T e n T h o u s a n d Consecutive Frozen Sections. A Retrospective Study Focusing on Accuracy and Quality Control

Transcription

1 T e n T h o u s a n d Consecutive Frozen Sections A Retrospective Study Focusing on Accuracy and Quality Control W. J. HOLADAY, M.D., AND D. ASSOR, M.D. Division of Surgical Pathology, The Ohio State University College of Medicine, 4 W. th Avenue, Columbus, Ohio 4 ABSTRACT Holaday, W. J., and Assor, D.: Ten thousand consecutive frozen sections. A retrospective study focusing on accuracy and quality control. Am. J. Clin. Pathol. 6: , 974. A review of, consecutive frozen section consultations performed over a 6'/-year period was undertaken in order to assess the accuracy of the method and to develop a quality-control mechanism. Frozen section interpretations of specimens of lung, tumors of skin, thyroid, parathyroid, and tissues from the female genital tract were in error in about.% of the cases. Specimens from the gastrointestinal system, otorhinolaryngologic regions, lymph nodes, central nervous system, and pancreas were incorrectly interpreted in fewer than % of instances. A system of periodic review of cases is suggested. (Key words: Frozen section; Quality control.) FROZEN-SECTION consultations serve the patient by providing diagnostic and staging monitoring during operation. The surgeon utilizes this information in a variety of ways, and also serves as a critical component of the diagnostic effort, in that he selects the tissue and circumstances under which the frozen section is done. No pathologist can overcome the handicap of being handed the wrong tissue. Consequently, both the surgeon and pathologist must be advised of the other's problems and limitations, if frozen-section consultations are to give maximum service. This study represents, consecutive frozen-section consultations, taking place over 6'/ years in two large university hospitals.* The major Received November 6, 97; received revised manuscript December, 97; accepted for publication January, 974. * The University of Texas Medical Branch, Galveston, Texas, and The Ohio State University Hospitals, Columbus, Ohio. 769 objective of this review is the development of a credible quality control mechanism for frozen-section consultation, based on periodic self-audit. The secondary objective is to substantiate the accuracy of the method. Method Frozen-section material received from the surgical suites is immediately examined and appropriate area(s) for frozen section are selected. The material is frozen using the standard stainless steel heat-sink built into the machine.t and is then sectioned and stained (rapid hematoxylin and eosin). The frozen-section block, from which the section was made, is then fixed and processed for permanent section, and is available for study and comparison with frozen-section material which has been t Ames Cryostat, Model "D." Downloaded from

2 77 HOLADAY AND ASSOR AJ.C.P. Vol. 6 Organ-System Breast Lung GI ENT Lymph node Skin Thyroid, Parathyroid GYN Soft tissue and bone Nerve and ganglion CNS Pancreas Prostate TOTAL Table., Consecutive Frozen Sections Total Cases,66,64, , F + 4 (.%) F (.88%) %F i.%.7%.4%.4%.7%.9%.6%.6%.%.% % 7.7% % DEF (.%) Grade Errors (.8%) % Total Errors.%.4%.6%.%.8%.6%.%.% 4% % %.% 9% % saved. Discrepancies in diagnosis are reviewed, and apparent errors are divided into four tentative groups: () falsepositive frozen sections (benign lesions called malignant); () false-negatives (malignant lesions called benign); () grading errors (incorrect histologic typing); (4) deferred diagnosis. Our protocols are constructed so that the frozen-section diagnosis and the initials of the pathologist(s) responsible for the frozen section appear at the top of the description, for example: Frozen diagnosis: Right breast biopsy, adenocarcinoma, colloid type: WJH When the case has been "signed out" and the final protocol is being prepared, we mark those cases considered as probable or tentative errors with an asterisk. This step simplifies finding "errors" for review at the time of audit. Surgical specimens in our laboratory are accessioned consecutively annually. Thus it is most convenient for us to institute our annual frozen-section audit during the first week of January, that is, following completion of an "accession year." Initially, a very complex anatomic categorization was used. For example, the gastrointestinal tract was divided into many parts: oral cavity, salivary gland, esophagus, stomach, small bowel, etc. However, with usage certain categories were combined, and at the present time the following major categories are used: breast, lung, gastrointestinal, ENT, lymph nodes, skin margins, thyroid, parathyroid, Gyn, soft tissue and bone, nerve and ganglion, CNS, pancreas, and prostate. Following this anatomic categorization, a second review was carried out in which false-positive, false-negative, grading error, and deferred diagnosis, in each of these categories, was studied case by case (Table ). The following report includes the statistical data and conclusions of this study. Discussion The most obvious conclusion concerns the accuracy of the method. Falsepositives occurred at the rate of about two per thousand (.%), and false-negatives at the rate of about %. Grading errors and deferred diagnosis combined occurred at a % incidence. Therefore, the overall accuracy of the method is 98%, if grading errors and deferred diagnosis are included. If they are excluded, in other words, if only false-negatives and false-positives are considered errors, accuracy is close to 99%. Downloaded from

3 June 974 FROZEN SECTION DIAGNOSIS 77 Also of interest is the marked difference between the false-positive and falsenegative percentages. False-negatives occur at a very low percentage, but still at six times the incidence of false-positives. There is no doubt that the overall attitude of the pathologist is one of extreme conservatism in handling frozen-section material. As a consequence, confronted with the situation in which the problem of neoplasia must be resolved, we are six times as likely to err on the side of conservatism. In reviewing previous publications relative to the accuracy of frozen sections, we are struck with the consistency of "par." For example, Ackerman's 99 study showed 98% accuracy in more than, cases, Lattes and associates, in 968, reported 98.6% accuracy in more than, cases, and other studies with similarly high reliability have been reported., Lattes went on to point out that many of his frozen sections had been done by Residents and Fellows in the Division of Surgical Pathology, and that this served as an excellent teaching opportunity without effect on the accuracy of the system, if it is understood that senior consultants are always available. We concur in this conclusion. Breast One false-positive error was made in the,6 breast cases. Microscopically this case was characterized, on the basis of both permanent and frozen-section blocks, as a sclerotic lesion with florid epithelial proliferation. The lobular pattern was obliterated and we felt it was carcinoma, despite the absence of necrosis. A radical mastectomy resulted. Detailed examination of the excised breast and axillary nodes showed no microscopic evidence of carcinoma. It is difficult to establish the incidence of false-positive frozen-section diagnosis of breast biopsies. Lattes, and associates, in a 968 publication concerning, consecutive frozen sections, mentioned one case of an atypical xanthofibroma which had been misinterpreted as adenocarcinoma; the diagnosis resulted in a simple mastectomy. This false-positive frozen-section error occurred in a total of 677 breast cases incorporated in the study. We have been unable to document any other published study containing false-positive frozen sections of breast lesions. Traditional texts warn of the pitfalls and identify the areas of maximum danger where, presumably, the authors have erred in the past. It has been our experience, in reviewing consultation material, that the greatest problem is the over-interpretation of the florid epithelial lesions (sclerosing adenosis) accompanying fibrocystic disease of the breast. We presume that this problem of misinterpretation is carried over into frozen-section diagnosis. The magnitude of the problem is unknown. We are also cognizant of the fact that two consecutive errors on the same case will cancel each other. The fact that the same diagnosis was made on the basis of both the frozen section and the permanent section does not guarantee that either diagnosis is correct. The technic that we have used with breast biopsy material starts with meticulous gross examination of the biopsy specimen; emphasis is placed on the identification of necrosis. This visual examination, plus the subjective digital examination in the hands of the experienced pathologist, has a high degree of accuracy in selecting the area for frozen section. Microscopically, we use the time-honored criteria for benign breast lesions, which in essence is maintainance of the lobular pattern. We have adopted the philosophy that all papillary lesions of the breast are "benign" on frozen section, and defer such cases for permanent-section examination. The low incidence (less than %) of papillary carcinoma of the breast, compared with the high incidence of benign papillary lesions, is overwhelming; thus, the odds favor a conservative attitude. Downloaded from

4 77 HOLADAY AND ASSOR A.J.C.P. Vol. 6 We have found that it is helpful to push beyond the diagnosis of "cancer" and attempt histologic typing (grading). This serves several purposes. It provides, first, conscious and subconscious reconfirmation of the loss of lobular pattern, and second, validation of the criteria used on permanent sections, for example, the Indian-file pattern of invasive lobular carcinoma. Pure intraductal carcinoma is rare, particularly if the entire breast is examined meticulously. However, it is not uncommon for the surgeon to select an area of pure intraductal carcinoma and submit it to the pathologist for frozen section. Eight of our breast frozen sections were false-negatives; of these, four were intraductal carcinomas. Ina review of these four cases the problem was technical, in that necrotic tumor fell from the ducts and obscured the diagnosis. Six breast frozen sections were deferred and, with only one exception, proved on permanent section to be intraductal carcinoma. Therefore, there is a significant problem in () preparing a specimen which is technically satisfactory, and () selecting for frozen section examination areas which contain material meeting established diagnostic criteria for intraductal carcinoma. The one exception in the "deferred error" group was a low-grade adenocarcinoma, which also proved to be a considerable problem on permanent sections. The four other false-negative frozen sections were highly desmoplastic invasive small-cell carcinomas, and malignant cells were not identified on frozen-section examination. There has been expanding use of the "lumpectomy," simple mastectomy, modified radical, and other therapeutic approaches less than the classic Halsted radical mastectomy for the treatment of carcinoma of the breast. In fact, at the present time, such therapeutic substitutes are commonplace in our institution, and excuses for doing these lesser procedures are often based on attempts by the pathologist at grading interpretation (i.e., histologic typing). Realizing that the major stumbling block was intraductal carcinoma, and the major difficulty the evaluation of "occult" invasive carcinoma in either the remaining biopsy or the breast, we examined, in sequence, six intraductal carcinoma cases. Multiple biopsies were submitted, and multiple sections were examined. We thought that each of the frozen sections showed pure intraductal carcinoma (i.e., in situ carcinoma); however, subsequent permanent sections showed stromal invasion. We are, therefore, reluctant to guarantee the noninvasive nature of such lesions, and so inform the surgeon. This is not a new observation. 6 Lobular carcinoma in situ is another problem. In our experience, lobular carcinoma in situ can be suspected on the basis of frozen section. However, we believe it prudent to defer such diagnosis until we can meticulously examine the permanent sections. Anticipating its occurrence is helpful in two regards: () ordering immediate serial sections of the total original biopsy, i.e., expediting the diagnosis, and () recommending blind biopsy of the upper outer quadrant of the opposite breast. 7 Lung and Mediastinum Of,64 frozen sections,.4% were in error; these fell into two major groups, () false-negatives, and () grading errors. The false-negative sections almost all represented selection errors, either by the surgeon, or by the pathologist. Mediastinal sampling prior to pulmonary resection may result in frozen sections of a series of lymph nodes, and two opportunities for error exist in this situation. First, the surgeon may select the wrong nodes, and second, the pathologist may select an uninvolved portion of a lymph node for frozen section. In our experience the surgeon is responsible for the greatest number of selection errors. The grading errors are almost uniformly the result of the inability to distinguish between oat-cell Downloaded from

5 June 974 FROZEN SECTION DIAGNOSIS 77 carcinoma and lymphosarcoma. This has not proven to be a major roadblock, primarily because sufficient radiographic and clinical information exists at the time of thoracotomy to substantiate a diagnosis of one or the other. We have seen one case of the diseases coexisting, but so far have not met this problem at the time of frozen section. Gastrointestinal Tract In, frozen sections from this organ system,.6% total errors occurred, the most noteworthy errors being the false-negatives. This relatively high incidence of false-negatives consists of a rare selection error made by the surgeon. However, most were the result of the misinterpretation of polypoid lesions. Seven of the false-negatives were superficial carcinoma (Dukes' A) arising in sessile villous polyps, one of which was in the stomach. The other seven were polypoid Dukes' A carcinoma of the colon, which were misdiagnosed as adenomatous polyps on frozen section. One case was a selection error by the surgeon, and represented an invasive carcinoma of the stomach. There is a problem in differentiating between gastric carcinoma and gastric lymphoma; so far we have been successful in accurately separating the two. Our rule is quite simple: we rely on the substantial desmoplasia that is apparendy constant with the carcinomas. ENT (Paranasal and Upper Respiratory Tract) All four false-positives occurred in tissue previously irradiated. Three of these were postirradiation epithelial changes, which were misinterpreted as either carcinoma in situ, or superficially invasive carcinoma; the fourth case represented an irradiated minor salivary gland which was misinterpreted as carcinoma in the margin of a known squamous-carcinoma resection specimen. The false-negatives occurred for essentially the same reason. Many of these were postirradiation cases with marked changes, including telangiectasia, atypical fibroblastic proliferation, and bizarre striated-muscle degeneration. The grading errors, of which there were seven, almost uniformly involved misinterpretation of major and minor salivary gland neoplasms. The error may occur either way; two of our errors consisted of confusing mixed tumor with adenocarcinoma, and vice versa. Interestingly enough, several of the grading errors occurred in cases where the diagnosis was already known. A second group consists of referred slides which posed perplexing problems so far as histologic type was concerned. They have included undifferentiated carcinomas of the paranasal sinus, lymphomatous infiltration of the gingiva, and so-called lymphoepithelioma with an obscure epithelial element. Re-exploration for biopsy and definitive surgery was done in many of these cases, and material was submitted for frozen section, in the hope of obtaining an "instant" definitive histologic type. This was rarely successful. Our surgeons persist in this practice despite our warnings as to its futility. Frozen-section examination of resection margins of postirradiated persistent neoplasms of the head and neck has become common practice. Margin examination may involve - frozen sections of the specimen, the margins often being selected by the surgeon. Several of our recent cases have been recrudescent after combined surgery and irradiation; adequacy of the margin, such as it is, is blamed on the pathologist. Lymph Node Frozen sections of lymphomas, i.e., lymph nodes suspected of harboring lymphoma, have been an emotional issue for many years. Dogmatic statements that lymphomas cannot, or should not, be diagnosed on the basis of frozen sections, have been reiterated time and again. Downloaded from

6 774 HOLADAY AND ASSOR A.J.C.P. Vol.6 However, a practical solution to the problem can certainly be found, whereby lymph nodes can be examined by frozen section to confirm the presence or absence of disease and thereby serve the patient. The one false-positive frozen section in the 84 lymph nodes examined consisted of reactive hyperplasia (sinus histiocytosis), which was interpreted as metastatic carcinoma. Pathologists who review lymph nodes with junior residents, particularly axillary lymph nodes from breast carcinomas, are familiar with the occasional intense sinus histiocytosis reaction and subsequent misinterpretation of this picture. Such was the case in the false-positive in question. The falsenegatives, of which there were five, constitute sampling errors, by both the pathologist and the surgeon; all were cases of metastatic carcinoma in which lymph node biopsy was done to establish stage of disease. The interesting cases are the deferred diagnoses and the grading errors. Deferred were nodular lymphomas, and/or reactive hyperplasias, in which nodular lymphoma could not be eliminated from the differential diagnosis. The infrequent grading errors demonstrate that in "classic cases" the final histologic typing on permanent section is most frequently in agreement with the frozen-section impression. The above discussion, however, is tangential to the real problem with lymph node biopsies submitted for frozen-section examination. It is imperative that one establish a routine whereby the frozen section does not obviate diagnosis on the basis of the permanent section. Distortion following frozen section may be quite severe, and blocks from which frozen sections have been taken may prove quite impossible for definitive diagnosis, histologic typing, or identifying cellular detail. Our routine is to submit only a portion of the lymph node for frozen section; if grossly this is uniformly involved with a process that may represent either metastatic carcinoma or lymphoma, frozen section is done following the preparation of three to six touch imprints. If the lymph node is involved with what grossly appears to be an inflammatory process, a portion is submitted for culture, or at least held for such use until sections are examined. The remainder of the node which is not frozen is thinly sliced and fixed, in whatever fashion suits the pathologist. Thus, the frozen section can be turned to both the patient's and the pathologist's advantage. Formalin-fixed lymph nodes do not lend themselves to bacterial culture. Therefore, examination of the unfixed gross specimen and frozen-section examination of a portion of the node have frequently proven to be of great help in directing subsequent diagnostic tests. We would not like to overlook another benefit which has recently proven to be of great interest to our colleagues in immunology, i.e., examining touch imprints and frozensection material for "T" and "B" cell typing. In the future there will undoubtedly be other uses of this material, and we presently encourage the surgeons to submit fresh unfixed, diagnostic lymph node biopsies to surgical pathology. Skin In the majority of frozen sections done in the 8 skin cases submitted, the specimens have been margins adjacent to cutaneous neoplasms. The major errors involve two areas, first, sampling, and second, confusing radiation changes. Sampling error is primarily that of the pathologist, and may be the result of poorly oriented blocks. It is imperative that sections be taken in such a manner that they include not only the neoplasm but a full thickness of the adjacent margins and underlying subcutaneous tissue. The subcutis, because of its consistency, is difficult to cut, and we have found no way to avoid this error. Irradiation changes, which may be confused with neoplasia, or Downloaded from

7 June 974 FROZEN SECTION DIAGNOSIS 77 obscure invasive carcinoma, have been discussed in the paragraph under ENT. Parathyroid and Thyroid Parathyroid and thyroid have had no significant false-positivies in the 78 cases examined; however, five false-negatives constitute sampling errors to which both the surgeon and the pathologist contributed. The cases in which the pathologist contributed were diseased thyroids, especially those with Hashimoto-like changes, and incidental papillary carcinoma. This occurred three times during the series. Lattes and associates have also commented on this problem. Gyn Very few significant errors occurred in the specimens submitted from this organ system; the two false-positives were atypical hyperplasias confused with carcinoma at the time of frozen section. We concur in the high degree of accuracy in both diagnosis and staging of cervical cancer by frozen section done at the time of cone biopsy. 4 Soft Tissue and Bone A small, but significant, number of errors occurs in this group, primarily in those specimens submitted from bone. Most of the errors were false-negatives, or deferred diagnosis, and there were nine grading errors. It is distressing that a number of problems are the result of the clinician's withholding information. We have repeatedly stressed the importance of briefing the pathologist prior to biopsy. The briefing should include a review of the x-ray material with a disinterested third party, namely the radiologist. The majority of true problem cases lie in the giant-cell group of osseous lesions, which includes the major differential "cluster" of chondroblastoma, aneurysmal bone cyst, giant-cell tumor, and osteosarcoma. Our present policy is to individualize each frozen section, and to visit the operating room and review the findings and radiographic changes at that time. The surgeon is advised of our diagnostic problems, and radical procedures, such as amputations, on the basis of frozen-section interpretation alone are discouraged. Central Nervous System The majority of the problems in this area involve the confusion of low-grade astrocytoma with reactive gliosis; this is also a problem in interpreting permanent sections. The surgeon must be advised of the difficulty and differential diagnosis, and urged to submit further diagnostic material if feasible. All central nervous system frozen-section consultations in this series were done by members of the surgical pathology staff; no neuropathologist participated. Pancreas In 49 lesions from the pancreas submitted for frozen section, there were no false-positives, five false-negatives, and five cases were either deferred diagnoses or grading errors. The "old saw" that pathologists are unable to diagnose pancreatic carcinoma accurately is not true. It is true, however, that pathologists are unable to diagnose some pancreatic neoplasms, the problem being almost exclusively adenocarcinoma, because it looks like, or may be confused with, chronic pancreatitis. The surgeon must be discouraged from proceeding with radical procedures (Whipple) on the basis of his gross interpretation; there is no reported quality control of surgeons' accuracy in this regard, nor is such a procedure justified in the erroneous impression that interpretations of frozen sections are not accurate. We urge the surgeon to repeat the biopsy, either needle or incisional, depending on the clinical status of the patient. We urge him to select biopsy sites, Downloaded from

8 776 HOLADAY AND ASSOR A.J.C.P. Vol. 6 such as the regional lymph nodes, where, if metastatic tissue is found, chronic pancreatitis is no longer a consideration. This attitude, in our experience to date, has prevented false-positives, and has resulted in only a limited number of falsenegatives. None of those cases in which the diagnoses were deferred were found to be carcinoma, and we have found that the overall error is extremely low. Overall accuracy is 97.%. Prostate The present state of the art does not produce an acceptable level of accuracy with regard to prostatic carcinoma. Our attitude has been one of conservatism, which has resulted in no false-positives; however, there have been falsenegatives (7.7%). The two cases in which the diagnoses were deferred were not neoplastic, and our overall error approaches %. As soon as we started collecting our frozen-section statistics, it became obvious that our accuracy with prostate tissue was not acceptable, and we so notified our colleagues in Urology. As a consequence, we have totally discouraged frozen sections of transperineal and transrectal biopsies of prostate nodules, so much so that frozen sections are now submitted at a rate of fewer than one per year. The problem with interpretation here, of course, is the fact that most prostatic adenocarcinomas are extremely well differentiated, so much so that they are frequently diagnostic problems on permanent section. Second, modern prostatebiopsy technic is the needle biopsy, and such specimens are small and fragile. If the surgeon is "lucky" enough to include a peripheral nerve which shows perineural space involvement, the pathologist may not be able to find this area on frozen section. If the pathologist resorts to serial sectioning, he may destroy the specimen so that permanent-section diagnosis is also obviated. Therefore, we urge that all prostatic biopsy specimens be submitted for subserial permanent sectioning. Rapid processing equipment is being developed to shorten the waiting interval necessary for permanent section; however, the urgency for diagnosis is probably more imaginary than real. Conclusions The primary objective of this study was the development of a self-audit which would aid in quality control and in identifying and solving problems. Dividing the errors into the four categories described (false-positive, false-negative, grading errors, and deferred diagnosis), and then studying the type of error occurring within each of the organ systems, is of great help in categorizing the problem areas. For example, quality control of breast frozen sections, in our opinion, can best be achieved by annual review of all breast lesions that were diagnosed as malignant on frozen-section examination. False-negatives occur in breast lesions with eight times the incidence of false-positives, but in our experience they have proven to be of litde practical importance. Most of the false-negatives are in situ lesions, or well-differentiated lesions, which are also extremely difficult to interpret on permanent section. In other words, there are rare cases that are impossible to diagnose on the basis of frozen section. Therefore, a review of breast lesions diagnosed as malignant on frozen-section consultation provides a concentrated overview of the pathologists' performance with lesions, without the chore of wading through a host of benign lesions. A review of benign diagnoses, plus deferred cases that subsequently turned out to be malignant, gives an index of the pathologist's conservatism. To us this is a "non-problem"; we believe the converse, i.e., false-posi tive errors, are the most dangerous and damaging to all Downloaded from

9 June 974 FROZEN SECTION DIAGNOSIS 777 concerned, and that our efforts should be concentrated there. The five organ-lesion systems of lung, tumor margins for skin lesions, thyroid, parathyroid, and gynecologic specimens should be audited on an annual or semiannual basis. "Par" for these groups is about.% total error. The most critical areas for review of this group are the false-negative and false-positive areas. An overview audit, including all such cases which were called cancer and were not, or were called benign and subsequently were called cancer, is the most rewarding, and provides a mechanism to concentrate on the meaningful problems. Here an error greater than % (false-positive and falsenegative conbined) should serve as a warning flag, and suggest that the audit interval should be shortened, so that the particular area of difficulty can be pinpointed and corrected. The five organ systems which include gastrointestinal, ENT, lymph nodes, central nervous system, and pancreas should not exceed a total overall error of %. False-positives occurring in the lymph node, or pancreas organ systems, should serve to initiate an immediate, critical review of the circumstances of that case, and the entire organ system should be audited to find out whether similar errors are occurring, and if so, with what frequency and consequences. A total falsepositive, false-negative error greater than % in this group should also serve as a significant warning. Simply stated, our goal is to identify problem areas using a system of error categories. Once the error has been identified, remedial action can start, and recurrence be prevented. To facilitate organization along these lines, it is convenient to group the errors in organ systems; then, when specimens from frozen section are examined, attention can be focused directly on the area of probable error. The annual audit, however, is the key to successful quality control of frozen-section consultations. It provides an opportunity for the pathologist to review all frozen-section diagnoses in an unemotional time-situation setting, completely detached from the pressures attending frozen-section cases. We believe this promotes the proper atmosphere for critical self-examination and objective conclusions. Our experience is that the first audit is the most difficult, but in the long run the most rewarding. Note: It is our policy to resolve problem cases, in which the staff cannot make a unanimous decision, by submitting the case to an outside consultant. A letter of introduction, outlining the situation under which the case has been submitted, has "sensitized" our consultants, and they uniformly have proved to be very responsive. We have agreed to accept the diagnoses of these "arbitrators," even though we may disagree, and their diagnoses have served asfinalin all cases in question in the above series. We would like to thank, in this regard, L.V. Ackerman, M.D., W. Bauer, M.D., W. Hartmann, M.D., F. Krauss, M.D., M. McGavran, M.D., and a man that holds a special place in our esteem, H. J. Spjut, M.D. References. Ackerman LV, Ramirez GA: The indications for and limitations of frozen section diagnosis. A review of 69 consecutive frozen sections. Br J Surg 46:6-, 99. Ackerman LV, Rossai J: The pathology of tumors, part three: Frozen sections, gross and microscopic examinations, ancillary studies. CA :7-8, 97. Funkhouser JW, Oosting M, Kelly M, et al: Evaluation of frozen sections using the cryostat in a community hospital. Ohio State Med J 66:46-49, Kaufman RJ, Janes OG, Cox HA: Cervical conization with frozen section diagnosis. Am J Obstet Gynecol 9:7-77, 96. Nakazawa H, Rosen P, Lane N, et al: Frozen section experience in cases; accuracy, limitations, and value in residency training. Am J Clin Pathol 49:4-, Stewart FW: Tumors of the breast, Atlas of Tumor Pathology, Section IX, Fascicle 4, 9, p8 7. Urban JA: Bilaterality of cancer of the breast, biopsy of the opposite breast. Cancer :867-87, 967 Downloaded from