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Epithelioid sarcoma: Clinical and histologic characteristics
Epithelioid sarcoma: Clinical and histologic characteristics Michael D. Zanolli, M D , Gregory Wilmoth, MD, JoAnn Shaw, MD,* Gary Poehling, M D , c and W a i n L. White, MD, b Winston-Salem, North Carolina Epithelioid sarcoma is a slow-growing sarcoma that typically occurs on an upper extremity of young men. It commonly arises as a deep soft tissue, subcutaneous, or as a dermal, woody, hard nodule. (J AM ACAD DERMATOL 1992;26:302-5.)
Epithelioid sarcoma ( E S ) is an uncommon soft tissue malignancy first characterized by Enzinger in 1970.1 This neoplasm usually appears on an upper extremity of young m e n as a solitary, subcutaneous nodule. The growth of this s a r c o m a is slow and m a y be along fibrous sheaths of tendons. T h e clinical course is usually one of local recurrence or distant metastasis in a 5- to 10-year period. The treatment of choice is resection with wide margins. W e report a characteristic example of this uncommon neoplasm. CASE REPORT
A 16-year-old black boy had a slowly enlarging tumor for 4 years on his left ring finger (Fig. 1). Examination revealed a 2 • 2.5 • 2.5 cm hard tumor on the volar aspect of his distal left ring finger that extended from'the distal interphalangeal joint to the tip of the phalanx. Ulceration and necrosis were present, but there was no active drainage. No epitrochlear, axillary, or supraclavicular adenopathy was detected. Radiographs revealed a soft tissue mass with punctate areas of calcification and erosion of the distal phalangeal tuft cortex. A distal interphalangeal amputation was performed. Tissue was submitted for histopathologic examination, and cultures were submitted to test for fungi, acid-fast bacilli, and bacteria. Microscopically, the neoplasm was composed of a large lobulated mass of coalescing areas of spindle-shaped cells, arranged in a palisaded fashion around central zones of necrosis (Figs. 2 and 3). The nuclei were vesicular, and Fromthe DepartmentsofDermatology,"Pathology,band Orthopedics,c BowmanGray Schoolof Medicineof Wake ForestUniversity. Reprints not available. *Dr. Shaw is now with the Departmentof Pathology,Universityof North Carolinaat Chapel Hill, 16/4/32155 302
Fig. 1. Tumor nodule extended from the distal tip of the ring finger. Focal ulceration is present. most contained a single nucleolus. The cells had variable amounts of eosinophilic cytoplasm that blended imperceptively into the dense collagenous stroma (Fig. 4). Pleomorphism was minimal, but a few large epithelioid tumor cells and multinucleated giant cells were observed. Mitotic figures, some atypical, were abundant. The overlying skin was ulcerated. A focally dense, lymphoplasmacytic infiltrate was present adjacent to the tumor. Results of special stains for microorganisms were negative. Although pseudocarcinomatous squamous hyperplasia was present adjacent to the ulcer, no squamous dysplasia or carcinoma was evident. Immunohistochemical studies of the neoplasms showed positive staining for cytokeratin and vimentin and negative staining for S-100 protein. Transmission electron microscopy revealed oval to polygonal cells that contained few cytoplasmic organelles; that is, rough endoplasmic retieula, polyribosomes, and mitochondria. However, most cells contained scant to moderately abundant, randomly oriented, wavy, cytoplasmic intermediate filaments. Rare cell junction-like structures were present, but no desmosomes were observed. The nuclei were oval and contained a prominent nucleolus.
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1
Fig. 2. Coalescing nodules of neoplasm fill the dermis and subcutaneous tissue and form a scalloped outline. (Hematoxylin-eosin stain; X2.)
Fig. 3. Neoplasm is composed ofepithelioid and spindle-shaped cells palisaded around central zones of necrosis. (Hematoxylin-eosin stain; X40.)
These light and electron microscopic features were diagnostic of ES. 1-4After computed tomographic scans of the neck and chest showed no signs of disease, a ray resection of the phalanx and metacarpal was recommended, but the patient refused further treatment. DISCUSSION This report demonstrates many characteristic features of ES. The tumor commonly arises in the distal extremities of young adults, with a male to female ratio of 1.8:1.1, 5,6 The most common tumor site is the hand and forearm (58% of cases), followed
by the lower extremities.S Significantly, it is the most common soft tissue sarcoma of the hand. 2 It usually presents as a solitary nodule of woody, hard consistency in the deep soft tissues, the subcutis, or the dermis. The tumor is commonly associated with tendon sheaths or other fibrous structures, such as joint capsules or neurovascular bundles. As many as 12% will have epidermal involvement with ulceration. 5 Locally recurrent disease tends to involve multiple sites and may appear as annular plaques. 6, 7 Pain is usually absent or mild, unless there is peripheral nerve involvement. Radiographic exam-
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Fig. 4. Neoplastic cells have oval vesicular nuclei and moderately abundant eosinophilic cytoplasm. Cell borders are indistinct. Adjacent to viable tumor are areas of necrosis. (Hematoxylin-eosin stain; • ination is nonspecific and reveals a soft tissue mass, occasionally containing fine flecks of calcification. Pressure erosion of the adjacent bone is a common finding. I The characteristic histologic appearance at the light microscopic level consists of nodular proliferations of plump, polygonal to round, epithelioid cells, which blend with a population of spindle-shaped cells. Commonly there is a geographic growth pattern, in which the polygonal cells surround areas of necrosis or acellularity and form nodules that m a y fuse into scalloped palisades. ~, 5, 8 The cells show little pleomorphism but do display large irregular nuclei with obvious nucleoli and variable numbers of mitotic figures (2 to 6 per high-powered field). 1 The cells tend to splay between collagen bundles and invade adjacent mesenchymal structures. 9 Frequently a peripheral chronic inflammatory infiltrate is evident. 1,6 Multinucleated tumor giant cells are present in less than 5% of cases, s Immunohistochemical stains are useful in differentiating ES from other entities. A t least 75% of epitheliod sarcomas will stain for cytokeratin, and approximately 50% will stain for epithelial membrane antigen.S, 10, t~ These markers help differentiate ES from most other sarcomas, malignant fibrous histiocytoma, and malignant melanoma. Although synovial sarcoma shares these markers, its distinctive biphasic histologic appearance usually allows differentiation. Monomorphous synovial sarcomas do not have the palisaded granulomatous appearance.
In addition, ES uniformly lacks common leukocyte antigens, thus aUowing differentiation from granulomatous and other inflammatory processes.l~ I 1 ES also lacks myoglobin and factor VIII-related antigen, seen in rhabdomyosarcoma and epithelioid hemangioendothelioma, respectively.t 1 The natural history of the disease commonly follows a long protracted course, with local recurrences and possible metastasis that may occur years after the initial diagnosis and excision. As many as 77% of tumors have local recurrence, often repeated, and approximately 45% of cases metastasize. The predominant sites for metastasis are regional nodes, followed by the lung, scalp, and skin. 5 ES can metastasize distantly, without first recurring locally or in regional lymph nodes. Overall survival is approximately 70% at 5 years and 50% at tO years. 6 Some factors associated with poor prognosis are tumors greater than 3 cm, tumors in deep subcutaneous locations, and tumors with focal necrosis. 6 Other factors that predict poor outcome are vascular invasion, tumor hemorrhage, and proximal or axial tumor site. s Women and young patients have a more favorable prognosis. 5 Treatment consists of aggressive, wide surgical excision or amputation. This is supported by the high rate of local recurrence, poor response to chemotherapy, slow, insidious growth, and an unpredictable mode of spread. 5, 6 Yet the extent of surgery does not necessarily correlate with survival or local recurrence. 12 Twenty percent of cases recur even
Volume 26 Number 2, Part 2 February 1992
after amputation, s There is no difference in survival between groups treated with wide, radical, or marginal excision, although patients in all of these groups did better than patients treated with incisional resection. 6 These findings suggest that the tumor extends imperceptively beyond the margins of the operative site as it invades along fibrous structures and argues for a wider resection than would normally be taken. In cases of advanced disease both radiation and chemotherapy have been used, but no definitive cures have been reported, and remissions are rare.S, 6, 13 Usually the best result was local control of tumor growth for a time. 12 Although patients have been treated with surgery and adjunctive radiation or chemotherapy, the follow-up has been inadequate to assess the efficacy. 5, 6, 13
REFERENCES 1. Enzinger FM. Epithelioid sarcoma: a sarcoma simulating a granuloma or carcinoma. Cancer 1970;26:1029-41. 2. Enzinger FM, Weiss SW. Soft Tissue Tumors. 2nd ed. St. Louis: The CV Mosby Co, 1988:936-45. 3. Meis JM, Mackay B, Ordonez NG. Epithelioid sarcoma: an immunohistochemical and ultrastructural study. Surg Pathol 1988;1:13-31.
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4. Mills SE, Fechner RE, Bruns ME, et al. Intermediate filaments in eosinophiliccells of epithelioid sarcoma: a lightmicroscopic,ultrastructural, and electrophoretic study. Am J Surg Pathol 1981;5:195-202. 5. Chase DR, Enzinger FM. Epithelioid sarcoma: diagnosis, prognostic indicators, and treatment. Am J Surg Pathol 1985;9:241-63. 6. Bos GD, Pritchard DJ, Reiman HM, et al. Epithelioid sarcoma: an analysis offifty-one cases. J Bone Joint Surg [Am] 1988;70:862-70. 7. Saxe N, Botha JBC. Epithelioid sarcoma: a distinctive clinical presentation. Arch Dermatol 1977;113:1106-8. 8. Heenan PJ, Quirk CJ, Papadimitriou JM. Epithelioid sarcoma: a diagnostic problem. Am J Derrnatopathol 1986;8:95-104. 9. Padilla RS, Flynn K, Headington JT. Epithelioid sarcoma: enzymatic histochemical and electron microscopicevidence of histiocyticdifferentiation. Arch Dermatol 1985;121:38993. 10. Wick MR, Manivel JC. Epithelioid sarcoma and isolated necrobiotic granuloma: a comparative immunocytochemical study. J Cutan Pathol 1986;13:253-60. 11. Manivel JC, Wick MR, Dehner LP, et al. Epithelioid sarcoma: an immunohistochemical study. Am J Clin Pathol 1987;87:319-26. 12. Wevers AC, Kroon BBR, Albus-Lutter CE, et al. Epithe[ioid sarcoma. Eur J Surg Oncol 1989;15:345-9. 13. Shimm DS, Suit HD. Radiation therapy of epithelioidsarcoma. Cancer 1983;52:1022-5.
Epithelioid sarcoma ( E S ) is an uncommon soft tissue malignancy first characterized by Enzinger in 1970.1 This neoplasm usually appears on an upper extremity of young m e n as a solitary, subcutaneous nodule. The growth of this s a r c o m a is slow and m a y be along fibrous sheaths of tendons. T h e clinical course is usually one of local recurrence or distant metastasis in a 5- to 10-year period. The treatment of choice is resection with wide margins. W e report a characteristic example of this uncommon neoplasm. CASE REPORT
A 16-year-old black boy had a slowly enlarging tumor for 4 years on his left ring finger (Fig. 1). Examination revealed a 2 • 2.5 • 2.5 cm hard tumor on the volar aspect of his distal left ring finger that extended from'the distal interphalangeal joint to the tip of the phalanx. Ulceration and necrosis were present, but there was no active drainage. No epitrochlear, axillary, or supraclavicular adenopathy was detected. Radiographs revealed a soft tissue mass with punctate areas of calcification and erosion of the distal phalangeal tuft cortex. A distal interphalangeal amputation was performed. Tissue was submitted for histopathologic examination, and cultures were submitted to test for fungi, acid-fast bacilli, and bacteria. Microscopically, the neoplasm was composed of a large lobulated mass of coalescing areas of spindle-shaped cells, arranged in a palisaded fashion around central zones of necrosis (Figs. 2 and 3). The nuclei were vesicular, and Fromthe DepartmentsofDermatology,"Pathology,band Orthopedics,c BowmanGray Schoolof Medicineof Wake ForestUniversity. Reprints not available. *Dr. Shaw is now with the Departmentof Pathology,Universityof North Carolinaat Chapel Hill, 16/4/32155 302
Fig. 1. Tumor nodule extended from the distal tip of the ring finger. Focal ulceration is present. most contained a single nucleolus. The cells had variable amounts of eosinophilic cytoplasm that blended imperceptively into the dense collagenous stroma (Fig. 4). Pleomorphism was minimal, but a few large epithelioid tumor cells and multinucleated giant cells were observed. Mitotic figures, some atypical, were abundant. The overlying skin was ulcerated. A focally dense, lymphoplasmacytic infiltrate was present adjacent to the tumor. Results of special stains for microorganisms were negative. Although pseudocarcinomatous squamous hyperplasia was present adjacent to the ulcer, no squamous dysplasia or carcinoma was evident. Immunohistochemical studies of the neoplasms showed positive staining for cytokeratin and vimentin and negative staining for S-100 protein. Transmission electron microscopy revealed oval to polygonal cells that contained few cytoplasmic organelles; that is, rough endoplasmic retieula, polyribosomes, and mitochondria. However, most cells contained scant to moderately abundant, randomly oriented, wavy, cytoplasmic intermediate filaments. Rare cell junction-like structures were present, but no desmosomes were observed. The nuclei were oval and contained a prominent nucleolus.
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1
Fig. 2. Coalescing nodules of neoplasm fill the dermis and subcutaneous tissue and form a scalloped outline. (Hematoxylin-eosin stain; X2.)
Fig. 3. Neoplasm is composed ofepithelioid and spindle-shaped cells palisaded around central zones of necrosis. (Hematoxylin-eosin stain; X40.)
These light and electron microscopic features were diagnostic of ES. 1-4After computed tomographic scans of the neck and chest showed no signs of disease, a ray resection of the phalanx and metacarpal was recommended, but the patient refused further treatment. DISCUSSION This report demonstrates many characteristic features of ES. The tumor commonly arises in the distal extremities of young adults, with a male to female ratio of 1.8:1.1, 5,6 The most common tumor site is the hand and forearm (58% of cases), followed
by the lower extremities.S Significantly, it is the most common soft tissue sarcoma of the hand. 2 It usually presents as a solitary nodule of woody, hard consistency in the deep soft tissues, the subcutis, or the dermis. The tumor is commonly associated with tendon sheaths or other fibrous structures, such as joint capsules or neurovascular bundles. As many as 12% will have epidermal involvement with ulceration. 5 Locally recurrent disease tends to involve multiple sites and may appear as annular plaques. 6, 7 Pain is usually absent or mild, unless there is peripheral nerve involvement. Radiographic exam-
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Fig. 4. Neoplastic cells have oval vesicular nuclei and moderately abundant eosinophilic cytoplasm. Cell borders are indistinct. Adjacent to viable tumor are areas of necrosis. (Hematoxylin-eosin stain; • ination is nonspecific and reveals a soft tissue mass, occasionally containing fine flecks of calcification. Pressure erosion of the adjacent bone is a common finding. I The characteristic histologic appearance at the light microscopic level consists of nodular proliferations of plump, polygonal to round, epithelioid cells, which blend with a population of spindle-shaped cells. Commonly there is a geographic growth pattern, in which the polygonal cells surround areas of necrosis or acellularity and form nodules that m a y fuse into scalloped palisades. ~, 5, 8 The cells show little pleomorphism but do display large irregular nuclei with obvious nucleoli and variable numbers of mitotic figures (2 to 6 per high-powered field). 1 The cells tend to splay between collagen bundles and invade adjacent mesenchymal structures. 9 Frequently a peripheral chronic inflammatory infiltrate is evident. 1,6 Multinucleated tumor giant cells are present in less than 5% of cases, s Immunohistochemical stains are useful in differentiating ES from other entities. A t least 75% of epitheliod sarcomas will stain for cytokeratin, and approximately 50% will stain for epithelial membrane antigen.S, 10, t~ These markers help differentiate ES from most other sarcomas, malignant fibrous histiocytoma, and malignant melanoma. Although synovial sarcoma shares these markers, its distinctive biphasic histologic appearance usually allows differentiation. Monomorphous synovial sarcomas do not have the palisaded granulomatous appearance.
In addition, ES uniformly lacks common leukocyte antigens, thus aUowing differentiation from granulomatous and other inflammatory processes.l~ I 1 ES also lacks myoglobin and factor VIII-related antigen, seen in rhabdomyosarcoma and epithelioid hemangioendothelioma, respectively.t 1 The natural history of the disease commonly follows a long protracted course, with local recurrences and possible metastasis that may occur years after the initial diagnosis and excision. As many as 77% of tumors have local recurrence, often repeated, and approximately 45% of cases metastasize. The predominant sites for metastasis are regional nodes, followed by the lung, scalp, and skin. 5 ES can metastasize distantly, without first recurring locally or in regional lymph nodes. Overall survival is approximately 70% at 5 years and 50% at tO years. 6 Some factors associated with poor prognosis are tumors greater than 3 cm, tumors in deep subcutaneous locations, and tumors with focal necrosis. 6 Other factors that predict poor outcome are vascular invasion, tumor hemorrhage, and proximal or axial tumor site. s Women and young patients have a more favorable prognosis. 5 Treatment consists of aggressive, wide surgical excision or amputation. This is supported by the high rate of local recurrence, poor response to chemotherapy, slow, insidious growth, and an unpredictable mode of spread. 5, 6 Yet the extent of surgery does not necessarily correlate with survival or local recurrence. 12 Twenty percent of cases recur even
Volume 26 Number 2, Part 2 February 1992
after amputation, s There is no difference in survival between groups treated with wide, radical, or marginal excision, although patients in all of these groups did better than patients treated with incisional resection. 6 These findings suggest that the tumor extends imperceptively beyond the margins of the operative site as it invades along fibrous structures and argues for a wider resection than would normally be taken. In cases of advanced disease both radiation and chemotherapy have been used, but no definitive cures have been reported, and remissions are rare.S, 6, 13 Usually the best result was local control of tumor growth for a time. 12 Although patients have been treated with surgery and adjunctive radiation or chemotherapy, the follow-up has been inadequate to assess the efficacy. 5, 6, 13
REFERENCES 1. Enzinger FM. Epithelioid sarcoma: a sarcoma simulating a granuloma or carcinoma. Cancer 1970;26:1029-41. 2. Enzinger FM, Weiss SW. Soft Tissue Tumors. 2nd ed. St. Louis: The CV Mosby Co, 1988:936-45. 3. Meis JM, Mackay B, Ordonez NG. Epithelioid sarcoma: an immunohistochemical and ultrastructural study. Surg Pathol 1988;1:13-31.
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4. Mills SE, Fechner RE, Bruns ME, et al. Intermediate filaments in eosinophiliccells of epithelioid sarcoma: a lightmicroscopic,ultrastructural, and electrophoretic study. Am J Surg Pathol 1981;5:195-202. 5. Chase DR, Enzinger FM. Epithelioid sarcoma: diagnosis, prognostic indicators, and treatment. Am J Surg Pathol 1985;9:241-63. 6. Bos GD, Pritchard DJ, Reiman HM, et al. Epithelioid sarcoma: an analysis offifty-one cases. J Bone Joint Surg [Am] 1988;70:862-70. 7. Saxe N, Botha JBC. Epithelioid sarcoma: a distinctive clinical presentation. Arch Dermatol 1977;113:1106-8. 8. Heenan PJ, Quirk CJ, Papadimitriou JM. Epithelioid sarcoma: a diagnostic problem. Am J Derrnatopathol 1986;8:95-104. 9. Padilla RS, Flynn K, Headington JT. Epithelioid sarcoma: enzymatic histochemical and electron microscopicevidence of histiocyticdifferentiation. Arch Dermatol 1985;121:38993. 10. Wick MR, Manivel JC. Epithelioid sarcoma and isolated necrobiotic granuloma: a comparative immunocytochemical study. J Cutan Pathol 1986;13:253-60. 11. Manivel JC, Wick MR, Dehner LP, et al. Epithelioid sarcoma: an immunohistochemical study. Am J Clin Pathol 1987;87:319-26. 12. Wevers AC, Kroon BBR, Albus-Lutter CE, et al. Epithe[ioid sarcoma. Eur J Surg Oncol 1989;15:345-9. 13. Shimm DS, Suit HD. Radiation therapy of epithelioidsarcoma. Cancer 1983;52:1022-5.