Using Artificial Intelligence as a Melanoma Screening Tool in Self-Referred Patients.

INTRODUCTION: Early detection of melanoma requires timely access to medical care. In this study, we examined the feasibility of using artificial intelligence (AI) to flag possible melanomas in self-referred patients concerned that a skin lesion might be cancerous. METHODS: Patients were recruited for the study through advertisements in 2 hospitals in Halifax, Nova Scotia, Canada. Lesions of concern were initially examined by a trained medical student and if the study criteria were met, the lesions were then scanned using the FotoFinder System®. The images were analyzed using their proprietary computer software. Macroscopic and dermoscopic images were evaluated by 3 experienced dermatologists and a senior dermatology resident, all blinded to the AI results. Suspicious lesions identified by the AI or any of the 3 dermatologists were then excised. RESULTS: Seventeen confirmed malignancies were found, including 10 melanomas. Six melanomas were not flagged by the AI. These lesions showed ambiguous atypical melanocytic proliferations, and all were diagnostically challenging to the dermatologists and to the dermatopathologists. Eight malignancies were seen in patients with a family history of melanoma. The AI's ability to diagnose malignancy is not inferior to the dermatologists examining dermoscopic images. CONCLUSION: AI, used in this study, may serve as a practical skin cancer screening aid. While it does have technical and diagnostic limitations, its inclusion in a melanoma screening program, directed at those with a concern about a particular lesion would be valuable in providing timely access to the diagnosis of skin cancer.

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.

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.

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.

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.

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.

Global PD-L1 Signals and Tumor-Infiltrating Lymphocytes: Markers of Immunogenicity in Different Subsets of Merkel Cell Carcinoma and Potential Therapeutic Implications.

We previously studied the genetic and immunohistochemical profiles of subsets of Merkel cell carcinoma (MCC) stratified by morphology and Merkel cell polyomavirus (MCPyV) status. Recent advances in the immunotherapy of this disease prompted us to examine markers of immunogenicity [PD-L1 expression and tumor-infiltrating lymphocytes (TILS) in these subsets]. The observed clinical responses to checkpoint inhibition of the PD-1/PD-L1 pathway have not correlated with PD-L1 expression by MCC cells, and recent evidence suggests that functions of this pathway within the immune tumor microenvironment may be relevant. We conducted a semiquantitative (high, moderate, and minimal) immunohistochemical evaluation of the global PD-L1 signal in 52 cases of MCC, segregated in 3 subsets [pure MCPyV-positive (n = 28), pure MCPyV-negative (n = 9), and combined MCPyV-negative (n = 15)]. TILS were categorized as brisk, nonbrisk, or absent. Intersubset comparisons revealed that high global PD-L1 signals were exclusively associated with pure MCPyV-positive MCCs contrasted with virus-negative cases (P = 0.0003). Moderate signals were seen across all 3 groups. Brisk TILS were significantly associated with MCPyV-positive MCCs compared with MCPyV-negative cases (P = 0.029). Neither parameter (PD-L1 or TILS) was significantly different between the MCPyV-negative groups. Of potential clinical relevance, MCPyV seems to convey greater immunogenicity to MCCs than the high mutational burden/greater neoantigen load of MCPyV-negative cases. Interesting too is the fact that subset-related profiles of these markers mirrored those noted at genetic and immunohistochemical levels, separating pure MCPyV-positive MCCs from the virus-negative subsets.

Cutaneous manifestations of angioimmunoblastic T-cell lymphoma: clinical and pathological characteristics.

Angioimmunoblastic T-cell lymphoma (AITL), an uncommon variant of peripheral T-cell lymphoma, affects the skin in approximately 50% of cases. Its protean clinical and histopathological cutaneous manifestations pose a challenge in diagnosis, particularly when these precede the diagnosis of AITL on a lymph node biopsy. In this retrospective study, we compared 11 cases of AITL with cutaneous manifestations (mean age 67 years; male:female ratio 1:0.8; 24 skin biopsies) with 20 control cases of inflammatory and non-AITL lymphomatous diseases (mean age 52 years; male:female ratio 1:1.5; 26 skin biopsies). Clinical, histopathological, immunohistochemical, and molecular data were documented. New insights into the clinical evolution of cutaneous involvement by AITL (C-AITL), from early macular, through papular to nodular stages, were observed. Microscopically, a parallel increment in the density of the dermal infiltrate and in the detection of lymphocyte cytological atypia was noted over time. Identification and quantification of follicular T-helper cells (Tfh), the neoplastic lineage, by immunohistochemistry helped to separate cases of C-AITL from inflammatory controls, offering promise as a useful diagnostic adjunct. The presence of T-cell clonality did not have discriminatory value between the 2 groups. Our work suggests that the early maculopapular phase of C-AITL eludes identification on pathological grounds alone and that features such as cytological atypia and high endothelial venules lack diagnostic specificity. In the context of (1) a rash that simulates a drug/viral exanthem or an acute manifestation of a connective tissue disorder, but proves recalcitrant, (2) constitutional abnormalities and/or lymphadenopathy that persist, and (3) a Tfh cell-rich perivascular dermatitis, the diagnosis of early C-AITL can be suspected, but not confirmed, without the benefit of a lymph node biopsy. The later nodular phase of C-AITL occurring in a similar constitutional background, can usually be discerned as lymphomatous, clinically and pathologically. Here a Tfh cell-rich infiltrate is a clue to the specific diagnosis, but confirmation by a nodal evaluation remains mandatory. Despite the difficulty in establishing a diagnosis of C-AITL in its early stages, and speculation that the initial eruptions might be reactive in nature, our sequential data support the concept that these are lymphomatous ab initio. To address the diagnostic challenge presented by this disease, meaningful integration of clinical and pathological data is imperative.

Epidermodysplasia verruciformis in lipoid proteinosis: case report and discussion of pathophysiology.

Lipoid proteinosis (LP) is a rare autosomal recessive genodermatosis caused by mutations in extracellular matrix protein 1 (ECM1) that involves deposition of basement membrane-like material in the skin and other organs. Epidermodysplasia verruciformis (EV) is also a rare autosomal recessive genodermatosis involving susceptibility to human papillomavirus (HPV) infections and squamous cell carcinoma, caused in most cases by homozygous mutations in EVER1 or EVER2. We describe a case of EV in a patient with LP and discuss the pathophysiology. A 3-year-old Lebanese girl presented with hoarseness, beaded papules along the eyelid margins, waxy papules and plaques on her head and neck, and lichenoid verrucous papules on the forearms and hands. Histopathology of the waxy papules exhibited deposition of periodic acid Schiff-positive basement membrane-like material in the superficial dermis, characteristic of LP. The verruca plana-like lesions exhibited acanthosis and enlarged keratinocytes with pale blue-grey cytoplasm and a perinuclear halo, consistent with verrucae and EV. Polymerase chain reaction amplification and sequencing of ECM1, EVER1, and EVER2 demonstrated a homozygous point mutation, c.389C>T (p.Thr130Met), in exon 6 of ECM1 and a heterozygous point mutation, c.917 A>T (p.Asn306Ile), in exon 8 in EVER2, known to cause EV in homozygous patients. The homozygous point mutation c.389C>T in ECM1 may be a novel mutation causing LP. Verruca plana-like lesions seen in LP appear to represent a form of acquired EV. In this patient, a heterozygous mutation in EVER2 at c.917 A>T may also have conferred susceptibility to HPV infection.

A unique case of glaucoma associated with heterotopic bone formation in the anterior chamber angle.

Purpose: To describe a unique case of unilateral open angle glaucoma secondary to heterotopic bone formation in the anterior chamber angle. Observations: A 57 year-old male with an unremarkable history presented with right eye pain. Anterior segment examination demonstrated a solid, white deposit overlying the trabecular meshwork and peripheral iris associated with an intraocular pressure of 44 mmHg. The left eye examination was unremarkable. Biopsy of the material surprisingly showed heterotopic bone. Removal of the material and medical treatment were unable to adequately control the intraocular pressure and a trabeculectomy was successfully performed. Conclusions and Importance: This case demonstrates a unique cause of secondary open angle glaucoma: heterotopic bone formation in the anterior chamber angle.

Abscopal responses in patients with metastatic melanoma involving skin and subcutaneous tissues treated with intralesional IL2 plus BCG.

Cutaneous melanoma is relatively common with increasing incidence and significant mortality. While the mainstay of therapy is surgical, patients with stage III and IV disease fare poorer than those with early-stage disease and often benefit from adjuvant therapies. While systemic immunotherapy has changed the landscape of melanoma treatment, for some patients systemic toxicities related to these treatments prohibit successful administration or completion of therapy. Moreover, it is becoming increasingly evident that nodal, regional, and in-transit disease appears to be resistant to systemic immunotherapy relative to responses observed in distant metastatic disease sites. In this scenario, intralesional immunotherapies may offer benefit. In this case series, we describe the use of intralesional IL-2 and BCG at our institution in ten patients with in-transit plus or minus distant cutaneous metastatic melanoma over the last twelve years. All patients received intralesional IL2 and BCG. Both treatments were very well tolerated with only grade 1/2 adverse events. In our cohort, complete clinical response was 60% (6/10), progressive disease in 20% (2/10), and no response in 20% (2/10) of patients. The overall response rate (ORR) was 70%. The median overall survival was 35.5 months and mean overall survival 43 months in this cohort. Herein we further highlight the clinical, histopathological, and radiological course of two complete responders, showing evidence of an abscopal effect with resolution of distant untreated metastasis. Together, this limited data supports the safe and effective use of intralesional IL2 and BCG for the treatment of metastatic or in-transit melanoma in this challenging patient cohort. To our knowledge, this is the first formal study to report on this combination therapy for the treatment of melanoma.

Merkel cell carcinoma: an update.

Merkel cell carcinoma (MCC) is an uncommon primary cutaneous neuroendocrine carcinoma associated with an adverse prognosis. In recent years, our understanding of MCC biology has markedly progressed. Since the discovery of the Merkel cell polyomavirus, it has become clear that MCC represents an ontogenetically dichotomous group of neoplasms with overlapping histopathology. Specifically, most MCCs arise secondary to viral oncogenesis, while a smaller subset is the direct result of UV-associated mutations. The distinction of these groups bears relevance in their immunohistochemical and molecular characterization, as well as in disease prognosis. Further recent developments relate to the landmark utilization of immunotherapeutics in MCC, providing optimistic options for the management of this aggressive disease. In this review, we discuss both fundamental and emerging concepts in MCC, with a particular focus on topics of practical relevance to the surgical or dermatopathologist.

Etanercept-induced cutaneous and pulmonary sarcoid-like granulomas resolving with adalimumab.

A 59-year-old female with rheumatoid arthritis on etanercept therapy presented with a 7-cm-large subcutaneous forearm mass. Multiple smaller nodules subsequently developed on the upper and lower extremities. Except for a new cough, the patient was systemically well. Biopsy of the mass showed sarcoidal type granulomatous inflammation with nodular aggregations of non-necrotizing epithelioid histiocytes in the subcutis. A chest computed tomography (CT) scan showed mediastinal adenopathy consistent with pulmonary sarcoidosis. Etanercept was discontinued, and the patient was started on adalimumab for rheumatoid arthritis control. The cutaneous nodules fully resolved in 6 months with no additional treatment. A 4-month follow-up CT scan showed significant regression of mediastinal adenopathy. The patient has since been maintained on adalimumab therapy for 2 years with no recurrence of sarcoid-like manifestations. Biologic response modifiers targeting tumor necrosis factor alpha (TNFα) are effective treatments of chronic inflammatory conditions such as rheumatoid arthritis and psoriasis. TNFα represents a major cytokine in granuloma formation, and TNFα inhibitors are sometimes efficacious in the treatment of sarcoidosis. Paradoxically, there is a small volume of literature implicating TNFα inhibitors in the development of sarcoid-like disease. We present this case to promote the recognition of TNFα inhibitor-induced sarcoidosis and to illustrate the wide clinicopathologic differential of sarcoidal type granulomas.

Scleromyxedema and the dermato-neuro syndrome: case report and review of the literature.

Scleromyxedema is a generalized form of lichen myxedematosus which is characterized by a papular and sclerodermoid skin eruption resulting from dermal fibroblast proliferation and mucin deposition. The majority of patients with scleromyxedema have a monoclonal gammopathy, and other systemic manifestations are common. Herein we describe a case of the 'dermato-neuro syndrome', a rare and sometimes fatal neurologic manifestation of scleromyxedema which consists of fever, convulsions and coma, often preceded by a flu-like prodrome. In addition, we provide a comprehensive summary of previously published cases of the dermato-neuro syndrome and discuss the current etiopathogenic theories and treatment options for this rare disease.

Necrobiotic xanthogranuloma associated with necrotizing scleritis.

A 57-year-old man presented to the ophthalmology clinic with a red right eye. He denied pain, diplopia, tearing, and blurred vision. His medical history included asymptomatic annular plaques on the trunk and extremities for at least a decade. Ophthalmological examination revealed a necrotizing scleritis of the right eye. Examination of the skin demonstrated variable sized annular plaques with central atrophy, some with prominent indurated border and yellow discoloration. No periorbital lesions were present. The ocular lesion rapidly progressed and areas of scleral melting developed in the right eye, which eventually required a scleral patch graft. The left eye also developed necrotizing scleritis with areas of scleral melting. Two sets of skin biopsies were performed a few weeks apart. An initial set of skin punch biopsies revealed extensive palisading granulomatous inflammation throughout the dermis, extending into the subcutis. The accompanying perivascular mononuclear infiltrate contained the collections of plasma cells. Scattered multinucleated giant cells were noted. The possibility of necrobiosis lipoidica diabeticorum was suggested. Subsequent skin biopsies showed more prominent and extensive necrobiosis, raising the possibility of necrobiotic xanthogranuloma. Protein electrophoresis was performed, which revealed an IgG λ monoclonal protein.

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.

Persistent pigmented purpuric dermatitis: granulomatous variant.

The persistent pigmented purpuric dermatitides (PPPD) are a spectrum of dermatologic disorders characterized by petechial and pigmented macules usually confined to the lower limbs. Their etiology is unknown and several clinical variants are recognized. At the microscopic level they are characterized by angiocentric lymphocytic inflammation, red blood cell extravasation and hemosiderin deposition. A granulomatous variant of the PPPD has recently been described and to date eleven cases have been reported in the literature. In contrast to the conventional type, this variant is characterized histopathologically by ill-defined, non-necrotizing granulomata admixed with the lymphocytic inflammatory background. Although initially the granulomatous variant of the PPPD was thought to occur only in Asian patients, this sole racial predilection has not been substantiated. A tenuous association with hyperlipidemia has been noted but this requires further study. The principal importance of recognizing this entity lies in the need to include it in the histopathological differential diagnosis of granulomatous dermal infiltrates. We report here an additional patient with the granulomatous variant of PPPD and elaborate on this entity in the context of existing information in the literature.

Case Report: Combined Intra-Lesional IL-2 and Topical Imiquimod Safely and Effectively Clears Multi-Focal, High Grade Cutaneous Squamous Cell Cancer in a Combined Liver and Kidney Transplant Patient.

Cutaneous squamous cell carcinoma (cSCC) is the second most common non-melanoma skin cancer worldwide, with ever increasing incidence and mortality. While most patients can be treated successfully with surgical excision, cryotherapy, or radiation therapy, there exist a subset of patients with aggressive cSCC who lack adequate therapies. Among these patients are solid organ transplant recipients who due to their immunosuppression, develop cSCC at a dramatically increased rate compared to the normal population. The enhanced ability of the tumor to effectively undergo immune escape in these patients leads to more aggressive tumors with a propensity to recur and metastasize. Herein, we present a case of aggressive, multi-focal cSCC in a double organ transplant recipient to frame our discussion and current understanding of the immunobiology of cSCC. We consider factors that contribute to the significantly increased incidence of cSCC in the context of immunosuppression in this patient population. Finally, we briefly review current literature describing experience with localized therapies for cSCC and present a strong argument and rationale for consideration of an IL-2 based intra-lesional treatment strategy for cSCC, particularly in this immunosuppressed patient population.

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.