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Cryostat examination of the cervical cone
Cryostat examination of the cervical cone THOMAS
A.
FRED
C.
Newport
News,
Forty-seven
WASH,
DAVIS,
M.D. M.D.
Virginia
cervical conization
sfiecimens were examined by the cryostat frozen section patients were saved a second operative procedure. There were 6 instances in which the cryostat and final diagnoses differed. None were significant in terms of patient treatment. While distinguishing between severe dysplasia and carcinoma in situ is slightly more dificult on cryostat section than parafin section, invasive carcinoma other than a rare focus of microinvasion should not be missed. When there is complete cooperation between the clinician and the pathologist with each having a clear understanding of the limitations of the procedure, there should be no reluctance to treat definitively the majority of patients at the time of conization.
technique.Thirty-one
FREEZING techniques have long been used as rapid methods of hardening tissue samples for sectioning. In evaluating cervical conization specimensby this method, the standard technique, utilizing a warm knife to cut tissue hardened by carbon dioxide expansion, has not been completely satisfactory in that a large number of wellstained sections cannot be produced in a reasonable length of time and the thickness of the sections makes microscopic interpretation of nuclear abnormalities unreliable, An improved freezing microtome, the cryostat,*, 2 uses a cold knife to cut frozen tissue in a cold environment and can produce large numbers of sections of quality almost comparable to good paraffin sectionsin a period of time acceptable to most pathologists and gynecologists. This instrument has been used at some larger medical centers for immediate histologic examination of cervical cone biopsy specimens.The resulting tissue diagnosis has allowed patients to be treated definitively at the time of conization in a
high percentage of cases.The advantages to the patient are many. In addition to avoiding a second anesthetic and an increased hospital stay, the patient does not risk the immediate complications of conization or the increased morbidity which sometimes follows delayed hysterectomy. The method has not come into universal use, however, probably because of the skepticism of some concerning the adequacy of the technique and the reluctance of many pathology departments to perform the procedure because of the time and effort involved. Our experience indicates that the examination of conization specimensby this method can be of practical use in a community hospital. Material
and
methods
From January, 1967, to Nov. 1, 1968, cold-knife conization of the cervix with cryostat examination has been performed on 47 patients at Riverside Hospital, Newport News, Virginia. This 450 bed general community hospital serves a population of approximately 250,000. Thirty-six of these patients were treated on private services by nine qualified gynecologists and general surgeons. Eleven were treated by residents under the supervision of an attending gynecologist. The procedure is scheduled in advance
From the Department of Obstetrics and Gynecology and the Department of Pathology, Riverside Hosfiital. Presented by invitation at the Thirty-first Annual Meeting of the South Atlantic Association of Obstetricians and Gynecologists, Hot Springs, Virginia, Feb. 2-5, 1969.
105
106
Wash and Davis
Table I ___-_____
----------____--
-.-..-.... .- -_-.---..-.
___-.--._ Final
__.-.-
_ ..- ---diagnosis
____
Dysfilasia --~--Cryostat Chronic
diagnosis cervicitis
Dysplasia Mild Moderate Severe Carcinoma
in
situ
Invasive carcinoma Microinvasion Staze Total
1A
No.
Same
1
1
6 8 10
6 5 8
18
17
1
1
3
3
47
41
with the pathology department so that the required personnel will be present at the proper time and so that pertinent information, such as Papanicolaou smears and biopsy reports, will be available. The cryostat technique involves the services of one technician and two pathologists for approximately 30 minutes. In those institutions where a histology technician routinely performs frozen sections, one pathologist may be replaced by a second technician. The cervical cone is delivered to the pathology department unfixed and intact and is then opened and completely cut by a pathologist into 3 to 4 mm. blocks. The pathologist then positions the tissue blocks on cryostat cutting stages. Mounting media may be used but is not essential. Two and sometimes three blocks can be placed on the same stage. Positioning of the blocks so that the long axis is perpendicular to the cutting edge of the cryostat knife aids ease of sectioning. The stages are placed within the cryostat and frozen. Each block is sectioned at three different levels. The slides, as prepared, are labeled and given to the staining technician. The staining procedure takes about 90 seconds. A routine hematoxylin and eosin method with clearing is used so that a permanent slide is produced. As each slide is
MiEd
Moderate
~.. ~. -~--
.-.. .-
_---.
..---.
;;cinoma’G;;; Severe
in situ
inunsiut
2 1
6
prepared, it is given to the pathologist for examination. This is a continuous process, so that while some sections are being cut, others are being stained, and the finished slides are being examined by a pathologist. An average of 30 sections are studied. The entire procedure takes an average of 25 minutes from the time the tissue reaches the pathology department until a diagnosis is relayed to the operating room. Following completion of the procedure, the residual tissue is removed from the cryostat stages and these blocks are placed in formalin-filled containers labeled to correspond to the cryostat sections. They are then routinely processed by the standard paraffin technique, 3 to 4 levels being cut from each block with approximately 30 additional sections being produced. Results
The cryostat sections have been found to be of good quality with sufficient cellular detail for accurate diagnosis. Histologic features are demonstrated in Figs. 1, 2, 3, and 4. They are, however, somewhat thicker than paraffin sections, being cut at 7 p as opposed to 5 p with the partin technique. Nuclear detail is not as good as that obtained in well-stained paraffin sections, al-
Volume Number
Cryostat
105 1
examination
of cervical
cone
107
Treatment Delayed
Immediate
Conization only
Vaginal hysterectomy
Abdominal hysterectomy
VaginaE hysterectomy and repairs
Cervicectomy
Radium
Vaginal hysterectomy
Vaginal hysterectomy and repairs
Abdominal hysterectomy
Radium
1 1 6 3
: 3
2
1
a
2 2
5
1
2 1
1
1
1 2 11
31
though nucleoli and mitotic figures are easily recognized. There is no loss of mucosa during the freezing procedure and there is no difficulty in obtaining the full plane of the section. The freezing process does not cause tissue distortion in either the cryostat or paraffin preparations. Of the 47 cone biopsy specimensexamined by the cryostat technique (Table I), one was diagnosed as chronic cervicitis without dysplasia, 24 as dysplasia (mild, moderate, or severe’), 18 as carcinoma in situ, and 4 as invasive carcinoma. The final diagnosis, after examination of paraffin sections, differed from the cryostat diagnosis in 6 instances. Three patients having moderate dysplasia on frozen section were found to have severe dysplasia on paraffin sections.Two of the 10 patients diagnosed by frozen section as having severe dysplasia were found to have carcinoma in situ on paraffin section. Seventeen of the 18 cryostat diagnoses of carcinoma in situ were confirmed. The one exception was a patient who was found to have a single small focus of minimal microinvasion present only in one paraffin section. Vaginal hysterectomy was performed at the time of conization. If the focal invasion had been detected in the cryostat procedure, the treatment would have been the same, since
1 5
it was the physician’s policy to treat minimal microinvasion with total hysterectomy. Immediate definitive treatment at the time of conization was performed in 31 of the 47 patients. One patient with chronic cervicitis and 12 with mild to severe dysplasia had hysterectomy at the time of conization for other reasons, the frozen section examination having been done to exclude invasive carcinoma. Three had a previous diagnosis of carcinoma in situ on punch biopsy; 5 needed vaginal hysterectomy and repair because of symptomatic pelvic relaxation; 2 clinic patients with moderate dysplasia were felt to be unreliable for follow-up. One patient with mild dysplasia had hysterectomy performed becauseof uncontrolled bleeding at the time of conization. Two patients with diagnosesof dysplasia had immediate hysterectomy becauseof repeated previous cytologic and histologic reports of moderate to severe cervical dysplasia. Fifteen of the 18 patients with a frozen section diagnosis of carcinoma in situ had definitive treatment at the time of conization. Eight had vaginal hysterectomy, 5 had abdominal hysterectomy, one had excision of a cervical stump, and one had vaginal hysterectomy and plastic repair of the vagina.
108
Wash and Davis
Fig.
1. Moderate
Fig. 2. In situ tendency
toward
dysplasia,
cryostat
section.
Surface
epidermoid carcinoma, cryostat surface maturation. (x150.)
Three of the 4 patients found to have invasive carcinoma had further treatment at the time of conization. One with microinvasion by frozen section study had total hysterectomy. Examination of the uterus failed to reveal residual carcinoma. Two patients had radium inserted. A total of 5 patients had definitive ther-
matumtion
section.
Loss
with
of
basal
cellular
palisading.
polarity
(x150.)
with
no
apy at a later date. Two patients with cryostat diagnoses of severe dysplasia had delayed hysterectomy. In one instance, the diagnosis was changed to carcinoma in situ following study of paraffin sections; in the other, there was continued uncontrolled bleeding from the conization site. Two patients who had diagnoses of carcinoma in situ on frozen
Volume 105 Number 1
Fig. 3. Invasive entiated epithelial
Fig. 4. Invasive in pleomorphic
Cryostat
epidermoid carcinoma, cells. (x150.)
epidermoid epithelial
cell
carcinoma, nuclei.
cryostat
cryostat (x550.)
section had delayed hysterectomy. One was pregnant at the time of conization. In the second, invasion could not definitely be ruled out during the cryostat examination. In one instance of invasive carcinoma where therapy was delayed, radium was not available.
section.
section.
examination
Infiltrating
Nuclear
nests
chromatin
of cervical
of
poorly
clumps
cone
109
differ-
apparent
Comment
Our series of cases compares favorably with other larger series,3l4 including one of 429 cases reported by Kaufman and associateC 6*‘I in which the cryostat diagnosis was changed in 46 instances.Eighteen of these
110
Wash
and
Davis
Srptember
1, 193
Am. ,I. Obst. & G~IIW.
were changes from one degree of dysplasia to another. Four patients with moderate dysplasia were subsequently found to have carcinoma in situ. Seventeen patients with severe dysplasia on cryostat examination were found to have carcinoma in situ. Five patients with a diagnosis of carcinoma in situ on frozen section were found to have severe or moderate dysplasia. Two patients with a frozen section diagnosis of carcinoma in situ were found to have invasive carcinoma on subsequent paraffin examination. One of these had microinvasion and total hysterectomy was felt to have been adequate treatment. The other had superficial invasion greater than microinvasion. Review of the frozen section slides revealed this invasion, thus proving an error in initial interpretation of the cryostat specimens. This was the only patient of the 429 who received inadequate treatment. Invasive carcinoma, other than minimal microinvasive foci, should not be missed on cryostat examination if the cone biopsy is adequate and the pathologist does not hesitate to cut additional sections when needed. A cryostat diagnosis of a lesser degree of histologic change than indicated by a Papanicolaou smear or cervical biopsy should be viewed with suspicion and additional sections should be examined or therapy should be deferred until the tissues can be more adequately evaluated. Since an added benefit of the cryostat examination is a doubling of the total number of sections examined and the frequency of diagnosing microinvasion is in direct proportion to the number of sections examined, the discovery of microinvasive carcinoma may be increased by the use of this technique. Small focal lesions may be present in paraffin sections only or in cryostat sections only. If it is the practice of the gynecologist to treat microinvasive carcinoma with total hysterectomy, then the occasional missed focus of microinvasive carcinoma will not affect therapy. There is no sharp division between severe dysplasia and carcinoma in situ, and pathologists will frequently disagree in interpreting these lesions. Distinguishing between these
two conditions is slightly more difficult on cryostat sections than on paraffin sections. In all series, the most frequently changed diagnosis was from a frozen section report of severe dysplasia to a paraffin section t-eport of epidermoid carcinoma in situ. Prior to operation, therefore, the gynecologist should decide with each individual patient what course he is going to pursue if he receives a cryostat diagnosis of severe dysplasia. The inconvenience of prolonging anesthesia for 20 to 30 minutes while waiting for a definitive diagnosis is not great when balanced against the many advantages of the frozen section technique. The most obvious of these is the avoidance of a second operation and anesthetic. A most important advantage of immediate hysterectomy is the avoidance of the increased morbidity which occurs with delayed hysterectomy. Malinak, Jeffrey, and Dunn8 found a significant increase in the febrile morbidity in those patients who had hysterectomy performed between 2 and 18 days after conization. In addition, all major postoperative complications occurred during this time. It is for this reason that many feel that hysterectomy should be delayed 6 weeks. Even if it is done within 48 hours after conization, during which time there supposedly is no significant increase in morbidity, each of us is aware of the increased technical difficulty resulting from the increased edema and vascularity of the tissues. Of the 47 patients in our series, 29 had definitive surgery performed immediately. There were no serious postoperative complications. The average hospital stay of these 29 patients was 9.5 days. In addition, histologic examination of the uterus following immediate hysterectomy is much more satisfactory, since inflammation which hinders the search for residual disease is minimal. In our series, in no instances were the pathologic findings in the uterus more severe than those found in the conization specimen. There are other advantages to frozen section diagnosis. The immediate complications of conization are avoided when definitive surgery is done at once. In the unreliable
Volume 105 Number 1
patient who may not return for treatment, immediate therapy at the time of conization is best. Patients requiring surgery for reasons other than cervical disease are sometimes found to have abnormal cervical smears necessitating tissue study. When invasive carcinoma is excluded by frozen section ex-
Cryostat examination
of cervical
cone
111
amination, the necessarysurgery can be performed immediately. There were 6 such instances in the present series. Finally, eliminating the waiting period between diagnostic studies and definitive treatment is psychologically and economically important to patients.
many
REFERENCES
1. Ibanez, L. I., Russell, W. O., Chang, J. P., and Speece, A. J.: Lab. Invest. 9: 98, 1960. 2. Nunally, R. M., and Abbott, J. P.: Am. J. Clin. Path. 35: 20, 1961. 3. Rutledge, F., and Ibanez, M. L.: AM. J. OBST. & GYNEC. 83: 1208, 1962. 4. Querriero, W. F., Cox, R., Tillery, W., and Race, G. J,: Obst. & Gynec. 24: 61, 1964. 5. Kaufman, R. H.: Clin. Obst. & Gynec. IO: 838, 1967. Discussion
DR. IDAVID G. STROUP,* East Point, Georgia. In the Atlanta area the cryostat examination is increasing in usage, having first been used in 1965. C)nly about one half of the hospitals are now using the procedure. Only one hospital reports using the procedure with any degree of frequency and this apparently is because of the enthusiasm of the pathologist for the procedure.
This procedurerequiresclosecoordinationbetween the gynecologist, pathologist, anesthesiologist, and operation room personnel.
Two main things seemto disturb the cliniciau regarding use of the procedure.First, is he forcing the pathologist to make quicker and less accurate decisions?Second,is he disturbing the operating room routine to a great degree and causing inefficiency in the use of time of operating room personnel, the anesthesiologist, his assistant, and himself? The pathologist, on the other hand, is using more of his time and equipment than for routine or 24 hour specimens. His equipment for cryostat is tied up for 15 to 4.5 minutes, precluding its use for other tissue. As a matter of fact, one pathologist in the Atlanta area gave this as a primary reason for not encouraging the use of the procedure. These objections, of course, are more apparent than real, although they seem to be quite valid in the Atla:nta area. Presently, the cryostat examina*By
invitation.
6. Kaufman, R. H., Abbott, J. P., and Scheihing, W. C.: Ax. J, OBST. & GYNEC. 84: 107, 1962. 7. Kaufman, R. H., Janes, 0. G., and Cox, H. A.: AM. J. OBST. & GYNEC. 92: 71, 1965. 8. Malinak, L. R., Jeffrey, R. A., Jr., and Dunn, W. J.: Obst. & Gynec. 23: 317, 1964. 12511 Warwick Newport News,
Boulevard Virginia
tion is used primarily in patients in whom a biopsy has shown carcinoma in situ or severe
dysplasia; thus, it is known in advance that further therapy is indicated. The procedure used to rule out invasive carcinoma.
is
Scientifically speaking,conization of the suspicious cervix with immediate definitive therapy is ideal for the physical well-being of the patient. The psychological health of the patient must not be forgotten, however. My personal feeling is that the younger (under 30) patient in whom the conization is done needs an adjustment period before definitive therapy is carried out. Admittedly, the patient does have periods of appre-
hensionin the interval of 6 to 8 weeks.However, I feel it is important that this adjustment be faced and made before the actual loss of the uterus and childbearing function takes place. As we all know, psychosomatic and psychoneurotic problems are more common in women who have had hysterectomies. I consider the waiting period
a part of preventive therapy and put to good use for these patients. This of course is not the case when the definitive therapy is known tu be
necessary,as proved by biopsy and in older women
who already have their families.
Cryostat evaluation with immediate hysterectomy, when done for suspicious lesions, without biopsy, is comparabIe to the patient with the
breast nodule who goesin expecting to have a nodule removed and comes out having undergone a radical breast resection. We know the two need not be equated as far as the relative
112
Wash and Davis
life-endangering potential is concerned. The psychic trauma, however, is the same. My impression is that the cryostat examination has a definite place in the evaluation of the patient with the suspicious lesion; however, I feel that the use should be predicated on a careful weighing of the actual technical practicality of the procedure as opposed to the urgency for the need of immediate diagnosis and therapy. As an added comment, I noted that Dr. Wash stated that one of the surgeons performed a simple hysterectomy for microinvasive carcinoma. In the Atlanta area the usual procedure for this is hysterectomy with excision of a cuff of the vagina. DR. WILLIAM B. HELTON, JR.,” Greer, South Carolina. The authors have pointed out the increased frequency with which the diagnosis of microinvasion and carcinoma in situ of the cervix can be made by increasing the number of sections taken of the conization specimen. I feel this technique would be of extreme advantage in those patients with questionable or mildly atypical smears who require surgery for some other condition in order to rule out any invasive carcinoma prior to proceeding with definitive surgery. Reluctance of many pathology departments is very real because of lack of confidence in the method, plus time involved. Our pathologists will do cryostat examinations of the cervix, but do not feel in their experience they are as good as permanent sections. They estimate the cost of preparing and reading the 30 cryostat and 30 permanent sections of each cervical specimen at $100.00. This price may discourage the use of cryostat examination of conizations. I don’t feel that cost should be a factor when we treat cancer, and I don’t feel it is when we consider the 1,000 Papanicolaou smears we do to pick up one carcinoma in situ of the cervix. Not considering the pathologist’s fee, which I’m sure would vary greatly, this is a more expensive procedure than waiting 48 hours due to the delay of 30 to 45 minutes. The cost of that much time in the operating room and the anesthesiologist fee
‘By
invitation.
would more than offset au increased stay of 48 hours. Our technique now is to wait 24 hours on the permanent sections of our conizations and proceed within 48 hours with definitive surgery if necessary. Dr. Wash has changed or modified the diagnosis in 12 per cent of his cases and Dr. Kaufman in 10 per cent of his large series. Many of these are minor changes, but both series show slightly over a 6 per cent significant change in diagnosis. In addition, both state the most frequent change in diagnosis is from crystat section report of severe dysplasia to paraffin section report of epidermoid carcinoma in situ. It is also interesting to note that no mention was made of ever increasing the severity of a diagnosis with the frozen sections over the permanent sections, although this might have occurred. Thus I am of thra opinion that the permanent paraffin sections will remain the standard by which other methods will be judged. Until we find one that increases the accuracy of our diagnosis, I do not feel wc should change from our present method. The cryostat method may result in undertreatment as well as ovcrtreatment. It is stated that the changes in diagnosis did not significantly change the proper treatment in Dr. Wash’s series and caused an error in treatment in only one of Dr. Kaufman’s series. We must remember, however, that patients are individuals and the way we treat them is 100 per cent for that individual. Finally, it is difficult enough lo explain the necessity of a conization to a frightened patient with a positive Papanicolaou smear. In my cxperience their immediate reaction is “Why don’t you go ahead and take it all out?” I don’t fvel that any patient should be asked to help decide definitive surgery prior to a positive diagnosis with the knowledge that she has a positive Papanicolaou smear. I feel the decision would be almost unanimous to go ahead with a hysterectomy regardless of cryostat diagnosis and increase the number of unnecessary hysterectomies done. Therefore, I will continue to wait 48 hours and proceed with treatment after a lengthy discussion of the diagnosis with the individual patient.
A.
FRED
C.
Newport
News,
Forty-seven
WASH,
DAVIS,
M.D. M.D.
Virginia
cervical conization
sfiecimens were examined by the cryostat frozen section patients were saved a second operative procedure. There were 6 instances in which the cryostat and final diagnoses differed. None were significant in terms of patient treatment. While distinguishing between severe dysplasia and carcinoma in situ is slightly more dificult on cryostat section than parafin section, invasive carcinoma other than a rare focus of microinvasion should not be missed. When there is complete cooperation between the clinician and the pathologist with each having a clear understanding of the limitations of the procedure, there should be no reluctance to treat definitively the majority of patients at the time of conization.
technique.Thirty-one
FREEZING techniques have long been used as rapid methods of hardening tissue samples for sectioning. In evaluating cervical conization specimensby this method, the standard technique, utilizing a warm knife to cut tissue hardened by carbon dioxide expansion, has not been completely satisfactory in that a large number of wellstained sections cannot be produced in a reasonable length of time and the thickness of the sections makes microscopic interpretation of nuclear abnormalities unreliable, An improved freezing microtome, the cryostat,*, 2 uses a cold knife to cut frozen tissue in a cold environment and can produce large numbers of sections of quality almost comparable to good paraffin sectionsin a period of time acceptable to most pathologists and gynecologists. This instrument has been used at some larger medical centers for immediate histologic examination of cervical cone biopsy specimens.The resulting tissue diagnosis has allowed patients to be treated definitively at the time of conization in a
high percentage of cases.The advantages to the patient are many. In addition to avoiding a second anesthetic and an increased hospital stay, the patient does not risk the immediate complications of conization or the increased morbidity which sometimes follows delayed hysterectomy. The method has not come into universal use, however, probably because of the skepticism of some concerning the adequacy of the technique and the reluctance of many pathology departments to perform the procedure because of the time and effort involved. Our experience indicates that the examination of conization specimensby this method can be of practical use in a community hospital. Material
and
methods
From January, 1967, to Nov. 1, 1968, cold-knife conization of the cervix with cryostat examination has been performed on 47 patients at Riverside Hospital, Newport News, Virginia. This 450 bed general community hospital serves a population of approximately 250,000. Thirty-six of these patients were treated on private services by nine qualified gynecologists and general surgeons. Eleven were treated by residents under the supervision of an attending gynecologist. The procedure is scheduled in advance
From the Department of Obstetrics and Gynecology and the Department of Pathology, Riverside Hosfiital. Presented by invitation at the Thirty-first Annual Meeting of the South Atlantic Association of Obstetricians and Gynecologists, Hot Springs, Virginia, Feb. 2-5, 1969.
105
106
Wash and Davis
Table I ___-_____
----------____--
-.-..-.... .- -_-.---..-.
___-.--._ Final
__.-.-
_ ..- ---diagnosis
____
Dysfilasia --~--Cryostat Chronic
diagnosis cervicitis
Dysplasia Mild Moderate Severe Carcinoma
in
situ
Invasive carcinoma Microinvasion Staze Total
1A
No.
Same
1
1
6 8 10
6 5 8
18
17
1
1
3
3
47
41
with the pathology department so that the required personnel will be present at the proper time and so that pertinent information, such as Papanicolaou smears and biopsy reports, will be available. The cryostat technique involves the services of one technician and two pathologists for approximately 30 minutes. In those institutions where a histology technician routinely performs frozen sections, one pathologist may be replaced by a second technician. The cervical cone is delivered to the pathology department unfixed and intact and is then opened and completely cut by a pathologist into 3 to 4 mm. blocks. The pathologist then positions the tissue blocks on cryostat cutting stages. Mounting media may be used but is not essential. Two and sometimes three blocks can be placed on the same stage. Positioning of the blocks so that the long axis is perpendicular to the cutting edge of the cryostat knife aids ease of sectioning. The stages are placed within the cryostat and frozen. Each block is sectioned at three different levels. The slides, as prepared, are labeled and given to the staining technician. The staining procedure takes about 90 seconds. A routine hematoxylin and eosin method with clearing is used so that a permanent slide is produced. As each slide is
MiEd
Moderate
~.. ~. -~--
.-.. .-
_---.
..---.
;;cinoma’G;;; Severe
in situ
inunsiut
2 1
6
prepared, it is given to the pathologist for examination. This is a continuous process, so that while some sections are being cut, others are being stained, and the finished slides are being examined by a pathologist. An average of 30 sections are studied. The entire procedure takes an average of 25 minutes from the time the tissue reaches the pathology department until a diagnosis is relayed to the operating room. Following completion of the procedure, the residual tissue is removed from the cryostat stages and these blocks are placed in formalin-filled containers labeled to correspond to the cryostat sections. They are then routinely processed by the standard paraffin technique, 3 to 4 levels being cut from each block with approximately 30 additional sections being produced. Results
The cryostat sections have been found to be of good quality with sufficient cellular detail for accurate diagnosis. Histologic features are demonstrated in Figs. 1, 2, 3, and 4. They are, however, somewhat thicker than paraffin sections, being cut at 7 p as opposed to 5 p with the partin technique. Nuclear detail is not as good as that obtained in well-stained paraffin sections, al-
Volume Number
Cryostat
105 1
examination
of cervical
cone
107
Treatment Delayed
Immediate
Conization only
Vaginal hysterectomy
Abdominal hysterectomy
VaginaE hysterectomy and repairs
Cervicectomy
Radium
Vaginal hysterectomy
Vaginal hysterectomy and repairs
Abdominal hysterectomy
Radium
1 1 6 3
: 3
2
1
a
2 2
5
1
2 1
1
1
1 2 11
31
though nucleoli and mitotic figures are easily recognized. There is no loss of mucosa during the freezing procedure and there is no difficulty in obtaining the full plane of the section. The freezing process does not cause tissue distortion in either the cryostat or paraffin preparations. Of the 47 cone biopsy specimensexamined by the cryostat technique (Table I), one was diagnosed as chronic cervicitis without dysplasia, 24 as dysplasia (mild, moderate, or severe’), 18 as carcinoma in situ, and 4 as invasive carcinoma. The final diagnosis, after examination of paraffin sections, differed from the cryostat diagnosis in 6 instances. Three patients having moderate dysplasia on frozen section were found to have severe dysplasia on paraffin sections.Two of the 10 patients diagnosed by frozen section as having severe dysplasia were found to have carcinoma in situ on paraffin section. Seventeen of the 18 cryostat diagnoses of carcinoma in situ were confirmed. The one exception was a patient who was found to have a single small focus of minimal microinvasion present only in one paraffin section. Vaginal hysterectomy was performed at the time of conization. If the focal invasion had been detected in the cryostat procedure, the treatment would have been the same, since
1 5
it was the physician’s policy to treat minimal microinvasion with total hysterectomy. Immediate definitive treatment at the time of conization was performed in 31 of the 47 patients. One patient with chronic cervicitis and 12 with mild to severe dysplasia had hysterectomy at the time of conization for other reasons, the frozen section examination having been done to exclude invasive carcinoma. Three had a previous diagnosis of carcinoma in situ on punch biopsy; 5 needed vaginal hysterectomy and repair because of symptomatic pelvic relaxation; 2 clinic patients with moderate dysplasia were felt to be unreliable for follow-up. One patient with mild dysplasia had hysterectomy performed becauseof uncontrolled bleeding at the time of conization. Two patients with diagnosesof dysplasia had immediate hysterectomy becauseof repeated previous cytologic and histologic reports of moderate to severe cervical dysplasia. Fifteen of the 18 patients with a frozen section diagnosis of carcinoma in situ had definitive treatment at the time of conization. Eight had vaginal hysterectomy, 5 had abdominal hysterectomy, one had excision of a cervical stump, and one had vaginal hysterectomy and plastic repair of the vagina.
108
Wash and Davis
Fig.
1. Moderate
Fig. 2. In situ tendency
toward
dysplasia,
cryostat
section.
Surface
epidermoid carcinoma, cryostat surface maturation. (x150.)
Three of the 4 patients found to have invasive carcinoma had further treatment at the time of conization. One with microinvasion by frozen section study had total hysterectomy. Examination of the uterus failed to reveal residual carcinoma. Two patients had radium inserted. A total of 5 patients had definitive ther-
matumtion
section.
Loss
with
of
basal
cellular
palisading.
polarity
(x150.)
with
no
apy at a later date. Two patients with cryostat diagnoses of severe dysplasia had delayed hysterectomy. In one instance, the diagnosis was changed to carcinoma in situ following study of paraffin sections; in the other, there was continued uncontrolled bleeding from the conization site. Two patients who had diagnoses of carcinoma in situ on frozen
Volume 105 Number 1
Fig. 3. Invasive entiated epithelial
Fig. 4. Invasive in pleomorphic
Cryostat
epidermoid carcinoma, cells. (x150.)
epidermoid epithelial
cell
carcinoma, nuclei.
cryostat
cryostat (x550.)
section had delayed hysterectomy. One was pregnant at the time of conization. In the second, invasion could not definitely be ruled out during the cryostat examination. In one instance of invasive carcinoma where therapy was delayed, radium was not available.
section.
section.
examination
Infiltrating
Nuclear
nests
chromatin
of cervical
of
poorly
clumps
cone
109
differ-
apparent
Comment
Our series of cases compares favorably with other larger series,3l4 including one of 429 cases reported by Kaufman and associateC 6*‘I in which the cryostat diagnosis was changed in 46 instances.Eighteen of these
110
Wash
and
Davis
Srptember
1, 193
Am. ,I. Obst. & G~IIW.
were changes from one degree of dysplasia to another. Four patients with moderate dysplasia were subsequently found to have carcinoma in situ. Seventeen patients with severe dysplasia on cryostat examination were found to have carcinoma in situ. Five patients with a diagnosis of carcinoma in situ on frozen section were found to have severe or moderate dysplasia. Two patients with a frozen section diagnosis of carcinoma in situ were found to have invasive carcinoma on subsequent paraffin examination. One of these had microinvasion and total hysterectomy was felt to have been adequate treatment. The other had superficial invasion greater than microinvasion. Review of the frozen section slides revealed this invasion, thus proving an error in initial interpretation of the cryostat specimens. This was the only patient of the 429 who received inadequate treatment. Invasive carcinoma, other than minimal microinvasive foci, should not be missed on cryostat examination if the cone biopsy is adequate and the pathologist does not hesitate to cut additional sections when needed. A cryostat diagnosis of a lesser degree of histologic change than indicated by a Papanicolaou smear or cervical biopsy should be viewed with suspicion and additional sections should be examined or therapy should be deferred until the tissues can be more adequately evaluated. Since an added benefit of the cryostat examination is a doubling of the total number of sections examined and the frequency of diagnosing microinvasion is in direct proportion to the number of sections examined, the discovery of microinvasive carcinoma may be increased by the use of this technique. Small focal lesions may be present in paraffin sections only or in cryostat sections only. If it is the practice of the gynecologist to treat microinvasive carcinoma with total hysterectomy, then the occasional missed focus of microinvasive carcinoma will not affect therapy. There is no sharp division between severe dysplasia and carcinoma in situ, and pathologists will frequently disagree in interpreting these lesions. Distinguishing between these
two conditions is slightly more difficult on cryostat sections than on paraffin sections. In all series, the most frequently changed diagnosis was from a frozen section report of severe dysplasia to a paraffin section t-eport of epidermoid carcinoma in situ. Prior to operation, therefore, the gynecologist should decide with each individual patient what course he is going to pursue if he receives a cryostat diagnosis of severe dysplasia. The inconvenience of prolonging anesthesia for 20 to 30 minutes while waiting for a definitive diagnosis is not great when balanced against the many advantages of the frozen section technique. The most obvious of these is the avoidance of a second operation and anesthetic. A most important advantage of immediate hysterectomy is the avoidance of the increased morbidity which occurs with delayed hysterectomy. Malinak, Jeffrey, and Dunn8 found a significant increase in the febrile morbidity in those patients who had hysterectomy performed between 2 and 18 days after conization. In addition, all major postoperative complications occurred during this time. It is for this reason that many feel that hysterectomy should be delayed 6 weeks. Even if it is done within 48 hours after conization, during which time there supposedly is no significant increase in morbidity, each of us is aware of the increased technical difficulty resulting from the increased edema and vascularity of the tissues. Of the 47 patients in our series, 29 had definitive surgery performed immediately. There were no serious postoperative complications. The average hospital stay of these 29 patients was 9.5 days. In addition, histologic examination of the uterus following immediate hysterectomy is much more satisfactory, since inflammation which hinders the search for residual disease is minimal. In our series, in no instances were the pathologic findings in the uterus more severe than those found in the conization specimen. There are other advantages to frozen section diagnosis. The immediate complications of conization are avoided when definitive surgery is done at once. In the unreliable
Volume 105 Number 1
patient who may not return for treatment, immediate therapy at the time of conization is best. Patients requiring surgery for reasons other than cervical disease are sometimes found to have abnormal cervical smears necessitating tissue study. When invasive carcinoma is excluded by frozen section ex-
Cryostat examination
of cervical
cone
111
amination, the necessarysurgery can be performed immediately. There were 6 such instances in the present series. Finally, eliminating the waiting period between diagnostic studies and definitive treatment is psychologically and economically important to patients.
many
REFERENCES
1. Ibanez, L. I., Russell, W. O., Chang, J. P., and Speece, A. J.: Lab. Invest. 9: 98, 1960. 2. Nunally, R. M., and Abbott, J. P.: Am. J. Clin. Path. 35: 20, 1961. 3. Rutledge, F., and Ibanez, M. L.: AM. J. OBST. & GYNEC. 83: 1208, 1962. 4. Querriero, W. F., Cox, R., Tillery, W., and Race, G. J,: Obst. & Gynec. 24: 61, 1964. 5. Kaufman, R. H.: Clin. Obst. & Gynec. IO: 838, 1967. Discussion
DR. IDAVID G. STROUP,* East Point, Georgia. In the Atlanta area the cryostat examination is increasing in usage, having first been used in 1965. C)nly about one half of the hospitals are now using the procedure. Only one hospital reports using the procedure with any degree of frequency and this apparently is because of the enthusiasm of the pathologist for the procedure.
This procedurerequiresclosecoordinationbetween the gynecologist, pathologist, anesthesiologist, and operation room personnel.
Two main things seemto disturb the cliniciau regarding use of the procedure.First, is he forcing the pathologist to make quicker and less accurate decisions?Second,is he disturbing the operating room routine to a great degree and causing inefficiency in the use of time of operating room personnel, the anesthesiologist, his assistant, and himself? The pathologist, on the other hand, is using more of his time and equipment than for routine or 24 hour specimens. His equipment for cryostat is tied up for 15 to 4.5 minutes, precluding its use for other tissue. As a matter of fact, one pathologist in the Atlanta area gave this as a primary reason for not encouraging the use of the procedure. These objections, of course, are more apparent than real, although they seem to be quite valid in the Atla:nta area. Presently, the cryostat examina*By
invitation.
6. Kaufman, R. H., Abbott, J. P., and Scheihing, W. C.: Ax. J, OBST. & GYNEC. 84: 107, 1962. 7. Kaufman, R. H., Janes, 0. G., and Cox, H. A.: AM. J. OBST. & GYNEC. 92: 71, 1965. 8. Malinak, L. R., Jeffrey, R. A., Jr., and Dunn, W. J.: Obst. & Gynec. 23: 317, 1964. 12511 Warwick Newport News,
Boulevard Virginia
tion is used primarily in patients in whom a biopsy has shown carcinoma in situ or severe
dysplasia; thus, it is known in advance that further therapy is indicated. The procedure used to rule out invasive carcinoma.
is
Scientifically speaking,conization of the suspicious cervix with immediate definitive therapy is ideal for the physical well-being of the patient. The psychological health of the patient must not be forgotten, however. My personal feeling is that the younger (under 30) patient in whom the conization is done needs an adjustment period before definitive therapy is carried out. Admittedly, the patient does have periods of appre-
hensionin the interval of 6 to 8 weeks.However, I feel it is important that this adjustment be faced and made before the actual loss of the uterus and childbearing function takes place. As we all know, psychosomatic and psychoneurotic problems are more common in women who have had hysterectomies. I consider the waiting period
a part of preventive therapy and put to good use for these patients. This of course is not the case when the definitive therapy is known tu be
necessary,as proved by biopsy and in older women
who already have their families.
Cryostat evaluation with immediate hysterectomy, when done for suspicious lesions, without biopsy, is comparabIe to the patient with the
breast nodule who goesin expecting to have a nodule removed and comes out having undergone a radical breast resection. We know the two need not be equated as far as the relative
112
Wash and Davis
life-endangering potential is concerned. The psychic trauma, however, is the same. My impression is that the cryostat examination has a definite place in the evaluation of the patient with the suspicious lesion; however, I feel that the use should be predicated on a careful weighing of the actual technical practicality of the procedure as opposed to the urgency for the need of immediate diagnosis and therapy. As an added comment, I noted that Dr. Wash stated that one of the surgeons performed a simple hysterectomy for microinvasive carcinoma. In the Atlanta area the usual procedure for this is hysterectomy with excision of a cuff of the vagina. DR. WILLIAM B. HELTON, JR.,” Greer, South Carolina. The authors have pointed out the increased frequency with which the diagnosis of microinvasion and carcinoma in situ of the cervix can be made by increasing the number of sections taken of the conization specimen. I feel this technique would be of extreme advantage in those patients with questionable or mildly atypical smears who require surgery for some other condition in order to rule out any invasive carcinoma prior to proceeding with definitive surgery. Reluctance of many pathology departments is very real because of lack of confidence in the method, plus time involved. Our pathologists will do cryostat examinations of the cervix, but do not feel in their experience they are as good as permanent sections. They estimate the cost of preparing and reading the 30 cryostat and 30 permanent sections of each cervical specimen at $100.00. This price may discourage the use of cryostat examination of conizations. I don’t feel that cost should be a factor when we treat cancer, and I don’t feel it is when we consider the 1,000 Papanicolaou smears we do to pick up one carcinoma in situ of the cervix. Not considering the pathologist’s fee, which I’m sure would vary greatly, this is a more expensive procedure than waiting 48 hours due to the delay of 30 to 45 minutes. The cost of that much time in the operating room and the anesthesiologist fee
‘By
invitation.
would more than offset au increased stay of 48 hours. Our technique now is to wait 24 hours on the permanent sections of our conizations and proceed within 48 hours with definitive surgery if necessary. Dr. Wash has changed or modified the diagnosis in 12 per cent of his cases and Dr. Kaufman in 10 per cent of his large series. Many of these are minor changes, but both series show slightly over a 6 per cent significant change in diagnosis. In addition, both state the most frequent change in diagnosis is from crystat section report of severe dysplasia to paraffin section report of epidermoid carcinoma in situ. It is also interesting to note that no mention was made of ever increasing the severity of a diagnosis with the frozen sections over the permanent sections, although this might have occurred. Thus I am of thra opinion that the permanent paraffin sections will remain the standard by which other methods will be judged. Until we find one that increases the accuracy of our diagnosis, I do not feel wc should change from our present method. The cryostat method may result in undertreatment as well as ovcrtreatment. It is stated that the changes in diagnosis did not significantly change the proper treatment in Dr. Wash’s series and caused an error in treatment in only one of Dr. Kaufman’s series. We must remember, however, that patients are individuals and the way we treat them is 100 per cent for that individual. Finally, it is difficult enough lo explain the necessity of a conization to a frightened patient with a positive Papanicolaou smear. In my cxperience their immediate reaction is “Why don’t you go ahead and take it all out?” I don’t fvel that any patient should be asked to help decide definitive surgery prior to a positive diagnosis with the knowledge that she has a positive Papanicolaou smear. I feel the decision would be almost unanimous to go ahead with a hysterectomy regardless of cryostat diagnosis and increase the number of unnecessary hysterectomies done. Therefore, I will continue to wait 48 hours and proceed with treatment after a lengthy discussion of the diagnosis with the individual patient.