Br. J. Surg. Vol. 63 (1976) 327-329
A retrospective analysis of the accuracy of immediate frozen section diagnosis in surgical pathology A. M . L E S S E L L S A N D J . G . S I M P S O N * SUMMARY
the accuracy of’ 3556 frozen section diugnoses over a 10-year period has been carried out. The overall accuracy rate was 97.4 per cent, with unimportant discrepancies present in a further 1.8 per cent. In only 28 cases (0.8 per cent) was a false negative or positive diagnosis of malignancy made. Of these, 4 patients underwent an unnecessary radical operation, while in 9 patients further surgery had to be carried out at a later date. The essential accuracy of the frozen section technique is confirmed. An evaluation
OJ
THEfrozen section technique is now a well-established procedure for the rapid diagnosis of surgical specimens. The major indication for the use of this method is to allow the surgeon to make an immediate therapeutic decision, thus sparing the patient possible reoperation and reducing the length and cost of hospital treatment. Since the diagnosis made by the pathologist from frozen section may have serious consequences for the treatment of the patient, a high degree of accuracy is mandatory and quality control is important. However, apart from North America where the method appears to be more widely used than elsewhere, little attention has been given to the assessment of the accuracy of the technique. Jennings and Landers (1957) in a study of 412 cases showed an overall accuracy rate of 98.5 per cent. Similar figures (97.5-98.4 per cent) were reported in the somewhat larger series of Pitts et al. (1958), Ackerman and Ramirez (1959), Winship and Rosvoll (1959) and Horn (1962). In the two largest series reported to date the total accuracy (excluding deferred diagnoses) was 98.5 per cent in 3000 cases (Nakazawa et al., 1968) and 99 per cent in 10 000 cases (Holaday and Assor, 1974). The only comparable British series (Desai, 1966) was limited to 1006 lesions of the breast. In none of these reports is there any indication as to the effect of inaccurate frozen section diagnosis on the subsequent management of the patient. The present study was instituted to assess the accuracy of frozen section diagnosis in a large British series of general surgical specimens. An attempt was also made to evaluate the effect of initially incorrect diagnoses on the later treatment of patients.
Materials and methods A retrospective survey was made of all surgical pathology specimens received in the Department of Pathology, University of Aberdeen, which is the sole histopathology department serving the north-east (Crampian) region of Scotland, during the years
1964-73. In this period 116 144 specimens were received, of which 3607 (3.1 per cent) were submitted for frozen section diagnosis, all from two large general hospitals. From each specimen submitted for frozen section, one or more blocks is taken and frozen rapidly using CO, gas and thin sections stained with both brilliant cresyl blue and haematoxylin and eosin. When the pathologist’s opinion has been conveyed to the surgeon, the remainder of the block is thawed and immersed in a rapid fixative (Carnoy’s fluid) to allow confirmation of the diagnosis within 24 hours. In addition, particularly when the specimen is large or the diagnosis in doubt, further blocks may be fixed and stained by slower, routine histopathological techniques. Complete case data (clinical records, initial frozen section and final pathological diagnoses) were available for 3556 (98.6 per cent) of the frozen section samples. Discrepancies between the histopathological diagnoses were recorded and, using the clinical records, divided into two main groups: cases in which the difference in opinion on frozen section and on the final fixed section was not considered important in terms of immediate patient management, and the important cases where an initial false positive or false negative diagnosis of malignancy had been made. Table I: TISSUE OF ORIGIN OF FROZEN SECTION SAMPLES Tissue Breast CNS Skin and subcutaneous tissue Alimentary tract Genito-urinary system Lymph nodes Thyroid, parathyroids and thymus Respiratory tract Other sites Total
No. of cases 2197 319 210 191 159 157 139 123 61
‘%; 61.8 9.0 5.8 5 4
4.5
4.4 3.9 3.5 1.7
3556
~
Results The site of origin of the frozen section specimens is shown in Table I . As would be expected, the majority (62 per cent) of specimens were breast lesions. The next major group-lesions of the central nervous systemformed a surprising 9 per cent of the total; in this region, however, the neurosurgeons tend to use the technique not so much as a guide to surgical management but rather as a means of rapidly assessing the
* Department of Pathology, University of Aberdeen. 327
A. M. Lessells and J. G. Simpson Table 11: CASES WITH UNIMPORTANT DISCREPANCIES BETWEEN FROZEN SECTION AND FINAL DIAGNOSES Examples of diagnoses No. of Difference cases Y Frozen section Final More precise diagnosis Different diagnosis Sampling error Deferred diagnosis Total
39 18 2 7 66
1.1 0.5 0.06 0.1 1.76
Anaplastic tumour Astrocytoma Dilated breast duct
Table 111: DETAILS OF 28 CASES WITH FALSE POSITIVE O R MALIGNANCY No. of Frozen section Group Tissue cases diagnosis False positive diagnosis Breast 1 Carcinoma of malignancy (6 cases, Subcutaneous I Malignant tumour 0.17%) Skin Recurrent 1 carcinoma Caecum I Carcinoma Brain 1 Malignant tumour Brain 1 Malignant tumour False negative diagnosis Breast 6 Benign of malignancy due to incorrect histological Brain 3 Meningioma interpretation (1 3 cases, 0.36%) Skin Cellular naeb 2 Thyroid I Hashimoto’s thyroiditis Salivary gland 1 Adenoma False negative diagnosis Breast 7 Benign of malignancy due to sampling error (9 cases, 0.25%) Prostate Benign 2
prognosis of the patient so that anxious relatives may be informed as soon as possible. In 3462 cases (97.4 per cent) there was no difference between the frozen section and final pathological diagnoses. Of the remainder, in 66 cases (1.8 per cent) the discrepancy between the diagnoses was not important in terms of immediate surgical management ; the number of and reasons for these discrepancies are shown in Table II. In only 28 cases (0.8 per cent) was there a major, therapeutically important, inaccuracy in the frozen section diagnosis; in 6 (0.17 per cent) malignancy was incorrectly diagnosed, while in 22 (0.61 per cent) malignancy was missed either because of incorrect interpretation of the histological features ( I 3 cases) or because of incorrect sampling of the tissue by the pathologist (9 cases). The tissue sites, incorrect and corrected diagnoses and effects on patient management in these 28 cases are shown in Table Ili. Of the 6 cases in which a false positive diagnosis was made, 4 patients were subjected to an unnecessary radical operation; the incorrect diagnosis did not influence the surgical treatment in the 2 neurosurgical cases. Of the 13 cases in which an incorrect histological opinion resulted in a false negative diagnosis of malignancy, only 3 patients underwent later radical surgery when the final diagnosis became known; in the remainder, wide local excisions had already been performed or postoperative radiotherapy was administered. Of the 9 cases in which incorrect sampling of 328
Fibrosarcoma Metastatic melanoma Intraduct papilloma
FALSE NEGATIVE DIAGNOSIS OF Final diagnosis
Effect of incorrect diagnosis o n case management
Fat necrosis Inflammatory Inflammatory
Radical mastectomy Wide local excision Wide local excision
Endometriosis Neurilemmoma Meningioma Carcinoma (4) Intraduct carcinoma (2) Metastatic melanoma Glioma Oligodendroglioma Malignant melanoma Reticulum cell sarcoma
Right hemicolectomy None None Radical surgery delayed (2) None (4) None (3) None-initial None
wide excision
Adenocarcinoma Radical surgery delayed Carcinoma (5) Radical surgery delayed ( 5 ) Intraduct carcinoma (2) None (2)-initial wide excision Carcinoma Orchidectomy delayed (1) None (1)Loestrogen theraov
the tissue resulted in a false negative diagnosis of malignancy, 6 patients had to have later surgical treatment.
Discussion The overall accuracy rate in the present study of 3556 frozen section diagnoses during a 10-year period was 97.4 per cent. Although a precise diagnosis is always preferable, the time available for the histological examination of frozen section specimens is limited and it is usually sufficient for the surgeon to know whether a lesion is neoplastic or not, and, if the former, whether benign or malignant, since his immediate therapeutic decision is made on the basis of such a broad diagnosis. When the group of minor differences is thus excluded, the diagnosis of malignancy or benignancy was correct in 99.2 per cent of the cases in the present series. This figure corresponds closely to those reported in the large series of Nakazawa et al. (1968) and Holaday and Assor (1974); comparison with many of the other series reported is difficult because of their small numbers, limitation to one tissue or failure to subdivide errors by cause. In the present series, excluding examples of sampling error, the ratio of false positive : false negative diagnoses of malignancy was approximately 1 : 2. This tends to emphasize the conservative approach of pathologists to frozen section diagnosis, most, presumably, taking the view that a false positive diagnosis of malignancy with the possibility of radical
Accuracy of immediate frozen section diagnosis surgery being performed would be regarded as a greater mistake. Although it is almost inevitable that the slightly poorer quality of frozen sections prevents the accuracy of diagnosis available from properly fixed tissue, certain of the errors in the present series could probably have been avoided if complete clinical information had been available to the pathologist and if the tissue submitted for examination had been properly sampled by him. (Accurate sampling by the surgeon is also, of course, essential; not included in the present series of pathological errors are cases where subsequent specimens from a patient revealed lesions not present in the original sample sent for frozen section.) Ideally, the pathologist should have ready access to the clinical record and either see the lesion in situ or have a n y suspicious area in a large specimen accurately indicated. Frozen section diagnosis is most commonly used in the surgical management of breast lesions. The present series does indicate, however, that inaccuracies are effectively no more common in other sites, so that there appears to be no contraindication to frozen section diagnosis being applied to any tissue. Its value in thoracic surgical and gynaecological material has been emphasized by Sjolin (1955) and DiMusto (1970). Of the 28 cases in which a false positive or negative diagnosis of malignancy was made, in only 4 (0.1 per cent of the total frozen sections) was radical surgery performed unnecessarily. In a further 9 patients (0.25 per cent), surgical treatment was delayed. (It is, of course, possible that more of the patients in whom a false negative diagnosis of malignancy was made would have undergone immediate further surgical therapy had the correct diagnosis been given to the surgeon at the time of frozen section.) Quality control studies should form an essential part of the routine commitment of any laboratory service.
The results of one such study in a department of histopathology indicate that the frozen section technique is an essentially accurate, and thus extremely useful, method of immediate diagnosis in surgical pathology.
References
v. and RAMIREZ G. A . (1959) The indications for and limitations of frozen section diagnosis. A review of 1269 consecutive frozen section diagnoses. Br. J. Surg. 46, 336-350. DESAI s. B. (1966) Uses and limitations of frozen section in diagnosis of lesions of the breast. Br. J . Surg. 53, 1038-1042. DIMUSTO J . C. (1970) Reliability of frozen sections in gynecologic surgery. Obstet. Gynecol. 35,235-240. HOLADAY W. J. and ASSOR D. (1974) Ten thousand consecutive frozen sections. A retrospective study focusing on accuracy and quality control. Am. J . Clin. Pathol. 61, 769-777. HORN R . c. (1962) What can be expected of the surgical pathologist from frozen section examinations. Surg. Clin. North Am. 42, 443454. JENNINGS E. R . and LANDERS J. w . (1957) The use of frozen section in cancer diagnosis. Surg. Gynecol. Obstet. 104, 60-62. NAKAZAWA H., ROSEN P., LANE N. and LATTES R. (1968) Frozen section experience in 3000 cases. Am. J . Clin. Pathol. 49, 41-51. PITTS H. H., STURDY J. H. and COADY c. J . (1958) Frozen sections. 11. Value in cases of suspected malignancy. Can. Med. Assoc. J . 79, 1 10-1 12. SJOLIN K.-E. (1955) On the routine use of frozen sections with a special view to diagnostic accuracy. Acta Pathol. Microbiol. (Suppl.) 105, 161-173. WINSHIP T. and ROSVOLL R . v. (1959) Frozen sections. An evaluation of 1,810 cases. Surgery 45, 462466. ACKERMAN L.
329
A retrospective analysis of the accuracy of immediate frozen section diagnosis in surgical pathology A. M . L E S S E L L S A N D J . G . S I M P S O N * SUMMARY
the accuracy of’ 3556 frozen section diugnoses over a 10-year period has been carried out. The overall accuracy rate was 97.4 per cent, with unimportant discrepancies present in a further 1.8 per cent. In only 28 cases (0.8 per cent) was a false negative or positive diagnosis of malignancy made. Of these, 4 patients underwent an unnecessary radical operation, while in 9 patients further surgery had to be carried out at a later date. The essential accuracy of the frozen section technique is confirmed. An evaluation
OJ
THEfrozen section technique is now a well-established procedure for the rapid diagnosis of surgical specimens. The major indication for the use of this method is to allow the surgeon to make an immediate therapeutic decision, thus sparing the patient possible reoperation and reducing the length and cost of hospital treatment. Since the diagnosis made by the pathologist from frozen section may have serious consequences for the treatment of the patient, a high degree of accuracy is mandatory and quality control is important. However, apart from North America where the method appears to be more widely used than elsewhere, little attention has been given to the assessment of the accuracy of the technique. Jennings and Landers (1957) in a study of 412 cases showed an overall accuracy rate of 98.5 per cent. Similar figures (97.5-98.4 per cent) were reported in the somewhat larger series of Pitts et al. (1958), Ackerman and Ramirez (1959), Winship and Rosvoll (1959) and Horn (1962). In the two largest series reported to date the total accuracy (excluding deferred diagnoses) was 98.5 per cent in 3000 cases (Nakazawa et al., 1968) and 99 per cent in 10 000 cases (Holaday and Assor, 1974). The only comparable British series (Desai, 1966) was limited to 1006 lesions of the breast. In none of these reports is there any indication as to the effect of inaccurate frozen section diagnosis on the subsequent management of the patient. The present study was instituted to assess the accuracy of frozen section diagnosis in a large British series of general surgical specimens. An attempt was also made to evaluate the effect of initially incorrect diagnoses on the later treatment of patients.
Materials and methods A retrospective survey was made of all surgical pathology specimens received in the Department of Pathology, University of Aberdeen, which is the sole histopathology department serving the north-east (Crampian) region of Scotland, during the years
1964-73. In this period 116 144 specimens were received, of which 3607 (3.1 per cent) were submitted for frozen section diagnosis, all from two large general hospitals. From each specimen submitted for frozen section, one or more blocks is taken and frozen rapidly using CO, gas and thin sections stained with both brilliant cresyl blue and haematoxylin and eosin. When the pathologist’s opinion has been conveyed to the surgeon, the remainder of the block is thawed and immersed in a rapid fixative (Carnoy’s fluid) to allow confirmation of the diagnosis within 24 hours. In addition, particularly when the specimen is large or the diagnosis in doubt, further blocks may be fixed and stained by slower, routine histopathological techniques. Complete case data (clinical records, initial frozen section and final pathological diagnoses) were available for 3556 (98.6 per cent) of the frozen section samples. Discrepancies between the histopathological diagnoses were recorded and, using the clinical records, divided into two main groups: cases in which the difference in opinion on frozen section and on the final fixed section was not considered important in terms of immediate patient management, and the important cases where an initial false positive or false negative diagnosis of malignancy had been made. Table I: TISSUE OF ORIGIN OF FROZEN SECTION SAMPLES Tissue Breast CNS Skin and subcutaneous tissue Alimentary tract Genito-urinary system Lymph nodes Thyroid, parathyroids and thymus Respiratory tract Other sites Total
No. of cases 2197 319 210 191 159 157 139 123 61
‘%; 61.8 9.0 5.8 5 4
4.5
4.4 3.9 3.5 1.7
3556
~
Results The site of origin of the frozen section specimens is shown in Table I . As would be expected, the majority (62 per cent) of specimens were breast lesions. The next major group-lesions of the central nervous systemformed a surprising 9 per cent of the total; in this region, however, the neurosurgeons tend to use the technique not so much as a guide to surgical management but rather as a means of rapidly assessing the
* Department of Pathology, University of Aberdeen. 327
A. M. Lessells and J. G. Simpson Table 11: CASES WITH UNIMPORTANT DISCREPANCIES BETWEEN FROZEN SECTION AND FINAL DIAGNOSES Examples of diagnoses No. of Difference cases Y Frozen section Final More precise diagnosis Different diagnosis Sampling error Deferred diagnosis Total
39 18 2 7 66
1.1 0.5 0.06 0.1 1.76
Anaplastic tumour Astrocytoma Dilated breast duct
Table 111: DETAILS OF 28 CASES WITH FALSE POSITIVE O R MALIGNANCY No. of Frozen section Group Tissue cases diagnosis False positive diagnosis Breast 1 Carcinoma of malignancy (6 cases, Subcutaneous I Malignant tumour 0.17%) Skin Recurrent 1 carcinoma Caecum I Carcinoma Brain 1 Malignant tumour Brain 1 Malignant tumour False negative diagnosis Breast 6 Benign of malignancy due to incorrect histological Brain 3 Meningioma interpretation (1 3 cases, 0.36%) Skin Cellular naeb 2 Thyroid I Hashimoto’s thyroiditis Salivary gland 1 Adenoma False negative diagnosis Breast 7 Benign of malignancy due to sampling error (9 cases, 0.25%) Prostate Benign 2
prognosis of the patient so that anxious relatives may be informed as soon as possible. In 3462 cases (97.4 per cent) there was no difference between the frozen section and final pathological diagnoses. Of the remainder, in 66 cases (1.8 per cent) the discrepancy between the diagnoses was not important in terms of immediate surgical management ; the number of and reasons for these discrepancies are shown in Table II. In only 28 cases (0.8 per cent) was there a major, therapeutically important, inaccuracy in the frozen section diagnosis; in 6 (0.17 per cent) malignancy was incorrectly diagnosed, while in 22 (0.61 per cent) malignancy was missed either because of incorrect interpretation of the histological features ( I 3 cases) or because of incorrect sampling of the tissue by the pathologist (9 cases). The tissue sites, incorrect and corrected diagnoses and effects on patient management in these 28 cases are shown in Table Ili. Of the 6 cases in which a false positive diagnosis was made, 4 patients were subjected to an unnecessary radical operation; the incorrect diagnosis did not influence the surgical treatment in the 2 neurosurgical cases. Of the 13 cases in which an incorrect histological opinion resulted in a false negative diagnosis of malignancy, only 3 patients underwent later radical surgery when the final diagnosis became known; in the remainder, wide local excisions had already been performed or postoperative radiotherapy was administered. Of the 9 cases in which incorrect sampling of 328
Fibrosarcoma Metastatic melanoma Intraduct papilloma
FALSE NEGATIVE DIAGNOSIS OF Final diagnosis
Effect of incorrect diagnosis o n case management
Fat necrosis Inflammatory Inflammatory
Radical mastectomy Wide local excision Wide local excision
Endometriosis Neurilemmoma Meningioma Carcinoma (4) Intraduct carcinoma (2) Metastatic melanoma Glioma Oligodendroglioma Malignant melanoma Reticulum cell sarcoma
Right hemicolectomy None None Radical surgery delayed (2) None (4) None (3) None-initial None
wide excision
Adenocarcinoma Radical surgery delayed Carcinoma (5) Radical surgery delayed ( 5 ) Intraduct carcinoma (2) None (2)-initial wide excision Carcinoma Orchidectomy delayed (1) None (1)Loestrogen theraov
the tissue resulted in a false negative diagnosis of malignancy, 6 patients had to have later surgical treatment.
Discussion The overall accuracy rate in the present study of 3556 frozen section diagnoses during a 10-year period was 97.4 per cent. Although a precise diagnosis is always preferable, the time available for the histological examination of frozen section specimens is limited and it is usually sufficient for the surgeon to know whether a lesion is neoplastic or not, and, if the former, whether benign or malignant, since his immediate therapeutic decision is made on the basis of such a broad diagnosis. When the group of minor differences is thus excluded, the diagnosis of malignancy or benignancy was correct in 99.2 per cent of the cases in the present series. This figure corresponds closely to those reported in the large series of Nakazawa et al. (1968) and Holaday and Assor (1974); comparison with many of the other series reported is difficult because of their small numbers, limitation to one tissue or failure to subdivide errors by cause. In the present series, excluding examples of sampling error, the ratio of false positive : false negative diagnoses of malignancy was approximately 1 : 2. This tends to emphasize the conservative approach of pathologists to frozen section diagnosis, most, presumably, taking the view that a false positive diagnosis of malignancy with the possibility of radical
Accuracy of immediate frozen section diagnosis surgery being performed would be regarded as a greater mistake. Although it is almost inevitable that the slightly poorer quality of frozen sections prevents the accuracy of diagnosis available from properly fixed tissue, certain of the errors in the present series could probably have been avoided if complete clinical information had been available to the pathologist and if the tissue submitted for examination had been properly sampled by him. (Accurate sampling by the surgeon is also, of course, essential; not included in the present series of pathological errors are cases where subsequent specimens from a patient revealed lesions not present in the original sample sent for frozen section.) Ideally, the pathologist should have ready access to the clinical record and either see the lesion in situ or have a n y suspicious area in a large specimen accurately indicated. Frozen section diagnosis is most commonly used in the surgical management of breast lesions. The present series does indicate, however, that inaccuracies are effectively no more common in other sites, so that there appears to be no contraindication to frozen section diagnosis being applied to any tissue. Its value in thoracic surgical and gynaecological material has been emphasized by Sjolin (1955) and DiMusto (1970). Of the 28 cases in which a false positive or negative diagnosis of malignancy was made, in only 4 (0.1 per cent of the total frozen sections) was radical surgery performed unnecessarily. In a further 9 patients (0.25 per cent), surgical treatment was delayed. (It is, of course, possible that more of the patients in whom a false negative diagnosis of malignancy was made would have undergone immediate further surgical therapy had the correct diagnosis been given to the surgeon at the time of frozen section.) Quality control studies should form an essential part of the routine commitment of any laboratory service.
The results of one such study in a department of histopathology indicate that the frozen section technique is an essentially accurate, and thus extremely useful, method of immediate diagnosis in surgical pathology.
References
v. and RAMIREZ G. A . (1959) The indications for and limitations of frozen section diagnosis. A review of 1269 consecutive frozen section diagnoses. Br. J. Surg. 46, 336-350. DESAI s. B. (1966) Uses and limitations of frozen section in diagnosis of lesions of the breast. Br. J . Surg. 53, 1038-1042. DIMUSTO J . C. (1970) Reliability of frozen sections in gynecologic surgery. Obstet. Gynecol. 35,235-240. HOLADAY W. J. and ASSOR D. (1974) Ten thousand consecutive frozen sections. A retrospective study focusing on accuracy and quality control. Am. J . Clin. Pathol. 61, 769-777. HORN R . c. (1962) What can be expected of the surgical pathologist from frozen section examinations. Surg. Clin. North Am. 42, 443454. JENNINGS E. R . and LANDERS J. w . (1957) The use of frozen section in cancer diagnosis. Surg. Gynecol. Obstet. 104, 60-62. NAKAZAWA H., ROSEN P., LANE N. and LATTES R. (1968) Frozen section experience in 3000 cases. Am. J . Clin. Pathol. 49, 41-51. PITTS H. H., STURDY J. H. and COADY c. J . (1958) Frozen sections. 11. Value in cases of suspected malignancy. Can. Med. Assoc. J . 79, 1 10-1 12. SJOLIN K.-E. (1955) On the routine use of frozen sections with a special view to diagnostic accuracy. Acta Pathol. Microbiol. (Suppl.) 105, 161-173. WINSHIP T. and ROSVOLL R . v. (1959) Frozen sections. An evaluation of 1,810 cases. Surgery 45, 462466. ACKERMAN L.
329
