabinol (marinol or ‘synthetic THC’), a pill containing the cannabis drug A-9 THC, is a Schedule II drug, like morphine and cocaine i.e., regarded as hazardous and having a high potential for abuse, but available for prescription. Cannabis-using AIDS and cancer patients and others have made claims that cannabis and dronabinol are not interchangeable because (a) cannabis smoking during emesis is more successful therapeutically than pill swallowing during emesis; (b) cannabis smoking offers more rapid relief and better dose titration than pill ingestion; (c) cannabis is less likely to cause some adverse reactions such as panic attacks or dysphoria; and (d) relief of some patients’ symptoms by cannabis is far better than with dronabinol possibly due to the presence in cannabis of variable amounts of proposed pharmacologically active agents other than THC. Opponents of cannabis use raise concerns about drug abuse, question the value of cannabis given the availability of other antiemetics, and raise theoretical risks of smoke carcino-

D. B. Busch / Crir. Rev. Oncol. Hematol. 15 (1993) 49-89

gens, plant pathogens, contaminants, and adulterants; while defenders of intended therapeutic cannabis use quote studies downplaying the toxicity of the drug [ 176,178,179,183] and note the medical availability of highly dangerous cancer therapy drugs. About nine of US patients are currently authorized to use cannabis in pharmacological research protocols. It is not certain whether their numbers will grow or decrease during the current administration. The illegal users are far more numerous. One published questionnaire study of clinical oncologists (ASCO members) [ 176,177] found that illegal use of cannabis by cancer patients is widespread and is often condoned by their physicians, with 44% of those participating in the survey having recommended cannabis use to at least one patient (43% response rate for questionnaires in the study). This would indicate that a minimum of 19% of ASCO members (0.43 x 44X, assuming all non-responders made no such recommendation), and probably more, have advocated illegal therapeutic cannabis use to a patient at least once. 29.6. Chronobiological and cell cycle effects in radiation and chemotherapy

This subject was not scheduled for discussion as part of the course, but is mentioned here because of concern expressed by one person about its non-inclusion in the course. The timing of administration of radiation and chemotherapy to cancer patients is an important determinant of the effects of the therapy [ 184,185], because cells have different sensitivities to these agents at different phases of the cell cycle. The circadian rhythms that affect such entities as the sleep/wake cycle and body temperature also affect the distribution of cells in different tissues within the cell cycle, so that at some times of the day stem cells may occupy a part of the cell cycle associated with greater sensitivity to radiation or chemotherapy than they do at other times. Moreover, radiation and chemotherapy may greatly alter the distribution of cells over the cell cycle [ 186,187]. They may preferentially kill cells during phases associated with relatively high sensitivity to the therapy, and also block the progression of the cells through the cycle, so that the cells are partly synchronized and thus as a group will show fluctuations in sensitivity with time after initial therapy, as they progress together through several cell cycles until they eventually again become randomly distributed through the cell cycle. 29.4.1. Circadian effects Researchers have found circadian effects (i.e., effects of organism’s intrinsic 20-28 h ‘biological clock’) for mitotic index and DNA synthesis in rodent stomach, duodenum, rectum, and marrow; and also in human

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marrow and rectal mucosa. These may be expected to cause fluctuations in cellular sensitivity to therapy over the course of the day. Similarly, circadian effects on tissue glutathione levels, renal function, hormone levels, and drug pharmacokinetics may affect the response to chemotherapeutic agents. Tumors also may show circadian changes in DNA synthesis levels and mitotic rate. Here are some known or possible consequences of circadian effects on cancer therapy in experimental models or patients. (1) The anthracycline drug epirubicin gave minimal lethality 6 h after initiation of daily illumination of mice, and maximum lethality if administered 12 h later in the day. In addition, toxicity was lower with late spring to early summer administration than with fall or winter administration. indicating apparent circannual rhythm (lo- 14 month ‘internal clock’) effects. (2) Human patients receiving cisplatin experienced higher urinary drug concentrations and greater kidney damage with morning administration than with evening administration. (3) Mice injected with FUdR had maximum mortality 10 h after light onset with low mortality 18-2 h after light onset in the 24-h cycle. (4) Cure of tumors in rodents is affected by the spacing of chemotherapy drugs over the 24-h sleep/wake cycle. with similar effects seen in limited studies with human patients. (5) Circadian rhythms for components of the immune system raise the question of whether immunotherapy may be sensitive to circadian effects. These and other findings discussed in the references raise the possibility that cancer therapy could be made both less toxic and more effective by proper manipulation of the effects of circadian rhythms. This could be important both with normal methods of administration, and with automatic delivery systems operating on a programmable schedule. 29.6.2. Cell cycle effects A related area is the subject of cell cycle effects and chemotherapy. The stage of the cell cycle occupied by a cell will affect its sensitivity to cancer therapeutic agents, and the presence of therapeutic agents may induce partial synchrony of an initially asynchronous cell population, by preferentially killing cells in some cycle phases or by causing cells to accumulate in one phase and blocking progression to the next phase. For example, S phase cells are killed by hydroxyurea, which interferes with deoxyribonucleotide synthesis and also blocks progression from Gl to S; M phase cells are blocked from progressing to Gl by the presence of mitotic spindle inhibitors such as vinca alkaloids; and the radiation sensitivity of M phase cells is greater than that of early G 1, late S, and G2 cells. In theory, the distribution of normal and malignant

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cells over the cell cycle could be manipulated in order to maximize tumor cell killing while sparing normal cells. For example, if the critical normal cells and tumor cells have different cell cycle lengths and the tumor cells are mostly cycling, one could apply a cell cycle blocking agent to allow both normal and tumor cells to accumulate at a specific point of the cycle. If the blocking agent is then removed by excretion, dialysis, or metabolism, the cells will all resume their progression through the cell cycle. Radiotherapy when the tumor cells synchronously reach M phase would then preferentially kill tumor cells while sparing normal cells in less sensitive phases of the cell cycle. Even without deliberate planning on the part of the therapist, it may safely be assumed that cancer therapy induces considerable cell synchronization effects that could be either detrimental or harmful, depending on the agents used and the time intervals between use of different agents. In vitro studies with cells, in vivo animal tumor models, and occasional studies of cancer patients in vivo will continue to contribute knowledge to this area and hopefully allow further optimization of cancer therapy. 30.

Military dedication

disclaimer,

acknowledgements

and

The opinions or assertions contained herein are the private views of the author, and are not to be construed as representing the views of the AFIP, the Department of the Army, the Department of Defense, or of other course faculty whose lecture material has been edited. I thank J. Martin Brown, James E. Cleaver, Louis S. Constine, Richard Davis, Barbara Egbert, Daniel F. Flynn, Luis Fajardo, William J.M. Hrushesky, Herman I. Libshitz, Andrew M. Morgan, Kent Nowels, Philip Rubin, Sol Silverman, Jr., and Kay Woodruff for their comments on the manuscript; and Roberta B. Albert for technical assistance with UDS slide and manuscript preparation. AFIP (APC #UBLG) and ARP research funds were used for the UDS slide research project, with fibroblast cultures donated by Dr. Jay Robbins. Some of the presented cases were seen at Veterans Administration hospitals. This article is in memory of Dr. David A. “Larry” Engstrand, Collier Co., Florida Medical Examiner and also a bone marrow transplant patient with AML; and also is dedicated to Dr. Dulce Villacampa. 31, Biography

David B. Busch obtained his Ph.D. at the University of California, Berkeley for research in Biophysics at the laboratory of Donald A. Glaser (FAECB). His thesis project was a large scale isolation of ultraviolet sensitive mutant rodent (CHO) cells, including the first rodent

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mutants damaged in rodent homologs of the human DNA repair genes ERCC3 (xeroderma pigmentosum (XP) group B gene), ERCC4 (suspected XP group F gene), and ERCC6 (Cockayne’s syndrome group B gene), with subsequent cloning of the ERCC4 and ERCC6 human DNA repair genes by research collaborators using his mutants. He concurrently isolated a new type of mutant mitomycin C sensitive rodent cell line, and the first UV mutant mammalian cells isolated from X-ray sensitive mutant cells. After obtaining his M.D. from the Ph.D. to M.D. Program in Miami, Florida he completed a residency training in Anatomic and Clinical Pathology at the University of Wisconsin, Madison. He then became Radiation Pathologist at the Armed Forces Institute of Pathology, where his work includes teaching about radiation pathology and performing laboratory identification of xeroderma pigmentosum patients and of UV mutant rodent cells. 32. Reviewer This paper was reviewed by Stephen Davis, M.D., J.D., Wayne NJ, USA. 33. References 1 Berdjis CC. Pathology of Irradiation. Baltimore, Williams and Wilkins, 1971. 2 Fajardo LF. Pathology of Radiation Injury. New York, Masson, 1982. P. Casarett GW. Clinical Radiation Pathology. 3 Rubin Philadelphia, WB Saunders, 1968. 4 White DC. An Atlas of Radiation Histopathology. Oak Ridge, USERDA Technical Information Center, 1975. In: Tannock IF, Hill 5 Hill RP. Cellular basis of radiotherapy. RP, eds. The Basic Science of Oncology, 1st ed. New York, Pergamon Press, 1987; 237-255. 6 Rubin. P. The Franz Buschke lecture: late effects of chemotherapy and radiation therapy: a new hypothesis. Int J Radiat Oncol Biol Phys 10: 5-34, 1984. 7 Rubin P. Constine LS, Van Ess JD. Special lecture: scoring of late toxic effects - interaction of two modalities, NC1 Monogr 6: 9-18, 1988. AM, Weichselbaum RR. Palliative radiotherapy. 8 Awan Hematol Oncol Clin North Am 4: 1169-1181, 1990. 9 Rubin P, Constine LS, Nelson DF. Late effects of cancer treatment: radiation and drug toxicity. In: Perez CA, Brady LW (eds). Principles and Practice of Radiation Oncology. Lippincott, Philadelphia, 1992, 125-161. 10 Irey NS. Adverse reactions to cytostatic agents. Ret Res Cancer Res 52: 36-41, 1975. II Libshitz HI. Diagnostic Roentgenology of Radiotherapy Change. Williams and Wilkins, Baltimore, 1979. 12 Maasilta P, Kivisaari L, Mattson K. Different imaging methods in the assessment of radiation-induced lung injury following hemithorax irradiation for pleural mesothelioma. Radiother Oncol 19: 157-167. 1990. HI, Shuman LS: Radiation-induced pulmonary 13 Libshitz change: CT findings. J Comput Assist Tomog 8: 15-19, 1984 14 Ikezoe J, Morimoto S. Takashima S, Takeuchi N, Arisawa J. Kozuka T. Acute radiation-induced pulmonary injury: computed tomography evaluation. Semin Ultrasound CT MR 11: 409-416, 1990.

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64 DeLeo VA, ed. Photosensitivity. Igaku-Shoin. New York, 1992. 65 Epstein JH. Photosensitivity: I. Mechanisms. Clin Dermatol 4: 81-87, 1986. 66 Epstein JH. Polymorphous light eruption. J Am Acad Dermatol 3: 329-343, 1980. 67 Fitzpatrick TB. Eisen AZ, Wolff D et al., eds. Dermatology in General Medicine. McGraw-Hill, New York, 1993. 68 Gilchrest BA. Skin aging and photoaging: an overview. J Am Acad Dermatol 21: 610-613. 1989. 69 Berthrong M, Fajardo LF. Radiation injury in surgical pathology. Part II. Alimentary tract. Am J Surg Pathol 5: 153-178, 1981. 70 Lewin KJ. Riddell RH. Weinstein WM. Gastrointestinal Pathology and its Clinical Implications. Igaku-Shoin. New York, 1992. 71 Fenoglio-Preiser CM, Lantz PE. Listrom MD. Daris M, Rilke FO. Gastrointestinal Pathology an Atlas and Text. Raven Press, New York, 1989. 72 Whitehead R (ed). Gastrointestinal and Oesophageal Pathology. Churchill Livingston, New York. 1989. 73 Ming S-C. Goldman H. Pathology of the Gastrointestinal Tract. WB Saunders. Philadelphia. 1992. 74 Fajardo LF. Ionizing radiation and neoplasia. In: FenoglioPreiser CM. Weinstein RS. Kaufman N. eds. New Concepts in Neoplasia as Applied to Diagnostic Pathology. IAP Monograph 27. Williams & Wilkins, Baltimore. 1986: 97-125. 75 Preston DL. Kato H. Kopecky KJ. Fujita S. Studies of the mortality of A-bomb survivors. 8. Cancer mortality. 1950-1982. Radiat Res III: 151-178. 1987. 76 Woodruff KH. Castro JR. Quivey JM, et al. Postmortem examination of 22 pancreatic carcinoma patients treated with helium ion irradiation. Cancer 53: 420-425, 1984. 77 Cohen L. Woodruff KH. Hendrickson FR. et al. Response of pancreatic cancer to local irradiation with high-energy neutrons. Cancer 56: 1235-1241. 1985. 78 Martinez-Madrigal F, Micheau C. Histology of the major salivary glands. Am J Surg Pathol 13: 879-899, 1989. 79 Jeffrey RB. Moss AA. Quivey JM. Federle MP. Wara WM. CT of radiation-induced hepatic injury. AJR 135: 445-448. 1980. 80 Lam KSL, Tse VKC. Wang C. Yeung RTT. Ho JHC. Effect of cranial irradiation on hypothalamic-pituitary function ~ a 5-year longitudinal study in patients with nasopharyngeal carcinoma. Quart J Med 78: 165-176. 1991. 81 Woodruff KH. Lyman JT, Lawrence JH. Tobias CA. Born JL. Fabrikant JI. Delayed sequelae of pituitary irradiation. Hum Pathol 15: 48-54. 1984. 82 Grigsby PW. Simpson JR. Fineberg B. Late regrowth of pituitary adenomas after irradiation and/or surgery. Cancer 63: 1308-1312. 1989. 83 Carr RF. LiVolsi VA. Morphologic changes in the thyroid after irradiation for Hodgkin’s and non-Hodgkin’s lymphoma. Cancer 64: 825-829, 1989. 84

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Hancock SL. Cox RS. McDougall IR. Thyroid disease after treatment of Hodgkin’s disease. N Eng J Med 325: 599-605. 1991. Beard CM, Heath H III. O’Fallon WM. Anderson JA. Earle JD. Melton LJ III. Therapeutic radiation and hyperparathyroidism. A case-control study in Rochester. Minn. Arch Int Med 149: 1887-1890, 1989. Chapman RM: Effect of cytotoxic therapy on sexuality and gonadal function. Semin Oncol 9: 84-94. 1982. Fairley KF, Barrie JU, Johnson W: Sterility and testicular atrophy related to cyclophosphamide therapy. Lancet i: 568-569. 1972. Lentz RD. Bergstein J. Steffes MW. et al. Postpubertal evaluation of gonadal function following cyclophosphamide therapy before and during puberty. J Ped 91: 385-394. 1977.

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88 89 Miller JJ Ill, Williams GF, Leissring JC: Multiple late complications of therapy with cyclophosphamide, including ovarian destruction. Am J Med 50: 530-535, 1971 90 Morgenfeld MC, Goldberg V, Parisier H, Bugnard SC, Bur GE: Ovarian lesions due to cytostatic agents during the treatment of Hodgkin’s disease. Surg Gynecol Obst 134: 826-828, 1972. 91 Rose DP. Davis TE: Ovarian function in patients receiving adJuvant chemotherapy for breast cancer. Lancet i: I 174-l 176, 1917. 92 Schilsky RL, Lewis BJ. Sherins RJ. Young RC: Gonadal dysfunction in patients receiving chemotherapy for cancer. Ann Intern Med 93: 109-I 14, 1980. 93 Sobrinho LG. Levine RA, DeConti RC: Amenorrhea in patients with Hodgkin’s disease treated with antineoplastic agents. Am J Obstet Gynecol 109: 135-139. 1971. 94 Warne GL, Fairley KF. Hobbs JB, Martin FIR: Cyclophosphamide-induced ovarian failure. N Engl J Med 289: 95

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