Epidermotropic neuroendocrine carcinoma Immunohistochemical differentiation from simuiators, including malignant meianoma Epidermotropic neuroendocrine carcinoma (NEC) is rare. Based on such a case in an 88-year-old woman with a facial NEC showing epidermotropism with a pagetoid growth pattern, we asked whether several similar tumors involving the epidermis could be easily differentiated by immunohistochemical methods. We constructed a panel of control cases (2 each) for NEC, clear cell Bowen's disease (CCBD), Paget's disease (PD), superficial basal cell carcinoma (SBCC), cutaneous T-cell lymphoma (CTTL), and superficial spreading malignant melanoma (SSMM) to compare with our patient. A panel of antibodies including epithelial membrane antigen (EMA), neuron specific enolase (NSE), AEl/3 cytokeratin (CK), carcinoembryonic antigen (CEA), leukocyte common antigen (LCA), S-100, and HMB-45 were applied. Cutaneous NEC controls and our patient's tumor were strongly positive for EMA and NSE and had paranuclear dot-like cytoplasmic positivity for CK. CCBD was moderate to strong for CK. PD was strong for CEA. SBCC was essentially negative for all. CTTL was strong for LCA. SSMM was strong for S-100 and HMB-45. Controls were either negative or weak for the antibodies not mentioned. We conclude that this antibody panel can reliably differentiate these epidermotropic or juxtaepidermal tumors in diagnostic dermatopathology and should be applied to lesions requiring separation beyond H&E capabilities, especially with superficial shave biopsies showing small cell "Pagetoid" growth patterns. Gillham SL,Morrison RG, Hurt MA. Epidermotropic neuroendocrine carcinoma. J Cutan Pathol 1991: 18: 120-127.
In 1972, Toker described as "trabecular" carcinoma, a malignant cutaneous tumor which almost always exclusively resides in the dermis (1). While the debate of the cell or origin of this tumor (Merkel Cells versus some other type of neurocristic cell or other undefined cell) continues, several points concerning its diflerentiation, both immunohistochemically and ultrastructurally, have been repeatedly documented in the literature. In brief, these are: small blue dermal cells with trabecular and diffuse growth, neuroendocrine and cytokeratin positive cell immunohistochemistry (2-6), and cytoplasmic neurosecretory granules and paranuclear condensations of intermediate filaments by ultrastructure (7, 8). In contrast, epidermotropic malignant melanoma usually can be differentiated from cutaneous NEC by the presence of Pagetoid spread, cytoplasmic melanin, nuclei with prominent nucleoli, irregular nuclei, and heterogeneous chromatin patterns. 120
S. L Gillham\ R. G. Momson^ M. A. Hurf ^ Department of Pathology, University of Texas Health Science Center, San Antonio ^Aiien iee Paris Laboratories, West Plains, Missouri, U.S.A.
Mark A, Hurt, Cutaneous Pathology, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78284-7750, U,S,A, Accepted May 9, 1990
It is distrinctly unusual for cutaneous NEC to show epidermotropism. To our knowledge, this phenomenon has been illustrated only eight times (911) and has taken the form of Pautrier-like microabscesses in 5 cases and epidermal clusters in 3 cases. We wish to report a case in which the epidermotropism was similar to the pattern seen in the final common pathway of spread ("Pagetoid") in the epidermal portions of superficial spreading melanoma, and we compare this to controls of tumors in the histological diflerential diagnosis. Case report
An 88-year-old white woman presented with a lesion of the right cheek in July 1989. In 1984, a skin lesion of unknown diagnosis was removed from her nose. In April 1989, she was seen again, but no mention of skin lesions was made. In July 1989, the
Epidermotropic neuroendocrine carcinoma
clinical impression of the cheek lesion was that of basal cell carcinoma. It was completely excised and, at a seven-month follow-up period, there was no evidence of local recurrence or systemic disease.
formed on all cases using the peroxidase-antiperoxidase method for the presence or absence of a panel of seven antigens including carcinoembryonic antigen (CEA; 1:50; monoclonal; ZYMED), AEl/3 cytokeratin (CK; 1:400; monoclonal; ICN), epithelial membrane antigen (EMA; 1:20; monoclonal; Materials and methods DAKO), human melanoma black (HMB-45; Tissue for light microscopy and immunocytoche1:1000; monoclonal; ENZO), leukocyte common mistry studies was fixed in 10% neutral-buffered antigen (LCA; 1:10; monoclonal; DAKO), neuron formalin and embedded in paraflin. The control specific enolase (NSE; 1:100; polyclonal; DAKO), cases consisted of two cases of basal cell carcinoma and SlOO Protein (SlOO; 1:200; monoclonal; Chemconfined closely to the epidermis and consisting of Con Immunologicals Inc.). In addition, tissue from small clear cells, 2 cases of superficial spreading the patient was removed from the paraffin block, melanoma showing pagetoid spread, 2 cases of cutaprocessed for electron microscopy, and examined in neous T-cell lymphoma {Mycosisfungoides)., 2 cases of a Jeol lOOCX electron microscope. extramammary Paget's disease, 2 cases of pagetoid Bowen's disease, and 2 cutaneous neuroendocrine Microscopic pathology carcinomas. Sections from the patient as well as the control Sections from the patient sample showed a small cell cases were cut at 4|a, and stained for hematoxylin neoplasm with epidermotropism (Eig. 1). The epiand eosin. Immunoperoxidase stains were perdermal portion showed theque-like and lentiginous
Fig. 1 A, B. These low-power views show the tumor with a dermal and epidermal component. The dermai portions are insular and trabecular.
121
Gillham et al.
growth (Fig. 2) while the dermal portion was nodular and extended into the deep reticular dermis. Cytologically, the tumor cells were of uniform size with diffusely speckled nuclei, measuring approximately lOfA in diameter. The mitotic index was 16 per mm^ (entire tumor examined). Immunocytochemistry
The patient, as well as the controls, are summarized in Table 1. In brief, these results showed that the neuroendocrine tumor could be differentiated from BCC, PD, CCBD, SSMM, and CTTL by the positive staining of the tumor cytoplasm with EMA (Fig. 3A), and NSE (Fig. 3B). The CK showed minimal positivity except for rare areas with paranuclear dot-like staining. In addition, it was observed that all other controls could be differentiated from each other by the panel.
Ultrastructural pathology
The epidermal tumor cells were of uniform size and showed circular nuclei which were relatively nondescript. Due to the fixation artifact, clear cytoplasmic details were obscured, but several tumor cells displayed paranuclear collections of filaments (Eig. 4).
Discussion The origin of the cutaneous small blue tumor with neuroendocrine differentiation has been debated for the last two decades (12-15). While opinions have varied from Merkel cell origin to speculations on a dermal or adnexal progenitor cell, it seems surprising to us that its cell of origin would be in the epidermis if so few cases have demonstrated epidermal involvement. What does seem clear is that the tumor is differentiated toward some neuroendocrine line or lines and has a biologically aggressive course in many cases. In some cases, these tumors have squamoid and or ductal differentiation, and a few
,,. *
122
Fig. IB.
Epidermotropic neuroendocrine carcinoma
Fig. 2. This view shows the nested or theque-like growth of the tumor, similar to that r the epidermal linal common pathway of malignant melanoma.
cases have been associated with an overlying squamous atypia or carcinoma-in-situ. In our case, the tumor was principally located within the dermis except for the epidermotropic component described above. The dermal growth pattern was diffuse, insular, and trabecular, which is compatible with cases described in the literature. Likewise, the immunostaining was compatible with typical literature cases as well as our own controls. With respect to the ultrastructural fmdings of our case, fixation artifact precluded recognition of cellular membranes and neurosecretory granules, but there was sufficient preservation of the whorled paranuclear filaments to substantiate our diagnosis (3).
Cutaneous neuroendocrine carcinomas most commonly arise in the elderly and they have a predilection for the upper body. The clinical differential diagnosis is typically non-specific. The histological diflerential diagnosis is usually limited due to its characteristic small cell dermal growth pattern in the form of trabecular cords or sheets. The other differential diagnoses are with small cell malignant melanoma, cutaneous lymphoma, neuroendocrine basal cell carcinoma (rarely) (16), and metastatic small cell carcinoma, the latter of which can usually be differentiated on clinicopathological grounds. With regard to epidermal involvement, of the approximately 80 papers reporting over 400 cases of
Table 1. Imnnunocytochemical panel of tunnor cell positivity. Patient NEC EMA NSE CK CEA LCA S-100 HMB
NEC Cntri
BCC Cntrl
cnL Cntri
SSMM Cntrl
PD Cntrl
CCBD Cntrl
-1+
-/+
Stainlng was graded 1 to 4 -i- or - , + / - or -/-^ indicated variable or weak staining, * Paranuclear cytoplasnnic dot-like positivity.
123
Gillham et al.
Fig. 3 A, B. Epithelial membrane antigen strongly decorates the cytoplasm of the epidermal tumor cells (A). A similar pattern is seen with neuron-specific enolase (B).
Epidermotropic neuroendocrine carcinoma
Fig. 4. Although the ultrastructure of the tumor was compromised from formalin fixation, paranuclear whorled filaments are seen in this view and were commonly seen in the cytoplasm of the tumor cells.
cutaneous NEC we reviewed, only 15 cases had been reported to show involvement with the epidermis (9-11, 13, 17-20). Of these 15 cases, only 5 cases have been described in which the tumor exhibited epidermotropism with Pautrier-like microabscesses (9-11) and 3 other cases showed clustered growth (17, 18), not lentiginous and theque-like growth as seen in our case. The rare finding of epidermal involvement in a case of neuroendocrine carcinoma must include a differential of other neoplasms which have the ability to either exhibit true epidermotropism (epidermal invasion) or to simulate it. The most common types of malignant tumors showing these features have been used as our controls in this study (Table ^)- We have, however, seen one case of metastatic epidermotropic small cell carcinoma from lung to skin (Fig. 5), but this patient had a confirmed diag-
nosis of the visceral lesion before the cutaneous lesion arose, which, to our knowledge, has been the usual clinical presentation of such secondary lesions. The findings of the primary cutaneous lesions in our control groups are similar to those of Glasgow et al. (21). From our data, it would seem to be relatively easy to differentiate these epidermal processes from each other (Table 1), especially in superficial shave biopsies in which a minimal dermal component can be assessed. We believe that awareness of this variant growth pattern of neuroendocrine carcinoma will facilitate its differentiation from the other lesions, especially small cell malignant melanoma.
125
Gillham et al. Fig. .5. This lesion shows metastatic small cell carcinoma frorn lung to skin, confirmed clinicopathologically in another patient. Note the Pautrier-like microabscess of tumor cells in the epidermis (arrow and inset).
Acknowledgements
The authors wish to thank Richard W. Brown and D. Craig Allred, for assistance with immunohistochemistry, and Donna Clarkson, for technical assistance with electron microscopy. We thank Saul Suster, Yale University Department of Pathology, New Haven, CT, for directing our literature review of this subject. Phred Petersen, director of photographic services (UTHSCSA), and Lester Rosebrock provided assistance with photomicrography. References 1. loker C. Trabecular carcinoma of the skin. Arch Dermatol 1972: 105: 107. 2. Gu J, Folak j M , Tapia FJ, Marangos PJ, Pearse AGE. Neuron-specific enoiase in the Merkel cells of mammalian skin. The use of specific antibody as a simple and reliable histologic marker. AmJ Pathol 1981: 104: 63.
126
3. Haneke E. Electron mieroscopy of Merkel cell carcinoma from formalin-fixed tissue. J Am Acad Dermatol 1985: 12: 487. 4. Sibley RK, Dahl D. Primary neuroendocrine (Merkel cell?) carcinoma of the skin. II. An immunocytochemical study of 21 ciises. AmJ Surg Pathol 1985: 9: 109. 5. Layfield L, Ulich T, Liao S, Barr R, Cheng L, Lewin KL. Neuroendocrine carcinoma of the skin: an immunohistochemical study of tumor markers and neuroendocrine products. J Cutan Pathol 1986: 13: 268. 6. Wick MR, Kaye VN, Sibley RK, Tyler R, Frizzera C. Primary neuroendocrine carcinoma and small-cell malignant lymphoma of the skin. J Cutan Pathol 1986: 13: 347. 7. Tang C-K, Toker C. Trabecular carcinoma of the skin. An ultrastructural study. Cancer 1978: 42: 2311. 8. Wick MR, Goellner JR, Scheithauer BW, Thomas JR III, Sanchez NP, Schroeter AL. Primary neuroendocrine carcinomas of the skin (Merkel cell tumors). A clinical, histologic, and ultrastructural study of thirteen cases. AmJ Clin Pathol 1983: 79: 6. 9. Sidhu GS, Mullins JD, Feiner H, Schaefler K, Flotte TJ, Sehultenover SJ. Merkel cell neoplasms. Histology, electron
Epidermotropic neuroendocrine carcinoma
10.
11.
12.
13.
14.
15.
microscopy, biology, and histogenesis. AmJ Dermatopathol 1980: 2: 101. Rocamora A, Badia N, Vives R, Carillo R, UUoa J, Ledo A. Epidermotropic primary neuroendoctine (Merkel cell) carcinoma of the skin with pautrier-like microabscesses. Report of three cases and review of the literature. J Am Acad Dermatol 1987: 16: 1163. Mamalis N, Medlock RD, Holds JB, Anderson RL, Crandall AS. Merkel cell tumor of the eyelid: a review and report of an unusual case. Ophfrhalmol Surg 1989: 20: 410. Winkelmann RK. The Merkel cell system and a comparison between it and the neurosecretory or APUD cell system. J Invest Dermatol 1977: 69: 41. Kroll MH, Toker C. Trabecular carcinoma of ther skin. Further clinicopathologic and morphologic study. Arch Pathol Lab Med 1982: 106: 404. Rosai J. On the nature and nomenclature of a primary small carcinoma of the skin exhibiting endocrine (? Merkel cell) differentiation. AmJ Dermatopathol 1982: 4: 501. Gould VE, Moll R, Moll I, Lee I, Franke WW. Neuroendocrine (Merkel) cells of the skin: hyperplasias, dysplasias, and neoplasms. Lab Invest 1985: 52: 334.
16 George E, Swanson PE, Wick MR. Neuroendocrine differ-
17
18.
19
20
21
entiation in basal cell carcinoma. Am J Dermatopathol 1989: 11: 131. Tang C-K, Nedwich A, Toker C, Zaman ANF. Unusual cutaneous carcinoma with features of small cell (oat celllike) and squamous cell carcinomas. A variant of malignant Merkel cell neoplasm. AmJ Dermatopathol 1982: 4: 537. Toker C. Patterns of intraepithelial tumor growth. In: Tumors. An atlas of differential diagnosis. Baltimore: University Park Press, 1983: p. 406 (Figs 613-614). Silva EG, Mackay B, Goepfert H, Burgess MA, Fields RS. Endocrine carcinoma of the skin (Merkel cell carcinoma). Pathol Ann 1984: 19(2): 1. Sibley RK, Dehner LP, Rosai J. Primary neuroendocrine (Merkei cell?) carcinoma of the skin. I. A clinicopathologie and ultrastructural study of43 cases. AmJ Surg Pathol 9: 95. Glasgow BJ, Wen D-R, Al-Jitawi S, Cochran AJ. Antibody to S-100 protein aids the separation of pagetoid melanoma from mammary and extramammary Paget's disease. J Cutan Pathol 1987: 14: 223.
127
In 1972, Toker described as "trabecular" carcinoma, a malignant cutaneous tumor which almost always exclusively resides in the dermis (1). While the debate of the cell or origin of this tumor (Merkel Cells versus some other type of neurocristic cell or other undefined cell) continues, several points concerning its diflerentiation, both immunohistochemically and ultrastructurally, have been repeatedly documented in the literature. In brief, these are: small blue dermal cells with trabecular and diffuse growth, neuroendocrine and cytokeratin positive cell immunohistochemistry (2-6), and cytoplasmic neurosecretory granules and paranuclear condensations of intermediate filaments by ultrastructure (7, 8). In contrast, epidermotropic malignant melanoma usually can be differentiated from cutaneous NEC by the presence of Pagetoid spread, cytoplasmic melanin, nuclei with prominent nucleoli, irregular nuclei, and heterogeneous chromatin patterns. 120
S. L Gillham\ R. G. Momson^ M. A. Hurf ^ Department of Pathology, University of Texas Health Science Center, San Antonio ^Aiien iee Paris Laboratories, West Plains, Missouri, U.S.A.
Mark A, Hurt, Cutaneous Pathology, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78284-7750, U,S,A, Accepted May 9, 1990
It is distrinctly unusual for cutaneous NEC to show epidermotropism. To our knowledge, this phenomenon has been illustrated only eight times (911) and has taken the form of Pautrier-like microabscesses in 5 cases and epidermal clusters in 3 cases. We wish to report a case in which the epidermotropism was similar to the pattern seen in the final common pathway of spread ("Pagetoid") in the epidermal portions of superficial spreading melanoma, and we compare this to controls of tumors in the histological diflerential diagnosis. Case report
An 88-year-old white woman presented with a lesion of the right cheek in July 1989. In 1984, a skin lesion of unknown diagnosis was removed from her nose. In April 1989, she was seen again, but no mention of skin lesions was made. In July 1989, the
Epidermotropic neuroendocrine carcinoma
clinical impression of the cheek lesion was that of basal cell carcinoma. It was completely excised and, at a seven-month follow-up period, there was no evidence of local recurrence or systemic disease.
formed on all cases using the peroxidase-antiperoxidase method for the presence or absence of a panel of seven antigens including carcinoembryonic antigen (CEA; 1:50; monoclonal; ZYMED), AEl/3 cytokeratin (CK; 1:400; monoclonal; ICN), epithelial membrane antigen (EMA; 1:20; monoclonal; Materials and methods DAKO), human melanoma black (HMB-45; Tissue for light microscopy and immunocytoche1:1000; monoclonal; ENZO), leukocyte common mistry studies was fixed in 10% neutral-buffered antigen (LCA; 1:10; monoclonal; DAKO), neuron formalin and embedded in paraflin. The control specific enolase (NSE; 1:100; polyclonal; DAKO), cases consisted of two cases of basal cell carcinoma and SlOO Protein (SlOO; 1:200; monoclonal; Chemconfined closely to the epidermis and consisting of Con Immunologicals Inc.). In addition, tissue from small clear cells, 2 cases of superficial spreading the patient was removed from the paraffin block, melanoma showing pagetoid spread, 2 cases of cutaprocessed for electron microscopy, and examined in neous T-cell lymphoma {Mycosisfungoides)., 2 cases of a Jeol lOOCX electron microscope. extramammary Paget's disease, 2 cases of pagetoid Bowen's disease, and 2 cutaneous neuroendocrine Microscopic pathology carcinomas. Sections from the patient as well as the control Sections from the patient sample showed a small cell cases were cut at 4|a, and stained for hematoxylin neoplasm with epidermotropism (Eig. 1). The epiand eosin. Immunoperoxidase stains were perdermal portion showed theque-like and lentiginous
Fig. 1 A, B. These low-power views show the tumor with a dermal and epidermal component. The dermai portions are insular and trabecular.
121
Gillham et al.
growth (Fig. 2) while the dermal portion was nodular and extended into the deep reticular dermis. Cytologically, the tumor cells were of uniform size with diffusely speckled nuclei, measuring approximately lOfA in diameter. The mitotic index was 16 per mm^ (entire tumor examined). Immunocytochemistry
The patient, as well as the controls, are summarized in Table 1. In brief, these results showed that the neuroendocrine tumor could be differentiated from BCC, PD, CCBD, SSMM, and CTTL by the positive staining of the tumor cytoplasm with EMA (Fig. 3A), and NSE (Fig. 3B). The CK showed minimal positivity except for rare areas with paranuclear dot-like staining. In addition, it was observed that all other controls could be differentiated from each other by the panel.
Ultrastructural pathology
The epidermal tumor cells were of uniform size and showed circular nuclei which were relatively nondescript. Due to the fixation artifact, clear cytoplasmic details were obscured, but several tumor cells displayed paranuclear collections of filaments (Eig. 4).
Discussion The origin of the cutaneous small blue tumor with neuroendocrine differentiation has been debated for the last two decades (12-15). While opinions have varied from Merkel cell origin to speculations on a dermal or adnexal progenitor cell, it seems surprising to us that its cell of origin would be in the epidermis if so few cases have demonstrated epidermal involvement. What does seem clear is that the tumor is differentiated toward some neuroendocrine line or lines and has a biologically aggressive course in many cases. In some cases, these tumors have squamoid and or ductal differentiation, and a few
,,. *
122
Fig. IB.
Epidermotropic neuroendocrine carcinoma
Fig. 2. This view shows the nested or theque-like growth of the tumor, similar to that r the epidermal linal common pathway of malignant melanoma.
cases have been associated with an overlying squamous atypia or carcinoma-in-situ. In our case, the tumor was principally located within the dermis except for the epidermotropic component described above. The dermal growth pattern was diffuse, insular, and trabecular, which is compatible with cases described in the literature. Likewise, the immunostaining was compatible with typical literature cases as well as our own controls. With respect to the ultrastructural fmdings of our case, fixation artifact precluded recognition of cellular membranes and neurosecretory granules, but there was sufficient preservation of the whorled paranuclear filaments to substantiate our diagnosis (3).
Cutaneous neuroendocrine carcinomas most commonly arise in the elderly and they have a predilection for the upper body. The clinical differential diagnosis is typically non-specific. The histological diflerential diagnosis is usually limited due to its characteristic small cell dermal growth pattern in the form of trabecular cords or sheets. The other differential diagnoses are with small cell malignant melanoma, cutaneous lymphoma, neuroendocrine basal cell carcinoma (rarely) (16), and metastatic small cell carcinoma, the latter of which can usually be differentiated on clinicopathological grounds. With regard to epidermal involvement, of the approximately 80 papers reporting over 400 cases of
Table 1. Imnnunocytochemical panel of tunnor cell positivity. Patient NEC EMA NSE CK CEA LCA S-100 HMB
NEC Cntri
BCC Cntrl
cnL Cntri
SSMM Cntrl
PD Cntrl
CCBD Cntrl
-1+
-/+
Stainlng was graded 1 to 4 -i- or - , + / - or -/-^ indicated variable or weak staining, * Paranuclear cytoplasnnic dot-like positivity.
123
Gillham et al.
Fig. 3 A, B. Epithelial membrane antigen strongly decorates the cytoplasm of the epidermal tumor cells (A). A similar pattern is seen with neuron-specific enolase (B).
Epidermotropic neuroendocrine carcinoma
Fig. 4. Although the ultrastructure of the tumor was compromised from formalin fixation, paranuclear whorled filaments are seen in this view and were commonly seen in the cytoplasm of the tumor cells.
cutaneous NEC we reviewed, only 15 cases had been reported to show involvement with the epidermis (9-11, 13, 17-20). Of these 15 cases, only 5 cases have been described in which the tumor exhibited epidermotropism with Pautrier-like microabscesses (9-11) and 3 other cases showed clustered growth (17, 18), not lentiginous and theque-like growth as seen in our case. The rare finding of epidermal involvement in a case of neuroendocrine carcinoma must include a differential of other neoplasms which have the ability to either exhibit true epidermotropism (epidermal invasion) or to simulate it. The most common types of malignant tumors showing these features have been used as our controls in this study (Table ^)- We have, however, seen one case of metastatic epidermotropic small cell carcinoma from lung to skin (Fig. 5), but this patient had a confirmed diag-
nosis of the visceral lesion before the cutaneous lesion arose, which, to our knowledge, has been the usual clinical presentation of such secondary lesions. The findings of the primary cutaneous lesions in our control groups are similar to those of Glasgow et al. (21). From our data, it would seem to be relatively easy to differentiate these epidermal processes from each other (Table 1), especially in superficial shave biopsies in which a minimal dermal component can be assessed. We believe that awareness of this variant growth pattern of neuroendocrine carcinoma will facilitate its differentiation from the other lesions, especially small cell malignant melanoma.
125
Gillham et al. Fig. .5. This lesion shows metastatic small cell carcinoma frorn lung to skin, confirmed clinicopathologically in another patient. Note the Pautrier-like microabscess of tumor cells in the epidermis (arrow and inset).
Acknowledgements
The authors wish to thank Richard W. Brown and D. Craig Allred, for assistance with immunohistochemistry, and Donna Clarkson, for technical assistance with electron microscopy. We thank Saul Suster, Yale University Department of Pathology, New Haven, CT, for directing our literature review of this subject. Phred Petersen, director of photographic services (UTHSCSA), and Lester Rosebrock provided assistance with photomicrography. References 1. loker C. Trabecular carcinoma of the skin. Arch Dermatol 1972: 105: 107. 2. Gu J, Folak j M , Tapia FJ, Marangos PJ, Pearse AGE. Neuron-specific enoiase in the Merkel cells of mammalian skin. The use of specific antibody as a simple and reliable histologic marker. AmJ Pathol 1981: 104: 63.
126
3. Haneke E. Electron mieroscopy of Merkel cell carcinoma from formalin-fixed tissue. J Am Acad Dermatol 1985: 12: 487. 4. Sibley RK, Dahl D. Primary neuroendocrine (Merkel cell?) carcinoma of the skin. II. An immunocytochemical study of 21 ciises. AmJ Surg Pathol 1985: 9: 109. 5. Layfield L, Ulich T, Liao S, Barr R, Cheng L, Lewin KL. Neuroendocrine carcinoma of the skin: an immunohistochemical study of tumor markers and neuroendocrine products. J Cutan Pathol 1986: 13: 268. 6. Wick MR, Kaye VN, Sibley RK, Tyler R, Frizzera C. Primary neuroendocrine carcinoma and small-cell malignant lymphoma of the skin. J Cutan Pathol 1986: 13: 347. 7. Tang C-K, Toker C. Trabecular carcinoma of the skin. An ultrastructural study. Cancer 1978: 42: 2311. 8. Wick MR, Goellner JR, Scheithauer BW, Thomas JR III, Sanchez NP, Schroeter AL. Primary neuroendocrine carcinomas of the skin (Merkel cell tumors). A clinical, histologic, and ultrastructural study of thirteen cases. AmJ Clin Pathol 1983: 79: 6. 9. Sidhu GS, Mullins JD, Feiner H, Schaefler K, Flotte TJ, Sehultenover SJ. Merkel cell neoplasms. Histology, electron
Epidermotropic neuroendocrine carcinoma
10.
11.
12.
13.
14.
15.
microscopy, biology, and histogenesis. AmJ Dermatopathol 1980: 2: 101. Rocamora A, Badia N, Vives R, Carillo R, UUoa J, Ledo A. Epidermotropic primary neuroendoctine (Merkel cell) carcinoma of the skin with pautrier-like microabscesses. Report of three cases and review of the literature. J Am Acad Dermatol 1987: 16: 1163. Mamalis N, Medlock RD, Holds JB, Anderson RL, Crandall AS. Merkel cell tumor of the eyelid: a review and report of an unusual case. Ophfrhalmol Surg 1989: 20: 410. Winkelmann RK. The Merkel cell system and a comparison between it and the neurosecretory or APUD cell system. J Invest Dermatol 1977: 69: 41. Kroll MH, Toker C. Trabecular carcinoma of ther skin. Further clinicopathologic and morphologic study. Arch Pathol Lab Med 1982: 106: 404. Rosai J. On the nature and nomenclature of a primary small carcinoma of the skin exhibiting endocrine (? Merkel cell) differentiation. AmJ Dermatopathol 1982: 4: 501. Gould VE, Moll R, Moll I, Lee I, Franke WW. Neuroendocrine (Merkel) cells of the skin: hyperplasias, dysplasias, and neoplasms. Lab Invest 1985: 52: 334.
16 George E, Swanson PE, Wick MR. Neuroendocrine differ-
17
18.
19
20
21
entiation in basal cell carcinoma. Am J Dermatopathol 1989: 11: 131. Tang C-K, Nedwich A, Toker C, Zaman ANF. Unusual cutaneous carcinoma with features of small cell (oat celllike) and squamous cell carcinomas. A variant of malignant Merkel cell neoplasm. AmJ Dermatopathol 1982: 4: 537. Toker C. Patterns of intraepithelial tumor growth. In: Tumors. An atlas of differential diagnosis. Baltimore: University Park Press, 1983: p. 406 (Figs 613-614). Silva EG, Mackay B, Goepfert H, Burgess MA, Fields RS. Endocrine carcinoma of the skin (Merkel cell carcinoma). Pathol Ann 1984: 19(2): 1. Sibley RK, Dehner LP, Rosai J. Primary neuroendocrine (Merkei cell?) carcinoma of the skin. I. A clinicopathologie and ultrastructural study of43 cases. AmJ Surg Pathol 9: 95. Glasgow BJ, Wen D-R, Al-Jitawi S, Cochran AJ. Antibody to S-100 protein aids the separation of pagetoid melanoma from mammary and extramammary Paget's disease. J Cutan Pathol 1987: 14: 223.
127
