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Changes in morphologic and biochemical characteristics of small cell carcinoma of the lung
Changes in Morphologic and Biochemical Characteristics of Small Cell Carcinoma of the Lung A Clinicopathologic Study
MARTIN D. ABELOFF, M.D. JOSEPH C. EGGLESTON, M.D. GEOFFREY MENDELSOHN, M.B., B.C.H. DAVID S. ETTINGER, M.D. STEPHEN B. BAYLIN, M.D.* Baltimore, Maryland
From the Oncology Center and Departments of Pathology and Medicine, The Johns Hopkins Hospital, Baltimore, Maryland. This work was supported by grants (ACS PDT-108) from the American Cancer Society and ROlCA-18404 from the National Cancer Institute. Requests for reprints should be addressed to Dr. Martin D. Abeloff, Room 128, Oncology Center, The Johns Hopkins Hospital, 601 N. Broadway, Baltimore, Maryland 21205. Manuscript accepted December 26,1978. * Recipient of a Research Career Development Award K04-CA-00027 from the National Institutes of Health.
Small cell carcinoma of the lung is considerably more responsive to cytotoxic chemotherapy and radiotherapy than the other histologic types of lung carcinoma. The therapeutic implications of making an accurate pathologic distinction between small cell carcinoma and other types of lung cancer stimulated this assessment of the pathologic homogeneity of small cell carcinoma. The records of 40 autopsy patients with biopsy proved small cell carcinoma seen at the The Johns Hopkins Hospital between 1970 and 1978 were reviewed. In five of the 40 patients, carcinoma [squamous carcinoma in three, adenocarcinoma in one and large cell undifferentiated carcinoma in one), but not small cell carcinoma, was seen at autopsy. Six cases were identified in which other histologic patterns of lung cancer were present in addition to the small cell carcinoma in the autopsy specimens. In order to determine whether the tumor at autopsy was biochemically as well as morphologically distinct from small cell carcinoma, histaminase and Gdopa decarboxylase activity were measured in the lung tumor and in mediastinal metastases in four cases in which no small cell carcinoma was present at autopsy. The levels of these enzymes in the tumors were markedly lower than the levels found in small cell carcinoma in previous studies. These changes in the pathologic and biochemical characteristics of these lung cancers could reflect the emergence of another tumor which was present from the outset, the development of a second tumor, differentiation of the. initial tumor or an effect of cytotoxic therapy on the morphology of small cell carcinoma. Determining the exact mechanisms for these morphologic and biochemical findings may provide the basis for more rationale therapy of small cell carcinoma and also has implications for studies of the biology and histogenesis of this tumor. Therapeutic programs utilizing combination chemotherapy and radiotherapy have resulted in significant increases in the objective response rate and survival for patients with small cell carcinoma of the lung [1,2],. These advances in therapy have increased the importance of making an accurate pathologic distinction between small cell carcinoma and the other histologic types of lung carcinoma. Since small cell carcinoma is no longer considered a surgically treatable disease, therapeutic decisions are most often made on the basis of small samples of tissue such as bronchial biopsy and cytology specimens. If appropriate clinical decisions are to be made, it is essential that these biopsy and cytology samples are representative of the entire tumor. Brereton and colleagues [3] have recently called attention to the incidence of mixed anaplastic small cell and squamous
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Journal of Medicine
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OF SMALL
CELL CARCINOMA-ABELOFF
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TABLE I
Clinical-Pathologic Findings in Patients with Nonsmaii Ceil Carcinoma At Autopsy SUNiDiagnostic
val
subClas-
Re-
SiliCalbn of Small
Race
Case No.
and Sax
Megnodlc Procedure
cell
Carciwna
Extent OfDkesw
at Olfqtosk
1
59,B,M
Mediastinoscopy
Oat cell
Right hilar mass
2
68,W,M
Branch biopsy
Intermediate-
Right hilar and right peritracheal mass: right pleural effusion Right hilar mass
cYto@lY
polygonal cell
3
44,B,F
Bronchial brushing
Interrnediatepolygonal cell
4
48,W.M
Bronchial
Intermediate-
biopsy
5
58,B,M
Supraclavicular ncde biopsy
spon.9
Date
lo lher-
ol Diagl!osis
spy
(days)
NR
291
PR
320
RadioRx + BCOP
CR
1,072
High dose cytoxan + COMB, VAP, RadioRx, Cisplatinum, high dose MTX
NR
774
Right lung mass RadioRx i- COMB VAP right supraclavicular node
PR
226
Right lung mass
polygonal cell
Intermediatepolygonal cell
High dose cytoxan + COMB. adriamycin RadioRx + COMB
lrom
AutopsyFhdings Moderately well differentiated squamous carcinoma of right lung Poorly differentiated squamous carcinoma of right lung
Poorly differentiated squamous carcinoma of right lung, mediastinal nodes, brain, pancreas, adrenal, perinephric tissue, rectum Poorly differentiated adenocarcinoma in bronchus of upper lobe of right lung with metastases both lungs, pleura, pericardium, brain and hilar carinal, peritracheal and paraaortic lymph nodes Large cell undifferentiated carcinoma with pleomkrphic giant cells in right lung, right hilum, brain
NOTE: COMB = cytoxan, oncovin, methotrexate, BCNU. BCOP = BCNU, cytoxan, oncovin, procarbazine. VAP = VP-16-123. adriamycin, procarbazine. MTX = methotrexate. CR = complete response, PR = partial response, NR = no response.
cell carcinoma of the lung. In an autopsy study of 21 patients with biopsy proved small cell carcinoma, these
investigators described one patient who had only squamous cell carcinoma at postmortem examination and an additional four patients who had mixed small cell carcinoma and squamous cell carcinoma at autopsy. In order to assess the degree of pathologic homogeneity of small cell carcinoma, a review of 40 autopsy patients with biopsy proved small cell carcinoma seen at The Johns Hopkins Hospital between 1970 and 1978 was undertaken. In this report we describe the clinical, pathologic and biochemical features of the cases in which only nonsmall cell carcinoma or mixed lung tumors were found at autopsy. The significance of these observations relative to the diagnosis, therapy and biology of lung cancer are discussed. PATIENTS
AND METHODS
The review of all autopsy patients with biopsy proved small cell carcinoma seen at The johns Hopkins Hospital between 1970 and 1978 was performed as part of a larger study of clinical, pathologic and biochemical characteristics of bronchogenie carcinoma. The majority of patients with small cell carcinoma were entered onto therapeutic protocols (combination chemotherapy regimens with or without radiotherapy to the primary tumor) in The johns Hopkins Oncology Center.
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These patients were carefully staged for extent of disease prior to initiation of therapy and were serially monitored in order to assess therapeutic response. Both the initial diagnostic histologic and cytologic material and the tumors obtained at autopsy were classified according to guidelines established by the World Health Organization (4). and the small cell carcinoma material was similarly further subclassified as oat cell or intermediate cell type. Tissue specimens were obtained at autopsy for biochemical studies of histaminase and L-dopa decarboxylase. enzymes which have previously been shown to be increased in tumor tissue in small cell carcinoma (51and in medullary carcinoma of the thyroid [6.7]. These tissues were obtained within 12 hours of the patient’s death and immediately placed on ice. Homogenates were prepared immediately in a Brinkman Polytron homogenizer as a 1:lO weight/volume mix!ure in 0.1 M, 6.8 pH phosphate buffer. Tissues adjacent to that used for each homogenate were processed for routine histologic examination. These specimens were analyzed without knowledge of corresponding histologic findings. Histaminase activity was measured by the modified method of Beavcn and Jacobsen [8] exactly as previously reported [9). Results arc expressed as units of enzyme activity per gram weight of tissue where I unit = 1 pmol of B-3-histamine dcaminated per hour of incubation. The intra-assay coefficient of variability is f 5 per cent as determined by assay of 10 or more replicates in the same incubation. L-dopa decarboxylase activity was measured by a modifi-
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Figure 1. Case 1. A, the peritracheal lymph node biopsy specimen from the patient was partially replaced by small cell carcinoma of the classic oat cell type. Hematoxylin and eosin stain; original magnification X 480, reduced by 10 per cent. 6, at autopsy the cancer was a moderately well differentiated squamous carcinoma with abundant keratin production. Hematoxylin and eosin stain; original magnification X 190, reduced by 10 per cent.
cation of a procedure used in previous studies [5,7]. Activity
ipsilateral supraclavicular nodes) whereas in most series
is expressed as nanomoles of radioactive labelled carbon dioxide (14C02)released from decarboxylated 14C-L-dopa per
70 per cent of the patients with small cell carcinoma present with extensive disease beyond the hemithorax [lo]. Also, at autopsy there was no evidence of tumor
hour of incubation per gram wet weight of tissue. The intraassay variability at the lowest activity level is f 20 per cent. RESULTS
Case Descriptions of Patients with Nonsmall Cell Carcinoma at Autopsy. Review of the records of 40 autopsy patients with biopsy proved small cell carcinoma revealed five cases in which only squamous car-
cinoma, large cell undifferentiated carcinoma or adenocarcinoma were seen at autopsy. Six cases were identified in which other histologic patterns of lung cancer were present in addition to small cell carcinoma in the autopsy specimens. In the remaining 29 cases, small cell carcinoma was the only tumor at autopsy. The clinical and pathologic findings of the five patients with small cell carcinoma who had only nonsmall cell tumors at autopsy are outlined in Table I, and the cases are described herein. In four of the five cases, the diagnostic biopsy specimen was subclassified as intermediate cell type, and in three of these, foci of large undifferentiated cells were present. It is interesting to note that all five patients clinically presented with localized disease (i.e., no tumor beyond hemithorax and
outside the right hemithorax in Cases 1 and 2. One patient (Case 2) had only small amounts of tumor at autopsy and died of pulmonary emboli. The clinical course of the tumor in two of these patients appeared to be more indolent than the typical case of small cell carcinoma. One patient (Case 3) had a long survival of almost three years after a complete remission was attained. More strikingly, an objective response was never attained in Case 4, but this patient survived almost two years. Case 1. This 59 year old black man presented in May 1976 with dyspnea and cough. A chest roentgenogram showed a right hilar mass with diffuse honeycomb fibrosis of both lower lung fields. Tumor invasion of the bronchus intermedius and the bronchus of the superior segment of the lower lobe of the right lung was seen at bronchoscopy. Mediastinoscopy was performed, and a biopsy specimen of the right peritracheal and subcarinal lymph nodes contained small cell carcinoma (Figure 1A). No evidence of extrathoracic metastases was found, and the patient was placed on an intensive chemotherapy regimen of high dose Cytoxan@ alternating with Cytoxan. 1.3-bis(&chlorocthyl)-I-nitrosourea Oncovin@, mcthotrexate.
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ET AL.
(COMB)
[II]. A remission was not achieved and adriamycin therapy was initiated. Progressive respiratory insufficiency ensued, and the patient died in March 1977. Autopsy revealed multiple pulmonary abnormalities including carcinomatous obstruction of the middle and lower lobes of the right lung with distal acute bronchopneumonia. At autopsy the tumor was a moderately well differentiated squamous carcinoma (Figure 1B); there was no evidence of extrathoracic spread and there was no small cell carcinoma.
Case 2. This 68 year old white man presented in November 1975 with recent anorexia, weight loss and exacerbation of chronic dyspnea. A roentgenogram of the chest showed right hilar and right peritracheal masses with narrowing of the right mainstem bronchus, severe loss of volume in the right lung and a small right pleural effusion. At bronchoscopy the distal trachea was displaced, and a mass compromised the opening of the right mainstem bronchus to 25 per cent of the normal lumen. Bronchoscopic biopsy, postbronchoscapic sputum, bronchial washings and pleural fluid all contained small cell carcinoma. No evidence of extrathoracic metastases was detected, and the patient received radiotherapy to the primary tumor (3,500 rads in split course] and monthly chemotherapy with COMB chemotherapy. A partial remission was achieved and the patient did well until September 1976 when he was admitted in a somnolent state with Cheyne-Stokes respiration. A pneumonia in the lower lobe of the right lung was diagnosed. Despite the administration of antibiotics and supportive measures, the patient died on the third hospital day. A limited amount of residual tumor was seen at autopsy in the middle and lower lobes of the right lung. The immediate cause of death was multiple bilateral pulmonary thromboemboli which were not tumor emboli. The histologic appearance of the tumor at autopsy was that of a poorly differentiated squamous carcinoma. No small cell carcinoma was identified at autopsy.
Case 3. This 44 year old black woman presented
Figure 2. Case 3. A, bronchoscopic brushing of the tumor in patient dislodged clumps of small cell carcinoma cells, whose nuclear detail is apparent in the cells at the edge of the clump. Papanicolaou stain; original magnification X 480, reduced by 10 per cent. B, at autopsy the tumor consisted almost entirely of large anaplastic cells with abundant cytoplasm and pleomorphic nuclei, including tumor giant cells. Rare individually keratinizing cells were also present. Hematoxylin and eosin stain; original magnification X 190, reduced by 10 per cent.
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in July 1974 with substernal chest pain, anorexia and weight loss. A right perihilar mass was detected on a chest roentgenogram, and bronchoscopy revealed a sessile mass in the posterior segment of the bronchus in the upper lobe of the right lung. Bronchostopic brushing revealed small cell carcinoma [Figure 2A). No extrathoracic metastases were found. The patient was treated with radiotherapy to the primary tumor (3,000 rads in 10 fractions] and monthly courses of BCNU, Cytoxan, Oncovin and procarbazine (BCOP) [12]. The therapy resulted in a complete remission and after one year of treatment, she was lost to follow-up. In June 1977, the patient returned with marked disorientation and lethargy. A chest film showed a mass in the right lung. Brain scan showed a mass lesion in the left temporal area, and serum calcium was 13 mg/lOO ml. The patient was treated with cranial radiotherapy and Decadronm and further radiotherapy to the tumor in the right lung. However, she experienced recurrent episodes of aspiration pneumonia and died in July 1977. Autopsy revealed extensive anaplastic large cell undifferentiated carcinoma with occasional individual cell keratinization [Figure 2B] in the upper and middle lobes of the right lung, with metastases to the brain, mediastinum, perinephric tissue, pancreas and rectum without any evidence of small cell carcinoma. The tumor was classified as a poorly differentiated squamous carcinoma on the basis of individual cell keratinization.
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ET AL.
Figure 3.
Case 4. A, endobronchial biopsy specimen of the tumor revealed small fragments of small cell carcinoma of the intermediate cell type. The cells are slightly larger and have more readily apparent cytoplasm than do those of the oat cell type. Hematoxylin and eosin stain; original magnification X 480, reduced by 10 per cent. B, at autopsy the tumor in all locations was extensively necrotic but in the preserved areas showed gland formation by large cells with abundant cytoplasm. Hematoxylin and eosin stain; original magnification X 190, reduced by IO per cent.
Case 4. This 48 year old white man was noted to have a mass in the upper lobe of the right lung on a chest roentgenogram in May 1976. Bronchoscopy revealed no obstruction, but the bronchoscopic biopsy specimen was positive for small cell carcinoma (Figure 3A). No evidence of spread of tumor outside the right side of the chest was detected. The patient was treated with high dose Cytoxan alternating with COMB chemotherapy, but bone metastases rapidly appeared. The patient was subsequently treated with a new chemotherapy regimenVP-16-123, adriamycin, procarbazine (VAP)-and radiotherapy to the primary tumor. However, no significant regression of tumor was achieved and in October 1977. brain metastases developed. The patient received cranial radiotherapy and subsequently further experimental chemotherapy with Cis-platinum and high dose methotrexate with folinic acid rescue. The patient suffered progressive pulmonary and central nervous system complications and died in June 1978. At autopsy, poorly differentiated adenocarcinoma with extensive necrosis was present in the bronchus of the upper lobe of the right lung with metastases to both lungs, pleura, pericardium, brain and hilar, carinal, peritracheal and para-aortic lymph nodes (Figure 3B). Small cell carcinoma was not present Case 5. This 58 year old black man was noted to have right supraclavicular adenopathy and a mass in the right mid-lung
field in February ‘1977. Biopsy of the supraclavicular node showed small cell carcinoma. Metastatic work-up was otherwise negative. The patient was treated with radiotherapy to the primary tumor. mediastinum and supraclavicular fossa (4,200 rads in split course), and was giveh monthly COMB chemotherapy. Partial regression of the lung mass and supraclavicular node was achieved. In September 1977, these lesions were noted to be enlarging and brain metastases developed. The patient was treated with VAP chemotherapy, cranial radiotherapy and steroids. However, progressive neurologic deterioration and pneumonia developed, and he died in October 1977. At autopsy, no small cell carcinoma was found, but an anaplastic large cell undifferentiated carcinoma
extended from the middle lobe of the right lung into the upper and lower lobes of the right lung. Metastases were present in the left cerebellum
and in the basal frontal lobe.
Patients with Mixed Lung Tumors at Autopsy. Of the remaining six patients in our autopsy series of mixed lung tumors, four patients at autopsy had predominantly small cell carcinoma, but the primary tumor contained single foci of glandular differentiation of the type characteristic of adenocarcinoma. Two of these patients
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igure 4. Comparison of histaminase and Ldopa decarboxylase activities in homogenates of tumor specimens obtainel at autopsy in patients with small cell carcinoma and nonsmall cell carcinoma. Data from small cell carcinoma tissue are those obtained in a previous study in our laboratory [5]. Open squares and circles represent homogenates of lung tumor and closed squares and circles represent homogenates of mediastinal metastases.
did not receive antitumor therapy. One patient had only a small focus of tumor at autopsy in a hilar lymph node which consisted of both small cell carcinoma and large cell undifferentiated carcinoma. The final patient had extensive involvement with small cell carcinoma at autopsy in both lungs, pleura, chest wall, liver and abdominal nodes but had a small focus of glandular differentiation in one lung and also a separate small poorly differentiated squamous cell carcinoma of the lung. Biochemical Studies. In order to assess whether the tumor at autopsy was biochemically as well as morphologically distinct from small cell carcinoma, histaminase and L-dopa decarboxylase activity was measured in the lung tumor and mediastinal metastases in Cases 1,2,3 and 4. In Figure 4, the results of the enzyme assays in these four cases of nonsmall cell carcinoma at autopsy are compared to the enzyme levels previously reported in patients with only small cell carcinoma at autopsy [5]. Although overlaps exist, the levels of histaminase (Figure 4A) and L-dopa decarboxylase (Figure 4B) in the nonsmall cell carcinoma tumors at autopsy are much lower than the levels found in small cell carcinoma in previous studies. COMMENTS
The finding of exclusively nonsmall cell carcinoma tumor tissue in five of 40 autopsy patients with an initial
762
biopsy-proved diagnosis of small cell carcinoma of the lung, and the identification of six additional patients in whom mixed histologic patterns were noted at autopsy raise important questions about clinical and biologic aspects of bronchogenic cancer. Examination of the clinical and pathologic characteristics of the five patients with nonsmall cell carcinoma at autopsy (Table I) for any unifying features reveals that these patients presented with relatively localized disease of intermediate cell type (four of five cases]. These findings are in contrast to the more common clinical presentation of extensive disease of oat cell type [lO,l3]. The course of tumor progression. in these patients also appeared to be more indolent than the typical case of small cell carcinoma, but the small number of patients and the retrospective nature of this study preclude any definite conclusions. The pathologic heterogeneity noted in this study may reflect (11the emergence of another tumor which was present from the outset, (2)the development of a second tumor or (3) a change in the tumor with time and/or therapy. If two tumor types are initially present, a clinically important possible explanation for these pathologic findings is that the antitumor therapy eliminates the small cell carcinoma and a second histologic type of lung cancer emerges. The clinical course in Case 3, i.e., a complete regression of small cell carcinoma and
May 1979 The American Journal of Medicine Volume 66
PATHOLOGY
an approximately three year disease-free survival, is compatible with this hypothesis. In Cases 1,2,4 and 5, it is also possible that the tumors were pleomorphic and that the antitumor therapy eliminated the more sensitive small cell populations and permitted the subsequent emergence of the more resistant squamous carcinoma, large cell undifferentiated carcinoma and adenocarcinoma. The development of another primary tumor in patients with small cell carcinoma is well documented [14-161. The development of a separate second primary tumor is a plausible explanation for the pathologic findings in Case 3 in which complete regression of the initial tumor was achieved. However, this does not appear to be as likely an explanation for Cases 1,2,4 and 5 in which complete disappearance of the initial tumor did not occur. The six cases in our autopsy review in which the patients had predominantly small cell carcinoma with focal areas of other types of differentiation, and Brereton’s four autopsy cases of mixed small cell carcinoma-squamous carcinoma [3] raise the third possibility that these mixed lung tumors represent different degrees of differentiation of the primary tumor. It has also been suggested that these mixed patterns result from an effect of cytotoxic therapy on the morphology of small cell carcinoma [3]. This hypothesis may account for some of our pathologic findings, but it does not explain the presence of foci of glandular differentiation within the small cell primary tumor which was seen at autopsy in two of our patients who did not receive any antitumor therapy. Although the mechanism for these pathologic results cannot be firmly determined, our data indicate that it is important to consider the possibility of pathologic heterogeneity when evaluating the newly diagnosed patient with small cell carcinoma. If the diagnosis of small cell carcinoma is based on a bronchoscopic biopsy specimen or cytologic examination, then the patient is considered inoperable and usually treated with a vigorous chemotherapy regimen with or without radiotherapy to the primary tumor. In view of the occurrence of other histologic types of lung cancer in as many as 28 per cent (11 of 40)of autopsy cases of small cell carcinoma, it would seem reasonable to obtain larger samples of biopsy material, such as biopsy specimens of accessible peripheral lymph nodes, prior to initiation of therapy whenever possible. Rebiopsy of accessible lesions in a patient whose tumor has been resistant to therapy or who has had a relapse after an initial response should also be considered.
OF SMALL CELL CARCINOMA-ABELOFF
ET AL.
The identification of mixed lung tumors also has implications for our understanding of the biologic properties of bronchogenic carcinoma. It has been hypothesized that small cell carcinoma of the lung is of neural crest origin and is related to the APUD (A = amines, PU = amine precursor uptake, D = L-aromatic amino acid decarboxylase) system of endocrine cells [17].Our previous work on the biochemistry and immunohistochemistry of small cell carcinoma has confirmed that this neoplasm can have APUD properties but also revealed a marked capacity for biochemical variation between patients and, most importantly, between lesions in the same patient [5]. The presence of small cell carcinoma and other histologic types of lung cancer in the same patient amplifies our previous biochemical findings regarding the heterogeneity of this neoplasm. The coexistence of small cell carcinoma with other lung tumors may also be interpreted as an indication of a histogenetic relationship between the various cell types and as evidence against a neural crest origin for small cell carcinoma. In this regard, evidence has accumulated that other epithelial cells with APUD features in the stomach, intestine and pancreas do not arise from the neural crest [18-211. On the basis of light microscopic, electron microscopic and ACTH radioimmunoassays in autopsy cases of lung cancer, Yesner [22] has proposed a unified concept of lung cancer in which there is a progressive differentiation from small cell carcinoma to large cell undifferentiated carcinoma and ultimately to squamous cell carcinoma and adenocarcinoma. Our data neither confirm nor refute Yesner’s hypothesis, but the light microscopic observations and biochemical assays described in this paper may provide a means of further elucidating the natural history and the histogenesis of small cell carcinoma and the other histologic types of lung cancer. In our present cases, the tumors at autopsy were not only morphologically but also biochemically distinguishable from most of our previously studied small cell carcinoma lesions. Unfortunately, adequate tissue samples were not available for the measurement of these enzymes in the biopsy specimens from those patients with small cell carcinoma who subsequently were found to have nonsmall cell carcinoma at autopsy. In selected patients with accessible tumor tissue, biochemical and/or immunohistochemical studies of tumor enzymes, hormones or other products may provide a means of studying the biologic behavior of tumor cells prior to therapy and during the course of clinical managemcnt of the neoplasm.
REFERENCES 1. Weiss RB: Small cell carcinoma of the lung: Therapeutic management. Ann Intern Med 88:522,1978. 2. Bunn PA, Cohen MH, Ihde DC, et al.: Advances in small cell bronchogenic carcinoma. Cancer Treat Rep 61: 333,
1977. 3. Brereton HD. Matthews MM, Costa 1, et al.: Mixed anaplastic small-cell and squamous-cell carcinoma of the lung. Ann Intern Med 88:805,1978.
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4. 5.
ET AL.
Kreyberg L: Histologic Typing of Lung Tumors, International Histologic Classification of Tumors, Geneva. World Health Organization. 1967. p 21. Bavlin SB. Weisburaer WR. Eggleston (C. et al.: Variable content of histammase, L-dopa decarboxylase and calcitonin in small cell carcinoma of the lung. N Engl - 1Med 299: 106.1978. Baylin SB. Beaven MA, Buja LM. et al.: Histaminase activity: a biochemical marker for medullary carcinoma of the thyroid. Am J Med 53: 723,1972. Atkins FL, Beaven MA, Keiser HR: Dopa decarboxylase in medullary carcinoma of the thyroid. N Engl J Med 269: 545, 1973.
Beaven MA, Jacobsen S: A new assay for histaminase activity: measurement of tritiated water from 0 (side chain label]-H3-histamine. J Pharmacol Exp Ther 176:52.1971. Bavlin SB. Abeloff MD. Wieman KC, et al.: Evaluated histaminase (diamine oxfdase) activity in small cell carcinoma of the lung. N Engl J Med 293: 1266.1975. 10. Muggia FM, Hansen HH. Lakskman RC: Diagnosis in Metastatic Sites in Lung Cancer. (Strauss, MJ ed). New York, Grune & Stratton, 1977. 11. Ettinger DS. Karp JE, Abeloff MD, et al.: Intermittent high dose cvcloohosohamide chemotherapv for small cell carcinomb of ihe lung. Cancer Treat Rep62: 413, 1976. 12. A,beloff MD, Ettinger DS, Baylin SB, et al.: Management of small cell carcinoma of the lung. Cancer 36: 1394.1976. 13. Hirsh F, Hansen HH. Dombcrnowsky P, et al.: Bone marrow examination in the staging of small-cell anaplastic carcinoma of the lung with special reference to subtyping.
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Cancer 39: 2563,1977. 14. Moblev DF. Martinez Al: Two histoloaicallv different orirnary carcinomas of the lung. Cancer22: 2t37.1966. ’ 15. Auerbach 0, Stout AP. Hammond EC, et al.: Multiple primary bronchial carcinomas. Cancer 20: 699, 1967. 16. Saccomanno G. Archer VE. Auerbach 0. et al.: Develonment of carcinoma of the lung as reflected fn exfoliated cells, Cancer 33: 256,1974. 17. Pearse AGE: The cytochemistry and ultrastructure of the polypeptide hormone producing cells of the APIJD series and the embryologic. physiologic and pathologic implications of the concept. J Histochem Cytochem 17: 393. 1969. 16. Pearse AGE: The diffuse neuroendocrine system and the APUD concept: related endocrine peptides in brain, intestine, pituitary, placenta, and anuran cutaneousglands. Med Bio155: 115.1977. 19. Andrew A: An experimental investigation into the possible neural crest origin of pancreatic APUD (islet) cells. J Embryol Exp Morpho135: 577.1976. 20. Fontaine J, LeDouarin NM: Analyses of endoderm formation in the avian blastoderm by the use of quailchick chimcms. Problem of the ncuroectodermal origin of the cells of the APUD series. J Embryo1 Exp Morphol41: 209.1977. 21. Pictet RP. Rail LB, Phelps P. et al.: The neural crest and the origin of the insulin producing and other gastrointestinal hormone producing cells. Science 191: 191. 1976. 22. Yesner R: A unified concept of lung cancer histopathology (abstract). Program of American Society of Clinical Oncology Proceedings, May 1977. Denver. Cola.. p 271.
Volume 66
MARTIN D. ABELOFF, M.D. JOSEPH C. EGGLESTON, M.D. GEOFFREY MENDELSOHN, M.B., B.C.H. DAVID S. ETTINGER, M.D. STEPHEN B. BAYLIN, M.D.* Baltimore, Maryland
From the Oncology Center and Departments of Pathology and Medicine, The Johns Hopkins Hospital, Baltimore, Maryland. This work was supported by grants (ACS PDT-108) from the American Cancer Society and ROlCA-18404 from the National Cancer Institute. Requests for reprints should be addressed to Dr. Martin D. Abeloff, Room 128, Oncology Center, The Johns Hopkins Hospital, 601 N. Broadway, Baltimore, Maryland 21205. Manuscript accepted December 26,1978. * Recipient of a Research Career Development Award K04-CA-00027 from the National Institutes of Health.
Small cell carcinoma of the lung is considerably more responsive to cytotoxic chemotherapy and radiotherapy than the other histologic types of lung carcinoma. The therapeutic implications of making an accurate pathologic distinction between small cell carcinoma and other types of lung cancer stimulated this assessment of the pathologic homogeneity of small cell carcinoma. The records of 40 autopsy patients with biopsy proved small cell carcinoma seen at the The Johns Hopkins Hospital between 1970 and 1978 were reviewed. In five of the 40 patients, carcinoma [squamous carcinoma in three, adenocarcinoma in one and large cell undifferentiated carcinoma in one), but not small cell carcinoma, was seen at autopsy. Six cases were identified in which other histologic patterns of lung cancer were present in addition to the small cell carcinoma in the autopsy specimens. In order to determine whether the tumor at autopsy was biochemically as well as morphologically distinct from small cell carcinoma, histaminase and Gdopa decarboxylase activity were measured in the lung tumor and in mediastinal metastases in four cases in which no small cell carcinoma was present at autopsy. The levels of these enzymes in the tumors were markedly lower than the levels found in small cell carcinoma in previous studies. These changes in the pathologic and biochemical characteristics of these lung cancers could reflect the emergence of another tumor which was present from the outset, the development of a second tumor, differentiation of the. initial tumor or an effect of cytotoxic therapy on the morphology of small cell carcinoma. Determining the exact mechanisms for these morphologic and biochemical findings may provide the basis for more rationale therapy of small cell carcinoma and also has implications for studies of the biology and histogenesis of this tumor. Therapeutic programs utilizing combination chemotherapy and radiotherapy have resulted in significant increases in the objective response rate and survival for patients with small cell carcinoma of the lung [1,2],. These advances in therapy have increased the importance of making an accurate pathologic distinction between small cell carcinoma and the other histologic types of lung carcinoma. Since small cell carcinoma is no longer considered a surgically treatable disease, therapeutic decisions are most often made on the basis of small samples of tissue such as bronchial biopsy and cytology specimens. If appropriate clinical decisions are to be made, it is essential that these biopsy and cytology samples are representative of the entire tumor. Brereton and colleagues [3] have recently called attention to the incidence of mixed anaplastic small cell and squamous
May 1979
The American
Journal of Medicine
Volume 66
757
PATHOLOGY
OF SMALL
CELL CARCINOMA-ABELOFF
ET AL,
TABLE I
Clinical-Pathologic Findings in Patients with Nonsmaii Ceil Carcinoma At Autopsy SUNiDiagnostic
val
subClas-
Re-
SiliCalbn of Small
Race
Case No.
and Sax
Megnodlc Procedure
cell
Carciwna
Extent OfDkesw
at Olfqtosk
1
59,B,M
Mediastinoscopy
Oat cell
Right hilar mass
2
68,W,M
Branch biopsy
Intermediate-
Right hilar and right peritracheal mass: right pleural effusion Right hilar mass
cYto@lY
polygonal cell
3
44,B,F
Bronchial brushing
Interrnediatepolygonal cell
4
48,W.M
Bronchial
Intermediate-
biopsy
5
58,B,M
Supraclavicular ncde biopsy
spon.9
Date
lo lher-
ol Diagl!osis
spy
(days)
NR
291
PR
320
RadioRx + BCOP
CR
1,072
High dose cytoxan + COMB, VAP, RadioRx, Cisplatinum, high dose MTX
NR
774
Right lung mass RadioRx i- COMB VAP right supraclavicular node
PR
226
Right lung mass
polygonal cell
Intermediatepolygonal cell
High dose cytoxan + COMB. adriamycin RadioRx + COMB
lrom
AutopsyFhdings Moderately well differentiated squamous carcinoma of right lung Poorly differentiated squamous carcinoma of right lung
Poorly differentiated squamous carcinoma of right lung, mediastinal nodes, brain, pancreas, adrenal, perinephric tissue, rectum Poorly differentiated adenocarcinoma in bronchus of upper lobe of right lung with metastases both lungs, pleura, pericardium, brain and hilar carinal, peritracheal and paraaortic lymph nodes Large cell undifferentiated carcinoma with pleomkrphic giant cells in right lung, right hilum, brain
NOTE: COMB = cytoxan, oncovin, methotrexate, BCNU. BCOP = BCNU, cytoxan, oncovin, procarbazine. VAP = VP-16-123. adriamycin, procarbazine. MTX = methotrexate. CR = complete response, PR = partial response, NR = no response.
cell carcinoma of the lung. In an autopsy study of 21 patients with biopsy proved small cell carcinoma, these
investigators described one patient who had only squamous cell carcinoma at postmortem examination and an additional four patients who had mixed small cell carcinoma and squamous cell carcinoma at autopsy. In order to assess the degree of pathologic homogeneity of small cell carcinoma, a review of 40 autopsy patients with biopsy proved small cell carcinoma seen at The Johns Hopkins Hospital between 1970 and 1978 was undertaken. In this report we describe the clinical, pathologic and biochemical features of the cases in which only nonsmall cell carcinoma or mixed lung tumors were found at autopsy. The significance of these observations relative to the diagnosis, therapy and biology of lung cancer are discussed. PATIENTS
AND METHODS
The review of all autopsy patients with biopsy proved small cell carcinoma seen at The johns Hopkins Hospital between 1970 and 1978 was performed as part of a larger study of clinical, pathologic and biochemical characteristics of bronchogenie carcinoma. The majority of patients with small cell carcinoma were entered onto therapeutic protocols (combination chemotherapy regimens with or without radiotherapy to the primary tumor) in The johns Hopkins Oncology Center.
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These patients were carefully staged for extent of disease prior to initiation of therapy and were serially monitored in order to assess therapeutic response. Both the initial diagnostic histologic and cytologic material and the tumors obtained at autopsy were classified according to guidelines established by the World Health Organization (4). and the small cell carcinoma material was similarly further subclassified as oat cell or intermediate cell type. Tissue specimens were obtained at autopsy for biochemical studies of histaminase and L-dopa decarboxylase. enzymes which have previously been shown to be increased in tumor tissue in small cell carcinoma (51and in medullary carcinoma of the thyroid [6.7]. These tissues were obtained within 12 hours of the patient’s death and immediately placed on ice. Homogenates were prepared immediately in a Brinkman Polytron homogenizer as a 1:lO weight/volume mix!ure in 0.1 M, 6.8 pH phosphate buffer. Tissues adjacent to that used for each homogenate were processed for routine histologic examination. These specimens were analyzed without knowledge of corresponding histologic findings. Histaminase activity was measured by the modified method of Beavcn and Jacobsen [8] exactly as previously reported [9). Results arc expressed as units of enzyme activity per gram weight of tissue where I unit = 1 pmol of B-3-histamine dcaminated per hour of incubation. The intra-assay coefficient of variability is f 5 per cent as determined by assay of 10 or more replicates in the same incubation. L-dopa decarboxylase activity was measured by a modifi-
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Figure 1. Case 1. A, the peritracheal lymph node biopsy specimen from the patient was partially replaced by small cell carcinoma of the classic oat cell type. Hematoxylin and eosin stain; original magnification X 480, reduced by 10 per cent. 6, at autopsy the cancer was a moderately well differentiated squamous carcinoma with abundant keratin production. Hematoxylin and eosin stain; original magnification X 190, reduced by 10 per cent.
cation of a procedure used in previous studies [5,7]. Activity
ipsilateral supraclavicular nodes) whereas in most series
is expressed as nanomoles of radioactive labelled carbon dioxide (14C02)released from decarboxylated 14C-L-dopa per
70 per cent of the patients with small cell carcinoma present with extensive disease beyond the hemithorax [lo]. Also, at autopsy there was no evidence of tumor
hour of incubation per gram wet weight of tissue. The intraassay variability at the lowest activity level is f 20 per cent. RESULTS
Case Descriptions of Patients with Nonsmall Cell Carcinoma at Autopsy. Review of the records of 40 autopsy patients with biopsy proved small cell carcinoma revealed five cases in which only squamous car-
cinoma, large cell undifferentiated carcinoma or adenocarcinoma were seen at autopsy. Six cases were identified in which other histologic patterns of lung cancer were present in addition to small cell carcinoma in the autopsy specimens. In the remaining 29 cases, small cell carcinoma was the only tumor at autopsy. The clinical and pathologic findings of the five patients with small cell carcinoma who had only nonsmall cell tumors at autopsy are outlined in Table I, and the cases are described herein. In four of the five cases, the diagnostic biopsy specimen was subclassified as intermediate cell type, and in three of these, foci of large undifferentiated cells were present. It is interesting to note that all five patients clinically presented with localized disease (i.e., no tumor beyond hemithorax and
outside the right hemithorax in Cases 1 and 2. One patient (Case 2) had only small amounts of tumor at autopsy and died of pulmonary emboli. The clinical course of the tumor in two of these patients appeared to be more indolent than the typical case of small cell carcinoma. One patient (Case 3) had a long survival of almost three years after a complete remission was attained. More strikingly, an objective response was never attained in Case 4, but this patient survived almost two years. Case 1. This 59 year old black man presented in May 1976 with dyspnea and cough. A chest roentgenogram showed a right hilar mass with diffuse honeycomb fibrosis of both lower lung fields. Tumor invasion of the bronchus intermedius and the bronchus of the superior segment of the lower lobe of the right lung was seen at bronchoscopy. Mediastinoscopy was performed, and a biopsy specimen of the right peritracheal and subcarinal lymph nodes contained small cell carcinoma (Figure 1A). No evidence of extrathoracic metastases was found, and the patient was placed on an intensive chemotherapy regimen of high dose Cytoxan@ alternating with Cytoxan. 1.3-bis(&chlorocthyl)-I-nitrosourea Oncovin@, mcthotrexate.
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(COMB)
[II]. A remission was not achieved and adriamycin therapy was initiated. Progressive respiratory insufficiency ensued, and the patient died in March 1977. Autopsy revealed multiple pulmonary abnormalities including carcinomatous obstruction of the middle and lower lobes of the right lung with distal acute bronchopneumonia. At autopsy the tumor was a moderately well differentiated squamous carcinoma (Figure 1B); there was no evidence of extrathoracic spread and there was no small cell carcinoma.
Case 2. This 68 year old white man presented in November 1975 with recent anorexia, weight loss and exacerbation of chronic dyspnea. A roentgenogram of the chest showed right hilar and right peritracheal masses with narrowing of the right mainstem bronchus, severe loss of volume in the right lung and a small right pleural effusion. At bronchoscopy the distal trachea was displaced, and a mass compromised the opening of the right mainstem bronchus to 25 per cent of the normal lumen. Bronchoscopic biopsy, postbronchoscapic sputum, bronchial washings and pleural fluid all contained small cell carcinoma. No evidence of extrathoracic metastases was detected, and the patient received radiotherapy to the primary tumor (3,500 rads in split course] and monthly chemotherapy with COMB chemotherapy. A partial remission was achieved and the patient did well until September 1976 when he was admitted in a somnolent state with Cheyne-Stokes respiration. A pneumonia in the lower lobe of the right lung was diagnosed. Despite the administration of antibiotics and supportive measures, the patient died on the third hospital day. A limited amount of residual tumor was seen at autopsy in the middle and lower lobes of the right lung. The immediate cause of death was multiple bilateral pulmonary thromboemboli which were not tumor emboli. The histologic appearance of the tumor at autopsy was that of a poorly differentiated squamous carcinoma. No small cell carcinoma was identified at autopsy.
Case 3. This 44 year old black woman presented
Figure 2. Case 3. A, bronchoscopic brushing of the tumor in patient dislodged clumps of small cell carcinoma cells, whose nuclear detail is apparent in the cells at the edge of the clump. Papanicolaou stain; original magnification X 480, reduced by 10 per cent. B, at autopsy the tumor consisted almost entirely of large anaplastic cells with abundant cytoplasm and pleomorphic nuclei, including tumor giant cells. Rare individually keratinizing cells were also present. Hematoxylin and eosin stain; original magnification X 190, reduced by 10 per cent.
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in July 1974 with substernal chest pain, anorexia and weight loss. A right perihilar mass was detected on a chest roentgenogram, and bronchoscopy revealed a sessile mass in the posterior segment of the bronchus in the upper lobe of the right lung. Bronchostopic brushing revealed small cell carcinoma [Figure 2A). No extrathoracic metastases were found. The patient was treated with radiotherapy to the primary tumor (3,000 rads in 10 fractions] and monthly courses of BCNU, Cytoxan, Oncovin and procarbazine (BCOP) [12]. The therapy resulted in a complete remission and after one year of treatment, she was lost to follow-up. In June 1977, the patient returned with marked disorientation and lethargy. A chest film showed a mass in the right lung. Brain scan showed a mass lesion in the left temporal area, and serum calcium was 13 mg/lOO ml. The patient was treated with cranial radiotherapy and Decadronm and further radiotherapy to the tumor in the right lung. However, she experienced recurrent episodes of aspiration pneumonia and died in July 1977. Autopsy revealed extensive anaplastic large cell undifferentiated carcinoma with occasional individual cell keratinization [Figure 2B] in the upper and middle lobes of the right lung, with metastases to the brain, mediastinum, perinephric tissue, pancreas and rectum without any evidence of small cell carcinoma. The tumor was classified as a poorly differentiated squamous carcinoma on the basis of individual cell keratinization.
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Figure 3.
Case 4. A, endobronchial biopsy specimen of the tumor revealed small fragments of small cell carcinoma of the intermediate cell type. The cells are slightly larger and have more readily apparent cytoplasm than do those of the oat cell type. Hematoxylin and eosin stain; original magnification X 480, reduced by 10 per cent. B, at autopsy the tumor in all locations was extensively necrotic but in the preserved areas showed gland formation by large cells with abundant cytoplasm. Hematoxylin and eosin stain; original magnification X 190, reduced by IO per cent.
Case 4. This 48 year old white man was noted to have a mass in the upper lobe of the right lung on a chest roentgenogram in May 1976. Bronchoscopy revealed no obstruction, but the bronchoscopic biopsy specimen was positive for small cell carcinoma (Figure 3A). No evidence of spread of tumor outside the right side of the chest was detected. The patient was treated with high dose Cytoxan alternating with COMB chemotherapy, but bone metastases rapidly appeared. The patient was subsequently treated with a new chemotherapy regimenVP-16-123, adriamycin, procarbazine (VAP)-and radiotherapy to the primary tumor. However, no significant regression of tumor was achieved and in October 1977. brain metastases developed. The patient received cranial radiotherapy and subsequently further experimental chemotherapy with Cis-platinum and high dose methotrexate with folinic acid rescue. The patient suffered progressive pulmonary and central nervous system complications and died in June 1978. At autopsy, poorly differentiated adenocarcinoma with extensive necrosis was present in the bronchus of the upper lobe of the right lung with metastases to both lungs, pleura, pericardium, brain and hilar, carinal, peritracheal and para-aortic lymph nodes (Figure 3B). Small cell carcinoma was not present Case 5. This 58 year old black man was noted to have right supraclavicular adenopathy and a mass in the right mid-lung
field in February ‘1977. Biopsy of the supraclavicular node showed small cell carcinoma. Metastatic work-up was otherwise negative. The patient was treated with radiotherapy to the primary tumor. mediastinum and supraclavicular fossa (4,200 rads in split course), and was giveh monthly COMB chemotherapy. Partial regression of the lung mass and supraclavicular node was achieved. In September 1977, these lesions were noted to be enlarging and brain metastases developed. The patient was treated with VAP chemotherapy, cranial radiotherapy and steroids. However, progressive neurologic deterioration and pneumonia developed, and he died in October 1977. At autopsy, no small cell carcinoma was found, but an anaplastic large cell undifferentiated carcinoma
extended from the middle lobe of the right lung into the upper and lower lobes of the right lung. Metastases were present in the left cerebellum
and in the basal frontal lobe.
Patients with Mixed Lung Tumors at Autopsy. Of the remaining six patients in our autopsy series of mixed lung tumors, four patients at autopsy had predominantly small cell carcinoma, but the primary tumor contained single foci of glandular differentiation of the type characteristic of adenocarcinoma. Two of these patients
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igure 4. Comparison of histaminase and Ldopa decarboxylase activities in homogenates of tumor specimens obtainel at autopsy in patients with small cell carcinoma and nonsmall cell carcinoma. Data from small cell carcinoma tissue are those obtained in a previous study in our laboratory [5]. Open squares and circles represent homogenates of lung tumor and closed squares and circles represent homogenates of mediastinal metastases.
did not receive antitumor therapy. One patient had only a small focus of tumor at autopsy in a hilar lymph node which consisted of both small cell carcinoma and large cell undifferentiated carcinoma. The final patient had extensive involvement with small cell carcinoma at autopsy in both lungs, pleura, chest wall, liver and abdominal nodes but had a small focus of glandular differentiation in one lung and also a separate small poorly differentiated squamous cell carcinoma of the lung. Biochemical Studies. In order to assess whether the tumor at autopsy was biochemically as well as morphologically distinct from small cell carcinoma, histaminase and L-dopa decarboxylase activity was measured in the lung tumor and mediastinal metastases in Cases 1,2,3 and 4. In Figure 4, the results of the enzyme assays in these four cases of nonsmall cell carcinoma at autopsy are compared to the enzyme levels previously reported in patients with only small cell carcinoma at autopsy [5]. Although overlaps exist, the levels of histaminase (Figure 4A) and L-dopa decarboxylase (Figure 4B) in the nonsmall cell carcinoma tumors at autopsy are much lower than the levels found in small cell carcinoma in previous studies. COMMENTS
The finding of exclusively nonsmall cell carcinoma tumor tissue in five of 40 autopsy patients with an initial
762
biopsy-proved diagnosis of small cell carcinoma of the lung, and the identification of six additional patients in whom mixed histologic patterns were noted at autopsy raise important questions about clinical and biologic aspects of bronchogenic cancer. Examination of the clinical and pathologic characteristics of the five patients with nonsmall cell carcinoma at autopsy (Table I) for any unifying features reveals that these patients presented with relatively localized disease of intermediate cell type (four of five cases]. These findings are in contrast to the more common clinical presentation of extensive disease of oat cell type [lO,l3]. The course of tumor progression. in these patients also appeared to be more indolent than the typical case of small cell carcinoma, but the small number of patients and the retrospective nature of this study preclude any definite conclusions. The pathologic heterogeneity noted in this study may reflect (11the emergence of another tumor which was present from the outset, (2)the development of a second tumor or (3) a change in the tumor with time and/or therapy. If two tumor types are initially present, a clinically important possible explanation for these pathologic findings is that the antitumor therapy eliminates the small cell carcinoma and a second histologic type of lung cancer emerges. The clinical course in Case 3, i.e., a complete regression of small cell carcinoma and
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PATHOLOGY
an approximately three year disease-free survival, is compatible with this hypothesis. In Cases 1,2,4 and 5, it is also possible that the tumors were pleomorphic and that the antitumor therapy eliminated the more sensitive small cell populations and permitted the subsequent emergence of the more resistant squamous carcinoma, large cell undifferentiated carcinoma and adenocarcinoma. The development of another primary tumor in patients with small cell carcinoma is well documented [14-161. The development of a separate second primary tumor is a plausible explanation for the pathologic findings in Case 3 in which complete regression of the initial tumor was achieved. However, this does not appear to be as likely an explanation for Cases 1,2,4 and 5 in which complete disappearance of the initial tumor did not occur. The six cases in our autopsy review in which the patients had predominantly small cell carcinoma with focal areas of other types of differentiation, and Brereton’s four autopsy cases of mixed small cell carcinoma-squamous carcinoma [3] raise the third possibility that these mixed lung tumors represent different degrees of differentiation of the primary tumor. It has also been suggested that these mixed patterns result from an effect of cytotoxic therapy on the morphology of small cell carcinoma [3]. This hypothesis may account for some of our pathologic findings, but it does not explain the presence of foci of glandular differentiation within the small cell primary tumor which was seen at autopsy in two of our patients who did not receive any antitumor therapy. Although the mechanism for these pathologic results cannot be firmly determined, our data indicate that it is important to consider the possibility of pathologic heterogeneity when evaluating the newly diagnosed patient with small cell carcinoma. If the diagnosis of small cell carcinoma is based on a bronchoscopic biopsy specimen or cytologic examination, then the patient is considered inoperable and usually treated with a vigorous chemotherapy regimen with or without radiotherapy to the primary tumor. In view of the occurrence of other histologic types of lung cancer in as many as 28 per cent (11 of 40)of autopsy cases of small cell carcinoma, it would seem reasonable to obtain larger samples of biopsy material, such as biopsy specimens of accessible peripheral lymph nodes, prior to initiation of therapy whenever possible. Rebiopsy of accessible lesions in a patient whose tumor has been resistant to therapy or who has had a relapse after an initial response should also be considered.
OF SMALL CELL CARCINOMA-ABELOFF
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The identification of mixed lung tumors also has implications for our understanding of the biologic properties of bronchogenic carcinoma. It has been hypothesized that small cell carcinoma of the lung is of neural crest origin and is related to the APUD (A = amines, PU = amine precursor uptake, D = L-aromatic amino acid decarboxylase) system of endocrine cells [17].Our previous work on the biochemistry and immunohistochemistry of small cell carcinoma has confirmed that this neoplasm can have APUD properties but also revealed a marked capacity for biochemical variation between patients and, most importantly, between lesions in the same patient [5]. The presence of small cell carcinoma and other histologic types of lung cancer in the same patient amplifies our previous biochemical findings regarding the heterogeneity of this neoplasm. The coexistence of small cell carcinoma with other lung tumors may also be interpreted as an indication of a histogenetic relationship between the various cell types and as evidence against a neural crest origin for small cell carcinoma. In this regard, evidence has accumulated that other epithelial cells with APUD features in the stomach, intestine and pancreas do not arise from the neural crest [18-211. On the basis of light microscopic, electron microscopic and ACTH radioimmunoassays in autopsy cases of lung cancer, Yesner [22] has proposed a unified concept of lung cancer in which there is a progressive differentiation from small cell carcinoma to large cell undifferentiated carcinoma and ultimately to squamous cell carcinoma and adenocarcinoma. Our data neither confirm nor refute Yesner’s hypothesis, but the light microscopic observations and biochemical assays described in this paper may provide a means of further elucidating the natural history and the histogenesis of small cell carcinoma and the other histologic types of lung cancer. In our present cases, the tumors at autopsy were not only morphologically but also biochemically distinguishable from most of our previously studied small cell carcinoma lesions. Unfortunately, adequate tissue samples were not available for the measurement of these enzymes in the biopsy specimens from those patients with small cell carcinoma who subsequently were found to have nonsmall cell carcinoma at autopsy. In selected patients with accessible tumor tissue, biochemical and/or immunohistochemical studies of tumor enzymes, hormones or other products may provide a means of studying the biologic behavior of tumor cells prior to therapy and during the course of clinical managemcnt of the neoplasm.
REFERENCES 1. Weiss RB: Small cell carcinoma of the lung: Therapeutic management. Ann Intern Med 88:522,1978. 2. Bunn PA, Cohen MH, Ihde DC, et al.: Advances in small cell bronchogenic carcinoma. Cancer Treat Rep 61: 333,
1977. 3. Brereton HD. Matthews MM, Costa 1, et al.: Mixed anaplastic small-cell and squamous-cell carcinoma of the lung. Ann Intern Med 88:805,1978.
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Kreyberg L: Histologic Typing of Lung Tumors, International Histologic Classification of Tumors, Geneva. World Health Organization. 1967. p 21. Bavlin SB. Weisburaer WR. Eggleston (C. et al.: Variable content of histammase, L-dopa decarboxylase and calcitonin in small cell carcinoma of the lung. N Engl - 1Med 299: 106.1978. Baylin SB. Beaven MA, Buja LM. et al.: Histaminase activity: a biochemical marker for medullary carcinoma of the thyroid. Am J Med 53: 723,1972. Atkins FL, Beaven MA, Keiser HR: Dopa decarboxylase in medullary carcinoma of the thyroid. N Engl J Med 269: 545, 1973.
Beaven MA, Jacobsen S: A new assay for histaminase activity: measurement of tritiated water from 0 (side chain label]-H3-histamine. J Pharmacol Exp Ther 176:52.1971. Bavlin SB. Abeloff MD. Wieman KC, et al.: Evaluated histaminase (diamine oxfdase) activity in small cell carcinoma of the lung. N Engl J Med 293: 1266.1975. 10. Muggia FM, Hansen HH. Lakskman RC: Diagnosis in Metastatic Sites in Lung Cancer. (Strauss, MJ ed). New York, Grune & Stratton, 1977. 11. Ettinger DS. Karp JE, Abeloff MD, et al.: Intermittent high dose cvcloohosohamide chemotherapv for small cell carcinomb of ihe lung. Cancer Treat Rep62: 413, 1976. 12. A,beloff MD, Ettinger DS, Baylin SB, et al.: Management of small cell carcinoma of the lung. Cancer 36: 1394.1976. 13. Hirsh F, Hansen HH. Dombcrnowsky P, et al.: Bone marrow examination in the staging of small-cell anaplastic carcinoma of the lung with special reference to subtyping.
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Cancer 39: 2563,1977. 14. Moblev DF. Martinez Al: Two histoloaicallv different orirnary carcinomas of the lung. Cancer22: 2t37.1966. ’ 15. Auerbach 0, Stout AP. Hammond EC, et al.: Multiple primary bronchial carcinomas. Cancer 20: 699, 1967. 16. Saccomanno G. Archer VE. Auerbach 0. et al.: Develonment of carcinoma of the lung as reflected fn exfoliated cells, Cancer 33: 256,1974. 17. Pearse AGE: The cytochemistry and ultrastructure of the polypeptide hormone producing cells of the APIJD series and the embryologic. physiologic and pathologic implications of the concept. J Histochem Cytochem 17: 393. 1969. 16. Pearse AGE: The diffuse neuroendocrine system and the APUD concept: related endocrine peptides in brain, intestine, pituitary, placenta, and anuran cutaneousglands. Med Bio155: 115.1977. 19. Andrew A: An experimental investigation into the possible neural crest origin of pancreatic APUD (islet) cells. J Embryol Exp Morpho135: 577.1976. 20. Fontaine J, LeDouarin NM: Analyses of endoderm formation in the avian blastoderm by the use of quailchick chimcms. Problem of the ncuroectodermal origin of the cells of the APUD series. J Embryo1 Exp Morphol41: 209.1977. 21. Pictet RP. Rail LB, Phelps P. et al.: The neural crest and the origin of the insulin producing and other gastrointestinal hormone producing cells. Science 191: 191. 1976. 22. Yesner R: A unified concept of lung cancer histopathology (abstract). Program of American Society of Clinical Oncology Proceedings, May 1977. Denver. Cola.. p 271.
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