Editorial Malignant Peripheral Nerve Sheath Tumors of the Skin In this issue of the Proceedings (pages 164 to 172), Dabski and colleagues describe a series of cutaneous "neurofibrosarcomas" (malignant peripheral nerve sheath tumors [MPNST]). Although these neoplasms are well known as deep soft tissue lesions, particularly in patients with neurofibromatosis, they have been described only rarely in the skin heretofore. Because of controversies over diagnostic criteria for MPNST and overlapping histologic features with nonneurogenic cutaneous spindle cell neoplasms, a certain proportion of these tumors are likely to be confused with other proliferations. 1 This point will be considered in more detail shortly. The article by Dabski and associates provides information that will be of use to pathologists in resolving such difficulties, and it emphasizes the fact that MPNST are not restricted to extracutaneous sites of origin. Because of the wealth of archival tumor specimens at the Mayo Clinic, I was somewhat surprised that the authors did not provide a statistical estimation of the actual frequency of this uncommon tumor. It would have been valuable to review all spindle cell and epithelioid lesions ofthe skin and superficial soft tissues to achieve this goal. It is generally accepted that MPNST are more common in patients with von Recklinghausen's disease (VRD) than in persons without this phakomatosis; however, relative figures on this point are difficult to obtain from the existing literature. My colleagues and I have found that nerve sheath sarcomas account for approximately 2% of cutaneous spindle cell malignant lesions and are associated with VRD in 67% of cases. 1 Nevertheless, these statistics resulted from a
Address reprint requests to Dr. M. R. Wick, Department of Pathology, Barnes Hospital, One Barnes Hospital Plaza, St. Louis, MO 63110. Mayo Clin Proc 65:279-282, 1990
study of only 230 tumors and must therefore be regarded as less than definitive. Another point that might have been emphasized concerns the diagnostic criteria for MPNST of the skin. As Dabski and co-workers indicate, most lesions of this type manifest a microscopic appearance that is at least suggestive of the diagnosis under consideration.f Serpiginous nuclear contours, myxoid stromal changes, and cellular organization into tactoids or whorling fascicles are histologic features consistent with this interpretation. A relationship to major nerves or contiguous neurofibromas and the presence ofVRD also must be considered in the diagnostic evaluation. Questions remain, however, about whether any ofthese criteria, alone or in combination, are sufficient to exclude all other possibilities. For example, patients with neurofibromatosis have a relative excess of soft tissue neoplasms in general," and other tumors of nonneurogenic origin may exhibit some ofthe aforementioned histologic attributes. 4 In fact, the clinicopathologic differential diagnosis of cutaneous MPNST is fairly broad, including leiomyosarcomas, superficial malignant fibrous histiocytomas, plexiform fibrous histiocytomas, "dedifferentiated" dermatofibrosarcomas, and neurotropic malignant melanomas.l-"? None of these entities is sufficiently characteristic on clinical grounds to allow definite identification by a dermatologist. Moreover, although "classic" examples of these lesions do demonstrate typical microscopic characteristics (Table 1), even experienced histopathologists may be unable to separate them with certainty in selected cases. In particular reference to this issue, other publications on "low-grade cutaneous malignant schwannoma" and "neurotropic malignant melanoma" of the skin are of interest. Because Schwann cells and melanocytes have similar embryologic origins, it is not surprising that neoplasms composed of such elements may strongly resemble one another. When one is confronted with a biopsy specimen that shows
279
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Mayo Clin Proc, February 1990, Vol 65
Table I.-Differential Diagnosis of Cutaneous Malignant Peripheral Nerve Sheath Tumors (MPNST) Based on Histologic Criteria*
Diagnosis MPNST Leiomyosarcoma Superficial MFH Plexiform fibrous histiocytoma Dedifferentiated DFSP Neurotropic melanoma Spindle cell squamous carcinoma
Serpiginous Myxoid stroma nuclei
StoriMarked PlexiJunctional' Cellular fonn nuclear Fibrillar melanocytic fonn tactoids growth pleomorphism growth cytoplasm proliferation
+ 0 0
± ± ±
± 0 0
± 0 ±
± 0 +
± 0 0
0 + 0
0 0 0
0 0 +
0 ± ±
0 0 ±
0 + ±
+ + 0
+ 0 0
0 0 0
0 0 ±
0
0
0
0
±
0
0
0
*DFSP = dermatofibrosarcoma protuberans; MFH = malignant fibrous histiocytoma; + = present; 0 = absent;± = variably present.
atypical junctional melanocytes overlying a vided. Because of these omissions, the study by cutaneous spindle cell tumor with 8chwann cell Dabski and colleagues leaves some room for features, the diagnosis of neurotropic malignant speculation on the true differentiation of those melanoma is straightforward. Nonetheless, this "MPN8T" without divergent rhabdomyoblastic constellation of findings is not observed in every elements (which are not seen in melanomas) or case. Wamer and colleagues's" described several an association with VRD. "schwannian" histologic, electron microscopic, Immunohistochemical studies, although and immunohistologic attributes in neurotropic somewhat downplayed in the authors' assessmalignant melanoma, and 8uster and asso- ment, do have the potential to identify differenciates!" suggested that certain malignant tial diagnostic alternatives to MPN8T with a schwannomas of the skin are, in reality, mela- reasonably high degree of certainty. In light of nocytic in nature. In their comprehensive trea- the knowledge that no single immunodetermitise on soft tissue tumors, Enzinger and Weiss"! nant is likely to provide a great deal ofmeaningalso implied that a distinction between superfi- ful information in isolation, a panel approach cial MPN8T and melanoma could be regarded as with several well-characterized antibodies should arbitrary in some instances. Both lesions ex- be used.l" For example, 8-100 protein is, as press 8-100 protein and nerve growth factor stated previously, expressed by melanomas as receptorP'P but lack the HMB-45 antigen, a well as by nerve sheath tumors; cutaneous leiodeterminant that characterizes malignant mela - myosarcomas likewise have the potential for nomas of nonneurotropic histologic types. 13 Their synthesis of this marker.' If keratin, vimentin, biologic behaviors are also similar. desmin, muscle-specific actin, glial fibrillary In view of these points, information on the acidic protein, and Leu-7 also are included as a histologic appearance ofthe epidermis would be battery of analytes, however, characteristic desirable in the series under analysis. More- immunoprofiles emerge that tend to be mutually over, ultrastructural data-with particular ref- exclusive diagnostically (Table 2). erence to overlapping cell processes, pericellular In summary, my personal view on the necesbasal lamina, and the presence of premelano- sary diagnostic criteria for cutaneous MPN8T somes in neoplastic cells l 4-would have been primarily centers on these points: (1) suitable valuable. In addition, a more detailed account of histopathologic attributes (as previously dislesional continuity with well-substantiated cu- cussed); (2) a lack of epidermal melanocytic taneous neurofibromas could have been pro- proliferation; (3) a well-substantiated associa-
Mayo Clin Proc, February 1990, Vol 65
EDITORIAL
281
Table 2.-Differential Diagnosis of Cutaneous Malignant Peripheral Nerve Sheath Tumors (MPNST) . Based on Immunohistochemistry* Diagnosis MPNST Leiomyosarcoma Superficial MFH Plexiform fibrous histiocytoma Dedifferentiated DFSP Neurotropic melanoma Spindle cell squamous carcinoma
Vimentin
Keratin
GFAP
Desmin
MSA
S-100
Leu-7
+ + +
0 0 0
± 0 0
0
±
+
+
± ± 0
± ± 0
+ + +
0 0 0
0 0 0
0 0
0
0 0 0
0 0 +
0 0 0
±
+
0
0
0
0
0
0
0
*DFSP =dermatofibrosarcoma protuberans; GFAP =glial fibrillary acidic protein; MFH =malignant fibrous histiocytoma; MSA = muscle-specific actin; + = present; 0 = absent; ± = variably present.
tion with clinical VRD or antecedent neurofibroma in the same anatomic location as the malignant lesion; and (4) ultrastructural evidence of Schwann cell differentiation with an absence of premelanosomes or concomitant immunoreactivity for at least two of the following antigens-S-l00 protein, Leu-7, myelin basic protein, and glial fibrillary acidic protein. In addition, the tumor under study should lack the expression of keratin. Yet another pertinent issue concerns the features of value, if any, that affect the prognosis of MPNST of the skin. An earlier study from the Mayo Clinic" concluded that histologic grade, divergent differentiation, and relative mitotic activity had no bearing on the biologic behavior of nerve sheath sarcomas in general. The data presented by Dabski and co-workers for cutaneous MPNST support these conclusions. An association with neurofibromatosis, incompleteness of excision, and a lesional size of more than 5 em seem to be the only factors that negatively influence the evolution of MPNST.2 I agree with the authors that wide excision is indicated for these tumors; the merits of adjunctive therapies have yet to be proved, and they should not be administered routinely. My critical comments should not be construed as a denigration of the report by Dabski and associates. Rather, they are merely intended to highlight the many uncertainties that still surround nerve sheath malignant tumors of the
skin and other sites. The work of Dabski and colleagues should stimulate further investigation of these fascinating neoplasms with use of molecular biologic assays to probe their clinicopathologic nuances. Physicians interested in diseases of the skin need to add information about these lesions to their data banks, in an effort to enhance our understanding of their diagnostic and behavioral features. Mark R. Wick, M.D. Department of Pathology Washington University School of Medicine and Barnes Hospital St. Louis, Missouri
REFERENCES 1. George E, Swanson PE, Wick MR: Malignant peripheral nerve sheath tumors ofthe skin. Am J Dermatopathol 11:213-221, 1989 2. Ducatman BS, Scheithauer BW, Piepgras DG, Reiman HM, Ilstrup DM: Malignant peripheral nerve sheath tumors: a clinicopathologic study of120 cases. Cancer 57:2006-2021, 1986 3. Schwartz RA (ed): Skin Cancer: Recognition and Management. New York, Springer-Verlag, 1988, pp 200-203 4. Swanson PE, Stanley MW, Scheithauer BW, Wick MR: Primary cutaneous leiomyosarcoma: a histological and immunohistochemical study of 9 cases, with ultrastructural correlation. J Cutan Pathol 15:129141, 1988
282
Mayo CUn Proc, February 1990, Vol 65
EDITORIAL
5.
Enzinger FM, Zhang R: Plexiform fibrohistiocytic tumor presenting in children and young adults: an analysis of 65 cases. Am J Surg Pathol 12:818-826, 1988 6. Silvis NG, Swanson PE, Manivel JC, Kaye VN, Wick MR: Spindle-cell and pleomorphic neoplasms of the skin: a clinicopathologic and immunohistochemical study of 30 cases, with emphasis on "atypical fibroxanthomas." Am J Dermatopathol 10:9-19, 1988 7. Reed RJ, Leonard DD: Neurotropic melanoma: a variant of desmoplastic melanoma. Am J Surg Pathol 3:301-311, 1979 8. Warner TFCS, Hafez GR, Finch RE, Brandenberg JH: Schwarm cell features in neurotropic melanoma. J Cutan Pathol 8:177-187, 1981 9. Warner TFCS, Lloyd RV, Hafez GR, Angevine JM: Immunocytochemistry of neurotropic melanoma. Cancer 53:254-257,1984 10. Suster S, Amazon K, Rosen LB, Ollague JM: Malignant epithelioid schwannoma of the skin: a low-grade
11. 12. 13.
14. 15.
neurotropic malignant melanoma? Am J Dermatopathol 11:338-344, 1989 Enzinger FM, Weiss SW: Soft Tissue Tumors. St Louis, CV Mosby Company, 1983, pp 644-648 Perosio PM, Brooks JJ: Expression of nerve growth factor receptor in paraffin-embedded soft tissue tumors. Am J Pathol 132:152-160,1988 Wick MR, Swanson PE, Rocamora A: Recognition of malignant melanoma by monoclonal antibody HMB45: an immunohistochemical study of 200 paraffinembedded cutaneous tumors. J Cutan Pathol 15:201207, 1988 ErlandsonRA, WoodruffJM: Peripheral nerve sheath tumors: an electron microscopic study of 43 cases. Cancer 49:273-287, 1982 Gray MH, Rosenberg AE, Dickersin GR, Bhan AK: Glial fibrillary acidic protein and keratin expression by benign and malignant nerve sheath tumors. Hum Pathol 20:1089-1096, 1989
Address reprint requests to Dr. M. R. Wick, Department of Pathology, Barnes Hospital, One Barnes Hospital Plaza, St. Louis, MO 63110. Mayo Clin Proc 65:279-282, 1990
study of only 230 tumors and must therefore be regarded as less than definitive. Another point that might have been emphasized concerns the diagnostic criteria for MPNST of the skin. As Dabski and co-workers indicate, most lesions of this type manifest a microscopic appearance that is at least suggestive of the diagnosis under consideration.f Serpiginous nuclear contours, myxoid stromal changes, and cellular organization into tactoids or whorling fascicles are histologic features consistent with this interpretation. A relationship to major nerves or contiguous neurofibromas and the presence ofVRD also must be considered in the diagnostic evaluation. Questions remain, however, about whether any ofthese criteria, alone or in combination, are sufficient to exclude all other possibilities. For example, patients with neurofibromatosis have a relative excess of soft tissue neoplasms in general," and other tumors of nonneurogenic origin may exhibit some ofthe aforementioned histologic attributes. 4 In fact, the clinicopathologic differential diagnosis of cutaneous MPNST is fairly broad, including leiomyosarcomas, superficial malignant fibrous histiocytomas, plexiform fibrous histiocytomas, "dedifferentiated" dermatofibrosarcomas, and neurotropic malignant melanomas.l-"? None of these entities is sufficiently characteristic on clinical grounds to allow definite identification by a dermatologist. Moreover, although "classic" examples of these lesions do demonstrate typical microscopic characteristics (Table 1), even experienced histopathologists may be unable to separate them with certainty in selected cases. In particular reference to this issue, other publications on "low-grade cutaneous malignant schwannoma" and "neurotropic malignant melanoma" of the skin are of interest. Because Schwann cells and melanocytes have similar embryologic origins, it is not surprising that neoplasms composed of such elements may strongly resemble one another. When one is confronted with a biopsy specimen that shows
279
280
EDITORIAL
Mayo Clin Proc, February 1990, Vol 65
Table I.-Differential Diagnosis of Cutaneous Malignant Peripheral Nerve Sheath Tumors (MPNST) Based on Histologic Criteria*
Diagnosis MPNST Leiomyosarcoma Superficial MFH Plexiform fibrous histiocytoma Dedifferentiated DFSP Neurotropic melanoma Spindle cell squamous carcinoma
Serpiginous Myxoid stroma nuclei
StoriMarked PlexiJunctional' Cellular fonn nuclear Fibrillar melanocytic fonn tactoids growth pleomorphism growth cytoplasm proliferation
+ 0 0
± ± ±
± 0 0
± 0 ±
± 0 +
± 0 0
0 + 0
0 0 0
0 0 +
0 ± ±
0 0 ±
0 + ±
+ + 0
+ 0 0
0 0 0
0 0 ±
0
0
0
0
±
0
0
0
*DFSP = dermatofibrosarcoma protuberans; MFH = malignant fibrous histiocytoma; + = present; 0 = absent;± = variably present.
atypical junctional melanocytes overlying a vided. Because of these omissions, the study by cutaneous spindle cell tumor with 8chwann cell Dabski and colleagues leaves some room for features, the diagnosis of neurotropic malignant speculation on the true differentiation of those melanoma is straightforward. Nonetheless, this "MPN8T" without divergent rhabdomyoblastic constellation of findings is not observed in every elements (which are not seen in melanomas) or case. Wamer and colleagues's" described several an association with VRD. "schwannian" histologic, electron microscopic, Immunohistochemical studies, although and immunohistologic attributes in neurotropic somewhat downplayed in the authors' assessmalignant melanoma, and 8uster and asso- ment, do have the potential to identify differenciates!" suggested that certain malignant tial diagnostic alternatives to MPN8T with a schwannomas of the skin are, in reality, mela- reasonably high degree of certainty. In light of nocytic in nature. In their comprehensive trea- the knowledge that no single immunodetermitise on soft tissue tumors, Enzinger and Weiss"! nant is likely to provide a great deal ofmeaningalso implied that a distinction between superfi- ful information in isolation, a panel approach cial MPN8T and melanoma could be regarded as with several well-characterized antibodies should arbitrary in some instances. Both lesions ex- be used.l" For example, 8-100 protein is, as press 8-100 protein and nerve growth factor stated previously, expressed by melanomas as receptorP'P but lack the HMB-45 antigen, a well as by nerve sheath tumors; cutaneous leiodeterminant that characterizes malignant mela - myosarcomas likewise have the potential for nomas of nonneurotropic histologic types. 13 Their synthesis of this marker.' If keratin, vimentin, biologic behaviors are also similar. desmin, muscle-specific actin, glial fibrillary In view of these points, information on the acidic protein, and Leu-7 also are included as a histologic appearance ofthe epidermis would be battery of analytes, however, characteristic desirable in the series under analysis. More- immunoprofiles emerge that tend to be mutually over, ultrastructural data-with particular ref- exclusive diagnostically (Table 2). erence to overlapping cell processes, pericellular In summary, my personal view on the necesbasal lamina, and the presence of premelano- sary diagnostic criteria for cutaneous MPN8T somes in neoplastic cells l 4-would have been primarily centers on these points: (1) suitable valuable. In addition, a more detailed account of histopathologic attributes (as previously dislesional continuity with well-substantiated cu- cussed); (2) a lack of epidermal melanocytic taneous neurofibromas could have been pro- proliferation; (3) a well-substantiated associa-
Mayo Clin Proc, February 1990, Vol 65
EDITORIAL
281
Table 2.-Differential Diagnosis of Cutaneous Malignant Peripheral Nerve Sheath Tumors (MPNST) . Based on Immunohistochemistry* Diagnosis MPNST Leiomyosarcoma Superficial MFH Plexiform fibrous histiocytoma Dedifferentiated DFSP Neurotropic melanoma Spindle cell squamous carcinoma
Vimentin
Keratin
GFAP
Desmin
MSA
S-100
Leu-7
+ + +
0 0 0
± 0 0
0
±
+
+
± ± 0
± ± 0
+ + +
0 0 0
0 0 0
0 0
0
0 0 0
0 0 +
0 0 0
±
+
0
0
0
0
0
0
0
*DFSP =dermatofibrosarcoma protuberans; GFAP =glial fibrillary acidic protein; MFH =malignant fibrous histiocytoma; MSA = muscle-specific actin; + = present; 0 = absent; ± = variably present.
tion with clinical VRD or antecedent neurofibroma in the same anatomic location as the malignant lesion; and (4) ultrastructural evidence of Schwann cell differentiation with an absence of premelanosomes or concomitant immunoreactivity for at least two of the following antigens-S-l00 protein, Leu-7, myelin basic protein, and glial fibrillary acidic protein. In addition, the tumor under study should lack the expression of keratin. Yet another pertinent issue concerns the features of value, if any, that affect the prognosis of MPNST of the skin. An earlier study from the Mayo Clinic" concluded that histologic grade, divergent differentiation, and relative mitotic activity had no bearing on the biologic behavior of nerve sheath sarcomas in general. The data presented by Dabski and co-workers for cutaneous MPNST support these conclusions. An association with neurofibromatosis, incompleteness of excision, and a lesional size of more than 5 em seem to be the only factors that negatively influence the evolution of MPNST.2 I agree with the authors that wide excision is indicated for these tumors; the merits of adjunctive therapies have yet to be proved, and they should not be administered routinely. My critical comments should not be construed as a denigration of the report by Dabski and associates. Rather, they are merely intended to highlight the many uncertainties that still surround nerve sheath malignant tumors of the
skin and other sites. The work of Dabski and colleagues should stimulate further investigation of these fascinating neoplasms with use of molecular biologic assays to probe their clinicopathologic nuances. Physicians interested in diseases of the skin need to add information about these lesions to their data banks, in an effort to enhance our understanding of their diagnostic and behavioral features. Mark R. Wick, M.D. Department of Pathology Washington University School of Medicine and Barnes Hospital St. Louis, Missouri
REFERENCES 1. George E, Swanson PE, Wick MR: Malignant peripheral nerve sheath tumors ofthe skin. Am J Dermatopathol 11:213-221, 1989 2. Ducatman BS, Scheithauer BW, Piepgras DG, Reiman HM, Ilstrup DM: Malignant peripheral nerve sheath tumors: a clinicopathologic study of120 cases. Cancer 57:2006-2021, 1986 3. Schwartz RA (ed): Skin Cancer: Recognition and Management. New York, Springer-Verlag, 1988, pp 200-203 4. Swanson PE, Stanley MW, Scheithauer BW, Wick MR: Primary cutaneous leiomyosarcoma: a histological and immunohistochemical study of 9 cases, with ultrastructural correlation. J Cutan Pathol 15:129141, 1988
282
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EDITORIAL
5.
Enzinger FM, Zhang R: Plexiform fibrohistiocytic tumor presenting in children and young adults: an analysis of 65 cases. Am J Surg Pathol 12:818-826, 1988 6. Silvis NG, Swanson PE, Manivel JC, Kaye VN, Wick MR: Spindle-cell and pleomorphic neoplasms of the skin: a clinicopathologic and immunohistochemical study of 30 cases, with emphasis on "atypical fibroxanthomas." Am J Dermatopathol 10:9-19, 1988 7. Reed RJ, Leonard DD: Neurotropic melanoma: a variant of desmoplastic melanoma. Am J Surg Pathol 3:301-311, 1979 8. Warner TFCS, Hafez GR, Finch RE, Brandenberg JH: Schwarm cell features in neurotropic melanoma. J Cutan Pathol 8:177-187, 1981 9. Warner TFCS, Lloyd RV, Hafez GR, Angevine JM: Immunocytochemistry of neurotropic melanoma. Cancer 53:254-257,1984 10. Suster S, Amazon K, Rosen LB, Ollague JM: Malignant epithelioid schwannoma of the skin: a low-grade
11. 12. 13.
14. 15.
neurotropic malignant melanoma? Am J Dermatopathol 11:338-344, 1989 Enzinger FM, Weiss SW: Soft Tissue Tumors. St Louis, CV Mosby Company, 1983, pp 644-648 Perosio PM, Brooks JJ: Expression of nerve growth factor receptor in paraffin-embedded soft tissue tumors. Am J Pathol 132:152-160,1988 Wick MR, Swanson PE, Rocamora A: Recognition of malignant melanoma by monoclonal antibody HMB45: an immunohistochemical study of 200 paraffinembedded cutaneous tumors. J Cutan Pathol 15:201207, 1988 ErlandsonRA, WoodruffJM: Peripheral nerve sheath tumors: an electron microscopic study of 43 cases. Cancer 49:273-287, 1982 Gray MH, Rosenberg AE, Dickersin GR, Bhan AK: Glial fibrillary acidic protein and keratin expression by benign and malignant nerve sheath tumors. Hum Pathol 20:1089-1096, 1989
