J Cutan Pathol 2015: 42: 353–360 doi: 10.1111/cup.12468 John Wiley & Sons. Printed in Singapore
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Journal of Cutaneous Pathology
Merkel cell carcinoma arising within a poroma: report of two cases Merkel cell carcinoma (MCC) has been reported in association with other types of cutaneous neoplasms within the same lesion, including squamous cell carcinoma, Bowen’s disease, actinic keratosis, follicular cysts, trichoblastoma and lentigo maligna, among others. However, the association of MCC and sweat gland tumors has never been described in the literature. We report two unique cases of MCC that developed within cutaneous poromas. A 56-year-old male (Patient 1) and an 81-year-old female (Patient 2) presented with nodules on the upper arm and lower back, respectively. Histopathologic study of both cases revealed a tumor in the dermis composed of poroid and cuticular cells intermingled with a proliferation of small round cells that showed characteristic histopathological and immunohistochemical features of MCC. In both cases, the two neoplasms were tightly admixed and distinct, suggesting that the MCC could have developed within a previously existing poroma. No morphological features of transition between the two tumors were seen. Neoplastic cells of MCC expressed immunoreactivity for chromogranin, synaptophysin, neuron-specific enolase, CAM 5.2 and cytokeratin 20, the last two markers showing the characteristic paranuclear dot-like pattern. In contrast, the poroma cells only expressed cytokeratin MNF116. Metastatic deposits were not identified in the regional lymph nodes or distantly. Keywords: adnexal tumors, dermatopathology, Merkel cell, Merkel cell carcinoma, poroma, Molina-Ruiz AM, Bernárdez C, Requena L, Rütten A. Merkel cell carcinoma arising within a poroma: report of two cases. J Cutan Pathol 2015; 42: 353–360. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Primary neuroendocrine carcinoma of the skin, commonly known as Merkel cell carcinoma (MCC), is a rare but highly aggressive skin cancer. It usually presents as a dermal nodule affecting mainly sun-exposed skin of elderly white individuals.1 The histogenesis of MCC is debatable.2 Most authors consider that MCC results from a neoplastic proliferation of Merkel cells, although conclusive proof of this concept is lacking. Other authors have suggested an origin from a primitive pluripotent stem cell that
Ana M. Molina-Ruiz1 , Claudia Bernárdez1 , Luis Requena1 and Arno Rütten2 1
Department of Dermatology, Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain and 2 Dermatopathologisches Gemeinschaftslabor, Friedrichshafen, Germany
Ana M. Molina-Ruiz, MD, Department of Dermatology, Fundación Jiménez Díaz, Avd. Reyes Católicos 2, 28040-Madrid, Spain Tel: +34 91 5447039 Fax: +34 91 5442636 e-mail: [email protected] Accepted for publication February 15, 2015
has the potential to differentiate along divergent phenotypes.3 Several reports have described the association of MCC of the skin with other cutaneous neoplasms, including Bowen’s disease,4,5 actinic keratosis,6 squamous cell carcinoma (SCC),7 – 11 lentigo maligna,12 benign follicular tumors,13 follicular cysts,14 – 18 trichoblastoma19 and sebaceous carcinoma.20 The most frequent association is with SCC, both in situ and invasive. However, both MCC and SCC share a common
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Fig. 1. Case 1. A) Scanning magnification showing a tumoral lesion in the dermis with no connection to the epidermis. B) Higher magnification with arrows pointing to a second cell population within the main tumor. C) Higher magnification showing that the tumor is composed of cords and broad columns of uniform poroid cells. D) Detail of the poroid cells. E) Still higher magnification showing a biphasic tumor composed of uniform poroid cells intertwined with small round basophilic cells. F) Detail of the small round basophilic cells showing high nuclear–cytoplasmic ratio, inconspicuous cytoplasm and vesicular nuclei with smudged or clear granular chromatin.
etiopathogenesis, and, therefore, these lesions have been better regarded as ‘composite’ or ‘collision’ tumors. Finally, the association of MCC with tumors of the adnexal glandular lineage has never been reported. We describe two cases of MCC arising within a cutaneous poroma and discuss if this association is just the result of a fortuitous collision between both tumors, or the MCC could have originated
354
from the Merkel cells normally present within the epithelium of the hair follicle. Reports of patients Patient 1 A 56-year-old Caucasian male patient presented with a 1.1 cm, asymptomatic, subcutaneous nodule on the left-upper arm. This lesion had grown
Merkel cell carcinoma arising within a poroma
Fig. 2. Case 2. A) Scanning magnification showing a tumor with no connection with the overlying epidermis. B) Note small aggregations of basophilic cells nests in the upper part of the poroid aggregations. C) Detail of the two neoplasms which are tightly admixed. D) Higher magnification of the small basophilic cells showing the characteristic nuclear and cytoplasmic features of the neoplastic cells of Merkel cell carcinoma.
slowly over the past 4 years. There was no history of previous biopsy at this site nor was there any evidence of internal malignancy. The remainder of the patient’s dermatologic history was unremarkable. The clinical diagnosis was ‘lipoma’, and the lesion was excised. After the initial histopathologic diagnosis of MCC arising within a poroma, the tumor was re-excised with a safe margin but only scar tissue was found in the re-excised specimen. Eight months later, there was no evidence of local recurrence or metastatic disease. Patient 2 An 81-year-old woman was sent for dermatological advice for a 0.9-cm tumor located on the lower back. The lesion had rapidly grown over the 6 months preceding the consultation but was otherwise asymptomatic. Under the clinical diagnosis of ‘inflamed follicular cyst’ the lesion was excised. After the initial histopathologic diagnosis of MCC arising within a poroma, the tumor was re-excised with 1.5-cm healthy margins, and only scar tissue was found. Clinical examination and imaging staging were otherwise negative.
After 4 years, there was no evidence of recurrence or metastasis. Histopathologic findings The two cases showed similar histopathologic findings. At scanning magnification, a dermal tumor with no connection with the overlying epidermis was observed (Figs. 1 and 2). The tumor was mainly composed of cords and broad columns of uniform poroid cells, but with higher magnification two distinct and tightly admixed cell populations were noted. The first consisted of small, uniformly cuboidal cells containing ovoid nuclei, scant eosinophilic cytoplasm and intercellular bridges, findings that were consistent with those of poroma. Ductal structures containing periodic acid-Schiff-positive (PAS) cuticles were observed within the tumor. No signs of sebaceous or apocrine differentiation were evident. The most striking feature in both cases was the presence of a second cell population consisting of solid aggregations of small round hyperchromatic basophilic cells that formed multiple small islands within the first cell population. These cells showed a high
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Fig. 3. Case 1. A) Immunostaining for cytokeratin 20. B) Higher magnification showing the characteristic dot-like pattern of staining in the neoplastic cells of the tumor. C) Immunostaining for CAM 5.2 showing a similar staining pattern to that of cytokeratin 20. D) Higher magnification showing CAM 5.2 immunoexpression only within the Merkel cell carcinoma component of the tumor. E) Positive immunostaining of the Merkel cell carcinoma (MCC) cells for chromogranin. F) Positive immunostaining of the MCC cells for synaptophysin.
nuclear-cytoplasmic ratio, scant cytoplasm, vesicular nuclei with smudged or clear granular chromatin and usually a single, centrally located small nucleolus (Figs. 1D and 2D). Numerous mitotic figures, single necrotic cells and small areas of necrosis en masse were present. These features were evocative of MCC arising in tight association with a poroma. In some areas, hyperplasia and pagetoid spreading of neoplastic cells of MCC were also seen within some of the epithelial strands. Finally, while in Case 1 MCC was strictly confined to the epithelial part of the
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poroma (MCC ‘in situ’), focal infiltration of the tumor stroma could not be completely excluded in Case 2. Immunohistochemical findings Immunohistochemistry showed that neoplastic small round basophilic cells expressed immunoreactivity for cytokeratin 20 (clone Ks 20.8, dilution 1 : 40; Dako, Glostrup, Denmark), pankeratin cocktail AE1/AE3 (dilution 1 : 500; Dako), CAM 5.2 (dilution 1 : 60; Becton
Merkel cell carcinoma arising within a poroma
Fig. 4. Case 1. A) Immunostaining for Ber-EP4. B) Higher magnification showing a positive staining of the neoplastic-small round cells, whereas the poroid cells resulted mostly negative. C) Immunostaining for Ki-67. D) Higher magnification showing a high proliferative index with immunoreactivity mainly within the Merkel cell carcinoma component of the tumor.
Dickinson, San Jose, CA, USA), synaptophysin (clone Sy38, dilution 1 : 10; Dako), chromogranin (clone DAKA3, dilution 1 : 2; Dako), neuron-specific enolase (clone BBS-NC-V, dilution 1 : 500; Dako), BerEP4 (clone Ber-EP4; dilution 1 : 200; Dako) and Ki-67 (clone MIB-1; dilution 1 : 500; Dako) (Figs. 3–5). The immunostaining of neoplastic cells for CAM 5.2 and cytokeratin 20 showed a characteristic dot-like pattern in neoplastic cells of both cases (Fig. 3). The poroid cells were only positive for cytokeratin MNF116 (dilution 1 : 50; Dako) and negative for all the other markers. Discussion We report two cases of MCC arising within a poroma. In both cases, the MCC and poroma cells were tightly admixed, albeit distinct, and no features of transition between the two tumors were evident. The presence of MCC arising within a poroma is an exceptional event and a thorough review of the current literature did not reveal any example of this peculiar association nor of the coexistence of MCC with other sweat gland neoplasms.
Poromas are benign cutaneous adnexal tumors composed microscopically of a variable admixture of poroid and cuticular cells arranged in lobules. Histopathologically, four main variants of poromas are recognized and distinguished according to their location in relation to the epidermis and the size of the neoplastic aggregates: (i) hidroacanthoma simplex, also known as intraepidermal poroma, composed of round nests of neoplastic cells confined within the epidermis; (ii) classic poroma, composed of lobules of neoplastic cell involving both epidermis and dermis; (iii) dermal duct tumor, characterized by small aggregates of neoplastic cells limited to the dermis, with no or few epidermal connection and (iv) poroid hidradenoma, characterized by single or few large solid neoplastic aggregates involving the dermis with cystic areas inside. We believe the two cases described here fit best within the spectrum of poroid hidradenoma. Also, based on histochemistry and electron microscopy, poromas have classically been thought to derive from the peripheral cells of the intraepithelial portion of the eccrine duct (the acrosyringium).21 These ducts embryologically
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Fig. 5. Case 2. A) Immunostaining for cytokeratin MNF116. Scanning power showing immunoreactivity of the epidermis, the adnexa and the poroid cells. B) Higher magnification showing the strong MNF116 immunoreactivity of the poroid cells while the neoplastic small round cells resulted mostly negative, with some background staining. C) Immunostaining for CAM 5.2. Scanning power showing immunoreactivity of the solid aggregations of Merkel cell carcinoma. D) Higher magnification showing the CAM 5.2 immunoexpression of the neoplastic cells of Merkel cell carcinoma and the negative results of the poroid cells composing the rest of the tumor. E) Immunostaining for cytokeratin 20. Scanning power showing positivity within the second cell component of the tumor. F) Higher magnification showing immunoreactivity of the Merkel cell carcinoma nests and the absence of immunoexpression within the poroid cells.
arise from ectodermal surface buds22 and are microscopically indistinguishable from apocrine ducts, which embryologically derive from the folliculo-sebaceous-apocrine unit. However, several well-illustrated reported cases have showed the existence of poromas with focal sebaceous, follicular and apocrine differentiation,23 – 25 suggesting apocrine lineage for some poromas.
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On the other hand, the origin of MCC is not well established. Ultrastructural findings have suggested a possible origin from Merkel cells of the skin1 because these are the only neuroendocrine cells known to be present in the epidermis. In addition, MCC share the same immunohistochemical profile with normal Merkel cells (positivity for cytokeratin 20, neuron-specific
Merkel cell carcinoma arising within a poroma enolase and chromogranin). However, the presence of squamous as well as glandular differentiation in MCC prompted investigators to suggest an epithelial origin of MCC from a primitive pluripotent stem cell located in either the epidermis or the adnexal epithelium that can differentiate along divergent phenotypes.2,11 Merkel cells are normal components of the basal layer of the epidermis, and recent studies have showed the presence of Merkel cells also in fetal and adult hair follicles, where they are grouped in two clusters: one in the deep infundibulum and the other one in the isthmus.26 Also, a relatively high concentration of Merkel cells was found at the level of the bulge. It has been proposed that because Merkel cells are numerous at the infundibulum and the isthmus, it is probable that MCC arising within follicular-derived neoplasms results from neoplastic proliferations of the normal Merkel cell constituents of the hair follicle. In fact, numerous Merkel cells have been found scattered within various neoplasms with follicular differentiation, including desmoplastic trichoepithelioma,27 trichoblastoma,28 follicular proliferation in nevus sebaceous,29 trichofolliculoma30 and fibroepithelioma of Pinkus.31 In these cases, Merkel cells were not neoplastic in contrast to the cases of MCC arising within follicular-derived neoplasms and our cases, where they were clearly malignant by virtue of numerous mitoses, pleomorphism and nuclear hyperchromasia. Finally, the presence of Merkel cells has not been described in sweat gland neoplasms. The architecture of the lesions reported here could represent just a fortuitous association of two different, unrelated neoplasms (MCC and poroma); however, the fact that the
two neoplasms were tightly admixed together and there was no extension of MCC outside the poroma (this last feature could not be completely excluded in Case 2), seem too coincidental to just be the result of a fortuitous association. A second proposed explanation is that these two cases represent poromas that originated in the apocrine ducts. Therefore, the origin of the associated MCCs arising within these ‘apocrine poromas’ could be the neoplastic proliferation of the normal Merkel cell constituents of the hair follicle. Supporting this last hypothesis is the fact that these two poromas did not show the palmoplantar location of the so-called eccrine poromas. Moreover, although the MCC cells were mostly arranged in nests, there were also single-atypical cells scattered throughout the epithelial strands of the poroma component of the tumor, strengthening the hypothesis that MCC may have arised from the Merkel cells present in the follicle. However, the fact that we could not find any morphological signs of apocrine, sebaceous or follicular differentiation within the poroma component of our tumors argues against this hypothesis. A final explanation would be that in our cases the MCC originated in primitive pluripotent stem cells located in the adnexal epithelium that can differentiate along divergent phenotypes. However, data to support this theory are lacking, and this relationship still remains speculative. In conclusion, our cases are unique in that they contained MCC arising within poromas, which may be regarded (at least Case 1) as in situ MCC arising within poromas, and for this reason have a relatively good prognosis. Because no similar cases have been reported in the literature to date, the real significance of this extraordinary association remains to be clarified.
References 1. Sibley RK, Dehner LP, Rosai J. Primary neuroendocrine (Merkel cell?) carcinoma of the skin. I. A clinicopathologic and ultrastructural study of 43 cases. Am J Surg Pathol 1985; 9: 95. 2. Foschini MP, Eusebi V. Divergent differentiation in endocrine and non- endocrine tumors of the skin. Semin Diagn Pathol 2000; 17: 162. 3. Gould E, Albores-Saavedra J, Dubner B, Smith W, Payne CM. Eccrine and squamous differentiation in Merkel cell carcinoma. An immunohistochemical study. Am J Surg Pathol 1988; 12: 768. 4. LeBoit PE, Crutcher WA, PE S. Pagetoid intraepidermal spread in Merkel cell (primary neuroendocrine) carcinoma of the skin. Am J Surg Pathol 1992; 16: 584.
5. Ishida M, Okabe H. Merkel cell carcinoma concurrent with Bowen’s disease: two cases, one with an unusual immunophenotype. J Cutan Pathol 2013; 40: 839. 6. Ferrara G, Goos SD, Stefanato CM. Merkel cell carcinoma in situ associated with actinic keratosis: fortuitous or serendipitous? J Cutan Pathol 2010; 37: 1112. 7. Tang C-K, Nedwich A, Toker C, Zaman ANF. Unusual cutaneous carcinoma with features of small cell (oat-cell like) and squamous cell carcinoma. Am J Dermatopathol 1982; 4: 537. 8. Gomez LG, Silva EG, DiMaio S, Mackay B. Association between neuroendocrine (Merkel cell) carcinoma and squamous
carcinoma of the skin. Am J Surg Pathol 1983; 7: 171. 9. Iacocca MV, Abernethy JL, Stefanato CM, Allan AE, Bhawan J. Mixed Merkel cell carcinoma and squamous cell carcinoma of the skin. J Am Acad Dermatol 1988; 39: 882. 10. Sirikanjanapong S, Melamed J, Patel RR. Intraepidermal and dermal Merkel cell carcinoma with squamous cell carcinoma in situ: a case report with review of literature. J Cutan Pathol 2010; 37: 881. 11. Al-Ahmadie HA, Mutasim DF, Mutema GK. A case of intraepidermal Merkel cell carcinoma within squamous cell carcinoma in-situ: Merkel cell carcinoma in-situ? Am J Dermatopathol 2004; 26: 230.
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Molina-Ruiz et al. 12. Forman SB, Vidmar DA, Ferringer TC. Collision tumor composed of Merkel cell carcinoma and lentigo maligna melanoma. J Cutan Pathol 2008; 35: 203. 13. Yamamoto O, Tanimoto A, Yasuda H, Suenaga Y, Asahi M. A combined occurrence of neuroendocrine carcinoma of the skin and a benign appendageal neoplasm. J Cutan Pathol 1993; 20: 173. 14. Perse RM, Klappenbach RS, Ragsdale BD. Trabecular (Merkel cell) carcinoma arising in the wall of an epidermal cyst. Am J Dermatopathol 1987; 9: 423. 15. Collina G, Bagni A, Fano RA. Combined neuroendocrine carcinoma of the skin (Merkel cell tumor) and trichilemmal cyst. Am J Dermatopathol 1997; 19: 545. 16. Ivan D, Bengana C, Lazar AJ, Diwan AH, Prieto VG. Merkel cell tumor in a trichilemmal cyst: collision or association. Am J Dermatopathol 2007; 29: 180. 17. Requena L, Jaqueti G, Rütten A, Mentzel T, Kutzner H. Merkel cell carcinoma within follicular cysts: report of two cases. J Cutan Pathol 2008; 35: 1127. 18. Su W, Kheir SM, Berberian B, Cockerell CJ. Merkel cell carcinoma in situ arising in a trichilemmal cyst: a case report and literature review. Am J Dermatopathol 2008; 30: 458.
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19. Battistella M, Durand L, Jouary T, Peltre B, Cribier B. Primary cutaneous neuroendocrine carcinoma within a cystic trichoblastoma: a nonfortuitous association? Am J Dermatopathol 2011; 33: 383. 20. Tanahashi J, Kashima K, Daa T, Yada N, Fujiwara S, Yokoyama S. Merkel cell carcinoma co-existent with sebaceous carcinoma of the eyelid. J Cutan Pathol 2009; 36: 983. 21. Abenoza P, Ackerman AB. Poromas. In Abenoza P, Ackerman AB, eds. Neoplasms with eccrine differentiation. Philadelphia: Lea & Febiger, 1990; 113. 22. Requena L, Kiryu H, Ackerman AB. Apocrine poroma. In Neoplasms with apocrine differentiation. Philadelphia: Lippincott-Raven, 1998; 545. 23. Hanau D, Grosshans E, Laplanche G. A complex poroma-like adnexal adenoma. Am J Dermatopathol 1984; 6: 567. 24. Zaim MT. Sebocrine adenoma: an adnexal adenoma with sebaceous and apocrine poroma-like differentiation. Am J Dermatopathol 1988; 10: 311. 25. Santos-Briz A, Rodríguez-Peralto JL, Miguélez A, López-Ríos F. Trichoblastoma arising within an apocrine poroma. Am J Dermatopathol 2002; 24: 59.
26. Moll I. Merkel cell distribution in human hair follicles of the fetal and adult scalp. Cell Tissue Res 1994; 227: 131. 27. Hartschuh W, Schulz T. Merkel cells are integral constituents of desmoplastic trichoepithelioma: an immunohistochemical and electron miscroscopic study. J Cutan Pathol 1995; 22: 413. 28. Schultz T, Hartschuh W. Merkel cells are absent in basal cell carcinomas but frequently found in trichoblastomas: an immunohistochemical study. J Cutan Pathol 1997; 24: 14. 29. Schultz T, Hartschuh W. Merkel cells in nevus sebaceus. Am J Dermatopathol 1995; 17: 570. 30. Hartschuh W, Schultz T. Immunohistochemical investigation of the different developmental stages of trichofolliculoma with special reference to the Merkel cells. Am J Dermatopathol 1999; 21: 8. 31. Hartschuh W, Schultz T. Merkel cell hyperplasia in chronic radiation- damaged skin: its possible relationship to fibroepithelioma of Pinkus. J Cutan Pathol 1997; 24: 477.
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Journal of Cutaneous Pathology
Merkel cell carcinoma arising within a poroma: report of two cases Merkel cell carcinoma (MCC) has been reported in association with other types of cutaneous neoplasms within the same lesion, including squamous cell carcinoma, Bowen’s disease, actinic keratosis, follicular cysts, trichoblastoma and lentigo maligna, among others. However, the association of MCC and sweat gland tumors has never been described in the literature. We report two unique cases of MCC that developed within cutaneous poromas. A 56-year-old male (Patient 1) and an 81-year-old female (Patient 2) presented with nodules on the upper arm and lower back, respectively. Histopathologic study of both cases revealed a tumor in the dermis composed of poroid and cuticular cells intermingled with a proliferation of small round cells that showed characteristic histopathological and immunohistochemical features of MCC. In both cases, the two neoplasms were tightly admixed and distinct, suggesting that the MCC could have developed within a previously existing poroma. No morphological features of transition between the two tumors were seen. Neoplastic cells of MCC expressed immunoreactivity for chromogranin, synaptophysin, neuron-specific enolase, CAM 5.2 and cytokeratin 20, the last two markers showing the characteristic paranuclear dot-like pattern. In contrast, the poroma cells only expressed cytokeratin MNF116. Metastatic deposits were not identified in the regional lymph nodes or distantly. Keywords: adnexal tumors, dermatopathology, Merkel cell, Merkel cell carcinoma, poroma, Molina-Ruiz AM, Bernárdez C, Requena L, Rütten A. Merkel cell carcinoma arising within a poroma: report of two cases. J Cutan Pathol 2015; 42: 353–360. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Primary neuroendocrine carcinoma of the skin, commonly known as Merkel cell carcinoma (MCC), is a rare but highly aggressive skin cancer. It usually presents as a dermal nodule affecting mainly sun-exposed skin of elderly white individuals.1 The histogenesis of MCC is debatable.2 Most authors consider that MCC results from a neoplastic proliferation of Merkel cells, although conclusive proof of this concept is lacking. Other authors have suggested an origin from a primitive pluripotent stem cell that
Ana M. Molina-Ruiz1 , Claudia Bernárdez1 , Luis Requena1 and Arno Rütten2 1
Department of Dermatology, Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain and 2 Dermatopathologisches Gemeinschaftslabor, Friedrichshafen, Germany
Ana M. Molina-Ruiz, MD, Department of Dermatology, Fundación Jiménez Díaz, Avd. Reyes Católicos 2, 28040-Madrid, Spain Tel: +34 91 5447039 Fax: +34 91 5442636 e-mail: [email protected] Accepted for publication February 15, 2015
has the potential to differentiate along divergent phenotypes.3 Several reports have described the association of MCC of the skin with other cutaneous neoplasms, including Bowen’s disease,4,5 actinic keratosis,6 squamous cell carcinoma (SCC),7 – 11 lentigo maligna,12 benign follicular tumors,13 follicular cysts,14 – 18 trichoblastoma19 and sebaceous carcinoma.20 The most frequent association is with SCC, both in situ and invasive. However, both MCC and SCC share a common
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Molina-Ruiz et al.
Fig. 1. Case 1. A) Scanning magnification showing a tumoral lesion in the dermis with no connection to the epidermis. B) Higher magnification with arrows pointing to a second cell population within the main tumor. C) Higher magnification showing that the tumor is composed of cords and broad columns of uniform poroid cells. D) Detail of the poroid cells. E) Still higher magnification showing a biphasic tumor composed of uniform poroid cells intertwined with small round basophilic cells. F) Detail of the small round basophilic cells showing high nuclear–cytoplasmic ratio, inconspicuous cytoplasm and vesicular nuclei with smudged or clear granular chromatin.
etiopathogenesis, and, therefore, these lesions have been better regarded as ‘composite’ or ‘collision’ tumors. Finally, the association of MCC with tumors of the adnexal glandular lineage has never been reported. We describe two cases of MCC arising within a cutaneous poroma and discuss if this association is just the result of a fortuitous collision between both tumors, or the MCC could have originated
354
from the Merkel cells normally present within the epithelium of the hair follicle. Reports of patients Patient 1 A 56-year-old Caucasian male patient presented with a 1.1 cm, asymptomatic, subcutaneous nodule on the left-upper arm. This lesion had grown
Merkel cell carcinoma arising within a poroma
Fig. 2. Case 2. A) Scanning magnification showing a tumor with no connection with the overlying epidermis. B) Note small aggregations of basophilic cells nests in the upper part of the poroid aggregations. C) Detail of the two neoplasms which are tightly admixed. D) Higher magnification of the small basophilic cells showing the characteristic nuclear and cytoplasmic features of the neoplastic cells of Merkel cell carcinoma.
slowly over the past 4 years. There was no history of previous biopsy at this site nor was there any evidence of internal malignancy. The remainder of the patient’s dermatologic history was unremarkable. The clinical diagnosis was ‘lipoma’, and the lesion was excised. After the initial histopathologic diagnosis of MCC arising within a poroma, the tumor was re-excised with a safe margin but only scar tissue was found in the re-excised specimen. Eight months later, there was no evidence of local recurrence or metastatic disease. Patient 2 An 81-year-old woman was sent for dermatological advice for a 0.9-cm tumor located on the lower back. The lesion had rapidly grown over the 6 months preceding the consultation but was otherwise asymptomatic. Under the clinical diagnosis of ‘inflamed follicular cyst’ the lesion was excised. After the initial histopathologic diagnosis of MCC arising within a poroma, the tumor was re-excised with 1.5-cm healthy margins, and only scar tissue was found. Clinical examination and imaging staging were otherwise negative.
After 4 years, there was no evidence of recurrence or metastasis. Histopathologic findings The two cases showed similar histopathologic findings. At scanning magnification, a dermal tumor with no connection with the overlying epidermis was observed (Figs. 1 and 2). The tumor was mainly composed of cords and broad columns of uniform poroid cells, but with higher magnification two distinct and tightly admixed cell populations were noted. The first consisted of small, uniformly cuboidal cells containing ovoid nuclei, scant eosinophilic cytoplasm and intercellular bridges, findings that were consistent with those of poroma. Ductal structures containing periodic acid-Schiff-positive (PAS) cuticles were observed within the tumor. No signs of sebaceous or apocrine differentiation were evident. The most striking feature in both cases was the presence of a second cell population consisting of solid aggregations of small round hyperchromatic basophilic cells that formed multiple small islands within the first cell population. These cells showed a high
355
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Fig. 3. Case 1. A) Immunostaining for cytokeratin 20. B) Higher magnification showing the characteristic dot-like pattern of staining in the neoplastic cells of the tumor. C) Immunostaining for CAM 5.2 showing a similar staining pattern to that of cytokeratin 20. D) Higher magnification showing CAM 5.2 immunoexpression only within the Merkel cell carcinoma component of the tumor. E) Positive immunostaining of the Merkel cell carcinoma (MCC) cells for chromogranin. F) Positive immunostaining of the MCC cells for synaptophysin.
nuclear-cytoplasmic ratio, scant cytoplasm, vesicular nuclei with smudged or clear granular chromatin and usually a single, centrally located small nucleolus (Figs. 1D and 2D). Numerous mitotic figures, single necrotic cells and small areas of necrosis en masse were present. These features were evocative of MCC arising in tight association with a poroma. In some areas, hyperplasia and pagetoid spreading of neoplastic cells of MCC were also seen within some of the epithelial strands. Finally, while in Case 1 MCC was strictly confined to the epithelial part of the
356
poroma (MCC ‘in situ’), focal infiltration of the tumor stroma could not be completely excluded in Case 2. Immunohistochemical findings Immunohistochemistry showed that neoplastic small round basophilic cells expressed immunoreactivity for cytokeratin 20 (clone Ks 20.8, dilution 1 : 40; Dako, Glostrup, Denmark), pankeratin cocktail AE1/AE3 (dilution 1 : 500; Dako), CAM 5.2 (dilution 1 : 60; Becton
Merkel cell carcinoma arising within a poroma
Fig. 4. Case 1. A) Immunostaining for Ber-EP4. B) Higher magnification showing a positive staining of the neoplastic-small round cells, whereas the poroid cells resulted mostly negative. C) Immunostaining for Ki-67. D) Higher magnification showing a high proliferative index with immunoreactivity mainly within the Merkel cell carcinoma component of the tumor.
Dickinson, San Jose, CA, USA), synaptophysin (clone Sy38, dilution 1 : 10; Dako), chromogranin (clone DAKA3, dilution 1 : 2; Dako), neuron-specific enolase (clone BBS-NC-V, dilution 1 : 500; Dako), BerEP4 (clone Ber-EP4; dilution 1 : 200; Dako) and Ki-67 (clone MIB-1; dilution 1 : 500; Dako) (Figs. 3–5). The immunostaining of neoplastic cells for CAM 5.2 and cytokeratin 20 showed a characteristic dot-like pattern in neoplastic cells of both cases (Fig. 3). The poroid cells were only positive for cytokeratin MNF116 (dilution 1 : 50; Dako) and negative for all the other markers. Discussion We report two cases of MCC arising within a poroma. In both cases, the MCC and poroma cells were tightly admixed, albeit distinct, and no features of transition between the two tumors were evident. The presence of MCC arising within a poroma is an exceptional event and a thorough review of the current literature did not reveal any example of this peculiar association nor of the coexistence of MCC with other sweat gland neoplasms.
Poromas are benign cutaneous adnexal tumors composed microscopically of a variable admixture of poroid and cuticular cells arranged in lobules. Histopathologically, four main variants of poromas are recognized and distinguished according to their location in relation to the epidermis and the size of the neoplastic aggregates: (i) hidroacanthoma simplex, also known as intraepidermal poroma, composed of round nests of neoplastic cells confined within the epidermis; (ii) classic poroma, composed of lobules of neoplastic cell involving both epidermis and dermis; (iii) dermal duct tumor, characterized by small aggregates of neoplastic cells limited to the dermis, with no or few epidermal connection and (iv) poroid hidradenoma, characterized by single or few large solid neoplastic aggregates involving the dermis with cystic areas inside. We believe the two cases described here fit best within the spectrum of poroid hidradenoma. Also, based on histochemistry and electron microscopy, poromas have classically been thought to derive from the peripheral cells of the intraepithelial portion of the eccrine duct (the acrosyringium).21 These ducts embryologically
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Fig. 5. Case 2. A) Immunostaining for cytokeratin MNF116. Scanning power showing immunoreactivity of the epidermis, the adnexa and the poroid cells. B) Higher magnification showing the strong MNF116 immunoreactivity of the poroid cells while the neoplastic small round cells resulted mostly negative, with some background staining. C) Immunostaining for CAM 5.2. Scanning power showing immunoreactivity of the solid aggregations of Merkel cell carcinoma. D) Higher magnification showing the CAM 5.2 immunoexpression of the neoplastic cells of Merkel cell carcinoma and the negative results of the poroid cells composing the rest of the tumor. E) Immunostaining for cytokeratin 20. Scanning power showing positivity within the second cell component of the tumor. F) Higher magnification showing immunoreactivity of the Merkel cell carcinoma nests and the absence of immunoexpression within the poroid cells.
arise from ectodermal surface buds22 and are microscopically indistinguishable from apocrine ducts, which embryologically derive from the folliculo-sebaceous-apocrine unit. However, several well-illustrated reported cases have showed the existence of poromas with focal sebaceous, follicular and apocrine differentiation,23 – 25 suggesting apocrine lineage for some poromas.
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On the other hand, the origin of MCC is not well established. Ultrastructural findings have suggested a possible origin from Merkel cells of the skin1 because these are the only neuroendocrine cells known to be present in the epidermis. In addition, MCC share the same immunohistochemical profile with normal Merkel cells (positivity for cytokeratin 20, neuron-specific
Merkel cell carcinoma arising within a poroma enolase and chromogranin). However, the presence of squamous as well as glandular differentiation in MCC prompted investigators to suggest an epithelial origin of MCC from a primitive pluripotent stem cell located in either the epidermis or the adnexal epithelium that can differentiate along divergent phenotypes.2,11 Merkel cells are normal components of the basal layer of the epidermis, and recent studies have showed the presence of Merkel cells also in fetal and adult hair follicles, where they are grouped in two clusters: one in the deep infundibulum and the other one in the isthmus.26 Also, a relatively high concentration of Merkel cells was found at the level of the bulge. It has been proposed that because Merkel cells are numerous at the infundibulum and the isthmus, it is probable that MCC arising within follicular-derived neoplasms results from neoplastic proliferations of the normal Merkel cell constituents of the hair follicle. In fact, numerous Merkel cells have been found scattered within various neoplasms with follicular differentiation, including desmoplastic trichoepithelioma,27 trichoblastoma,28 follicular proliferation in nevus sebaceous,29 trichofolliculoma30 and fibroepithelioma of Pinkus.31 In these cases, Merkel cells were not neoplastic in contrast to the cases of MCC arising within follicular-derived neoplasms and our cases, where they were clearly malignant by virtue of numerous mitoses, pleomorphism and nuclear hyperchromasia. Finally, the presence of Merkel cells has not been described in sweat gland neoplasms. The architecture of the lesions reported here could represent just a fortuitous association of two different, unrelated neoplasms (MCC and poroma); however, the fact that the
two neoplasms were tightly admixed together and there was no extension of MCC outside the poroma (this last feature could not be completely excluded in Case 2), seem too coincidental to just be the result of a fortuitous association. A second proposed explanation is that these two cases represent poromas that originated in the apocrine ducts. Therefore, the origin of the associated MCCs arising within these ‘apocrine poromas’ could be the neoplastic proliferation of the normal Merkel cell constituents of the hair follicle. Supporting this last hypothesis is the fact that these two poromas did not show the palmoplantar location of the so-called eccrine poromas. Moreover, although the MCC cells were mostly arranged in nests, there were also single-atypical cells scattered throughout the epithelial strands of the poroma component of the tumor, strengthening the hypothesis that MCC may have arised from the Merkel cells present in the follicle. However, the fact that we could not find any morphological signs of apocrine, sebaceous or follicular differentiation within the poroma component of our tumors argues against this hypothesis. A final explanation would be that in our cases the MCC originated in primitive pluripotent stem cells located in the adnexal epithelium that can differentiate along divergent phenotypes. However, data to support this theory are lacking, and this relationship still remains speculative. In conclusion, our cases are unique in that they contained MCC arising within poromas, which may be regarded (at least Case 1) as in situ MCC arising within poromas, and for this reason have a relatively good prognosis. Because no similar cases have been reported in the literature to date, the real significance of this extraordinary association remains to be clarified.
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