neuroendocrine differentiation of skin tumors: a

CME ARTICLE

Neuroendocrine Differentiation of Skin Tumors: AComprehensive Review

Lamiaa Hamie, MD,* Ossama Abbas, MD,† and Jag Bhawan, MD‡

Abstract: Neuroendocrine differentiation is characterized byendocrine and neuronal features with prominent dense secretorygranules and neuropeptides. Neuroendocrine differentiation of skintumors is of unknown clinical significance. Nonetheless, theacknowledgment of this line of differentiation is important toprevent diagnostic pitfalls and subsequent inappropriate manage-ment. This review aims at summarizing the skin neoplasms that canexpress neuroendocrine markers.

Key Words: cutaneous carcinoid tumors, Merkel cell carcinoma,neuroendocrine differentiation

(Am J Dermatopathol 2020;42:899–910)

LEARNING OBJECTIVESAfter participating in this activity, physicians should be

better able to

1. Describe the main features of neuroendocrine differentia-tion and the role of histopathology in this field;

2. Identify the main tumors that can portray neuroendocrinedifferentiation; and

3. Distinguish these tumors from their mimickers using his-tological and immunohistochemical findings.

INTRODUCTIONThe skin can be characterized as a peripheral neuroen-

docrine organ. Cutaneous signals are mediated throughvarious cell types that are arranged into endocrine units.These units are localized in the epidermis, dermis, andadnexal structures and can trigger cascades through autocrineand paracrine mechanisms to ensure skin homeostasis. Insome instances, neuroendocrine stimuli can promote

tumorigenesis by maintaining a chronic state of inflammationamong others.1

The term “neuroendocrine” describes the presence ofa shared phenotype of both endocrine and neuronal featuresand does not necessarily mean a shared developmental line-age.2 Microscopically, neuroendocrine differentiation is char-acterized by dense-core secretory granules and the detectionof neuropeptides, such as adrenocorticotropic hormone, cal-citonin, or somatostatin, and other neuroendocrine markers[synaptophysin (SYP) and chromogranin A (Cr-A) orneuron-specific enolase (NSE)].3 SYP is a transmembraneglycoprotein that has an essential role in the packaging, stor-age, and release of neurotransmitters and also acts as a mem-brane channel protein. Cr-A is a calcium-binding proteinmember of the granin family and is stored in the dense coregranules of neural and neuroendocrine cells.4 Both SYP andCr-A are widely used markers for neuroendocrine histopath-ological diagnosis.5

The prototype of the primary neuroendocrine skin tumorsis the Merkel cell carcinoma (MCC). MCs are mechanoreceptorsthat are oval-shaped, with an indented nucleus and desmo-somes.2 Their cytoplasm contains dense cytoplasmic neurose-cretory granules, neurofilaments, and intermediate filaments.The source of MC remains controversial.2 There are varioushypotheses, including a neural crest origin, a deviation fromamine precursor uptake and decarboxylation cells and derivationfrom epidermal stem cells that can differentiate into both kera-tinocytes and neuroendocrine cells (Fig. 1).2 This article pro-vides a comprehensive review of the skin tumors that canhave neuroendocrine differentiation and offers a brief insightinto the suggested pathogenesis (Tables 1 and 2).

Tumors that Consistently DisplayNeuroendocrine Differentiation

Merkel Cell CarcinomaMCC (primary neuroendocrine carcinoma) is derived

from the MCs of the skin.3 It consists of small blue dermalcells with neuroendocrine- and cytokeratin-positive immuno-histochemistry and cytoplasmic neurosecretory granules.6

MCC uniquely expresses CK-20; consequently, this markeris used to differentiate MCC from other neuroendocrine car-cinomas. MCC shows predilection for the sun-exposed headand neck regions and fair-skinned elderly patients.7 Despitebeing rare, MCC is an aggressive tumor with 3 times thedisease-specific mortality (46%) when compared with malig-nant melanoma.8 Its behavior includes rapid progression,common local recurrences, and frequent metastasis to locallymph nodes and occasionally systemic involvement.9

From the *Dermatology Resident, Dermatology Department, AmericanUniversity of Beirut Medical Center, Beirut, Lebanon; †Professor,Dermatology Department, American University of Beirut MedicalCenter, Beirut, Lebanon; and ‡Professor, Dermatopathology Section,Department of Dermatology, Boston University School of Medicine,Boston, MA.

All authors, faculty, and staff in a position to control the content of this CMEactivity and their spouses/life partners (if any) have disclosed that theyhave no financial relationships with, or financial interests in, anycommercial organizations relevant to this educational activity.

Correspondence: Jag Bhawan, MD, Guido Majno Professor of Dermatologyand Pathology, Head, Dermatopathology Section, Vice Chairman,Department of Dermatology, Boston University School of Medicine,609 Albany Street, J-308, Boston, MA 02118 (e-mail: [email protected]).

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Copyright © 2020 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.

An increased incidence of MCC is associated withimmune deficiencies, and more than 80% of these tumors arelinked with the presence of the MC polyomavirus (MCPyV).The discovery of this virus aided in the understanding of thepathogenesis of MCC. The MCPyV interacts with p53 andother important tumor suppressor genes that are implicated inthe aggressive behavior of MCC. On the other hand, in localizedMCC, MCPyV positivity is associated with a better prognosiscompared with MCPyV-negative MCC.9,10 Other prognosticfactors are CK20, anaplastic lymphoma kinase positivity, andincreased neuroendocrine differentiation as reflected by the pres-ence of cytoplasmic SYP and Cr-A. The latter are associatedwith better overall survival and decreased tumor size.9

Histologically, MCC exhibits a sheet-like growth patternbut can have nested, trabecular, and mixed types. The tumor isusually restricted to the dermis (Fig. 2), resulting in a grenz zonecomposed of dermal collagen, but there are reports of MCC in

situ (Fig. 3), MCC with subcutaneous fat, fascia, and muscleinvasion, and even cases with prominent epidermotropism.10

There are variants with basal cell carcinoma (BCC)–likedifferentiation because of the presence of a nested growth pattern,mucinous stroma, and cleft formation.10 In these cases, confirm-ing the expression of common MC immunohistochemicalmarkers, such as CK20, NSE, CD56 (NCAM), pancytokeratin,chromogranin, and SYP, and the absence of CK-7, thyroid tran-scription factor-1 (TTF-1), S100, and leukocyte common antigenis crucial for the correct diagnosis. Besides this subtype, here arereports of melanocytic, lymphomatous, ductular, small cell, squa-mous, sarcomatous, muscular and fibroxanthoma-like differenti-ation based on various histological findings and occasionallyaberrant immune reactivity (Fig. 4).10

It is also important to recognize that MCC can arise withinother cutaneous tumors. The most frequent associated tumor issquamous cell carcinoma; both the invasive and in situ subtypes.

FIGURE 1. The origin of the MC. Because the MCcontains both neuroendocrine and epithelialcharacteristics, many hypotheses were suggestedregarding its origin. The 3 main hypothesis arediscussed in the figure with the “primitive epi-dermal cell origin” being the most popular.2 Brn-3c and Math 1 are transcription factors which arepredominantly expressed by neural tissue. APUD,amine precursor uptake and decarboxylation cells;KC, keratinocyte.

TABLE 1. Tumors Expressing Neuroendocrine Differentiation

Entities Exhibiting Neuroendocrine Differentiation

Entities Consistently DisplayingNeuroendocrine Differentiation

Entities Commonly DisplayingNeuroendocrine Differentiation

Entities Rarely DisplayingNeuroendocrine Differentiation

MCC BCC AS

LGNECS GT

CHEa

Cellular neurothekeoma

SCC

SmCC

Trichilemmal carcinoma

Cutaneous neuroendocrine adenoma

Adnexal tumors

Melanoma

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There are rare reports describing the presence of MCC withinadnexal tumors, such as poromas and follicular cysts.11,12 In thesereports, the MCC component had typical immunohistochemicalfeatures, whereas the neighboring tumor cells expressed onlycytokeratin MNF116. Normally, MCs are found in the epidermis,at the basal layer, around the isthmus of the hair follicle and thedeep infundibulum. It has been suggested that these MCs can beentrapped in such tumors. With that being said, intraepidermalproliferation of MC can also be hyperplastic in nature.13 Thesecells can be distinguished from MCC in situ by the minimal/absent pleomorphism, atypia, and individual necrotic cells,13 butbetter understanding of this phenomenon is required.14–16

Low-Grade Neuroendocrine Carcinoma of theSkin

In contrast to the high-grade neuroendocrine tumorMCC, there are low-grade neuroendocrine tumors (NETs)

that arise primarily in the skin (Fig. 5).17 Carcinoid tumorsare very rare and often require extensive workup to rule outvisceral primary involvement. When skin involvement isencountered, these tumors most commonly representmetastasis from carcinoid tumors of bronchopulmonary orgastroenteropancreatic tracts such as small/large cell lungand gastroenteropancreatic carcinoma. These carcinoid tu-mors are often associated with increased serotonin levelsby enterochromaffin-producing cells.18

There are only a few reports of primary cutaneousorigin. When restricted to the skin, these tumors are calledlow-grade neuroendocrine carcinoma of the skin(LGNECS).19 Histologically, LGNECS are composed ofround cells with finely stippled nuclear chromatin, occasion-ally ductal differentiation can be observed.20 The tumors cellsstain for SYP, chromogranin, and CD56. These features over-lap with metastatic carcinoid tumors, but staining for TTF-1and the homeobox protein CDX-2 can support a tumor of

TABLE 2. Characteristic Features of Tumors Expressing Neuroendocrine Differentiation

Tumors With Neuroendocrine Differentiation

MCC MC Hyperplasia LGNECS BCCDiffuse dermal atypical small blue cells withminimal cytoplasm, in clusters, rosettes, andcords in the dermis and mitotic figures.

Positive markers: CK20, CK5/6, CK7, Cr, SYP,somatostatin, calcitonin, and VIP

Negative markers: TTF-1 (metastatic SmCC ofthe lung), S100 (melanoma), and CD45/LCA(lymphoma)

Scattered, pagetoid, or clustered MCs that lackpleomorphism, atypia, and individual necrotic

cells that are present in MCC

Positive markers: CK20, CK5/6, CK7, Cr, SYP,somatostatin, calcitonin, and VIP

Negative markers: TTF-1 and S100

Round cells with finely stippled nuclearchromatin. Ductal differentiation can be

observed.

Positive markers: SYP, Cr, and CD56.

Negative markers: TTF-1 (lung carcinoid tumor),CDX-2 (liver carcinoid tumor), CK20 (MCC),

CK5/6, and p63 (adnexal tumors).

Palisading of peripheral cells with retraction ofthe adjacent stroma. Presence of apoptosis and

mitoses.

Positive markers: BerEP4, 34bE12, p53, BCL2,and p63

CD56 expression is high, whereas Cr-A and SYPare relatively low

Patchy CD56 staining is more likely to occur inBCC-NE, whereas in MCC CD56 is more diffuse

SmCC Melanoma Cellular neurothekeoma SCCSmall cells with hyperchromatic, occasionallyspindle-shaped nuclei and scanty cytoplasm.

Negative markers: CK20 and TTF-1

Positive markers: HMB-45, S100 protein, Melan-A, tyrosinase, and microphthalmia transcription

factor

Positive markers: vimentin, NKI/C3, CD10,smooth muscle actin, and CD68

Positive markers: CK (AE1/AE3), CK–HWM(34bE12), EMA, p53, and focally positive for Cr-

A, SYP

Cutaneous NE adenoma Adnexal tumors Vascular tumorsRare skin involvement (NSE+, SYP + but CK20-

and chromogranin)EMPSGC: Sweat gland tumor characterized bymucin production, low nuclear grade, and NE

differentiation

Positive markers: CK 5/6, CK7, CK8, CK18,CAM5.2, EMA, ER, and PR

Negative markers: CK20.

PCMC: Pools of mucin with floating basaloidislands.

May also have infiltrating ductal pattern.

Can be contiguous with EMPSGC

Positive markers: Sialomucin.

Negative markers: Sulphomucins (metastaticgastrointestinal mucinous carcinoma)

AC: High grade cytologic atypia exceeding that ofEMPSGC, usually no mucin production

ACC: Biphasic salivary gland tumor, composed ofductal and myoepithelial cells (CK7+, CAM 5.2+,SMA+, S100+, calponin+, p40+, p63+, GFAP+

and cytokeratins)

Trichilemmal carcinoma: Bands of squamousepithelium with trichilemmal-type keratinization

with prominent atypia and pleomorphism(CD342)

Trichogerminoma: Various lobules composed ofbasaloid tumor cells differentiating toward hairgerm epithelium. Peripheral palisading but no

clefting artifact

AS: Atypical vascular spaces lined by endothelialcells with cytologic atypia

Positive markers: CD31, FLI1, and ERG (MCCcan be FLI1+)

CHE: Poorly circumscribed with infiltrativeborders, centered in the deep dermis, and subcutiscomposed of an admixture of different vascular

components

Positive markers: CD31, CD34, ERG, FLI1, andfactor VIII.

GT: Tumors consisting of glomus cells, vessels,and smooth muscle cells

Positive markers: Vimentin, smooth muscle actin,CD34, and calponin

CK, cytokeratin; EMA, epithelial membrane antigen; ER, estrogen receptor; CK-HMW, high-molecular-weight cytokeratin; Cr-A, chromogranin-A; LCA, leukocyte commonantigen; MITF, melanocyte-inducing transcription factor; PR, progesterone receptor; SCC, squamous cell carcinoma; SMA, smooth muscle actin; SYP, synaptophysin; TTF-1, thyroidtranscription factor-1; VIP, vasoactive intestinal polypeptide.

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primary lung or liver origin, respectively.20 Up-to-date, dif-ferentiating between primary and metastatic carcinoid tumorof the skin is still a diagnostic challenge. The clinical pictureis often a nonspecific dermal nodule and the symptoms asso-ciated with carcinoid syndrome, such as flushing, and diar-rhea, affect only 10% of visceral cases.17,20 In addition, thereare few cases where carcinoid tumor of the skin appearsbefore visceral involvement. Because LGNECS are charac-terized by an indolent behavior unlike their metastatic coun-terpart, extensive evaluation is advised to rule out systemicinvolvement.20

It is utmost importance to differentiate LGNECS fromthe high-grade neuroendocrine carcinoma of the skin (MCC)and sebaceous and adnexal neoplasms with a carcinoid-likepattern. LGNECS are negative for CK20, CK5, CK6, andp63, whereas MCC is CK20 positive and adnexal neoplasmsare immunoreactive for CK5/6 and p63.20 Furthermore,sebaceous neoplasms retain the characteristic sebaceous dif-ferentiation in some areas and consistently stain for

adipophilin, facilitating its histological diagnosis.LGNECS are overall benign neoplasms, and surgical exci-sion is often curative.17

Tumors That Commonly DisplayNeuroendocrine Differentiation

BCCBCC is the most common malignant cutaneous neo-

plasm. Fitting its ability to have many histological subtypes,there are cases of BCC with neuroendocrine differentiation(BCC-NE).21 Carcinoid-like BCC is defined by demonstrat-ing the secretory granules and neuropeptides. In BCC-NE,CD56 expression is high, whereas Cr-A and SYP are rela-tively low.22 Some argue that the detection of these neuro-peptides does not prove true neuroendocrine differentiation.These peptides could have been absorbed and not producedby tumor cells.21 Upon analysis of some cases, electronmicroscopy failed to show true neuroendocrine granules.

FIGURE 2. MCC: Representative histology (A, B) and CK20 immunostaining expression (C).

FIGURE 3. MCC in situ: representa-tive histology (A, B) and CK20 im-munostaining expression (C).




On the other hand, because trichoblastomas can showincreased numbers of MCs, some authors suggest that theBCC-NE is misdiagnosed case of trichoblastoma.21

Most importantly, it is necessary to differentiateBCC-NE from MCC (Fig. 6) because these tumors differin their clinical behavior. Ideally, CK20 can identifyMCC, but in cases of CK20-negative MCC, it has beensuggested that a patchy CD56 expression as comparedwith a more diffuse pattern would be helpful in distin-guishing BCC from MCC.23 Nevertheless, whetherBCCs truly have a neuroendocrine nature remainscontroversial.21

Tumors That Rarely Display NeuroendocrineDifferentiation

Adnexal TumorsSweat gland carcinomas are rare neoplasms that can

either have apocrine or eccrine origins.24 Endocrine mucin-

producing sweat gland carcinoma (EMPSGC) is a low-gradeadnexal tumor with neuroendocrine differentiation (Fig. 7). Ithas a predilection to the eyelids, most commonly in elderlywomen. Histologically, it is characterized by low nucleargrade, mucin production, and neuroendocrine differentia-tion.24,25 The EMPSGC cells have variable neuroendocrinemarker immunoreactivity for SYP, chromogranin, or NSE butcan express CK 5/6, CK7, CK8, CK18, CAM5.2, EMA,estrogen, and progesterone receptors. CK20 is generally neg-ative.24,26 EMPSGC can have both in situ and invasive com-ponents and shares many morphological features withpapillary carcinoma of the breast. These analogous featuresare not uncommon because sweat glands and mammary tissueshare a common embryological origin.27

Additionally, EMPSGC shares some clinical featureswith primary cutaneous mucinous carcinoma (PCMC).PCMC is a slowly growing solitary mass, and likeEMPSGC, there is periocular and predilection but can befound on other sites. Elderly female patients are most

FIGURE 4. MCC variants. The early identification of MCC is critical for prompt diagnosis and management.7,10,46 CEA, carci-noembryonic antigen; CF-1, cystic fibrosis-1; CK, cytokeratin; HMW-CK, high-molecular-weight cytokeratin; MITF, melanocyte-inducing transcription factor; SCC, squamous cell carcinoma; SMA, smooth muscle actin.

FIGURE 5. Carcinoid: Representative histology(A, B).




commonly affected.25 Histologically, PCMC is characterizedby floating low-grade tumor cells in a mucinous matrix.28

PCMC is thought to be of apocrine origin but because of itsmucinous nature, metastasis from other sites, such as breast orcolon, need to be ruled out. The acidic mucin, sulfomucins ishighly distinctive of gastrointestinal origin, whereas PCMCcontains sialomucins.29 In PCMC, there are rare cases ofneuroendocrine differentiation. The tumor cells in these cases

show strong chromogranin, SYP, and grimelius positivitywith ultrastructural visualization of the dense neuroendocrinegranules.29,30 In EMPSGC and PCMC, neuroendocrine dif-ferentiation is not associated with an altered prognosis.24

Apocrine carcinoma (AC) is a rare malignant neoplasmof apocrine differentiation. It is very rare in the skin and oftenaffects the axilla and anogenital regions without a genderpredilection. Histologically, it is composed of tumor cells

FIGURE 6. MCC mimicking BCC: Representative histology (A) with loss of commonly expressed low-molecular-weight cyto-keratin (B) and positivity for synaptophysin (C).

FIGURE 7. EMPSGC: Representativehistology (A, B) and immunostainingexpression pattern with ER (C), PR(D), synaptophysin (E), and EMA (F).




arranged in a micronodules separated by densely fibroblasticstroma. In addition, scattered glandular structures represent-ing ductal lumens can be identified within the tumor nodules.Cutaneous AC can mimic breast cancer metastasis to the skinor AC arising in ectopic breast tissue.31 Similar to EMPSGCand PCMC, neuroendocrine differentiation of AC is rare. Inthese few reports, the tumor cells express CEA, GCDFP-15,CK7, and chromogranin A. These neurosecretory granulescan be visualized with electron microscopy. This AC subtypenot only has morphological similarities with mammary neu-roendocrine carcinoma with apocrine differentiation but alsoexpresses progesterone and androgen receptors, suggesting anoverlap in histological features and biologic behavior that thepathologist must be aware of.31

Adenoid cystic carcinoma (ACC) in the skin is anotheradnexal neoplasm that rarely expresses neuroendocrinedifferentiation. Histologically, epithelial and myoepithelialcells can be identified with mucin deposition in tumor cellsand ductal lumens.32

There are uncommon reports of trichilemmal carcinomaand trichogerminoma displaying neuroendocrine differentia-tion. These cases were confirmed by the focal presence ofchromogranin, SYP, and CD56.33 This line of differentiationis intriguing because MCC have been reported to be associ-ated with adnexal lesions and are typically dermally located,strengthening the hypothesis of a common pluripotent stemcell origin.33

MelanomaThe histological diversity of melanoma adds to its

diagnostic difficulty.34 In some cases, in primary and metastaticmelanoma, divergent neuroendocrine differentiation can beobserved.34–37 Immunohistochemically, this subtype is charac-terized by the demonstration of chromogranin, SYP, and neuro-filament protein, accompanying the typical melanocytic markers,such as HMB-45, S100 protein, Melan-A, tyrosinase, and micro-phthalmia transcription factor.35 Moreover, the neuroendocrineexpression pattern has been genetically confirmed.35

The origin of this line of differentiation is hypothesizedto be either from the basal epithelial melanocytes thataccumulate aberrant mutations or from the neodifferentiationof the cancerous melanoma cells because of local environ-mental factors.34 This subtype is underreported because somepathologists prefer to consider this immunohistochemical pro-file as aberrant staining rather than actual differentiation.35

Nonetheless, despite the unknown clinical significance of thissubtype, future studies using adequate immunohistochemicalstaining and electron microscopy can provide confirmatorysupport regarding the nature of this differentiation.34

Vascular NeoplasmsTessier Cloutier et al4 have reported 3 cases of angio-

sarcoma (AS) with aberrant expression of the neuroendocrinemarkers, SYP and Cr-A. AS are uncommon sarcomas withendothelial differentiation.4 The histologic diagnosis is madeby the identification of vascular channel formation by malig-nant cells with hobnailed to epithelioid morphology. Asaforementioned, the NE markers were mainly found in the

poorly differentiated areas of the tumor,4,38 requiring furtherstudies to understand their origin.4

Immunohistochemical staining for CD31, FLI1, and ERGcan be additionally used to confirm the diagnosis of ASespecially in cases with poorly differentiated cells that canmimic other tumors.4 CD31 is a widely used endothelial markerthat is highly sensitive and specific for AS; however, it is impor-tant to keep in mind that CD31 can be found in intratumoralmacrophages in nonendothelial tumors. FLI-1 and ERG arenuclear markers of endothelial differentiation and are used incases where CD31 is difficult to interpret. Even so, FLI-1 andERG can be expressed in nonendothelial entities. In particular,FLI-1 can be expressed in MCC, Ewing sarcomas, some mela-nomas, and adenocarcinomas. Surprisingly, the 3 reported caseswere negative for the endothelial marker CD34. Whether thisfinding qualifies as an expression pattern specific to AS with NEdifferentiation is yet to be determined.4,38 Awareness regardingthese tumors is crucial to avoid misdiagnosis and incorrect ther-apy in the setting of their aggressive nature.4

Composite hemangioendothelioma (CHE) is anothervascular tumor that has been reported to display neuroendocrinedifferentiation.39 It is defined as a locally aggressive, rarelymetastasizing vascular tumor containing a mixture of histologi-cally distinct components. CHE exhibits distinctive admixture ofretiform, nested, and solid/epithelioid areas. In subtypes whereAS-like areas are present, differentiating CHE from AS can beproblematic. Perry et al39 recently described 11 cases of CHEthat express CD56 and SYP. The authors suspect that this neu-roendocrine marker expression profile is not sufficient to indictCHE of differentiating toward a neuroendocrine lineage, but itsacknowledgment is critical because this expression pattern ischaracterized by a more aggressive nature.39

Glomus TumorsGlomus tumors (GT) consist of the benign proliferation

of glomus cells associated with small vessels. In the skin,only 1 report of a malignant glomus tumor with neuroendo-crine differentiation has been described.40 Neuroid differen-tiation was clearly seen associated with relatively matureneurons with prominent tumor cell staining for NSE,NCAM, SYP, and chromogranin. Neuroendocrine differenti-ation is typically reported in GT of the stomach and has beenobserved in glomus jugular tumors in the carotid arteries. It isimportant to note that embryonic and fetal smooth musclecells from the gastrointestinal tract show neuroendocrine anti-gens, which could support the observation that smooth mus-cle tumors (GTs) can portray neuroendocrine markers.40

Cellular NeurothekeomaNeurothekeoma is a benign cutaneous tumor that has

been divided histogenetically into 2 types: myxoid andcellular.41 The cellular type lacks supporting evidence forneural differentiation and is characterized histologically bya hypercellular, multinodular architecture immunoreactivefor vimentin, NKI/C3, CD10, smooth muscle actin, andCD68. Unlike the myxoid subtype, S100 staining is absent.Interestingly, despite its doubtful neurological origin, 2 re-ports of cellular neurothekeoma have been shown to express




neuroendocrine markers, such as NSE, chromogranin A, syn-aptophysin, and CD56.41,42

Squamous Cell CarcinomaHead and neck carcinomas can rarely display neuroen-

docrine differentiation.5 The biologic significance of this lineof differentiation remains obscure. It is hypothesized that theproduced neuropeptides using autocrine and paracrine signal-ing might stimulate tumor growth.5 In the skin, reports ofsquamous cell carcinoma with neuroendocrine differentiationare scarce.43 Histologically, these tumors display tumor cellsimmunoreactive for cytokeratins (AE1/AE3), CK–HWM(34bE12), EMA, and p53 and are focally positive for CR-A, SYP, and NSE. Electron microscopy also show tonofila-ments and neurosecretory granules in the cytoplasm confirm-ing the dual phenotype.43

Small Cell CarcinomaSmall cell carcinoma (SmCC) is an epithelial malignant

neoplasm with an aggressive clinical behavior.44 It is charac-terized by small cells with hyperchromatic, occasionallyspindle-shaped nuclei and scanty cytoplasm. Primary cutane-ous SmCC is extremely rare.44 A case of oral SmCC havebeen reported with focal immunoreactivity to SYP andCD56.44 This tumor was KIT (CD117) positive butPDGFRA negative, in contrast to SmCC of other organs thatare usually immunoreactive for both markers. Furthermore,a facial SmCC have been reported with focal NSE, NCAM,SYP, chromogranin, KIT, and PDGFRA positivity.19 Duringworkup, the absence of CK20 staining and nucleoli can assistin differentiating these tumors from MCC. Naturally, cutane-ous metastasis from SmCC of other organs should be elimi-nated. Imaging and TTF-1 staining, which is negative inextrapulmonary SmCC, would certainly be helpful in deter-mining secondary skin involvement.19,44

Cutaneous Neuroendocrine AdenomaIn the skin, neoplasms with neuroendocrine differen-

tiation are generally malignant in nature.45 Exceptionally,

there is a report of a cutaneous neuroendocrine adenomaof the external ear (Fig. 8), immunoreactive to NSE andSYP but negative for CK20 and chromogranin. Once thisentity is encountered, it is necessary to exclude secondaryextension to the skin from a neuroendocrine adenoma of themiddle ear. These tumors are benign neuroendocrine andglandular proliferations, which uncommonly present ini-tially on the skin but must be kept in mind to rule outmiddle-ear disease.45

CONCLUSIONSIn conclusion, with increased reliance upon immuno-

histochemistry for the diagnosis of most skin tumors, therehas come the need for differentiating various staining patternsand their histological significance. Neuroendocrine differen-tiation has been demonstrated in a variety of skin tumors. Inmost of the entities, the presence of neuroendocrine features isof undetermined prognostic significance. To avoid diagnosticpitfalls, pathologists must be aware of aberrant immunostain-ing versus actual neuroendocrine differentiation; hence, it isadvised to perform ultrastructural studies to confirm the actualpresence of the characteristic dense secretory granules in thedescribed clinical entities.

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FIGURE 8. Cutaneous neuroendocrine adenoma:Representative histology.




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22. Terada T. Expression of NCAM (CD56), chromogranin A, synaptophy-sin, c-KIT (CD117) and PDGFRA in normal non-neoplastic skin andbasal cell carcinoma: an immunohistochemical study of 66 consecutivecases. Med Oncol. 2013;30:444.

23. Panse G, McNiff JM, Ko CJ. Basal cell carcinoma: CD56 and cytoker-atin 5/6 staining patterns in the differential diagnosis with Merkel cellcarcinoma. J Cutan Pathol. 2017;44:553–556.

24. Mulay K, Menon V, Lahane S, et al. Endocrine mucin-producing sweatgland carcinoma (EMPSGC) of the eyelid: clinicopathologic features,immunohistochemical findings and review of literature. Indian JOphthalmol. 2019;67:1374–1377.

25. Emanuel PO, de Vinck D, Waldorf HA, et al. Recurrent endocrine mucin-producing sweat gland carcinoma. Ann Diagn Pathol. 2007;11:448–452.

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27. Brett MA, Salama S, Gohla G, et al. Endocrine mucin-producing sweat glandcarcinoma, a histological challenge. Case Rep Pathol. 2017;2017:6343709.

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CME EXAM

INSTRUCTIONS FOR OBTAINING AMA PRA CATEGORY 1 CREDITSTM

The American Journal of Dermatopathology includes CME-certified content that is designed to meet the educationalneeds of its readers.

An annual total of 12 AMA PRA Category 1 Credits™ is available through the twelve 2020 issues of The AmericanJournal of Dermatopathology. This activity is available for credit through November 30, 2022.

Accreditation Statement

Lippincott Continuing Medical Education Institute, Inc, is accredited by the Accreditation Council for Continuing MedicalEducation to provide continuing medical education for physicians.

Credit Designation Statement

Lippincott Continuing Medical Education Institute, Inc., designates this journal-based CME activity for a maximum of one(1) AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participationin the activity.

To earn CME credit, you must read the article in The American Journal of Dermatopathology and complete thequiz, answering at least 80 percent of the questions correctly. Mail the Answer Sheet along with a check or money orderfor the $15 processing fee, to Lippincott CME Institute, Inc., Wolters Kluwer Health, Two Commerce Square, 2001Market Street, 3rd Floor, Philadelphia, PA 19103. Only the first entry will be considered for credit and must bepostmarked by the expiration date. Answer sheets will be graded and certificates will be mailed to each participantwithin 6 to 8 weeks of participation. Visit http://cme.lww.com for immediate results, other CME activities, and yourpersonalized CME planner tool.

CME EXAMINATIONDecember 2020

Please mark your answers on the ANSWER SHEET.

After completing this CME activity, the physician should be better able to: 1. Describe the main features ofneuroendocrine differentiation and the role of histopathology in this field; 2. Identify the main tumors which can portrayneuroendocrine differentiation; and 3. Distinguish these tumors from their mimickers using histological and immunohis-tochemical findings.

CME QUESTIONS

1. Which feature is not associated with a better prognosis in Merkel cell carcinoma?a. Presence of the Merkel cell polyomavirusb. CK20+c. ALK+d. Absence of cytoplasmic SYP and Cr-Ae. Smaller tumor size

2. Which of the following statements is false?a. Merkel cell carcinoma is always CK20 positive.b. Merkel cell carcinoma can arise within other adnexal tumors.c. Merkel cell carcinoma is a rare tumor with an aggressive behavior characterized by common local recurrences and regional

metastasis.d. Merkel cell carcinoma can show melanocytic differentiation.e. Merkel cells can be found in association with the hair follicle.

3. Which of the following can assist in differentiating between primary and metastatic carcinoid tumor of the skin originating inthe lung?a. SYPb. Chromograninc. CD56d. TTF-1e. Homeobox protein CDX-2




http://cme.lww.com

4. All of the following markers can be used to identify angiosarcoma despite the neuroendocrine differentiation, except:a. CD31b. FLI1c. ERGd. CD34

5. In addition to CK20, which immunostaining is also positive in Merkel cell carcinoma?a. CK7b. NSEc. S100d. TTF-1e. CEA




ANSWER SHEET FOR THE AMERICAN JOURNAL OF DERMATOPATHOLOGYCME PROGRAM EXAM

DECEMBER 2020Please answer the questions on pages 908-909 by filling in the appropriate circles on the answer sheet below. Mark the one best answer and fill in the circle until the letter is no longer visible. To process your exam, you must also provide the following information:Name (please print):Street AddressCity/State/ZipDaytime PhoneSpecialty

Your evaluation of this CME activity will help guide future planning. Please respond to the following questions below.

Please rate these activities 1 (minimally) to 5 (completely):These activities were effective in meeting the educational objectives.These activities were appropriately evidence-based.These activities were relevant to my practice.

Please rate your ability to achieve the following objectives, both before and after this activity:1 (minimally) to 5 (completely)

After completing this CME activity, physicians should be better able to:

Do you expect that these activities will help you improve your skill or judgment within the next 6 months? (1 — definitely will not change, 5 — definitely will change)

How will you apply what you learned from these activities? (Mark all that apply).

Please list at least one (1) change you will make to your practice as a result of this activity:

[ ] Yes! I am interested in receiving future CME programs from Lippincott CME Institute! (Please place a check mark in the box.)

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How long did it take you to complete these activities? ______hours ______minutes What are your biggest clinical challenges related to dermatopathology?

How committed are you to applying this activity to your practice in the ways you indicated above?(1 — definitely will not change, 5 — definitely will change)

O In diagnosing patientsO In monitoring patientsO In educating students and colleaguesO As part of the quality or performance improvement projectO For maintenance of board certification

O In making treatment decisionsO As a foundation to learn moreO In educating patients and their caregiversO To confirm current practiceO For maintenance of licensure

How many patients are likely to be impacted by what you learned from this activity?O <20% O 20-40% O 40-60% O 60-80% O >80%

a b c da b c da b c da b c da b c d

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1.2.3.4.5.

Mail the completed Answer Sheet and a check or money order for the $15 processing fee by November 30, 2022 to:Lippincott CME Institute, Inc.

Wolters Kluwer HealthTwo Commerce Square

2001 Market Street, 3rd FloorPhiladelphia, PA 19103

1 2 3 4 5O O O O O

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1. Describe the main features of neuroendocrine differentiation and the role of histopathology in this field.

2. Identify the main tumors which can portray neuroendocrine differentiation.

3. Distinguish these tumors from their mimickers using histological and immunohistochemical findings.




neuroendocrine differentiation of skin tumors: a

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