International Journal of Surgical Pathology http://ijs.sagepub.com/
Primary Carcinoid Tumor of the Skin: A Literature Review Jaroslaw Jedrych and Melissa Pulitzer INT J SURG PATHOL published online 7 January 2014 DOI: 10.1177/1066896913516672 The online version of this article can be found at: http://ijs.sagepub.com/content/early/2014/01/06/1066896913516672 A more recent version of this article was published on - Mar 24, 2014
Published by: http://www.sagepublications.com
Additional services and information for International Journal of Surgical Pathology can be found at: Email Alerts: http://ijs.sagepub.com/cgi/alerts Subscriptions: http://ijs.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav
Version of Record - Mar 24, 2014 >> OnlineFirst Version of Record - Jan 7, 2014 What is This?
Downloaded from ijs.sagepub.com at UNIV OF WINNIPEG on September 10, 2014
516672
research-article2014
IJSXXX10.1177/1066896913516672International Journal of Surgical PathologyJedrych and Pulitzer
Original Article
Primary Carcinoid Tumor of the Skin: A Literature Review
International Journal of Surgical Pathology 1–7 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1066896913516672 ijs.sagepub.com
Jaroslaw Jedrych, MD1 and Melissa Pulitzer, MD2
Abstract Primary carcinoid tumor of the skin (PCTS) is an uncommon indolent neoplasm, with 10 cases described in the literature. The tumors affect patients in the sixth to ninth decades of life (mean = 66.3 years) with an equal gender distribution and predilection for the head and trunk. They present as slowly enlarging nodules of variable duration, ranging from 1 to 60 years (mean = 11.4 years). PCTS is characterized by architectural, cytomorphologic, ultrastructural, and immunohistochemical features typical of a low-grade neoplasm with neuroendocrine differentiation. PCTS typically follows a benign clinical course and therefore has to be distinguished from cutaneous metastases of visceral carcinoid tumors, which herald dissemination of malignancy and poor prognosis. While the distinction from other histologically similar entities can be achieved by histopathological examination, PCTS can be distinguished from a visceral metastasis only by a judicious clinicopathologic correlation. Herein we describe the clinical presentation, histological appearance, and management of these tumors. Keywords skin carcinoid tumor, skin tumor, neuroendocrine tumor
Introduction
Results
Carcinoid tumors (well-differentiated neuroendocrine tumors) are uncommon neoplasms with diverse biology and clinical behavior. Their overall incidence approximates 5.25/100 000.1 Tumors are composed of epithelial cells with neuroendocrine differentiation and can be found in most anatomic locations,2 with the gastrointestinal (73.7% of cases in one large study) and bronchopulmonary (25.1%) systems being most frequently affected.3 Other primary sites are uncommon. Only 10 such tumors have been reported to arise in the skin.4-13 The differential diagnosis of a cutaneous tumor with a low-grade neuroendocrine morphology identified in the skin may be challenging. From the clinicopathologic standpoint, the major diagnostic dilemma in such cases is the distinction of a primary skin neoplasm from a metastasis of visceral malignancy. Herein we review previously described reports of primary carcinoid tumor of the skin (PCTS) and summarize the clinical presentation, histological appearance, and management of these tumors.
Clinical Features
Materials and Methods
The clinical features of patients with PCTS are summarized in Table 1. Patients’ ages ranged from 40 to 87 years (mean = 66.3 years), with a close to 1:1 male-to-female ratio. The tumors presented as single, firm, fixed to the skin, flesh-colored, nonulcerated cutaneous nodules, usually dome-shaped or protruding above the skin surface. Tumors had grown over 1 to 60 years (mean = 11.4 years) prior to excision and ranged in size from 1 to 9.5 cm (mean = 3.2 cm). Four cases involved the scalp and 6 the trunk. Most lesions were asymptomatic; however, some patients reported an episode of bleeding4 or tumor-associated tenderness and pruritus.5,11 Clinically, the lesions were felt to represent primary skin growths including pilar cyst,4 neurofibroma,7 and sebaceous cyst.10 Although one patient reported facial flushing, which subsided after tumor removal,4 the exact etiology of these symptoms was not clear. Otherwise, the patients had no symptoms suggestive of carcinoid syndrome. On diagnosis and 1
University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Memorial Sloan-Kettering Cancer Center, New York, NY, USA
2
Cases were identified in the English literature using PubMed search engine. The search resulted in the identification of 10 single PCTS case descriptions reported between 1975 and 2013.
Corresponding Author: Jaroslaw Jedrych, UPP Dermatopathology, Presbyterian South Tower, 200 Lothrop Street, Suite 3725, Pittsburgh, PA 15213, USA. Email: [email protected]
Downloaded from ijs.sagepub.com at UNIV OF WINNIPEG on September 10, 2014
2
International Journal of Surgical Pathology
Table 1. Primary Carcinoid Tumor of the Skin: Main Clinical and Follow-Up Summary.
Reference Van Dijk and ten Seldam4 Smith and Chappell5 Collina et al6 Bart et al7 Sakamoto et al8 Courville et al9 MacKenzie et al10 Cokonis et al11 Eloy-Garcia Carrasco et al12 Kropinak et al13
Age (years) and Gender 72, female 62, female 80, male 40, male 87, female 60, male 70, female 64, male 58, female 70, female
Location
Tumor Size (cm) and Duration (years)
Clinical Diagnosis
Treatment
Scalp Anterior chest Scalp Epigastrium Anterior chest Anterior chest Scalp Middle back Scalp Eyelid
3/10 1.5/10 4/1 1/4 9.5/60 NC/NC 3/NC 2/2 4/1 1/3
Pilar cyst NC NC Neurofibroma NC NC Sebaceous cyst NC NC NC
Excision Excision Excision Excision Excision Excision Excision Excision Excision Excision
Follow-Up (years) Recurrence 3.5 0.9 1.75 1.9 NC 4 6 1 1 0.67
No No No No No No Yesa No No No
Abbreviation: NC, not communicated. a Regional lymph node metastasis was present at the time of the initial diagnosis, and 4 and 6 years thereafter.
follow-up, none of the patients have been found to have any evidence of internal malignancy by extensive clinical, imaging, endoscopic, and biochemical evaluation.
Treatment and Clinical Course All patients underwent surgical excision of the tumor. Follow-up was documented for 9 patients, ranging from 0.67 to 6 years (mean = 2.4 years). In one case the skin neoplasm was associated with concurrent regional lymph node metastasis.10 In addition, this patient experienced tumor relapse in regional lymph nodes 4 and 6 years after the initial diagnosis. However, no distal metastasis was documented. All other patients remained free of disease and with no clinical evidence of loco-regional or distant recurrence.
Histopathological Features Gross inspection of the excision specimens demonstrated well-delineated dermal masses with homogenous orange to gray-yellow cut surfaces that became brown after formalin fixation.4,5 The morphological features of the PCTS are summarized in Table 2. Tumors were characterized by a single well-demarcated, nonencapsulated, nodular proliferation occupying the dermis and extending into the subcutaneous fat in most cases. None of the neoplasms showed any connection to the overlying intact epidermis or adnexal structures. Neoplastic aggregates exhibited a lobular organoid neuroendocrine growth pattern with variably sized and shaped nests, cords, and islands of tumor cells, some with vague cellular palisading at the edges.4 One case displayed peculiar long and narrowly branching thin trabecular architecture.6 Most cases showed areas of pseudoglandular formation. Tumor stroma was described as fibrovascular, and cellular in one case,6 separating
epithelial aggregates with thin septa. In 3 cases, the stroma contained significant amounts of mucin.8,12,13 In one of these cases, nests of neoplastic epithelium floated in an abundantly mucinous matrix, imparting a mucinous carcinoma-like histological appearance.8 Cytologically, the tumor cells were fairly uniform, polygonal, or cuboidal to columnar, with round to oval regular nuclei, eosinophilic and finely granular cytoplasm, and indistinct borders. Cell polarization was occasionally seen in tumor epithelium forming pseudoglandular structures. Nuclei demonstrated variably dispersed chromatin with small nucleoli in some cases and an overall neuroendocrine appearance. Mitotic figures were variably present with a reported range from none4 through occasional5,7-9,12 to numerous,6,13 but not specifically quantified in the majority of cases. No intravascular or perineural invasion or cellular atypia or necrosis was present.
Histochemical and Immunohistochemical Features In all cases, the morphologic impression of neuroendocrine differentiation was supported by the results of ancillary studies. A neuroendocrine phenotype was evidenced by histochemical techniques, including argentaffin (Fontana-Masson) and argyrophilic (Grimelius) stains, and immunohistochemistry, revealing expression of chromogranin A and synaptophysin by the tumor cells. Each tumor displayed expression of one or more neuroendocrine markers. In cases where electron microscopy studies were performed,5,7-9 the presence of dense membrane-bound secretory granules was revealed at the ultrastructural level. Most tumors showed expression of carcinoembryonic antigen and cytokeratins, including AE1/AE3, MNF, Cam5.2, high molecular weight cytokeratins, and cytokeratin 7. Cytokeratin 20 and thyroid
Downloaded from ijs.sagepub.com at UNIV OF WINNIPEG on September 10, 2014
3
Downloaded from ijs.sagepub.com at UNIV OF WINNIPEG on September 10, 2014
Tumor Location
Architectural Pattern
+ − − −
+ + − −
+
−
+
+
−
−
+
−
+
−
−
Mucinous Stroma
+
PseudoGlands
+/ND/+/−
ND/ND/+/+
ND/ND/+/+
ND/ND/+/+
+/+/+/ND
−/+/+/ND
+/+/+/ND
−/+/+/ND
+/+/ND/ND
+/ND/ND/ND
Argentaffin (Fontana-Masson), Argyrophilic (Grimelius), Chromogranin A, and Synaptophysin Stains
+(AE1/AE3), −(CK7 and CK20)/ ND/−(ER, PR, GCDFP-15, and TTF1)
+(MNF, Cam5.2 and CK7), −(AE1/ AE3 and CK20)/+/−(TTF-1) +(CK7), −(CK20)/+/−(TTF-1)
+/+
+/ND
ND/+
+/ND
+(HMW)/ND
ND/ND
ND/ND
Cytokeratin, CEA, and Other Stains
ND
ND
ND
ND
+
+
+
ND
+
ND
Electron Microscopya
Abbreviations: ND, not done; CEA, carcinoembryonic antigen; HMW, high molecular weight; CK, cytokeratin; TTF-1, thyroid transcription factor; ER, estrogen receptor; PR, progesterone receptor; GCDFP, gross cystic disease protein. a Electron microscopy demonstrating the presence of membrane-bound, dense-core cytoplasmic secretory granules.
Eloy-Garcia Dermis and superficial Nests and ribbons Carrasco et al12 subcutis Kropinak et al13 Dermis Nests and trabecules
Van Dijk and ten Dermis and superficial Solid masses and Seldam4 subcutis cords Smith and Dermis and superficial Sheets, cords and Chappell5 subcutis trabecules Collina et al6 Dermis Long, narrow branching trabecules Dermis and superficial Nest and cords Bart et al7 subcutis Sakamoto et al8 Dermis and superficial Solid cribriform subcutis lobules and cords Courville et al9 Dermis Lobules, cord and island MacKenzie et al10 Dermis and superficial Nests and cords subcutis Cokonis et al11 Dermis Nests and cords
Reference
Table 2. Primary Carcinoid Tumor of the Skin: Main Pathologic Features Summary.
4
International Journal of Surgical Pathology
transcription factor 1 were negative in 3 of 3 tumors stained for these markers.11-13 One case was tested for the expression of estrogen and progesterone receptors, and gross cystic disease fluid protein 15, with negative results.13
Discussion PCTS is an exceedingly rare cutaneous neoplasm of unknown etiology. Since the first description by Van Dijk and ten Seldam in 1975,4 only 9 additional cases have been reported.5-13 The tumors occur on the head and trunk of middle-aged or elderly patients without an overt gender predilection. No association with sun-exposure, immunosuppression, genodermatoses, or other predisposing factors has been documented. Typically, they present as asymptomatic dermal nodules with a nonspecific appearance; therefore, other more common cutaneous conditions are clinically favored. Overall, PCTS are benign neoplasms and surgical excision is curative. Although one tumor was associated with regional lymph node involvement and recurred locally after prolonged periods of dormancy, no distant metastasis or tumor-related mortality was documented in any of the cases. This is an important feature distinguishing PCTS from visceral carcinoid tumors, which disseminate systematically and frequently follow a malignant clinical course with an average 5-year survival rate close to 50% regardless of primary site.2 PCTS are characterized by distinctive architectural and cytologic features. Tumors demonstrated a prototypical organoid pattern of growth with a well-demarcated outline, lack of significant cellular atypia, fibrous to mucinous stroma, and nuclear and cytoplasmic features typical for a low-grade neuroendocrine neoplasm. If seen in combination, these morphological features are highly suggestive of PCTS. The definitive evidence of neuroendocrine differentiation may be provided by the results of ancillary studies demonstrating expression of general neuroendocrine markers by tumor cells. However, due to their rarity in the skin and the lack of exposure to such tumors in pathology training, the correct diagnosis may prove to be challenging. As mentioned above, due to diametrically different biologic behavior and clinical management of skin and visceral carcinoid tumors, every attempt should be made to distinguish PCTS from a metastatic deposit. In addition, some primary skin tumors, including Merkel cell carcinoma, sebaceous neoplasms and melanoma with carcinoid-like architecture, endocrine mucin producing sweat gland carcinoma, and primary skin tumors with neuroendocrine differentiation, may enter into the histologic differential of PCTS. Visceral carcinoid tumors metastasize with a rate close to 30%, and the most frequent sites of tumor dissemination
include the lymph nodes, liver, and peritoneum.2 The skin is uncommonly affected by metastases of these neoplasms.14-19 Cutaneous involvement is typically multifocal and follows the diagnosis of internal malignancy.9 However, in some cases, a cutaneous metastasis was the initial presentation leading to the detection of an underlying visceral carcinoid tumor.20-23 As the discovery of a skin metastasis often indicates widespread neoplasm dissemination, the correct characterization of a tumor as metastatic has an important bearing on a patient’s prognosis.24 Each PCTS in this series was found to be indistinguishable from a metastatic tumor on morphological and immunohistochemical grounds (Figure 1). The diagnosis of a primary lesion was made only after extensive clinical evaluation excluded a primary tumor elsewhere in the body. However, only some of these cases had documented an adequately long period of time prior to the tumor diagnosis (>3 years)4,5,7,8 and/or lengthy follow-up time after the tumor diagnosis (>2 years).4,9,10 As cases of carcinoid tumors initially presenting with metastasis, preceding by years the detection of a visceral primary, have been described,25 one should remain cautious with the diagnosis of PCTS. For the aforementioned reasons and the fact that cutaneous metastases of carcinoid tumors are more frequent than PCTS, any proliferation with a well-differentiated neuroendocrine morphology discovered in the skin should be initially considered to represent a metastasis, even in a patient with no history of internal malignancy. In the absence of a known primary, an extensive evaluation for a visceral neoplasm is necessary. If inconclusive, it is still possible that an occult primary tumor is undetectable by means of available diagnostic modalities and will declare itself on prolonged follow-up. The most frequent primary cutaneous tumor of concern in the differential diagnosis of PCTS is Merkel cell carcinoma (MCC), also referred to as primary neuroendocrine carcinoma of the skin. In some cases, MCC may show relatively good demarcation, an organoid growth pattern, and formation of trabecules and pseudoglands.26 However, a diffuse nodular or infiltrative involvement of the cutaneous and subcutaneous tissue is more commonly encountered in this tumor. Features of aggressive neoplasia, including rapid growth, ulceration, significantly increased nuclear to cytoplasmic ratio, brisk mitotic and apoptotic activity, nuclear molding, and necrosis should aid in the distinction of MCC from PCTS.12 A paranuclear punctate pattern of cytokeratin 20 expression and positivity for neurofilament protein in most MCC cases may further aid in establishing the diagnosis.26 Sebaceous neoplasms with a carcinoid-like pattern of growth may closely mimic PCTS.27 These tumors predominately occur on the scalp of middle-age to elderly patients and present as solitary non-ulcerated nodules measuring 1 to 3 cm. Morphologically, they feature multilobular
Downloaded from ijs.sagepub.com at UNIV OF WINNIPEG on September 10, 2014
5
Jedrych and Pulitzer
Figure 1. Two examples (A-C and D-F) of cutaneous metastases of visceral carcinoid tumors. These tumors are pathologically indistinguishable from primary carcinoid tumor of the skin: (A) Low-power view demonstrates a lobulated and well-demarcated tumor involving the deep dermis and superficial subcutis of the scalp. A previous biopsy site is present on top of this resection (hematoxylin–eosin [H&E], 40×). (B) Higher magnification shows solid and trabecular architecture of the neoplastic epithelium, fibrosclerotic stroma, and prominent pools of extravasated erythrocytes (H&E, 100×). (C) High magnification demonstrates lowgrade neuroendocrine cytomorphologic features including regular round to oval nuclei with evenly distributed chromatin and eosinophilic cytoplasm (H&E, 200×). (D) This metastatic deposit predominantly occupies the subcutaneous fat and shows areas of cystic change (H&E, 40×). (E) On higher power, small tumor nests and narrow trabecules embedded in fibrohyaline stroma are seen (H&E, 100×). (F) High magnification demonstrates low-grade neuroendocrine morphology (H&E, 200×).
Downloaded from ijs.sagepub.com at UNIV OF WINNIPEG on September 10, 2014
6
International Journal of Surgical Pathology
architecture with trabecular and ribbon-like patterns and occasional rosette formation. The areas of sebaceous differentiation are present at least focally, allowing for the correct morphologic diagnosis. Tumors are immunohistochemically negative for neuroendocrine markers including chromogranin A, synaptophysin, or serotonin. These features are not seen in PCTS. A distinct organoid carcinoid-like pattern of growth with formation of ribbons, trabeculae, islands, and rosettes can rarely be encountered in melanoma.28 Such tumors may demonstrate relatively bland cytology with mild to moderate pleomorphism and inconspicuous mitotic activity, further mimicking an indolent entity. Nevertheless, the pattern of antigen expression is typical for melanoma: S-100, HMB-45, Melan-A, and tyrosinase positive, while chromogranin A, synaptophysin, and serotonin negative. The presence of cytoplasmic melanin, intranuclear pseudoinclusions, marked nuclear pleomorphism, areas of necrosis, and areas of conventional-appearing melanoma or residual nevus may serve as a clue to the correct diagnosis. Endocrine mucin producing sweat gland carcinoma (EMCSGC) is a rare indolent cutaneous neoplasm composed of bland cells with neuroendocrine nuclear and cytoplasmic features forming nodules and cribriform arrangements embedded in variably mucinous stroma. Tumors express neuroendocrine markers.29 These features are shared by PCTS as the presence of matrical mucin deposition has been described in few such tumors. Despite significant morphologic overlap, both tumors most likely represent separate entities. EMPSCG typically affects elderly women and presents in the eyelid or periorbital skin. The distinctive pathologic features include expression of estrogen and progesterone receptors and the presence of a myoepithelial cell layer surrounding tumor nests evidenced by calponin, p63, and smooth muscle actin immunostains. EMPSGC is commonly associated with invasive mucinous carcinoma and may be a precursor thereof. Lastly, divergent neuroendocrine differentiation has been infrequently reported in various other primary cutaneous neoplasms such as basal cell carcinoma and sweat gland apocrine and eccrine carcinomas.30,31 However, neuroendocrine features are typically present only focally in these neoplasms, which otherwise show conventional morphology,32 allowing distinction from PCTS. In conclusion, PCTS is a rare tumor that should be included in the differential diagnosis of low-grade cutaneous neuroendocrine proliferations. It is distinguished from other entities by morphologic and immunohistochemical features. From a practical standpoint, cutaneous tumors with a low-grade neuroendocrine morphology have to be approached as metastases until an extensive clinical evaluation excludes internal malignancy. The definitive diagnosis of a skin primary may require prolonged follow-up as a cutaneous metastasis may be the
first manifestation preceding the discovery of a visceral carcinoid tumor by months to years. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. Yao JC, Hassan M, Phan A, et al. One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008;26:3063-3072. 2. Klimstra DS, Modlin IR, Coppola D, Lloyd RV, Suster S. The pathologic classification of neuroendocrine tumors: a review of nomenclature, grading, and staging systems. Pancreas. 2010;39:707-712. 3. Modlin IM, Sandor A. An analysis of 8305 cases of carcinoid tumors. Cancer. 1997;79:813-829. 4. Van Dijk C, ten Seldam RE. A possible primary cutaneous carcinoid. Cancer. 1975;36:1016-1020. 5. Smith PA, Chappell RH. Another possible primary carcinoid tumour of skin? Virchows Arch A Pathol Anat Histopathol. 1985;408:99-103. 6. Collina G, Quarto F, Eusebi V. Trabecular carcinoid of the skin with cellular stroma. Am J Dermatopathol. 1988;10:430435. 7. Bart RS, Kamino H, Waisman J, Lindner A, Colen S. Carcinoid tumor of skin: report of a possible primary case. J Am Acad Dermatol. 1990;22:366-370. 8. Sakamoto F, Ito M, Matumura G, Sato Y, Kimura S. Ultrastructural study of a mucinous carcinoid of the skin. J Cutan Pathol. 1991;18:128-133. 9. Courville P, Joly P, Thomine E, et al. Primary cutaneous carcinoid tumour. Histopathology. 2000;36:566-567. 10. MacKenzie DN, McCormick CSF, Morris RJ. Lymph node metastasis from a primary skin carcinoid tumour. Br J Plast Surg. 2003;56:718-721. 11. Cokonis CD, Green JJ, Manders SM. Primary car cinoid tumor of the skin. J Am Acad Dermatol. 2004;51:S146-S148. 12. Eloy-Garcia Carrasco C, Benguigui Benadiva J, Martinez Garcia S, Sanz Trelles A, Palacios S. Atypical primary carcinoid tumour of the skin. J Cutan Pathol. 2006;33(suppl 2):32-34. 13. Kropinak M, Sims L, Iacob C, McCormick SA, Milman T. Primary typical carcinoid tumor of the eyelid. Ophthal Plast Reconstr Surg. 2009;25:318-320. 14. Puri PK, Galan A, Glusac EJ, Cowper SE. Metastatic cutaneous carcinoid tumor mimicking an adnexal poroid neoplasm. J Cutan Pathol. 2008;35:54-57. 15. Blochin E, Stein JA, Wang NS. Atypical carcinoid metastasis to the skin. Am J Dermatopathol. 2010;32:735-739.
Downloaded from ijs.sagepub.com at UNIV OF WINNIPEG on September 10, 2014
7
Jedrych and Pulitzer 16. Archer CB, Wells RS, MacDonald DM. Metastatic cutaneous carcinoid. J Am Acad Dermatol. 1985;13:363-366. 17. Steele CW. Malignant carcinoid. Metastasis to skin and production of carcinoid syndrome, hypertension, diarrhea, dementia, and hypopotassemia: a case report. Arch Intern Med. 1962;110:763-768. 18. Rudner EJ, Lentz C, Brown J. Bronchial carcinoid tumor with skin metastases. Arch Dermatol. 1965;92:73-75. 19. Bean SF, Fusaro RM. An unusual manifestation of the carcinoid syndrome. Report of a case. Arch Dermatol. 1968;98:268-269. 20. Brody HJ, Stallings WP, Fine RM, Someren A. Carcinoid in an umbilical nodule. Arch Dermatol. 1978;114:570-572. 21. Rodriguez G, Villamizar R. Carcinoid tumor with skin metastasis. Am J Dermatopathol. 1992;14:263-269. 22. Ereno C, Lopez JI, Sanchez JM. Atypical carcinoid of larynx: presentation with scalp metastases. J Laryngol Otol. 1997;111:89-91. 23. Santi R, Massi D, Mazzoni F, Antonuzzo L, Comin CE. Skin metastasis from typical carcinoid tumor of the lung. J Cutan Pathol. 2008;35:418-422. 24. Schoenlaub P, Sarraux A, Grosshans E, Heid E, Cribier B. Survival after cutaneous metastasis: a study of 200 cases. Ann Dermatol Venereol. 2001;128:1310-1315. 25. Naschitz JE, Yeshurun D, Nash E, Lev L, Shajrawi I, Boss JH. Cervical soft tissue metastasis of typical carcinoid
tumor preceding diagnosis of ileal primary by 4 years. Am J Gastroenterol. 1992;87:1665-1668. 26. Pulitzer MP, Amin BD, Busam KJ. Merkel cell carcinoma: review. Adv Anat Pathol. 2009;16:135-144. 27. Kazakov DV, Kutzner H, Rutten A, Mukensnabl P, Michal M. Carcinoid-like pattern in sebaceous neoplasms: another distinctive, previously unrecognized pattern in extraocular sebaceous carcinoma and sebaceoma. Am J Dermatopathol. 2005;27:195-203. 28. Kacerovska D, Michal M, Sosna B, et al. Carcinoid-like pattern in melanoma: report of 4 cases. Am J Dermatopathol. 2009;31:542-550. 29. Zembowicz A, Garcia CF, Tannous ZS, Mihm MC, Koerner F, Pilch BZ. Endocrine mucin-producing sweat gland carcinoma: twelve new cases suggest that it is a precursor of some invasive mucinous carcinomas. Am J Surg Pathol. 2005;29:1330-1339. 30. Eusebi V, Mambelli V, Tison V, De Lellis R, Betts CM. Endocrine differentiation in basal cell carcinoma. Tumori. 1979;65:191-199. 31. Foschini MP, Eusebi V. Divergent differentiation in endocrine and nonendocrine tumors of the skin. Semin Diagn Pathol. 2000;17:162-168. 32. Krokowski M, Hoch J, Feller AC, Bernd HW, Thorns C, Krueger S. Basal cell carcinoma with neuroendocrine differentiation arising in a scar: a case report. Dermatol Online J. 2009;15(10):4.
Downloaded from ijs.sagepub.com at UNIV OF WINNIPEG on September 10, 2014
Primary Carcinoid Tumor of the Skin: A Literature Review Jaroslaw Jedrych and Melissa Pulitzer INT J SURG PATHOL published online 7 January 2014 DOI: 10.1177/1066896913516672 The online version of this article can be found at: http://ijs.sagepub.com/content/early/2014/01/06/1066896913516672 A more recent version of this article was published on - Mar 24, 2014
Published by: http://www.sagepublications.com
Additional services and information for International Journal of Surgical Pathology can be found at: Email Alerts: http://ijs.sagepub.com/cgi/alerts Subscriptions: http://ijs.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav
Version of Record - Mar 24, 2014 >> OnlineFirst Version of Record - Jan 7, 2014 What is This?
Downloaded from ijs.sagepub.com at UNIV OF WINNIPEG on September 10, 2014
516672
research-article2014
IJSXXX10.1177/1066896913516672International Journal of Surgical PathologyJedrych and Pulitzer
Original Article
Primary Carcinoid Tumor of the Skin: A Literature Review
International Journal of Surgical Pathology 1–7 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1066896913516672 ijs.sagepub.com
Jaroslaw Jedrych, MD1 and Melissa Pulitzer, MD2
Abstract Primary carcinoid tumor of the skin (PCTS) is an uncommon indolent neoplasm, with 10 cases described in the literature. The tumors affect patients in the sixth to ninth decades of life (mean = 66.3 years) with an equal gender distribution and predilection for the head and trunk. They present as slowly enlarging nodules of variable duration, ranging from 1 to 60 years (mean = 11.4 years). PCTS is characterized by architectural, cytomorphologic, ultrastructural, and immunohistochemical features typical of a low-grade neoplasm with neuroendocrine differentiation. PCTS typically follows a benign clinical course and therefore has to be distinguished from cutaneous metastases of visceral carcinoid tumors, which herald dissemination of malignancy and poor prognosis. While the distinction from other histologically similar entities can be achieved by histopathological examination, PCTS can be distinguished from a visceral metastasis only by a judicious clinicopathologic correlation. Herein we describe the clinical presentation, histological appearance, and management of these tumors. Keywords skin carcinoid tumor, skin tumor, neuroendocrine tumor
Introduction
Results
Carcinoid tumors (well-differentiated neuroendocrine tumors) are uncommon neoplasms with diverse biology and clinical behavior. Their overall incidence approximates 5.25/100 000.1 Tumors are composed of epithelial cells with neuroendocrine differentiation and can be found in most anatomic locations,2 with the gastrointestinal (73.7% of cases in one large study) and bronchopulmonary (25.1%) systems being most frequently affected.3 Other primary sites are uncommon. Only 10 such tumors have been reported to arise in the skin.4-13 The differential diagnosis of a cutaneous tumor with a low-grade neuroendocrine morphology identified in the skin may be challenging. From the clinicopathologic standpoint, the major diagnostic dilemma in such cases is the distinction of a primary skin neoplasm from a metastasis of visceral malignancy. Herein we review previously described reports of primary carcinoid tumor of the skin (PCTS) and summarize the clinical presentation, histological appearance, and management of these tumors.
Clinical Features
Materials and Methods
The clinical features of patients with PCTS are summarized in Table 1. Patients’ ages ranged from 40 to 87 years (mean = 66.3 years), with a close to 1:1 male-to-female ratio. The tumors presented as single, firm, fixed to the skin, flesh-colored, nonulcerated cutaneous nodules, usually dome-shaped or protruding above the skin surface. Tumors had grown over 1 to 60 years (mean = 11.4 years) prior to excision and ranged in size from 1 to 9.5 cm (mean = 3.2 cm). Four cases involved the scalp and 6 the trunk. Most lesions were asymptomatic; however, some patients reported an episode of bleeding4 or tumor-associated tenderness and pruritus.5,11 Clinically, the lesions were felt to represent primary skin growths including pilar cyst,4 neurofibroma,7 and sebaceous cyst.10 Although one patient reported facial flushing, which subsided after tumor removal,4 the exact etiology of these symptoms was not clear. Otherwise, the patients had no symptoms suggestive of carcinoid syndrome. On diagnosis and 1
University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Memorial Sloan-Kettering Cancer Center, New York, NY, USA
2
Cases were identified in the English literature using PubMed search engine. The search resulted in the identification of 10 single PCTS case descriptions reported between 1975 and 2013.
Corresponding Author: Jaroslaw Jedrych, UPP Dermatopathology, Presbyterian South Tower, 200 Lothrop Street, Suite 3725, Pittsburgh, PA 15213, USA. Email: [email protected]
Downloaded from ijs.sagepub.com at UNIV OF WINNIPEG on September 10, 2014
2
International Journal of Surgical Pathology
Table 1. Primary Carcinoid Tumor of the Skin: Main Clinical and Follow-Up Summary.
Reference Van Dijk and ten Seldam4 Smith and Chappell5 Collina et al6 Bart et al7 Sakamoto et al8 Courville et al9 MacKenzie et al10 Cokonis et al11 Eloy-Garcia Carrasco et al12 Kropinak et al13
Age (years) and Gender 72, female 62, female 80, male 40, male 87, female 60, male 70, female 64, male 58, female 70, female
Location
Tumor Size (cm) and Duration (years)
Clinical Diagnosis
Treatment
Scalp Anterior chest Scalp Epigastrium Anterior chest Anterior chest Scalp Middle back Scalp Eyelid
3/10 1.5/10 4/1 1/4 9.5/60 NC/NC 3/NC 2/2 4/1 1/3
Pilar cyst NC NC Neurofibroma NC NC Sebaceous cyst NC NC NC
Excision Excision Excision Excision Excision Excision Excision Excision Excision Excision
Follow-Up (years) Recurrence 3.5 0.9 1.75 1.9 NC 4 6 1 1 0.67
No No No No No No Yesa No No No
Abbreviation: NC, not communicated. a Regional lymph node metastasis was present at the time of the initial diagnosis, and 4 and 6 years thereafter.
follow-up, none of the patients have been found to have any evidence of internal malignancy by extensive clinical, imaging, endoscopic, and biochemical evaluation.
Treatment and Clinical Course All patients underwent surgical excision of the tumor. Follow-up was documented for 9 patients, ranging from 0.67 to 6 years (mean = 2.4 years). In one case the skin neoplasm was associated with concurrent regional lymph node metastasis.10 In addition, this patient experienced tumor relapse in regional lymph nodes 4 and 6 years after the initial diagnosis. However, no distal metastasis was documented. All other patients remained free of disease and with no clinical evidence of loco-regional or distant recurrence.
Histopathological Features Gross inspection of the excision specimens demonstrated well-delineated dermal masses with homogenous orange to gray-yellow cut surfaces that became brown after formalin fixation.4,5 The morphological features of the PCTS are summarized in Table 2. Tumors were characterized by a single well-demarcated, nonencapsulated, nodular proliferation occupying the dermis and extending into the subcutaneous fat in most cases. None of the neoplasms showed any connection to the overlying intact epidermis or adnexal structures. Neoplastic aggregates exhibited a lobular organoid neuroendocrine growth pattern with variably sized and shaped nests, cords, and islands of tumor cells, some with vague cellular palisading at the edges.4 One case displayed peculiar long and narrowly branching thin trabecular architecture.6 Most cases showed areas of pseudoglandular formation. Tumor stroma was described as fibrovascular, and cellular in one case,6 separating
epithelial aggregates with thin septa. In 3 cases, the stroma contained significant amounts of mucin.8,12,13 In one of these cases, nests of neoplastic epithelium floated in an abundantly mucinous matrix, imparting a mucinous carcinoma-like histological appearance.8 Cytologically, the tumor cells were fairly uniform, polygonal, or cuboidal to columnar, with round to oval regular nuclei, eosinophilic and finely granular cytoplasm, and indistinct borders. Cell polarization was occasionally seen in tumor epithelium forming pseudoglandular structures. Nuclei demonstrated variably dispersed chromatin with small nucleoli in some cases and an overall neuroendocrine appearance. Mitotic figures were variably present with a reported range from none4 through occasional5,7-9,12 to numerous,6,13 but not specifically quantified in the majority of cases. No intravascular or perineural invasion or cellular atypia or necrosis was present.
Histochemical and Immunohistochemical Features In all cases, the morphologic impression of neuroendocrine differentiation was supported by the results of ancillary studies. A neuroendocrine phenotype was evidenced by histochemical techniques, including argentaffin (Fontana-Masson) and argyrophilic (Grimelius) stains, and immunohistochemistry, revealing expression of chromogranin A and synaptophysin by the tumor cells. Each tumor displayed expression of one or more neuroendocrine markers. In cases where electron microscopy studies were performed,5,7-9 the presence of dense membrane-bound secretory granules was revealed at the ultrastructural level. Most tumors showed expression of carcinoembryonic antigen and cytokeratins, including AE1/AE3, MNF, Cam5.2, high molecular weight cytokeratins, and cytokeratin 7. Cytokeratin 20 and thyroid
Downloaded from ijs.sagepub.com at UNIV OF WINNIPEG on September 10, 2014
3
Downloaded from ijs.sagepub.com at UNIV OF WINNIPEG on September 10, 2014
Tumor Location
Architectural Pattern
+ − − −
+ + − −
+
−
+
+
−
−
+
−
+
−
−
Mucinous Stroma
+
PseudoGlands
+/ND/+/−
ND/ND/+/+
ND/ND/+/+
ND/ND/+/+
+/+/+/ND
−/+/+/ND
+/+/+/ND
−/+/+/ND
+/+/ND/ND
+/ND/ND/ND
Argentaffin (Fontana-Masson), Argyrophilic (Grimelius), Chromogranin A, and Synaptophysin Stains
+(AE1/AE3), −(CK7 and CK20)/ ND/−(ER, PR, GCDFP-15, and TTF1)
+(MNF, Cam5.2 and CK7), −(AE1/ AE3 and CK20)/+/−(TTF-1) +(CK7), −(CK20)/+/−(TTF-1)
+/+
+/ND
ND/+
+/ND
+(HMW)/ND
ND/ND
ND/ND
Cytokeratin, CEA, and Other Stains
ND
ND
ND
ND
+
+
+
ND
+
ND
Electron Microscopya
Abbreviations: ND, not done; CEA, carcinoembryonic antigen; HMW, high molecular weight; CK, cytokeratin; TTF-1, thyroid transcription factor; ER, estrogen receptor; PR, progesterone receptor; GCDFP, gross cystic disease protein. a Electron microscopy demonstrating the presence of membrane-bound, dense-core cytoplasmic secretory granules.
Eloy-Garcia Dermis and superficial Nests and ribbons Carrasco et al12 subcutis Kropinak et al13 Dermis Nests and trabecules
Van Dijk and ten Dermis and superficial Solid masses and Seldam4 subcutis cords Smith and Dermis and superficial Sheets, cords and Chappell5 subcutis trabecules Collina et al6 Dermis Long, narrow branching trabecules Dermis and superficial Nest and cords Bart et al7 subcutis Sakamoto et al8 Dermis and superficial Solid cribriform subcutis lobules and cords Courville et al9 Dermis Lobules, cord and island MacKenzie et al10 Dermis and superficial Nests and cords subcutis Cokonis et al11 Dermis Nests and cords
Reference
Table 2. Primary Carcinoid Tumor of the Skin: Main Pathologic Features Summary.
4
International Journal of Surgical Pathology
transcription factor 1 were negative in 3 of 3 tumors stained for these markers.11-13 One case was tested for the expression of estrogen and progesterone receptors, and gross cystic disease fluid protein 15, with negative results.13
Discussion PCTS is an exceedingly rare cutaneous neoplasm of unknown etiology. Since the first description by Van Dijk and ten Seldam in 1975,4 only 9 additional cases have been reported.5-13 The tumors occur on the head and trunk of middle-aged or elderly patients without an overt gender predilection. No association with sun-exposure, immunosuppression, genodermatoses, or other predisposing factors has been documented. Typically, they present as asymptomatic dermal nodules with a nonspecific appearance; therefore, other more common cutaneous conditions are clinically favored. Overall, PCTS are benign neoplasms and surgical excision is curative. Although one tumor was associated with regional lymph node involvement and recurred locally after prolonged periods of dormancy, no distant metastasis or tumor-related mortality was documented in any of the cases. This is an important feature distinguishing PCTS from visceral carcinoid tumors, which disseminate systematically and frequently follow a malignant clinical course with an average 5-year survival rate close to 50% regardless of primary site.2 PCTS are characterized by distinctive architectural and cytologic features. Tumors demonstrated a prototypical organoid pattern of growth with a well-demarcated outline, lack of significant cellular atypia, fibrous to mucinous stroma, and nuclear and cytoplasmic features typical for a low-grade neuroendocrine neoplasm. If seen in combination, these morphological features are highly suggestive of PCTS. The definitive evidence of neuroendocrine differentiation may be provided by the results of ancillary studies demonstrating expression of general neuroendocrine markers by tumor cells. However, due to their rarity in the skin and the lack of exposure to such tumors in pathology training, the correct diagnosis may prove to be challenging. As mentioned above, due to diametrically different biologic behavior and clinical management of skin and visceral carcinoid tumors, every attempt should be made to distinguish PCTS from a metastatic deposit. In addition, some primary skin tumors, including Merkel cell carcinoma, sebaceous neoplasms and melanoma with carcinoid-like architecture, endocrine mucin producing sweat gland carcinoma, and primary skin tumors with neuroendocrine differentiation, may enter into the histologic differential of PCTS. Visceral carcinoid tumors metastasize with a rate close to 30%, and the most frequent sites of tumor dissemination
include the lymph nodes, liver, and peritoneum.2 The skin is uncommonly affected by metastases of these neoplasms.14-19 Cutaneous involvement is typically multifocal and follows the diagnosis of internal malignancy.9 However, in some cases, a cutaneous metastasis was the initial presentation leading to the detection of an underlying visceral carcinoid tumor.20-23 As the discovery of a skin metastasis often indicates widespread neoplasm dissemination, the correct characterization of a tumor as metastatic has an important bearing on a patient’s prognosis.24 Each PCTS in this series was found to be indistinguishable from a metastatic tumor on morphological and immunohistochemical grounds (Figure 1). The diagnosis of a primary lesion was made only after extensive clinical evaluation excluded a primary tumor elsewhere in the body. However, only some of these cases had documented an adequately long period of time prior to the tumor diagnosis (>3 years)4,5,7,8 and/or lengthy follow-up time after the tumor diagnosis (>2 years).4,9,10 As cases of carcinoid tumors initially presenting with metastasis, preceding by years the detection of a visceral primary, have been described,25 one should remain cautious with the diagnosis of PCTS. For the aforementioned reasons and the fact that cutaneous metastases of carcinoid tumors are more frequent than PCTS, any proliferation with a well-differentiated neuroendocrine morphology discovered in the skin should be initially considered to represent a metastasis, even in a patient with no history of internal malignancy. In the absence of a known primary, an extensive evaluation for a visceral neoplasm is necessary. If inconclusive, it is still possible that an occult primary tumor is undetectable by means of available diagnostic modalities and will declare itself on prolonged follow-up. The most frequent primary cutaneous tumor of concern in the differential diagnosis of PCTS is Merkel cell carcinoma (MCC), also referred to as primary neuroendocrine carcinoma of the skin. In some cases, MCC may show relatively good demarcation, an organoid growth pattern, and formation of trabecules and pseudoglands.26 However, a diffuse nodular or infiltrative involvement of the cutaneous and subcutaneous tissue is more commonly encountered in this tumor. Features of aggressive neoplasia, including rapid growth, ulceration, significantly increased nuclear to cytoplasmic ratio, brisk mitotic and apoptotic activity, nuclear molding, and necrosis should aid in the distinction of MCC from PCTS.12 A paranuclear punctate pattern of cytokeratin 20 expression and positivity for neurofilament protein in most MCC cases may further aid in establishing the diagnosis.26 Sebaceous neoplasms with a carcinoid-like pattern of growth may closely mimic PCTS.27 These tumors predominately occur on the scalp of middle-age to elderly patients and present as solitary non-ulcerated nodules measuring 1 to 3 cm. Morphologically, they feature multilobular
Downloaded from ijs.sagepub.com at UNIV OF WINNIPEG on September 10, 2014
5
Jedrych and Pulitzer
Figure 1. Two examples (A-C and D-F) of cutaneous metastases of visceral carcinoid tumors. These tumors are pathologically indistinguishable from primary carcinoid tumor of the skin: (A) Low-power view demonstrates a lobulated and well-demarcated tumor involving the deep dermis and superficial subcutis of the scalp. A previous biopsy site is present on top of this resection (hematoxylin–eosin [H&E], 40×). (B) Higher magnification shows solid and trabecular architecture of the neoplastic epithelium, fibrosclerotic stroma, and prominent pools of extravasated erythrocytes (H&E, 100×). (C) High magnification demonstrates lowgrade neuroendocrine cytomorphologic features including regular round to oval nuclei with evenly distributed chromatin and eosinophilic cytoplasm (H&E, 200×). (D) This metastatic deposit predominantly occupies the subcutaneous fat and shows areas of cystic change (H&E, 40×). (E) On higher power, small tumor nests and narrow trabecules embedded in fibrohyaline stroma are seen (H&E, 100×). (F) High magnification demonstrates low-grade neuroendocrine morphology (H&E, 200×).
Downloaded from ijs.sagepub.com at UNIV OF WINNIPEG on September 10, 2014
6
International Journal of Surgical Pathology
architecture with trabecular and ribbon-like patterns and occasional rosette formation. The areas of sebaceous differentiation are present at least focally, allowing for the correct morphologic diagnosis. Tumors are immunohistochemically negative for neuroendocrine markers including chromogranin A, synaptophysin, or serotonin. These features are not seen in PCTS. A distinct organoid carcinoid-like pattern of growth with formation of ribbons, trabeculae, islands, and rosettes can rarely be encountered in melanoma.28 Such tumors may demonstrate relatively bland cytology with mild to moderate pleomorphism and inconspicuous mitotic activity, further mimicking an indolent entity. Nevertheless, the pattern of antigen expression is typical for melanoma: S-100, HMB-45, Melan-A, and tyrosinase positive, while chromogranin A, synaptophysin, and serotonin negative. The presence of cytoplasmic melanin, intranuclear pseudoinclusions, marked nuclear pleomorphism, areas of necrosis, and areas of conventional-appearing melanoma or residual nevus may serve as a clue to the correct diagnosis. Endocrine mucin producing sweat gland carcinoma (EMCSGC) is a rare indolent cutaneous neoplasm composed of bland cells with neuroendocrine nuclear and cytoplasmic features forming nodules and cribriform arrangements embedded in variably mucinous stroma. Tumors express neuroendocrine markers.29 These features are shared by PCTS as the presence of matrical mucin deposition has been described in few such tumors. Despite significant morphologic overlap, both tumors most likely represent separate entities. EMPSCG typically affects elderly women and presents in the eyelid or periorbital skin. The distinctive pathologic features include expression of estrogen and progesterone receptors and the presence of a myoepithelial cell layer surrounding tumor nests evidenced by calponin, p63, and smooth muscle actin immunostains. EMPSGC is commonly associated with invasive mucinous carcinoma and may be a precursor thereof. Lastly, divergent neuroendocrine differentiation has been infrequently reported in various other primary cutaneous neoplasms such as basal cell carcinoma and sweat gland apocrine and eccrine carcinomas.30,31 However, neuroendocrine features are typically present only focally in these neoplasms, which otherwise show conventional morphology,32 allowing distinction from PCTS. In conclusion, PCTS is a rare tumor that should be included in the differential diagnosis of low-grade cutaneous neuroendocrine proliferations. It is distinguished from other entities by morphologic and immunohistochemical features. From a practical standpoint, cutaneous tumors with a low-grade neuroendocrine morphology have to be approached as metastases until an extensive clinical evaluation excludes internal malignancy. The definitive diagnosis of a skin primary may require prolonged follow-up as a cutaneous metastasis may be the
first manifestation preceding the discovery of a visceral carcinoid tumor by months to years. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. Yao JC, Hassan M, Phan A, et al. One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008;26:3063-3072. 2. Klimstra DS, Modlin IR, Coppola D, Lloyd RV, Suster S. The pathologic classification of neuroendocrine tumors: a review of nomenclature, grading, and staging systems. Pancreas. 2010;39:707-712. 3. Modlin IM, Sandor A. An analysis of 8305 cases of carcinoid tumors. Cancer. 1997;79:813-829. 4. Van Dijk C, ten Seldam RE. A possible primary cutaneous carcinoid. Cancer. 1975;36:1016-1020. 5. Smith PA, Chappell RH. Another possible primary carcinoid tumour of skin? Virchows Arch A Pathol Anat Histopathol. 1985;408:99-103. 6. Collina G, Quarto F, Eusebi V. Trabecular carcinoid of the skin with cellular stroma. Am J Dermatopathol. 1988;10:430435. 7. Bart RS, Kamino H, Waisman J, Lindner A, Colen S. Carcinoid tumor of skin: report of a possible primary case. J Am Acad Dermatol. 1990;22:366-370. 8. Sakamoto F, Ito M, Matumura G, Sato Y, Kimura S. Ultrastructural study of a mucinous carcinoid of the skin. J Cutan Pathol. 1991;18:128-133. 9. Courville P, Joly P, Thomine E, et al. Primary cutaneous carcinoid tumour. Histopathology. 2000;36:566-567. 10. MacKenzie DN, McCormick CSF, Morris RJ. Lymph node metastasis from a primary skin carcinoid tumour. Br J Plast Surg. 2003;56:718-721. 11. Cokonis CD, Green JJ, Manders SM. Primary car cinoid tumor of the skin. J Am Acad Dermatol. 2004;51:S146-S148. 12. Eloy-Garcia Carrasco C, Benguigui Benadiva J, Martinez Garcia S, Sanz Trelles A, Palacios S. Atypical primary carcinoid tumour of the skin. J Cutan Pathol. 2006;33(suppl 2):32-34. 13. Kropinak M, Sims L, Iacob C, McCormick SA, Milman T. Primary typical carcinoid tumor of the eyelid. Ophthal Plast Reconstr Surg. 2009;25:318-320. 14. Puri PK, Galan A, Glusac EJ, Cowper SE. Metastatic cutaneous carcinoid tumor mimicking an adnexal poroid neoplasm. J Cutan Pathol. 2008;35:54-57. 15. Blochin E, Stein JA, Wang NS. Atypical carcinoid metastasis to the skin. Am J Dermatopathol. 2010;32:735-739.
Downloaded from ijs.sagepub.com at UNIV OF WINNIPEG on September 10, 2014
7
Jedrych and Pulitzer 16. Archer CB, Wells RS, MacDonald DM. Metastatic cutaneous carcinoid. J Am Acad Dermatol. 1985;13:363-366. 17. Steele CW. Malignant carcinoid. Metastasis to skin and production of carcinoid syndrome, hypertension, diarrhea, dementia, and hypopotassemia: a case report. Arch Intern Med. 1962;110:763-768. 18. Rudner EJ, Lentz C, Brown J. Bronchial carcinoid tumor with skin metastases. Arch Dermatol. 1965;92:73-75. 19. Bean SF, Fusaro RM. An unusual manifestation of the carcinoid syndrome. Report of a case. Arch Dermatol. 1968;98:268-269. 20. Brody HJ, Stallings WP, Fine RM, Someren A. Carcinoid in an umbilical nodule. Arch Dermatol. 1978;114:570-572. 21. Rodriguez G, Villamizar R. Carcinoid tumor with skin metastasis. Am J Dermatopathol. 1992;14:263-269. 22. Ereno C, Lopez JI, Sanchez JM. Atypical carcinoid of larynx: presentation with scalp metastases. J Laryngol Otol. 1997;111:89-91. 23. Santi R, Massi D, Mazzoni F, Antonuzzo L, Comin CE. Skin metastasis from typical carcinoid tumor of the lung. J Cutan Pathol. 2008;35:418-422. 24. Schoenlaub P, Sarraux A, Grosshans E, Heid E, Cribier B. Survival after cutaneous metastasis: a study of 200 cases. Ann Dermatol Venereol. 2001;128:1310-1315. 25. Naschitz JE, Yeshurun D, Nash E, Lev L, Shajrawi I, Boss JH. Cervical soft tissue metastasis of typical carcinoid
tumor preceding diagnosis of ileal primary by 4 years. Am J Gastroenterol. 1992;87:1665-1668. 26. Pulitzer MP, Amin BD, Busam KJ. Merkel cell carcinoma: review. Adv Anat Pathol. 2009;16:135-144. 27. Kazakov DV, Kutzner H, Rutten A, Mukensnabl P, Michal M. Carcinoid-like pattern in sebaceous neoplasms: another distinctive, previously unrecognized pattern in extraocular sebaceous carcinoma and sebaceoma. Am J Dermatopathol. 2005;27:195-203. 28. Kacerovska D, Michal M, Sosna B, et al. Carcinoid-like pattern in melanoma: report of 4 cases. Am J Dermatopathol. 2009;31:542-550. 29. Zembowicz A, Garcia CF, Tannous ZS, Mihm MC, Koerner F, Pilch BZ. Endocrine mucin-producing sweat gland carcinoma: twelve new cases suggest that it is a precursor of some invasive mucinous carcinomas. Am J Surg Pathol. 2005;29:1330-1339. 30. Eusebi V, Mambelli V, Tison V, De Lellis R, Betts CM. Endocrine differentiation in basal cell carcinoma. Tumori. 1979;65:191-199. 31. Foschini MP, Eusebi V. Divergent differentiation in endocrine and nonendocrine tumors of the skin. Semin Diagn Pathol. 2000;17:162-168. 32. Krokowski M, Hoch J, Feller AC, Bernd HW, Thorns C, Krueger S. Basal cell carcinoma with neuroendocrine differentiation arising in a scar: a case report. Dermatol Online J. 2009;15(10):4.
Downloaded from ijs.sagepub.com at UNIV OF WINNIPEG on September 10, 2014
