The Journal of Dermatology Vol. 17: 569-574,1990
Intradermal Spitz Nevus Differentiated from Reticulohistiocytic Granuloma by Immunoreactivity to S-100 Protein Naoko Kato and Hiroo Ueno* Abstract
A firm, dark reddish, smooth surfaced nodule on the forearm of a 16-year-old boy was diagnosed as a Spitz nevus with the aid of a strong positive reactivity to S-100 protein. Histological examination revealed an intradermal epithelioid cell tumor with prominent multinucleated giant cells, suggesting the diagnosis of reticulohistiocytic granuloma. However, immunoperoxidase staining of the tumor cells showed strong positive reactivity to S-100 protein and vimentin; it was negative for lysozyme and alpha-l antitrypsin. Although a few melanosomes in the tumor cells seen in electron microscopic examination provided crucial proof for the diagnosis of Spitz nevus, the positive reactivity to S-100 protein in ordinary formalin-fixed, paraffin-embedded tissues proved to be veryuseful in the differentiation of Spitz nevus from tumors of histiocytic origin, especially those of the mononuclear phagocytic system. Key words: Spitz nevus; immunohistochemistry; S-100 protein; melanosome; reticulohistiocytic granuloma
Introduction Epithelioid cell-spindle cell nevomelanocytic nevi have also been called Spitz nevi since Sophie Spitz described 13 cases of "melanomas in childhood" in 1948 (l). They are usually acquired benign melanocytic tumors. Like usual nevomelanocytic nevi, Spitz nevi have three histological types depending on the location of the nevus cells, which are either junctional, compound, or intradermal. Spitz nevi are potentially difficult to differentiate from tumors originating from histiocytes, since epithelioid nevus cells and histiocytes are quite similar in hematoxylin-eosin (HE) stained sections. In this paper, we describe a 16-year-old Japanese male patient who had a shiny dark reddish nodule on his forearm which was Received May 30, 1990; accepted for publicationjuly 12, 1990. Department of Dennato1ogy, Otaru City General Hospital,Otaru,japan. *Department of Pathology, Otaru City General Hospital, Otaru, japan. Reprint requests to: Dr. Naoko Kato, Department of Dermatology, Otaru City General Hospital, 2-1, Wakamatsu J-Chome, Otaru, 047,japan.
Fig. 1. A dark reddish nodule with a shiny smooth surface on right the forearm. diagnosed as a pyogenic granuloma clinically, but rediagnosed as a Spitz nevus histologically on the basis of strong immunoreactivity to S100 protein and the presence of melanosomes in the tumor cells on electron microscopic examination.
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Fig. 2A. A hematoxylin-eosin stained specimen shows a relatively sharply demarcated, symmetrical, intradermal tumor mass without any tumor cell nests in the epidermis (x20).
Fig. 2B. High-power view of the upper portion of the tumor. Epithelioid cells are scattered widely and intermingled with inflammatory infiltrates mainly composed oflymphoid cells (xIOO).
Fig. 2C. One of the distinctive multinucleated giant cells. It has multiple peripherally arranged nuclei and fine-ground-glass-like cytoplasm (x400).
Intradermal Epithelioid Spitz Nevus
571
Fig. 3A. Immunoperoxidase staining for 5-100 protein is strongly positive in the tumor cell cytoplasm and nuclei (x40).
Fig. 3B. Multinucleated giant cells stained for S-100 protein show intense, sharp staining (x200).
Case Report A 16-year-old senior high school student visited our clinic in June of 1989 with a 5-year history of a small, firm, dome-shaped nodule on his right forearm. He first noticed a brownish-black tiny papule, which slowly enlarged to 6 x 5 x 4 mm in size and bled several times. During its growth, the nodule changed to dark red with a shiny smooth surface (Fig. 1). A clinical diagnosis of pyogenic granuloma was based on its reddish color and the frequent episodes of bleeding. Total resection of the nodule was performed 4 days after his first visit. A HE-stained specimen showed a relatively sharply demarcated, symmetrical, intradermal tumor mass without any tumor cell nests in the epidermis (Fig. 2A). In the upper portion of the tumor, epithelioid cells were scattered widely (Fig. 2B), while, near the
bottom, the tumor cells formed small nests, in perpendicular linear patterns. The cells were epithelioid with large basophilic nuclei and eosinophilic cytoplasm. There were also many distinctive multinucleated giant cells with peripherally arranged nuclei and eosinophilic, fine-ground-glass-like cytoplasm (Fig. 2C). There were almost no spindle shaped cells or mitotic figures. It was difficult to find melanin pigments in the HE or Fontana-Masson stained sections. They were intermingled with inflammatory infiltrates composed mainly of lymphoid cells. Eosinophilic globules in the epidermis or dermal papillae, so called Kamino bodies (2), were rarely observed. The most probable diagnosis was reticulohistiocytic granuloma, particularly in view of the large, multinucleated, giant cells. Immunoperoxidase staining with rabbit anti-5100 protein polyclonal antibody was strongly posi-
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Kato and Ueno
Fig. 4A. Electron micrograph of tumor cells. They are relatively dark and possess abundant cytoskeletal microfilaments (f), They have clear basal laminae (BL). Nu: nucleus (xlO,OOO). tive in the tumor cell cytoplasm and nuclei (Fig. 3A). It helped to clarify the tumor cell nests and to sharply outline the multinucleated giant cells (Fig. 3B). Vimentin (using monoclonal mouse antibody) was also strongly positive in the tumor cell cytoplasm. Immunostaining for desmin, NSE (neuronspecific enolase), EMA (epithelial membrane antigen), lysozyme, and alpha-l antitrypsin was negative in the tumor cells. Infiltrated lymphoid cells reacted positively to MT-I (pan-T marker) but were negative for L-26 (pan-B marker). Electron microscopic examination revealed that the tumor cells were relatively dark and possessed abundant cytoskeletal microfilaments (Fig. 4A, f). They had clear basal laminae (BL). Some of the nuclei were indented. Not all, but some of the tumor cells near the upper part of the tumor had a few melanosomes (Fig. 4B, m). They seemed to be relatively young ones, at stage II or III.
Comment The relative incidences of the three histological types of Spitz nevi, junctional, com-
pound and intradermal, were reported by Paniago-Pereira et al. (3) as comprising 9.5%, 66% and 24.5% respectively in 200 specimens. Merot and Frenk (4) also reviewed 89 cases of Spitz nevi. Of these, 14 cases (15.7%) were intradermal; the average age of these cases was significantly higher than the other groups. They speculated that intradermal Spitz nevi are less active and more mature than other types. About 20% of these tumors are composed of epithelioid cells only despite their other name of epithelioid cell-spindle cell nevomelanocytic nevi. This minor group of intradermal epithelioid Spitz nevi is sometimes difficult to differentiate from tumors of histiocytic origin, such as reticulohistiocytic granuloma, histiocytoma, and juvenile xanthogranuloma, in HE-stained specimens. The absence of detectable melanin in ordinary tissue specimens and the presence of large multinucleated giant cells in some nevi further complicate the differential diagnosis. The use of immunohistochemistry and/or electron microscopy provides a means for dis-
Intradermal Epithelioid Spitz Nevus
573
Fig. 4B. Some tumor cells have a few melanosomes (m). RE: rough endoplasmic reticulum (x48,OOO).
tinguishing these tumors. S-100 protein, a Ca 2+-binding acidic protein of 21,000 daltons (5), is present in many different kinds of normal cells and their benign and malignant tumors (6-12). Reports of the positive reactivity of different cell series and their tumors to this protein are increasing (13-15). In Spitz nevi, which are unique, usually acquired, benign, melanocytic tumors, the reactivity to S-100 protein is reported to be strongly positive, as it is in the intradermal type of ordinary nevomelanocytic nevus and amelanotic melanoma (16, 17). It is well known that histiocytes have at least a dual cell origin. One of them possesses 5-100+ lys (lysozyme)" NCA (nonspecific cross reacting antigen with carcinoembryonic antigen)" immunohistochemical characteristics which include Langerhans cells, that is, the T-zone histiocyte lineage. The other possesses S-100lys" NCA+ immunohistochemical characteristics, that is, the monocyte-macrophage system (MPS). Tumors originating from histiocytes of
the latter group, such as reticulohistiocytic granuloma, juvenile xanthogranuloma, histiocytoma, and malignant fibrous histiocytoma, are reported to react with alpha-I antitrypsin and alpha-l antichymotrypsin (18). In the present case, epithelioid cells formed many multinucleated giant cells with eosinophilic granular cytoplasm, resembling ground glass. These are the cells which are characteristically observed in matured reticulohistiocytosis or solitary reticulohistiocytic granuloma. Nevertheless, the diagnosis of Spitz nevus was confirmed in this case because of the strong positive reactivity to S-100 protein and negative reactivity to lysozyme and alpha-I antitrypsin. A similar experience was reported by Winkelmann and Peters (18). They differentiated Spitz nevus from atypical fibroxanthoma with the aid of a strong positive reactivity to S-100 protein in the tumor cells. However, the strong positive reactivity to vimentin could not help us differentiate this nevus from a histiocytic tumor. Although vimentin enables a differential diag-
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nosis between fibrohistiocytic and leiomyocytic tumors, positive reactivity to this intermediate filament protein has been reported in neoplastic cells of fibrohistiocytic tumors, nevomelanocytic nevi, melanomas, hemangiomas, glomus tumors, and lymphomas (19). Another problem in the diagnosis of Spitz nevus is its differentiation from malignant melanoma, especially from amelanotic melanoma, since both usually show strong positivity to S-100 protein (12). Some Spitz nevi show lymphatic invasion (20) and recurrent Spitz nevus has been reported by Omura and Kheir (21). Merot and Frenk (4) maintain that the involvement of the suprabasal epidermis with pagetoid spread, nesting of cells, and transepidermal elimination, are not features of Spitz nevi in adults. They recommend that the diagnosis of malignant melanoma should be considered in such cases. In the present case, the lack of involvement of the suprabasal epidermis, the absence of tumor invasion into surrounding collagen tissues, the symmetrical growth of the tumor, and the lack of mitosis in the tumor cells were all helpful in differentiating it from an amelanotic melanoma. Although the presence of a few melanosomes on electron microscopic examination provided definite proof for a diagnosis of tumor of nevomelanocytic origin, the importance and efficacy of immunohistochemistry, using formalin-fixed, paraffin-embedded tissues was verified for the proper diagnosis of intradermal epithelioid Spitz nevus. References 1) Spitz S: Melanomas of childhood, Am] Pathol, 24: 591-609,1948. 2) Kamino H, Jagirdar J: Fibronectin in eosinophilic globules of Spitz's nevi, Am] Dermatopathol, 6(suppl 1): 313-316, 1984. 3) Paniago-Pereira C, MaizeJC, Ackerman B: Nevus of large spindle and/or epithelioid cells (Spitz's nevus), Arch Dermatol, 114: 1811-1823,1978. 4) Merot Y, Frenk E: Spitz nevus (large spindle cell and/or epithelioid cell nevus). Age-related involvement of the suprabasal epidermis, VirchowsArch, 415: 97-101, 1989. 5) Herrera GA, Turbat-Herrera EA, Lott RL: S-100
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12)
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14)
15)
16)
17)
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19)
20) 21)
protein expression by primary and metastatic adenocarcinomas, Am] Clin Pathol, 89: 168-176, 1988. Gaynor R, Herschman HR, Irie R,Jones P, Morton D, Cochran A: S-IOO protein: a marker for human malignant melanomas?, Lancet, i: 869-871, 1981. Nakajima T, Watanabe S, Sato Y, Kameya T, Shimosato Y, Ishihara K: Immunohistochemical demonstration of S-100 protein in malignant melanoma and pigmented nevus and its diagnostic application, Cancer, 50: 912-918, 1982. Nakazato Y, Ishizeki j, Takahashi K, Yamaguchi H: Immunohistochemical localization of S-100 protein in granular cell myoblastoma, Cancer, 49: 1624-1628, 1982. Cocchia D, Fabrizio M, Donato R: Immunochemical and immunocytochemical localization of S-100 antigen in normal human skin, Nature, 294: 85-87, 1981. Watanabe S, Nakajima T, Shimosato Y, Sato Y, Shimizu K: Malignant histiocytosis and Letterer-Siwe disease, Cancer, 51: 1412-1424,1983. Nakamura Y, Becker LE, Marks A: S-100 protein in tumors of cartilage and bone,-An immunohistochemical study, Cancer, 52: 1820-1824,1983. Takahashi K: S-100 immunoreactivity in normal human peripheral blood lymphocytes, Am] Clin Pathol, 89: 453-454, 1988. Sansoni P, Rowden G, Manara GC, Ferrari C, Torresani C, Panfilis G: Immunoelectronmicroscopic demonstration ofS-100 protein in hairy cell leukemia cells, Am] Coin Pathol, 89: 374-377, 1988. Miettinen M: Gastrointestinal stromal tumors,-An immunohistochemical study of cellular differentiation, Am] Clin Pathol, 89: 601-610, 1988. Hjermstad BM, Sobin LH, Helwig EB: Stromal tumors of the gastrointestinal tract: myogenic or neurogenic?, Am] Surg Pathol, 11: 383-386, 1987. Takahashi H, Maeda K, Maeda K, Akutsu Y, Horikoshi T, Jimbow K: Immunohistochemical characterization of Spitz's nevus: differentiation from common melanocytic nevus, dysplastic melanocytic nevus and malignant melanoma,] Dermatol (Tokyo), 14: 533-541, 1987. Palazzo J, Duray PH: Typical, dysplastic, congenital, and Spitz nevi: a comparative immunohistochemial study, Hum Pathol, 20: 341-346, 1989. Winkelmann RK, Peters M: Atypical fibroxanthoma,-A study with antibody to S-100 protein, Arch Dermatol, 121: 753-755, 1985. Miettinen M, Lehto V-P, Virtanen I: Antibodies to intermediate filament proteins. The differential diagnosis of cutaneous tumors, Arch Dermatol, 121: 736-741,1985. Howat Aj, Variend S: Lymphatic invasion in Spitz nevi, Am] Surg Pathol, 9: 125-128, 1985. Omura EF, Kheir SM: Recurrent Spitz's nevus, Am] Dermatopathol, 6: 207-212, 1984.
Intradermal Spitz Nevus Differentiated from Reticulohistiocytic Granuloma by Immunoreactivity to S-100 Protein Naoko Kato and Hiroo Ueno* Abstract
A firm, dark reddish, smooth surfaced nodule on the forearm of a 16-year-old boy was diagnosed as a Spitz nevus with the aid of a strong positive reactivity to S-100 protein. Histological examination revealed an intradermal epithelioid cell tumor with prominent multinucleated giant cells, suggesting the diagnosis of reticulohistiocytic granuloma. However, immunoperoxidase staining of the tumor cells showed strong positive reactivity to S-100 protein and vimentin; it was negative for lysozyme and alpha-l antitrypsin. Although a few melanosomes in the tumor cells seen in electron microscopic examination provided crucial proof for the diagnosis of Spitz nevus, the positive reactivity to S-100 protein in ordinary formalin-fixed, paraffin-embedded tissues proved to be veryuseful in the differentiation of Spitz nevus from tumors of histiocytic origin, especially those of the mononuclear phagocytic system. Key words: Spitz nevus; immunohistochemistry; S-100 protein; melanosome; reticulohistiocytic granuloma
Introduction Epithelioid cell-spindle cell nevomelanocytic nevi have also been called Spitz nevi since Sophie Spitz described 13 cases of "melanomas in childhood" in 1948 (l). They are usually acquired benign melanocytic tumors. Like usual nevomelanocytic nevi, Spitz nevi have three histological types depending on the location of the nevus cells, which are either junctional, compound, or intradermal. Spitz nevi are potentially difficult to differentiate from tumors originating from histiocytes, since epithelioid nevus cells and histiocytes are quite similar in hematoxylin-eosin (HE) stained sections. In this paper, we describe a 16-year-old Japanese male patient who had a shiny dark reddish nodule on his forearm which was Received May 30, 1990; accepted for publicationjuly 12, 1990. Department of Dennato1ogy, Otaru City General Hospital,Otaru,japan. *Department of Pathology, Otaru City General Hospital, Otaru, japan. Reprint requests to: Dr. Naoko Kato, Department of Dermatology, Otaru City General Hospital, 2-1, Wakamatsu J-Chome, Otaru, 047,japan.
Fig. 1. A dark reddish nodule with a shiny smooth surface on right the forearm. diagnosed as a pyogenic granuloma clinically, but rediagnosed as a Spitz nevus histologically on the basis of strong immunoreactivity to S100 protein and the presence of melanosomes in the tumor cells on electron microscopic examination.
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Kato and Ueno
Fig. 2A. A hematoxylin-eosin stained specimen shows a relatively sharply demarcated, symmetrical, intradermal tumor mass without any tumor cell nests in the epidermis (x20).
Fig. 2B. High-power view of the upper portion of the tumor. Epithelioid cells are scattered widely and intermingled with inflammatory infiltrates mainly composed oflymphoid cells (xIOO).
Fig. 2C. One of the distinctive multinucleated giant cells. It has multiple peripherally arranged nuclei and fine-ground-glass-like cytoplasm (x400).
Intradermal Epithelioid Spitz Nevus
571
Fig. 3A. Immunoperoxidase staining for 5-100 protein is strongly positive in the tumor cell cytoplasm and nuclei (x40).
Fig. 3B. Multinucleated giant cells stained for S-100 protein show intense, sharp staining (x200).
Case Report A 16-year-old senior high school student visited our clinic in June of 1989 with a 5-year history of a small, firm, dome-shaped nodule on his right forearm. He first noticed a brownish-black tiny papule, which slowly enlarged to 6 x 5 x 4 mm in size and bled several times. During its growth, the nodule changed to dark red with a shiny smooth surface (Fig. 1). A clinical diagnosis of pyogenic granuloma was based on its reddish color and the frequent episodes of bleeding. Total resection of the nodule was performed 4 days after his first visit. A HE-stained specimen showed a relatively sharply demarcated, symmetrical, intradermal tumor mass without any tumor cell nests in the epidermis (Fig. 2A). In the upper portion of the tumor, epithelioid cells were scattered widely (Fig. 2B), while, near the
bottom, the tumor cells formed small nests, in perpendicular linear patterns. The cells were epithelioid with large basophilic nuclei and eosinophilic cytoplasm. There were also many distinctive multinucleated giant cells with peripherally arranged nuclei and eosinophilic, fine-ground-glass-like cytoplasm (Fig. 2C). There were almost no spindle shaped cells or mitotic figures. It was difficult to find melanin pigments in the HE or Fontana-Masson stained sections. They were intermingled with inflammatory infiltrates composed mainly of lymphoid cells. Eosinophilic globules in the epidermis or dermal papillae, so called Kamino bodies (2), were rarely observed. The most probable diagnosis was reticulohistiocytic granuloma, particularly in view of the large, multinucleated, giant cells. Immunoperoxidase staining with rabbit anti-5100 protein polyclonal antibody was strongly posi-
572
Kato and Ueno
Fig. 4A. Electron micrograph of tumor cells. They are relatively dark and possess abundant cytoskeletal microfilaments (f), They have clear basal laminae (BL). Nu: nucleus (xlO,OOO). tive in the tumor cell cytoplasm and nuclei (Fig. 3A). It helped to clarify the tumor cell nests and to sharply outline the multinucleated giant cells (Fig. 3B). Vimentin (using monoclonal mouse antibody) was also strongly positive in the tumor cell cytoplasm. Immunostaining for desmin, NSE (neuronspecific enolase), EMA (epithelial membrane antigen), lysozyme, and alpha-l antitrypsin was negative in the tumor cells. Infiltrated lymphoid cells reacted positively to MT-I (pan-T marker) but were negative for L-26 (pan-B marker). Electron microscopic examination revealed that the tumor cells were relatively dark and possessed abundant cytoskeletal microfilaments (Fig. 4A, f). They had clear basal laminae (BL). Some of the nuclei were indented. Not all, but some of the tumor cells near the upper part of the tumor had a few melanosomes (Fig. 4B, m). They seemed to be relatively young ones, at stage II or III.
Comment The relative incidences of the three histological types of Spitz nevi, junctional, com-
pound and intradermal, were reported by Paniago-Pereira et al. (3) as comprising 9.5%, 66% and 24.5% respectively in 200 specimens. Merot and Frenk (4) also reviewed 89 cases of Spitz nevi. Of these, 14 cases (15.7%) were intradermal; the average age of these cases was significantly higher than the other groups. They speculated that intradermal Spitz nevi are less active and more mature than other types. About 20% of these tumors are composed of epithelioid cells only despite their other name of epithelioid cell-spindle cell nevomelanocytic nevi. This minor group of intradermal epithelioid Spitz nevi is sometimes difficult to differentiate from tumors of histiocytic origin, such as reticulohistiocytic granuloma, histiocytoma, and juvenile xanthogranuloma, in HE-stained specimens. The absence of detectable melanin in ordinary tissue specimens and the presence of large multinucleated giant cells in some nevi further complicate the differential diagnosis. The use of immunohistochemistry and/or electron microscopy provides a means for dis-
Intradermal Epithelioid Spitz Nevus
573
Fig. 4B. Some tumor cells have a few melanosomes (m). RE: rough endoplasmic reticulum (x48,OOO).
tinguishing these tumors. S-100 protein, a Ca 2+-binding acidic protein of 21,000 daltons (5), is present in many different kinds of normal cells and their benign and malignant tumors (6-12). Reports of the positive reactivity of different cell series and their tumors to this protein are increasing (13-15). In Spitz nevi, which are unique, usually acquired, benign, melanocytic tumors, the reactivity to S-100 protein is reported to be strongly positive, as it is in the intradermal type of ordinary nevomelanocytic nevus and amelanotic melanoma (16, 17). It is well known that histiocytes have at least a dual cell origin. One of them possesses 5-100+ lys (lysozyme)" NCA (nonspecific cross reacting antigen with carcinoembryonic antigen)" immunohistochemical characteristics which include Langerhans cells, that is, the T-zone histiocyte lineage. The other possesses S-100lys" NCA+ immunohistochemical characteristics, that is, the monocyte-macrophage system (MPS). Tumors originating from histiocytes of
the latter group, such as reticulohistiocytic granuloma, juvenile xanthogranuloma, histiocytoma, and malignant fibrous histiocytoma, are reported to react with alpha-I antitrypsin and alpha-l antichymotrypsin (18). In the present case, epithelioid cells formed many multinucleated giant cells with eosinophilic granular cytoplasm, resembling ground glass. These are the cells which are characteristically observed in matured reticulohistiocytosis or solitary reticulohistiocytic granuloma. Nevertheless, the diagnosis of Spitz nevus was confirmed in this case because of the strong positive reactivity to S-100 protein and negative reactivity to lysozyme and alpha-I antitrypsin. A similar experience was reported by Winkelmann and Peters (18). They differentiated Spitz nevus from atypical fibroxanthoma with the aid of a strong positive reactivity to S-100 protein in the tumor cells. However, the strong positive reactivity to vimentin could not help us differentiate this nevus from a histiocytic tumor. Although vimentin enables a differential diag-
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Kato and Ueno
nosis between fibrohistiocytic and leiomyocytic tumors, positive reactivity to this intermediate filament protein has been reported in neoplastic cells of fibrohistiocytic tumors, nevomelanocytic nevi, melanomas, hemangiomas, glomus tumors, and lymphomas (19). Another problem in the diagnosis of Spitz nevus is its differentiation from malignant melanoma, especially from amelanotic melanoma, since both usually show strong positivity to S-100 protein (12). Some Spitz nevi show lymphatic invasion (20) and recurrent Spitz nevus has been reported by Omura and Kheir (21). Merot and Frenk (4) maintain that the involvement of the suprabasal epidermis with pagetoid spread, nesting of cells, and transepidermal elimination, are not features of Spitz nevi in adults. They recommend that the diagnosis of malignant melanoma should be considered in such cases. In the present case, the lack of involvement of the suprabasal epidermis, the absence of tumor invasion into surrounding collagen tissues, the symmetrical growth of the tumor, and the lack of mitosis in the tumor cells were all helpful in differentiating it from an amelanotic melanoma. Although the presence of a few melanosomes on electron microscopic examination provided definite proof for a diagnosis of tumor of nevomelanocytic origin, the importance and efficacy of immunohistochemistry, using formalin-fixed, paraffin-embedded tissues was verified for the proper diagnosis of intradermal epithelioid Spitz nevus. References 1) Spitz S: Melanomas of childhood, Am] Pathol, 24: 591-609,1948. 2) Kamino H, Jagirdar J: Fibronectin in eosinophilic globules of Spitz's nevi, Am] Dermatopathol, 6(suppl 1): 313-316, 1984. 3) Paniago-Pereira C, MaizeJC, Ackerman B: Nevus of large spindle and/or epithelioid cells (Spitz's nevus), Arch Dermatol, 114: 1811-1823,1978. 4) Merot Y, Frenk E: Spitz nevus (large spindle cell and/or epithelioid cell nevus). Age-related involvement of the suprabasal epidermis, VirchowsArch, 415: 97-101, 1989. 5) Herrera GA, Turbat-Herrera EA, Lott RL: S-100
6)
7)
8)
9)
10)
11)
12)
13)
14)
15)
16)
17)
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20) 21)
protein expression by primary and metastatic adenocarcinomas, Am] Clin Pathol, 89: 168-176, 1988. Gaynor R, Herschman HR, Irie R,Jones P, Morton D, Cochran A: S-IOO protein: a marker for human malignant melanomas?, Lancet, i: 869-871, 1981. Nakajima T, Watanabe S, Sato Y, Kameya T, Shimosato Y, Ishihara K: Immunohistochemical demonstration of S-100 protein in malignant melanoma and pigmented nevus and its diagnostic application, Cancer, 50: 912-918, 1982. Nakazato Y, Ishizeki j, Takahashi K, Yamaguchi H: Immunohistochemical localization of S-100 protein in granular cell myoblastoma, Cancer, 49: 1624-1628, 1982. Cocchia D, Fabrizio M, Donato R: Immunochemical and immunocytochemical localization of S-100 antigen in normal human skin, Nature, 294: 85-87, 1981. Watanabe S, Nakajima T, Shimosato Y, Sato Y, Shimizu K: Malignant histiocytosis and Letterer-Siwe disease, Cancer, 51: 1412-1424,1983. Nakamura Y, Becker LE, Marks A: S-100 protein in tumors of cartilage and bone,-An immunohistochemical study, Cancer, 52: 1820-1824,1983. Takahashi K: S-100 immunoreactivity in normal human peripheral blood lymphocytes, Am] Clin Pathol, 89: 453-454, 1988. Sansoni P, Rowden G, Manara GC, Ferrari C, Torresani C, Panfilis G: Immunoelectronmicroscopic demonstration ofS-100 protein in hairy cell leukemia cells, Am] Coin Pathol, 89: 374-377, 1988. Miettinen M: Gastrointestinal stromal tumors,-An immunohistochemical study of cellular differentiation, Am] Clin Pathol, 89: 601-610, 1988. Hjermstad BM, Sobin LH, Helwig EB: Stromal tumors of the gastrointestinal tract: myogenic or neurogenic?, Am] Surg Pathol, 11: 383-386, 1987. Takahashi H, Maeda K, Maeda K, Akutsu Y, Horikoshi T, Jimbow K: Immunohistochemical characterization of Spitz's nevus: differentiation from common melanocytic nevus, dysplastic melanocytic nevus and malignant melanoma,] Dermatol (Tokyo), 14: 533-541, 1987. Palazzo J, Duray PH: Typical, dysplastic, congenital, and Spitz nevi: a comparative immunohistochemial study, Hum Pathol, 20: 341-346, 1989. Winkelmann RK, Peters M: Atypical fibroxanthoma,-A study with antibody to S-100 protein, Arch Dermatol, 121: 753-755, 1985. Miettinen M, Lehto V-P, Virtanen I: Antibodies to intermediate filament proteins. The differential diagnosis of cutaneous tumors, Arch Dermatol, 121: 736-741,1985. Howat Aj, Variend S: Lymphatic invasion in Spitz nevi, Am] Surg Pathol, 9: 125-128, 1985. Omura EF, Kheir SM: Recurrent Spitz's nevus, Am] Dermatopathol, 6: 207-212, 1984.
