Assessment of Biopsy Techniques and Histopathologic Interpretations of Primary Cutaneous Malignant Melanoma DANIEL F. ROSES, M.D.,* A. BERNARD ACKERMAN, M.D., MATTHEW N. HARRIS, M.D., GEORGE R. WEINHOUSE, M.D., STEPHEN L. GUMPORT, M.D.
The biopsy techniques utilized for diagnosis in 1,161 patients with primary cutaneous malignant melanoma treated at the New York University Medical Center were reviewed. Eight hundred sixty-four (74%) biopsies were of the excisional type and 269 (23%) were incisional. Twenty-eight biopsies (3%) could not be assessed. Two hundred fifty-two consecutive patients referred for treatment of malignant melanoma to the authors for the last three years were studied to determine. whether standard techniques of biopsy and uniform criteria for histopathologic diagnosis and staging were being utilized. One hundred forty-nine of these patients (59%) had total excisional biopsies of their lesions and 103 (41%) had incisional biopsies. Of the latter group, 66 (64%) were for lesions less than 2 cm in diameter and were situated in areas other than the face. The biopsy specimens obtained from 123 patients were reviewed by at least one other pathologist as well as our own (A.B.A.). For these 123 patients a difference of histologic diagnosis between pathologists occurred in 11 (9%). In 58 (47%) there was a discrepancy in assignment of Clark levels or a failure to assess Clark levels. Tumor thicknesses as measured by Breslow were read in only 22 (18%) of these 123 patients. The inadequacies. of many of the biopsy specimens and discrepancies in histopathologic interpretation indicate that acceptable biopsy techniques and reproducible diagnostic criteria have not yet been generally adapted for primary cutaneous malignant melanomas.
IT HAS LONG BEEN RECOGNIZED that the deeper the
penetration of a malignant melanoma into the skin, the worse the prognosis. Recently described systems of histopathologic classification have refined this concept."'1 2 Clark and his associates4 assess primary cutaneous malignant melanoma by using "levels of invasion" and Breslow' has introduced the concept of tumor thickness and cross-sectional area to gauge prognosis for this malignant neoplasm. As a result of the correlation between increasing depth of invasion and tumor thickness on the one hand with the incidence of regional lymph node metastases and survival on the other, these histopathologic criteria have become crucial for determining * American Cancer Society, Junior Faculty Clinical Fellow. Reprint requests: Daniel F. Roses, M.D., 566 First Avenue, New
York, New York 10016. Supported in part by Sylvia and Mortimer Hyams Memorial Fund. Submitted for publication: June 27, 1978.
From the Tumor Service, Department of Surgery and the Departments of Dermatology and Pathology, New York University School of Medicine, New York, New York
the extent of surgical therapy.2'9'16 Clinical trials undertaken to assess various therapeutic approaches also utilize these measurements.36"5 Because a properly performed biopsy is necessary for accurate histopathologic interpretation, we reviewed the biopsy techniques performed on all patients treated at the New York University Medical Center to determine if sufficient pathologic material had been submitted for primary cutaneous malignant melanoma. We also reviewed the pathologic material in all instances of primary malignant melanoma referred to the authors during the past three year period in order to further determine if uniform staging of the primary lesion had been followed by pathologists since the acceptance of the Clark and Breslow systems. Many patients were referred to us for surgical care after evaluation of the pathology at other institutions. In these instances the histopathologic material was reviewed and restudied using criteria for diagnosis of malignant melanoma that are employed by the Dermatopathology Section at New York University. 13 Materials and Methods
For a 30 year period, from January, 1949 through February, 1978, 1,161 primary cutaneous malignant melanomas were treated by the Tumor Service of the Department of Surgery of the New York University Medical Center. The type of biopsy initially performed varied. We define incisional biopsy as one in which the lesion was not completely removed for pathologic evaluation by such techniques, for example, as partial excision, punch excision, shave excision, and curettage. Total excisional biopsy we define as the removal of the entire visible lesion to a depth of and including subcutaneous fat. The histopathologic features and the biopsy technique
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in 252 consecutive patients referred for treatment of malignant melanoma over the last three year period to our surgical group were also reviewed. This recent three year period was selected for study because enough time has elapsed for pathologists to utilize the methods proposed by Clark and Breslow for gauging prognosis of primary cutaneous malignant melanoma. Interpretation of histologic material was done by at least one pathologist at another institution as well as our own in 123 of the patients. The histopathologic evaluation of the material by the other pathologist was compared to that of the dermatopathologist at our Medical Center (A.B.A.). In instances where a portion of the lesion remained after incisional biopsy, we subsequently performed a total excisional biopsy before the definitive surgery, provided that primary closure could be obtained. This material was then reviewed by our pathologist and reclassified if necessary. The histologic criteria for the diagnosis of malignant melanoma utilized by our Dermatopathology Section are as follows. A) Architectural pattern. 1. Increased number of atypical melanocytes, singly and/or in nests within the epidermis. 2) Horizontal extension of atypical melanocytes, singly and/or in nests, within the epidermis beyond the bulk of the intraepidermal and intradermal components of the neoplasm. 3) Failure of nuclei of the atypical melanocytes to become smaller with progressive descent into the dermis. 4) Atypical melanocytes present singly and/or in nests at all levels of the epidermis, even including the cornified layer. 5) Variation in size and shape of intraepidermal and intradermal nests of atypical melanocytes. 6) Confluence of the nests of atypical melanocytes within the epidermis and the dermis. 7) Extension of atypical melanocytes, singly and/or in nests, down epithelial structures of the adnexa. B) Cytologic features. 1) Atypical melanocytes with large, hyperchromatic, pleomorphic nuclei and prominent nucleoli. 2) Melanocytes in mitosis within the epidermis and the dermis. 3) Necrotic melanocytes. In addition to the histologic description, judgments were made about: 1) the histologic type of malignant melanoma, i.e., superficial spreading, nodular, acral lentiginous, lentigo maligna, or those that did not conform to the classification. 2) The measurement of the level of invasion according to the Clark classification listed below. Level I: all the neoplastic cells are above the epidermal basement membrane. Level II: the neoplastic cells lie beyond the basement membrane and extend to some degree into the papillary dermis, but not quite to the reticular dermis. Level III: the melanoma cells fill the papillary dermis
and reach the interface between papillary and reticular dermis. Level IV: the neoplastic cells extend into the reticular dermis. Level V: the neoplastic cells extend into the subcutaneous fat. 3) The measurement of the thickness of the neoplasm according to Breslow's method. 4) Presence or absence of a pre-existing melanocytic nevus. 5) Additional histopathologic information which might have some significance to prognosis, e.g., ulceration, nodularity, pedunculation, invasion of blood vessels or lymphatics, mitotic figures and their number per high power field, types of neoplastic melanocytes, inflammatory-cell infiltrate and its density, and presence of neoplastic cells at the margin of the specimen. Results
Of the 1,161 malignant melanomas reviewed, there were 864 (74%) excisional biopsies and 269 (23%) incisional biopsies. Twenty-eight malignant melanomas (3%) could not be accurately assessed on the basis of material available for review. Of the 252 consecutive patients studied over the past three years, 149 (59%) had a total excisional biopsy of the primary lesion while 103 (41%) had an incisional biopsy. Of these 103 patients, 66 (64%) were for lesions less than 2 cm in diameter and situated in areas other than the face. Therefore, of the 252 patients, 66 (26%) had a less than optimal biopsy according to criteria previously described.78 Of the 123 patients in whom the histopathologic material was interpreted by another pathologist as well as our own, there was a difference in diagnosis in 1 1 (9%). In five instances the discrepancy was in diagnosing the lesion as a Spitz nevus (benign juvenile melanoma) as opposed to a malignant melanoma. The discrepancy in one was in diagnosing a freckle of Hutchinson as opposed to an "'invasive'' malignant melanoma; in two, atypical melanocytic hyperplasia as opposed to "invasive" malignant melanomas; in two, benign nevi as opposed to malignant melanoma; and in one, atypical spindle cell neoplasm as opposed to malignant melanoma. Thirty-one lesions (25%) were not classified as to level of invasion by referring pathologists. Of the remaining 81, there was a difference in the assessment of levels of invasion in 27 (22%). Of these 27 lesions, thirteen involved a difference in assignment of either a Clark level III or IV. Therefore, of the 123 lesions in which histopathologic comparisons were made, there was a discrepancy in either diagnosis, in level of invasion, or in a failure to assign level of invasion in 58 (47%) (Table 1). Of the 58 instances in which these discrepancies or
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TABLE i. Histopathologic Interpretation of AMalignant Melanoma in 123 Patients Evaluated by More than One Pathologist
Interpretation
Discrepancy in diagnosis of malignant melanoma Clark level not assigned Difference in assignment of Clark level Tumor thickness by technique of Breslow not measured
Number and Per Cent of Patients 11 (9%) 31 (25%) 27 (22%)*
101 (82%)
* Difference in assignment of: Clark level I vs II: 1. Clark level II vs III: 11. Clark level II vs IV: 2. Clark level III vs IV: 13.
insufficiencies were found, 29 (50%) had less than total excisional biopsies. Of the 123 lesions interpreted histologically by another pathologist only 22 (18%) had tumor thickness measured by the technique of Breslow. Discussion
The survival of patients with primary cutaneous malignant melanoma has been shown to be inversely related to the level of invasion of the neoplastic cells. Das Gupta5 has recently reported five year survival rates of 100% for patients with Clark level II lesions, 95% for Clark level III, 50% for Clark level IV, and 37% for Clark level V. Breslow,' in 1970, supported the concept that tumor thickness was an important gauge for prognosis of primary cutaneous malignant melanoma. He measured the thickness of malignant melanomas in histopathologic sections with a micrometer in the oculat of the microscope. The thickness is measured from the uppermost part of the granular layer of the epidermis to the deepest portion of the neoplasm as seen in histologic sections. Lesions less than 0.76 mm in thickness were shown to have an excellent prognosis whereas lesions greater than 1.50 mm were associated with a higher incidence of mortality.' The clinical diagnosis of a malignant melanoma is based on the gross morphologic appearance and the history of change in the lesion. Kopf and coworkers'0 found but a 64% accuracy rate in diagnosing malignant melanoma by physicians in the Oncology Section of the Skin and Cancer Unit at the New York University Medical Center. The need for firm histologic criteria for diagnosis of malignant melanoma becomes even more important if clinical judgments are so imperfect. If the clinical diagnosis of malignant melanoma is suspected, it should be established, when possible, by a total excisional biopsy. Total excisional biopsy, which implies removal of the entire lesion as visualized grossly in breadth and depth, is used when the wound can be closed by a simple primary suture technique. In most
Ann. Surg. * March 1979
instances this can be readily accomplished with lesions up to 2 cm in size. Exceptions are lesions that are so large or so situated anatomically, such as on the face, that total removal for purposes of biopsy would involve a disfiguring procedure or one in which closure cannot be accomplished per primum. in these instances of large lesions, incisional biopsy of a portion is indicated provided that a representative sample of the deepest portion of penetration is selected. In such situations selecting the most nodular area and extending the incision into the subcutaneous fat will provide the greatest accuracy as to the actual depth of the neoplasm. All biopsy material should be serially sectioned at right. angles to the long axis of the specimen. Our data indicate that despite the emphasis in the literature on the need for an adequate assessment of the histopathology, the number of partial biopsies rather than complete, excisional biopsies for malignatt melanomas seen at the New York University Medical Center for further treatment has increased over the past three years. Of note is that 64% of these biopsies were in patients seen for treatment of lesions less than 2 cm in maximum diameter. The less than optimal quality of the biopsy material in 26% of the patients studied, discrepancies in diagnoses in 11%, and the difference in assignment of levels of invasion or failure to include levels of invasion in 47% indicates that uniform techniques of biopsy and histopathology have not been generally adapted by dermatologists, pathologists, and surgeons. A specific area of difficulty in histopathologic diagnosis is the differentiation of a Spitz nevus (benign juvenile melanoma) from malignant melanoma.5 This discrepancy applied to five lesions. The Clark classification of levels of invasion presents some problems for pathologists and surgeons. This classification is subjective and competent pathologists may come to different conclusions in reviewing the same material. Of the 27 lesions in which there was a difference of opinion in assigning Clark levels, thirteen discrepancies involved assignment of Clark levels III or IV. While the incidence of discrepancies in assigning levels was higher in our series than in the report of Suffin and coworkers,'4 their survey indicated that only a relatively smdll number of "community" pathologists (23%) employed the Clark system of classification. The Breslow classification is more objective but it too has problems. There may be differences in the normal thickness of the epidermis in different anatomic sites, the epidermis may be hyperplastic and ulceration of the specimen may make determination of the granular zone impossible. Nevertheless the measurement of malignant melanoma as proposed by Breslow may be the most reproducible means of predicting prognosis
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yet available. It is important to note that in only 22 (18%) of lesions examined by a pathologist at another institution was the tumor thickness as measured by Breslow reported. Recent studies on the therapy of malignant melanoma demonstrate the need for optimal biopsy techniques and uniform assessment of the histopathology of the primary lesion. In an evaluation of immediate node dissection in stage I malignant melanoma of the limbs, Veronesi and associates15 reviewed the pathology in 557 patients. Four were considered questionable or doubtful and were not accepted for inclusion in the therapeutic trial. Three hundred nine patients had lesions considered suitable for evaluation of maximum thicknSss. Two hundred eighty-three were reclassified according to levels of invasion, and, of these, 246 were classified histologically according to Clark's criteria. In the other patients, the quality of the pathologic material, aithough adequate for the diagnosis of malignant melanoma, was not considered suitable for this type of evaluation. In another study concerning the width of resection margin for melanomas less than 0.76 mm in thickness, Breslow and Macht3 have asserted that such thin lesions may be treated conservatively, i.e. , with width of resection depending upon the anatomic location of the tumor and in most instances not requiring a skin graft. Such an approach, however, presumes a uniformity of histopathologic interpretation of a sufficient biopsy specimen.
Conclusion THe inadequacies of the biopsy material and discrepanlcies in histopathologic interpretation in our study indicates that there may be risks in adopting therapeutic principles that depend entirely on routine histologic assessment. In ourjudgment, the treatment of malignant melanoma requires a sufficient biopsy specimen and reproducible standards of histopathologic diagnosis. Unless strict criteria for each are adhered to, appropriate selection of therapy, extent of surgery, and subsequent
evaluation of the clinical behavior of the malignant melanoma may not be possible.
References 1. Breslow, A.: Thickness, Cross-sectional Area and Depth of Invasion in the Prognosis of Cutaneous Melanoma. Ann. Surg., 172:902, 1970. 2. Breslow, A.: Tumor Thickness, Level of Invasion and Node Dissection in Stage I Cutaneous Melanoma. Ann. Surg., 182:572, 1975. 3. Breslow, A. and Macht, S. D.: Optimal Size of Resection Margin for Thin Cutaneous Melanoma. Surg. Gynecol. Obstet., 145:691, 1977. 4. Clark, W. H., Jr., From, L., Bernardino, E. H. and Mihm, M. C.: The Histogenesis and Biologic Behavior of Primary Human Malignant Melanomas of the Skin. Cancer Res., 29:705, 1969. 5. Connors, R. C., Chalet, M. D. and Ackerman, A. B.: Benign Juvenile Melanoma (Spitz Nevus) vs. Superficial Spreading Malignant Melanoma! Criteria for Histologic Differentiation. J. Dermatol. Surg., 1:14, 1975. 6. Das Gupta, T. K.: Results of Treatment of 269 Patients with Primary Cutaneous Melanoma: A Five-year Prospective Study. Ann. Surg., 186:201, 1977. 7. Harris, M. N. and Gumport, S. L.: Total Excisional Biopsy for Primary Malignant Melanoma. JAMA, 226:354, 1973. 8. Harris, M. N. and Gumport, S. L.: Biopsy Technique for Malignant Melanoma. J. Dermatol. Surg., 1:24, 1975. 9. Holmes, E. C., Moseley, H. S., Morton, D. L., et al.: A Rational Approach to the Surgical Management of Melanoma. Ann. Surg., 186:481, 1977. 10. Kopf, A. W., Mintzis, M. and Bart, R. S.: Diagnostic Accuracy in Malignant Melanoma. Arch. Dermatol., 111: 1291, 1975. 11. McGovern, V. J., Caldwell, R. A., Duncan, C. A., et al.: Moles and Malignant Melanoma: Terminology and Classification. Med. J. Aust., 1:123, 1967. 12. Mehnert, J. H. and Heard, J. L.: Staging of Malignant Melanoma by Depth of Invasion: A Proposed Index to Prognosis. Am. J. Surg., 110: 168, 1965. 13. Price, N. M., Rywlin, A. M. and Ackerman, A. B.: Histologic Criteria for the Diagnosis of Superficial Spreading Malignant Melanoma: Formulated on the Basis of Proven Metastatic Lesion. Cancer, 38:2434, 1976. 14. Suffin, S. C., Waisman, J., Clark, W. H., Jr. and Morton, D. L.: Comparison of the Classification by Microscopic Level (Stage) of Malignant Melanoma by Three Independent Groups of Pathologists. Cancer, 40:3112, 1977. 15. Veronesi, U., Adamus, J., Bandiera, D. C., et al.: Inefficacy of Immediate Node Dissection in Stage I Melanoma of the Limbs. N. Engl. J. Med., 297:627, 1977. 16. Wanebo, H. J., Fortner, J. G., Woodruff, J., et al.: Selection of the Optimum Surgical Treatment of Stage I Melanoma by Depth of Microinvasion. Ann. Surg., 182:302, 1975.
The biopsy techniques utilized for diagnosis in 1,161 patients with primary cutaneous malignant melanoma treated at the New York University Medical Center were reviewed. Eight hundred sixty-four (74%) biopsies were of the excisional type and 269 (23%) were incisional. Twenty-eight biopsies (3%) could not be assessed. Two hundred fifty-two consecutive patients referred for treatment of malignant melanoma to the authors for the last three years were studied to determine. whether standard techniques of biopsy and uniform criteria for histopathologic diagnosis and staging were being utilized. One hundred forty-nine of these patients (59%) had total excisional biopsies of their lesions and 103 (41%) had incisional biopsies. Of the latter group, 66 (64%) were for lesions less than 2 cm in diameter and were situated in areas other than the face. The biopsy specimens obtained from 123 patients were reviewed by at least one other pathologist as well as our own (A.B.A.). For these 123 patients a difference of histologic diagnosis between pathologists occurred in 11 (9%). In 58 (47%) there was a discrepancy in assignment of Clark levels or a failure to assess Clark levels. Tumor thicknesses as measured by Breslow were read in only 22 (18%) of these 123 patients. The inadequacies. of many of the biopsy specimens and discrepancies in histopathologic interpretation indicate that acceptable biopsy techniques and reproducible diagnostic criteria have not yet been generally adapted for primary cutaneous malignant melanomas.
IT HAS LONG BEEN RECOGNIZED that the deeper the
penetration of a malignant melanoma into the skin, the worse the prognosis. Recently described systems of histopathologic classification have refined this concept."'1 2 Clark and his associates4 assess primary cutaneous malignant melanoma by using "levels of invasion" and Breslow' has introduced the concept of tumor thickness and cross-sectional area to gauge prognosis for this malignant neoplasm. As a result of the correlation between increasing depth of invasion and tumor thickness on the one hand with the incidence of regional lymph node metastases and survival on the other, these histopathologic criteria have become crucial for determining * American Cancer Society, Junior Faculty Clinical Fellow. Reprint requests: Daniel F. Roses, M.D., 566 First Avenue, New
York, New York 10016. Supported in part by Sylvia and Mortimer Hyams Memorial Fund. Submitted for publication: June 27, 1978.
From the Tumor Service, Department of Surgery and the Departments of Dermatology and Pathology, New York University School of Medicine, New York, New York
the extent of surgical therapy.2'9'16 Clinical trials undertaken to assess various therapeutic approaches also utilize these measurements.36"5 Because a properly performed biopsy is necessary for accurate histopathologic interpretation, we reviewed the biopsy techniques performed on all patients treated at the New York University Medical Center to determine if sufficient pathologic material had been submitted for primary cutaneous malignant melanoma. We also reviewed the pathologic material in all instances of primary malignant melanoma referred to the authors during the past three year period in order to further determine if uniform staging of the primary lesion had been followed by pathologists since the acceptance of the Clark and Breslow systems. Many patients were referred to us for surgical care after evaluation of the pathology at other institutions. In these instances the histopathologic material was reviewed and restudied using criteria for diagnosis of malignant melanoma that are employed by the Dermatopathology Section at New York University. 13 Materials and Methods
For a 30 year period, from January, 1949 through February, 1978, 1,161 primary cutaneous malignant melanomas were treated by the Tumor Service of the Department of Surgery of the New York University Medical Center. The type of biopsy initially performed varied. We define incisional biopsy as one in which the lesion was not completely removed for pathologic evaluation by such techniques, for example, as partial excision, punch excision, shave excision, and curettage. Total excisional biopsy we define as the removal of the entire visible lesion to a depth of and including subcutaneous fat. The histopathologic features and the biopsy technique
0003-4932/79/0300/0294 $00.70 C J. B. Lippincott Company
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Vol. 189 * No. 3
295
ASSESSMENT OF BIOPSY TECHNIQUES
in 252 consecutive patients referred for treatment of malignant melanoma over the last three year period to our surgical group were also reviewed. This recent three year period was selected for study because enough time has elapsed for pathologists to utilize the methods proposed by Clark and Breslow for gauging prognosis of primary cutaneous malignant melanoma. Interpretation of histologic material was done by at least one pathologist at another institution as well as our own in 123 of the patients. The histopathologic evaluation of the material by the other pathologist was compared to that of the dermatopathologist at our Medical Center (A.B.A.). In instances where a portion of the lesion remained after incisional biopsy, we subsequently performed a total excisional biopsy before the definitive surgery, provided that primary closure could be obtained. This material was then reviewed by our pathologist and reclassified if necessary. The histologic criteria for the diagnosis of malignant melanoma utilized by our Dermatopathology Section are as follows. A) Architectural pattern. 1. Increased number of atypical melanocytes, singly and/or in nests within the epidermis. 2) Horizontal extension of atypical melanocytes, singly and/or in nests, within the epidermis beyond the bulk of the intraepidermal and intradermal components of the neoplasm. 3) Failure of nuclei of the atypical melanocytes to become smaller with progressive descent into the dermis. 4) Atypical melanocytes present singly and/or in nests at all levels of the epidermis, even including the cornified layer. 5) Variation in size and shape of intraepidermal and intradermal nests of atypical melanocytes. 6) Confluence of the nests of atypical melanocytes within the epidermis and the dermis. 7) Extension of atypical melanocytes, singly and/or in nests, down epithelial structures of the adnexa. B) Cytologic features. 1) Atypical melanocytes with large, hyperchromatic, pleomorphic nuclei and prominent nucleoli. 2) Melanocytes in mitosis within the epidermis and the dermis. 3) Necrotic melanocytes. In addition to the histologic description, judgments were made about: 1) the histologic type of malignant melanoma, i.e., superficial spreading, nodular, acral lentiginous, lentigo maligna, or those that did not conform to the classification. 2) The measurement of the level of invasion according to the Clark classification listed below. Level I: all the neoplastic cells are above the epidermal basement membrane. Level II: the neoplastic cells lie beyond the basement membrane and extend to some degree into the papillary dermis, but not quite to the reticular dermis. Level III: the melanoma cells fill the papillary dermis
and reach the interface between papillary and reticular dermis. Level IV: the neoplastic cells extend into the reticular dermis. Level V: the neoplastic cells extend into the subcutaneous fat. 3) The measurement of the thickness of the neoplasm according to Breslow's method. 4) Presence or absence of a pre-existing melanocytic nevus. 5) Additional histopathologic information which might have some significance to prognosis, e.g., ulceration, nodularity, pedunculation, invasion of blood vessels or lymphatics, mitotic figures and their number per high power field, types of neoplastic melanocytes, inflammatory-cell infiltrate and its density, and presence of neoplastic cells at the margin of the specimen. Results
Of the 1,161 malignant melanomas reviewed, there were 864 (74%) excisional biopsies and 269 (23%) incisional biopsies. Twenty-eight malignant melanomas (3%) could not be accurately assessed on the basis of material available for review. Of the 252 consecutive patients studied over the past three years, 149 (59%) had a total excisional biopsy of the primary lesion while 103 (41%) had an incisional biopsy. Of these 103 patients, 66 (64%) were for lesions less than 2 cm in diameter and situated in areas other than the face. Therefore, of the 252 patients, 66 (26%) had a less than optimal biopsy according to criteria previously described.78 Of the 123 patients in whom the histopathologic material was interpreted by another pathologist as well as our own, there was a difference in diagnosis in 1 1 (9%). In five instances the discrepancy was in diagnosing the lesion as a Spitz nevus (benign juvenile melanoma) as opposed to a malignant melanoma. The discrepancy in one was in diagnosing a freckle of Hutchinson as opposed to an "'invasive'' malignant melanoma; in two, atypical melanocytic hyperplasia as opposed to "invasive" malignant melanomas; in two, benign nevi as opposed to malignant melanoma; and in one, atypical spindle cell neoplasm as opposed to malignant melanoma. Thirty-one lesions (25%) were not classified as to level of invasion by referring pathologists. Of the remaining 81, there was a difference in the assessment of levels of invasion in 27 (22%). Of these 27 lesions, thirteen involved a difference in assignment of either a Clark level III or IV. Therefore, of the 123 lesions in which histopathologic comparisons were made, there was a discrepancy in either diagnosis, in level of invasion, or in a failure to assign level of invasion in 58 (47%) (Table 1). Of the 58 instances in which these discrepancies or
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TABLE i. Histopathologic Interpretation of AMalignant Melanoma in 123 Patients Evaluated by More than One Pathologist
Interpretation
Discrepancy in diagnosis of malignant melanoma Clark level not assigned Difference in assignment of Clark level Tumor thickness by technique of Breslow not measured
Number and Per Cent of Patients 11 (9%) 31 (25%) 27 (22%)*
101 (82%)
* Difference in assignment of: Clark level I vs II: 1. Clark level II vs III: 11. Clark level II vs IV: 2. Clark level III vs IV: 13.
insufficiencies were found, 29 (50%) had less than total excisional biopsies. Of the 123 lesions interpreted histologically by another pathologist only 22 (18%) had tumor thickness measured by the technique of Breslow. Discussion
The survival of patients with primary cutaneous malignant melanoma has been shown to be inversely related to the level of invasion of the neoplastic cells. Das Gupta5 has recently reported five year survival rates of 100% for patients with Clark level II lesions, 95% for Clark level III, 50% for Clark level IV, and 37% for Clark level V. Breslow,' in 1970, supported the concept that tumor thickness was an important gauge for prognosis of primary cutaneous malignant melanoma. He measured the thickness of malignant melanomas in histopathologic sections with a micrometer in the oculat of the microscope. The thickness is measured from the uppermost part of the granular layer of the epidermis to the deepest portion of the neoplasm as seen in histologic sections. Lesions less than 0.76 mm in thickness were shown to have an excellent prognosis whereas lesions greater than 1.50 mm were associated with a higher incidence of mortality.' The clinical diagnosis of a malignant melanoma is based on the gross morphologic appearance and the history of change in the lesion. Kopf and coworkers'0 found but a 64% accuracy rate in diagnosing malignant melanoma by physicians in the Oncology Section of the Skin and Cancer Unit at the New York University Medical Center. The need for firm histologic criteria for diagnosis of malignant melanoma becomes even more important if clinical judgments are so imperfect. If the clinical diagnosis of malignant melanoma is suspected, it should be established, when possible, by a total excisional biopsy. Total excisional biopsy, which implies removal of the entire lesion as visualized grossly in breadth and depth, is used when the wound can be closed by a simple primary suture technique. In most
Ann. Surg. * March 1979
instances this can be readily accomplished with lesions up to 2 cm in size. Exceptions are lesions that are so large or so situated anatomically, such as on the face, that total removal for purposes of biopsy would involve a disfiguring procedure or one in which closure cannot be accomplished per primum. in these instances of large lesions, incisional biopsy of a portion is indicated provided that a representative sample of the deepest portion of penetration is selected. In such situations selecting the most nodular area and extending the incision into the subcutaneous fat will provide the greatest accuracy as to the actual depth of the neoplasm. All biopsy material should be serially sectioned at right. angles to the long axis of the specimen. Our data indicate that despite the emphasis in the literature on the need for an adequate assessment of the histopathology, the number of partial biopsies rather than complete, excisional biopsies for malignatt melanomas seen at the New York University Medical Center for further treatment has increased over the past three years. Of note is that 64% of these biopsies were in patients seen for treatment of lesions less than 2 cm in maximum diameter. The less than optimal quality of the biopsy material in 26% of the patients studied, discrepancies in diagnoses in 11%, and the difference in assignment of levels of invasion or failure to include levels of invasion in 47% indicates that uniform techniques of biopsy and histopathology have not been generally adapted by dermatologists, pathologists, and surgeons. A specific area of difficulty in histopathologic diagnosis is the differentiation of a Spitz nevus (benign juvenile melanoma) from malignant melanoma.5 This discrepancy applied to five lesions. The Clark classification of levels of invasion presents some problems for pathologists and surgeons. This classification is subjective and competent pathologists may come to different conclusions in reviewing the same material. Of the 27 lesions in which there was a difference of opinion in assigning Clark levels, thirteen discrepancies involved assignment of Clark levels III or IV. While the incidence of discrepancies in assigning levels was higher in our series than in the report of Suffin and coworkers,'4 their survey indicated that only a relatively smdll number of "community" pathologists (23%) employed the Clark system of classification. The Breslow classification is more objective but it too has problems. There may be differences in the normal thickness of the epidermis in different anatomic sites, the epidermis may be hyperplastic and ulceration of the specimen may make determination of the granular zone impossible. Nevertheless the measurement of malignant melanoma as proposed by Breslow may be the most reproducible means of predicting prognosis
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ASSESSMENT OF BIOPSY TECHNIQUES
yet available. It is important to note that in only 22 (18%) of lesions examined by a pathologist at another institution was the tumor thickness as measured by Breslow reported. Recent studies on the therapy of malignant melanoma demonstrate the need for optimal biopsy techniques and uniform assessment of the histopathology of the primary lesion. In an evaluation of immediate node dissection in stage I malignant melanoma of the limbs, Veronesi and associates15 reviewed the pathology in 557 patients. Four were considered questionable or doubtful and were not accepted for inclusion in the therapeutic trial. Three hundred nine patients had lesions considered suitable for evaluation of maximum thicknSss. Two hundred eighty-three were reclassified according to levels of invasion, and, of these, 246 were classified histologically according to Clark's criteria. In the other patients, the quality of the pathologic material, aithough adequate for the diagnosis of malignant melanoma, was not considered suitable for this type of evaluation. In another study concerning the width of resection margin for melanomas less than 0.76 mm in thickness, Breslow and Macht3 have asserted that such thin lesions may be treated conservatively, i.e. , with width of resection depending upon the anatomic location of the tumor and in most instances not requiring a skin graft. Such an approach, however, presumes a uniformity of histopathologic interpretation of a sufficient biopsy specimen.
Conclusion THe inadequacies of the biopsy material and discrepanlcies in histopathologic interpretation in our study indicates that there may be risks in adopting therapeutic principles that depend entirely on routine histologic assessment. In ourjudgment, the treatment of malignant melanoma requires a sufficient biopsy specimen and reproducible standards of histopathologic diagnosis. Unless strict criteria for each are adhered to, appropriate selection of therapy, extent of surgery, and subsequent
evaluation of the clinical behavior of the malignant melanoma may not be possible.
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