Plexiform Melanocytic Schwannoma: Report of a Second Case and Overview of a Rare Entity.

ABSTRACT: The seminal case report of plexiform melanocytic schwannoma, published a decade ago, indicated that this is a rare variant of schwannoma demonstrating immunohistochemical expression of melanocytic markers, electron microscopic evidence of melanosome formation, and genetic features of a benign schwannoma. We report herein, a second example of this entity. Of added interest, our case showed pseudoglandular features, as previously recorded in other variants of schwannoma. A 66-year-old man presented with a cutaneous papule on the abdomen. Histopathologically, a vertically oriented, exoendophytic, folliculocentric, dermal tumor with a plexiform architecture was observed. This was composed of nodules and diverging fascicles of bland spindle-shaped cells. Notable interstitial mucin deposition conveyed a pseudoglandular appearance to the lesion. The spindled cells co-expressed S100, SOX10, and HMB45. A minority of cells expressed Melan-A and MiTF. EMA and claudin-1 stained capsular and perifascicular perineurial cells. Melanin was absent. Plexiform melanocytic schwannoma represents one of several nerve sheath tumors that peculiarly display evidence of melanocytic differentiation. These include melanocytoneuroma, pigmented neurofibroma (or melanocytic neurofibroma), and malignant melanotic schwannian tumor. Of importance, these proliferations can be mistaken for melanocytic tumors, including melanoma. In expanding the literature on this topic, we discuss steps required to distinguish plexiform melanocytic schwannoma from melanoma and other nerve sheath tumors with melanocytic differentiation. The possible pathogenesis of these unusual neoplasms is also addressed.

RB1-deficient squamous cell carcinoma: the proposed source of combined Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine (NE) carcinoma arising from integration of Merkel cell polyomavirus (MCPyV) DNA into a host cell or from ultraviolet light-induced genetic damage (proportions vary geographically). Tumors in the latter group include those with "pure" NE phenotype and those "combined" with other elements, most often squamous cell carcinoma (SCC). We performed comprehensive genomic profiling (CGP) of MCPyV+ and MCPyV- (pure and combined) tumors, to better understand their mutational profiles and shed light on their pathogenesis. Supplemental immunohistochemistry for Rb expression was also undertaken. After eliminating low quality samples, 37 tumors were successfully analyzed (14 MCPyV+, 8 pure MCPyV- and 15 combined MCPyV-). The SCC and NE components were sequenced separately in 5 combined tumors. Tumor mutational burden was lower in MCPyV+ tumors (mean 1.66 vs. 29.9/Mb, P < 0.0001). MCPyV- tumors featured frequent mutations in TP53 (95.6%), RB1 (87%), and NOTCH family genes (95.6%). No recurrently mutated genes were identified in MCPyV+ tumors. Mutational overlap in the NE and SCC components of combined tumors was substantial ('similarity index' >24% in 4/5 cases). Loss of Rb expression correlated with RB1 mutational (P < 0.0001) and MCPyV- status (P < 0.0001) in MCCs and it was observed more frequently in the SCC component of combined MCC than in a control group of conventional cutaneous SCC (P = 0.0002). Our results (i) support existing evidence that MCPyV+ and MCPyV- MCCs are pathogenetically distinct entities (ii) concur with earlier studies linking the NE and SCC components of combined MCCs via shared genetic profiles and (iii) lend credence to the proposal that an Rb-deficient subset of SCC's is the source of phenotypically divergent combined MCCs.

Morphological patterns of metastases from combined Merkel cell carcinomas: study of an eastern Canadian cohort of cases.

Combined Merkel cell carcinomas are hybrid tumors composed of neuroendocrine and other phenotypic (usually squamous) elements. They form a minority of Merkel cell carcinomas (MCCs) as a whole, are usually Merkel cell polyomavirus-negative, and have rarely been segregated for specific study. Sporadic reports have indicated that metastases from these tumors can show a combined phenotype. We retrospectively studied 38 cases (24 men [63%], 14 women [37%], mean age 78 years [range, 46-99 years]) of combined MCC. Metastases occurred in 20 patients (53%) (at presentation and/or in follow-up [mean 38 months (range, 0.6-185 months)]). Those from 17 individuals (45%) were examined microscopically. These were mainly nodal in distribution. In 12 patients (71%), the secondary deposits were of pure neuroendocrine type, whereas in 5 (29%), combined deposits were identified. Squamous elements were the most common divergent component, in the primary and secondary tumors. The combined metastases varied from obvious squamous nests in a neuroendocrine background to scattered bizarre tumor giant cells expressing CK5/6 on immunohistochemistry. In one case, individual nodes within a single basin displayed purely squamous or purely neuroendocrine deposits. The mean overall survival in the cohort was 48 months (range, 30-67 months) and the mortality was 82%. Our work sheds light on the frequency and patterns of metastases in combined MCCs. In concert with the poor outcome data documented by others, it also raises a question as to the potential prognostic significance of a combined phenotype per se, independent of a virus-negative status and other variables. This issue deserves further study.

Dataset for the Reporting of Merkel Cell Carcinoma: Recommendations From the International Collaboration on Cancer Reporting (ICCR).

Accurate and complete pathology reports are critical for the optimal management of cancer patients. Protocols for the pathologic reporting of Merkel cell carcinoma (MCC) have been developed independently by the Royal College of Pathologists (UK) and the College of American Pathologists. In this study, data elements for pathologic reporting of MCC were analyzed by an international panel of pathologists and clinicians with the aim of developing a common, internationally agreed upon dataset useful for clinical practice. The International Collaboration on Cancer Reporting expert review panel developed a protocol containing "core" (required) and "noncore" (recommended) elements. Core elements were defined as those that had evidentiary support and were unanimously agreed upon by the review panel as essential for the clinical management, staging, and/or assessment of prognosis in patients with MCC. Noncore elements were those considered to be clinical of interest, but with lesser degrees of supportive evidence or nonactionable implications. Ten core data elements for pathology reports on primary MCC were defined. Development and agreement on this evidence-based protocol at an international level was accomplished in a timely and efficient manner. The template developed for melanoma reporting was used as a structural base for this initiative. It is applicable to, and may facilitate the development of, protocols for other tumor types. Widespread utilization of an internationally agreed upon structured pathology dataset for MCC can be expected to lead to improved patient management. It should also facilitate collaborative clinical research.

Endocrine Mucin-Producing Sweat Gland Carcinoma: Emerging Evidence of Multicentric Cutaneous Origin and Occasional Concurrence With Analogous Breast Tumors.

INTRODUCTION: Endocrine mucin-producing sweat gland carcinoma (EMPSGC) is a low-grade carcinoma with predilection for the eyelid. It is analogous to solid papillary carcinoma of the breast with both expressing neuroendocrine markers and the potential to progress to invasive mucinous carcinoma (IMC). Although over 80 cases of EMPSGC have been reported, few multicentric cases have been described in the literature. In this article, we report 9 cases of EMPSGC including 3 with multicentric disease. METHODS: A computerized search was performed for EMPSGC and IMC of the eyelid from January 2000 to February 2021. Records were reviewed for age, sex, tumor location, and clinical impression. RESULTS: Eight EMPSGC (7 associated with IMC) and 1 IMC of the eyelid were identified. Lesions were slightly more common in men (55%) than women. The mean age of presentation was 76 years (range, 59-98 years). Lesions ranged from 2.5 to 12 mm. Three cases had multicentric synchronous lesions on the skin. Histologically, these were well-circumscribed dermal tumors with solid or partially cystic nodules. Tested tumors expressed at least 1 neuroendocrine marker and were positive for CK7, ER/PR, 1 or more of GCDFP-15, mammaglobin, and GATA-3. One case had an associated IMC of the breast, and another case was associated with an intraductal papilloma of the breast in a man. There was no evidence of metastasis. CONCLUSION: EMPSGC is a low-grade adnexal neoplasm, commonly affecting the eyelid of the elderly. Lesions often progress to IMC, metastases being exceptionally rare. EMPSGC can be bilateral and multicentric. Concurrence with breast neoplasms has been observed and deserves investigation.

Epithelioid Fibrous Histiocytoma With Chondroblastoma-Like Features: A Report of a Rare Entity and Discussion of Related Diagnostic Challenges.

ABSTRACT: Epithelioid fibrous histiocytoma (EFH) is an uncommon benign skin lesion. It is distinct from FH by virtue of its recurrent anaplastic lymphoma kinase (ALK) gene rearrangements and immunohistochemical expression of ALK protein. It often poses a challenge in interpretation. Clinically, it is characterized by a flesh-colored papule/nodule on an extremity of a young to middle-aged individual. Microscopically, it is represented by a circumscribed dermal papule/nodule composed of sheets of plump epithelioid cells, forming whorled aggregates around numerous intralesional vessels. Immunohistochemistry, notably ALK positivity and relevant negative stains, serves to distinguish EFH from its morphological mimics. Rare examples of chondroblastoma-like EFH and EFH with osseous metaplasia are recorded in the literature. Our case is of a 58-year-old man who attended an oculoplastic surgeon because of an exophytic cutaneous nodule on the right upper eyelid. The lesion was excised. Microscopically, it displayed morphological and immunohistochemical features of EFH. Of interest, discrete foci of chondro-osseous change, including chondroblastoma-like pericellular calcification, osteoid formation, and osteoclast-like giant cells, were noted throughout the lesion. A diagnosis of EFH with chondroblastoma-like features was made. Of interest, the changes observed in this EFH serve to link the previously reported examples of pure chondroblastoma-like EFH and EFH with osseous metaplasia. This morphological variant of EFH adds to the existing diagnostic challenge presented by these lesions, particularly in the distinction from other calcifying tumors of the skin.

Primary Hyperoxaluria Type 1 (PH1) Presenting With End-Stage Kidney Disease and Cutaneous Manifestations in Adulthood: A Case Report.

RATIONALE: Primary hyperoxaluria (PH) is a rare autosomal recessive disorder more commonly diagnosed in children or adolescents. Owing to its rarity and heterogeneous phenotype, it is often underrecognized, resulting in delayed diagnosis, including diagnosis after end-stage kidney disease (ESKD) has occurred or recurrence after kidney-only transplantation. CASE PRESENTATION: A 40-year-old Caucasian Canadian woman with a history of recurrent nephrolithiasis since age 19 presented with ESKD and cutaneous symptoms. She had no known prior kidney disease and no family history of kidney disease or nephrolithiasis. DIAGNOSIS: A diagnosis of primary hyperoxaluria type 1 (PH1) due to homozygous splice donor mutation (AGXT c.680+1G>A) was made with kidney and cutaneous pathology demonstrating calcium oxalate deposition and ultrasound suggestive of nephrocalcinosis. INTERVENTIONS: She was initiated on frequent, high-efficiency, high-flux conventional hemodialysis and oral pyridoxine. Lumasiran was added 11 months later, after she developed bilateral swan-neck deformities. OUTCOMES: After 14 months of high-intensity dialysis and 3 months of lumasiran, there have been no signs of renal recovery, and extra-renal involvement has increased with progressive swan-neck deformities, reduced cardiac systolic function, and pulmonary hypertension. The patient has been waitlisted for kidney-liver transplantation. TEACHING POINTS: This case report describes an adult presentation of PH1. The case highlights the importance of timely workup of metabolic causes of recurrent nephrolithiasis or nephrocalcinosis in adults which can be a presenting sign of PH and genetic testing for PH to facilitate early diagnosis and treatment especially in the era of novel therapeutics that may alter disease course and outcomes. The case also demonstrates the value of testing for PH in adults presenting with unexplained ESKD and a history of recurrent nephrolithiasis or nephrocalcinosis due to implications for organ transplantation strategy and presymptomatic family screening.

JUSTIFICATION: L'hyperoxalurie primaire (HP) est un trouble récessif autosomique rare plus souvent rencontré chez les enfants ou les adolescents. En raison de sa rareté et de son phénotype hétérogène, cette affection est fréquemment sous-reconnue, ce qui entraîne un retard dans le diagnostic, et ce, même après l'apparition d'une insuffisance rénale terminale (IRT) ou une récidive suivant une greffe simple de rein. PRÉSENTATION DU CAS: Nous présentons le cas d'une Canadienne de race blanche âgée de 40 ans avec des antécédents de néphrolithiase récurrente depuis l'âge de 19 ans. La patiente était atteinte d'IRT et présentait des symptômes cutanés. Elle n'avait aucun antécédent connu de maladie rénale ou antécédent familial de maladie rénale ou de néphrolithiase. DIAGNOSTIC: Une pathologie rénale et cutanée montrant des dépôts d'oxalate de calcium et une échographie suggérant une néphrocalcinose ont permis de poser un diagnostic d'hyperoxalurie primaire de type 1 (HP1) due à une mutation de donneur d'épissage homozygote (AGXT c.680+1G>A). INTERVENTIONS: La patiente a amorcé des traitements d'hémodialyse conventionnelle à grande fréquence, à haut rendement et à flux élevé, et a reçu de la pyridoxine par voie orale. Un traitement par lumasiran a été ajouté 11 mois plus tard, après le développement de déformations bilatérales en col de cygne. RÉSULTATS: Après quatorze mois de dialyze à haute intensité et trois mois de lumasiran, aucun signe de récupération rénale n'a été observé. L'intervention d'épuration extra-rénale a été augmentée en raison de déformations progressives en col de cygne, d'une réduction de la fonction cardiaque systolique et d'une hypertension pulmonaire. La patiente a été placée sur la liste d'attente pour une transplantation rénale et hépatique. ENSEIGNEMENTS TIRÉS: Ce rapport de cas décrit une présentation adulte d'HP1. Ce cas souligne l'importance de traiter rapidement les causes métaboliques de la néphrolithiase ou de la néphrocalcinose récidivante chez les adultes, car celles-ci peuvent être des signes d'hyperoxalurie primaire (HP). Ce cas souligne en outre l'importance de procéder à des tests génétiques pour l'HP afin de permettre le diagnostic et le traitement précoces, en particulier à l'ère de nouveaux traitements susceptibles d'infléchir l'évolution et les résultats de la maladie. Enfin, il démontre la valeur du dépistage de l'HP chez les adultes présentant une IRT inexpliquée et des antécédents de néphrolithiase ou de néphrocalcinose récidivante, en raison de ses implications sur la stratégie de transplantation d'organes et sur le dépistage pré-symptomatique de la famille.

Relationship between p63 and p53 expression in Merkel cell carcinoma and corresponding abnormalities in TP63 and TP53: a study and a proposal.

Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous neuroendocrine carcinoma. Oncogenesis occurs via Merkel cell polyomavirus-mediated (MCPyV+) and/or ultraviolet radiation-associated (MCPyV-) pathways. Advanced clinical stage and an MCPyV- status are important adverse prognostic indicators. There is mounting evidence that p63 expression is a negative prognostic indicator in MCC and that it correlates with MCPyV- status. p63 is a member of the p53 family of proteins among which complex interactions occur. It has two main isoforms (proapoptotic TAp63 and oncogenic ΔNp63). Paradoxically, TAp63 predominates in MCC. To explore this quandary, we examined relationships between p63 and p53 expression and corresponding abnormalities in the TP63 and TP53 genes in MCC. A cohort of 26 MCCs (12 MCPyV+ and 14 MCPyV-) was studied. Comparative immunohistochemical expression of p63 and p53 was evaluated semiquantitatively (H scores) and qualitatively (aberrant patterns). The results were compared with genetic abnormalities in TP63 and TP53 via next-generation sequencing. p63 was positive in 73% of cases. p53 showed "wild-type" expression in 69%, with "aberrant" staining in 31%. TP63 mutations (predominantly low-level copy gains; 23% of cases) and mainly pathogenic mutations in TP53 (50% of cases) featured in the MCPyV- subset of cases. p63 expression correlated quantitatively with p53 expression and qualitatively with aberrant patterns of the latter. Increased expression of p63 and p53 and aberrant p53 staining correlated best with TP53 mutation. We propose that p63 expression (ie, proapoptotic TAp63) in MCC is most likely functionally driven as a compensatory response to defective p53 tumor suppressor activity.

Independent primary cutaneous and mammary apocrine carcinomas with neuroendocrine differentiation: Report of a case and literature review.

Cutaneous apocrine carcinomas share common features with their counterparts in the breast; hence, metastatic mammary carcinoma must be excluded before such lesions can be designated primary cutaneous neoplasms. Primary tumors from either source rarely exhibit neuroendocrine differentiation. We report a case of a 72-year-old female with a painless 1.2-cm scalp nodule. An incisional biopsy revealed dermal involvement by an invasive apocrine carcinoma juxtaposed to a benign apocrine cystic lesion. Immunohistochemically, the carcinoma expressed neuroendocrine proteins including synaptophysin, chromogranin, and CD56. A primary cutaneous apocrine carcinoma with neuroendocrine differentiation was favored, but additional investigations to exclude breast origin were recommended. These revealed a 1.1-cm nodule in the right breast, which proved to be an invasive ductal carcinoma, morphologically and immunophenotypically similar to the scalp lesion. This confounded the case, yet factors militating against metastatic breast carcinoma to skin included (a) the small size of the mammary tumor, (b) absence of other metastatic disease, and (c) juxtaposition of the scalp carcinoma to a putative benign precursor. Molecular studies were undertaken to resolve the diagnostic quandary. Single nucleotide polymorphism microarray analysis revealed distinct patterns of chromosomal copy number alterations in the two tumors, supporting the concept of synchronous and unusual primary neoplasms.

A Case of Whipple Disease With Cutaneous Manifestations.

ABSTRACT: Whipple disease (WD) is a rare bacterial infectious disease that is classically characterized by years of arthralgia, followed by malabsorption, diarrhea, and weight loss. However, WD may manifest in virtually any organ system, and patients with WD rarely develop subcutaneous erythema nodosum-like lesions. We report a case of a 51-year-old man diagnosed with WD who subsequently developed widely distributed erythematous subcutaneous nodules after 5 months of antibiotic therapy.

Basal cell carcinosarcoma of the eyelid with osteosarcomatous transformation.

A carcinosarcoma is a neoplasm with malignant epithelial and mesenchymal components. It is thought to arise by mesenchymal transformation of the epithelial elements. The cutaneous form of carcinosarcoma is rare and is associated with sun exposure; most cases arise in the head and neck. The epithelial component may be a basal cell carcinoma, a squamous cell carcinoma, or an adnexal carcinoma. The mesenchymal component may be an osteosarcoma, a pleomorphic undifferentiated sarcoma, or another type of sarcoma. Only a few cases of cutaneous carcinosarcoma have been described in the periocular skin. We present a case of basal cell carcinosarcoma with osteosarcoma and pleomorphic undifferentiated sarcoma arising in the lower eyelid of an elderly man.

Merkel cell carcinoma of the eyelid and periocular region: A review.

Merkel cell carcinoma (MCC) is a rare primary cutaneous neuroendocrine carcinoma with a high mortality rate. It typically affects elderly Caucasians, with a slight predilection for males. It is associated with chronic sun exposure and/or immunosuppression. Almost half of all cases occur on the head or neck and an estimated 2.5%-10% arise on the eyelids or periocular skin. It ranks as the 5th most common malignant tumor at these sites, preceded in frequency by basal cell, squamous cell and sebaceous carcinoma, as well as melanoma. Its clinical presentation as a violaceous nodule/plaque lacks specificity, and it can be mistaken for cysts, chalazia or basal cell carcinomas. Sub-specialized histopathological and immunohistochemical evaluations are required for diagnosis. Clinical staging defines the extent of disease and governs management. This includes surgery and adjuvant radiotherapy for localized tumors and of late, immunotherapy for metastatic disease. Significant advances in our understanding of the dual etiopathogenesis (Merkel cell polyomavirus- and Ultraviolet radiation-induced) and the biology of the neoplasm have been achieved in recent years. Issuing from the tumor's known susceptibility to host immunity, a recent therapeutic breakthrough has occurred whereby immune checkpoint inhibition has been shown to mitigate advanced disease. These factors and the increased global incidence of the tumor have brought it to the forefront of medical attention. This review provides a clinically relevant update on MCC, with special reference to cases arising on the eyelid/periocular region.

The use of noninvasive imaging techniques in the diagnosis of melanoma: a prospective diagnostic accuracy study.

BACKGROUND: Early detection of melanoma is crucial to improving the detection of thin curable melanomas. Noninvasive, computer-assisted methods have been developed to use at the bedside to aid in diagnoses but have not been compared directly in a clinical setting. OBJECTIVE: We conducted a prospective diagnostic accuracy study comparing a dermatologist's clinical examination at the bedside, teledermatology, and noninvasive imaging techniques (FotoFinder, MelaFind, and Verisante Aura). METHODS: A total of 184 patients were recruited prospectively from an outpatient dermatology clinic, with lesions imaged, assessed, and excised. Skin specimens were assessed by 2 blinded pathologists, providing the gold standard comparison. RESULTS: Fifty-nine lesions from 56 patients had a histopathologic diagnosis of melanoma, whereas 150 lesions from 128 patients were diagnosed as benign. Sensitivities and specificities were, respectively, MelaFind (82.5%, 52.4%), Verisante Aura (21.4%, 86.2%), and FotoFinder Moleanalyzer Pro (88.1%, 78.8%). The sensitivity and specificity of the teledermoscopist (84.5% and 82.6%, respectively) and local dermatologist (96.6% and 32.2%, respectively) were also compared. LIMITATIONS: There are inherent limitations in using pathology as the gold standard to compare sensitivities and specificities. CONCLUSION: This study demonstrates that the highest sensitivity and specificity of the instruments were established with the FotoFinder Moleanalyzer Pro, which could be a valuable tool to assist with, but not replace, clinical decision making.

Merkel cell carcinoma: A review.

Merkel cell carcinoma has been a focus of active scientific investigation in recent years and new information on the topic has emerged. Although uncommon, this primary cutaneous neuroendocrine carcinoma, usually involving the head/neck of elderly individuals, has a poor prognosis. Within the past two decades, an increase in the incidence of the tumor and the discovery of its link to the Merkel cell polyomavirus have focused medical attention on the lesion. The resulting studies have improved our understanding of the biology of the neoplasm and contributed to clinical care. Specifically, two pathogenic subsets of the tumor have come to light, the majority due to Merkel cell polyomavirus and the minority caused by ultraviolet radiation-induced genetic damage. This dichotomy carries prognostic implications favoring the former subset. In addition, having capitalized on the known susceptibility of the tumor to immune influences, investigators have recently discovered its responsiveness to immune checkpoint inhibition. This revelation has constituted a therapeutic milestone at the clinical level. Herein we provide an overview of the topic, outline updates in the field and place an emphasis on dermatopathologic aspects of Merkel cell carcinoma.

Apocrine Hidradenoma and Adenomyoepithelioma: Entities on a Biological Continuum of Adnexal Neoplasia.

Apocrine hidradenomas (AH) once believed to harbor myoepithelial cells are now considered pure epithelial neoplasms. They are categorized separately from adenomyoepitheliomas which consist of apocrine epithelial and myoepithelial components. Reports of myoepithelial tumors arising in AH have suggested a link between the 2. Our goal was to explore whether cases diagnosed on routine microscopy as AH harbored occult myoepithelial elements, which would be disclosed by an immunohistochemical evaluation. Twenty-nine such cases, derived from a teaching collection of one of the authors, formed the basis of the study. Clinical and demographic data were documented, and morphological details of the cases were recorded. A panel of immunohistochemistry (AE1AE3, CK8/18, epithelial membrane antigen, p63, S100 protein, glial fibrillary acid protein, calponin, alpha actin, and others), designed to identify myoepithelial cells, was used. The population consisted of 14 women and 15 men (mean age 55.8; range 26-82 years). The tumors, located on the head/neck (14), limbs (10), and trunk (5), were solid (2) and solid/cystic (27). They exhibited varied (often combined) cytological elements (clear, squamoid, polygonal, and mucinous cells). On immunohistochemistry, aggregates of myoepithelial cells were identified in 5 (17%) cases. Four were calponin+ and AE1AE3+; they occupied ≤30% of tumor volumes and exhibited fusiform cytomorphology. One was S100 protein+ and AE1AE3+; it occupied 70% of tumor volume and exhibited polygonal cytomorphology. The gradation in the volume of myoepithelial elements disclosed by immunohistochemistry in a subset of our cases suggests that AH and adenomyoepitheliomas exist on a biological continuum of adnexal neoplasia. The diagnostic categorization of lesions with dual elements requires further study, but we propose that the term adenomyoepithelioma be restricted to those in which myoepithelial cells constitute ≥25% of tumor volume.

p63 expression in Merkel cell carcinoma: comparative immunohistochemistry invokes TAp63 as the dominant isoform involved.

The literature suggests that p63 expression in Merkel cell carcinoma (MCC) is associated with a poor prognosis. p63 immunohistochemistry marks the 2 main isoforms of this transcriptional protein: TAp63 (tumor suppressor-like properties) and ∆Np63 (oncogenic properties). Little information about the isoform of relevance in MCC exists. p40 immunohistochemistry specifically marks ∆Np63, and using comparative, semiquantitative expression of p63 and p40, we sought to clarify the issue. Our cohort of 53 cases (28 men and 25 women, median age 79 years, interquartile range 71-88) was stratified by morphology and viral status. Immunohistochemistry (p63, p40, and cytokeratin 5/6) was performed, H-scores for nuclear expression of p63 and p40 were derived (2 observers; positivity ≥ 10), and interobserver agreement was evaluated. Clinical, pathological, and outcome data were documented. The results were analyzed statistically. Mortality amounted to 57% (median follow-up 686 days, interquartile range 292-1599). Positivity for Merkel cell polyomavirus was observed in 29 (55%) of cases. Expression of p63 and p40 was present in 36 (69%) and 4 (8%) of cases, respectively. Increased age (P = .0241), negative Merkel cell polyomavirus status (P = .0185), and p63 positivity (P = .0012) were significantly associated with mortality. The latter 2 variables were highly correlated (P = .004). The interclass correlation between the 2 sets of H-scores was 0.95. Our findings support an association between p63 expression and reduced overall survival in MCC and show consistency in scoring this prognostic parameter. TAp63 is the dominant isoform of the protein involved. The paradoxical tumor suppressor-like activity of this isoform in p63-positive MCCs with reduced overall survival requires further study.