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Since their first approval 25 years ago, monoclonal antibodies (mAbs) have become important targeted cancer therapeutics. However, dermatologic toxicities associated with non-immune checkpoint inhibitor (non-ICI) mAbs may complicate the course of cancer treatment. Data on the incidence and types of these reactions are limited.A comprehensive review was conducted on dermatologic toxicities associated with different classes of non-ICI mAbs approved for treatment of solid tumors and hematologic malignancies. The review included prospective Phase 1, 2, and 3 clinical trials; retrospective literature reviews; systematic reviews/meta-analyses; and case series/reports.Dermatologic toxicities were associated with several types of non-ICI mAbs. Inflammatory reactions were the most common dermatologic toxicities, manifesting as maculopapular, urticarial, papulopustular/acneiform, and lichenoid/interface cutaneous adverse events (cAEs) with non-ICI mAbs. Immunobullous reactions were rare and a subset of non-ICI mAbs were associated with the development of vitiligo cAEs.Dermatologic toxicities of non-ICI mAbs are diverse and mostly limited to inflammatory reactions. Awareness of the spectrum of the histopathologic patterns of cAE from non-ICI mAbs therapy is critical in the era of oncodermatology and oncodermatopathology.

The immunohistochemical (IHC) marker PReferentially expressed Antigen in MElanoma (PRAME) has shown promise in the diagnosis of melanocytic lesions. A few studies have investigated PRAME IHC expression in acral melanomas, but PRAME expression in subungual melanomas is largely unknown. We evaluated the utility of PRAME IHC expression in distinguishing subungual melanomas (SUM) and non-subungual acral melanomas (AM) from acral nevi (AN).Twenty-two SUM, 20 AM, and 14 AN were identified. IHC studies were performed using an anti-PRAME antibody. The percentage of lesional cells with PRAME expression was recorded and categorized as follows: 0%, 0; 1%-25%, 1+; 26%-50%, 2+; 51%-75%, 3+; and75%, 4+. Patient demographics and other relevant clinicopathologic parameters were recorded.Diffuse (4+) PRAME IHC expression was identified in 55% (12/22) SUM and 70% (14/20) AM, respectively. Any PRAME expression (1+ to 4+) was identified in 73% (16/22) SUMs and 95% (19/20) AM, respectively. One of 14 (7%) AN exhibited PRAME expression; interestingly, the pattern of expression was diffuse.In our study, PRAME IHC expression was useful in identifying AM, including SUM. However, there are exceptions of PRAME-negative melanomas and PRAME-positive nevi.

Merkel cell carcinoma (MCC) is an aggressive, highly metastatic, cutaneous neuroendocrine malignancy with poor prognosis. Here, we describe a MCC excision specimen with a rare case of tumor-associated amyloid deposition in the absence of residual tumor cells. A 72-year-old man presented with a lesion of 5-6 months' duration on his left elbow, clinically thought to be a ganglion cyst. The biopsy specimen revealed a Stage IIA MCC with classic histomorphologic and immunophenotypic findings, with tumor extending to the tissue edges. The patient underwent wide local excision with negative margins and a negative sentinel lymph node biopsy. Although the patient did not receive any presurgical chemotherapy, immunotherapy, or targeted therapy, the re-excision specimen showed only amphophilic, feathery deposits that were salmon-pink with Congo red stain and further confirmed as amyloid by electron microscopy; there were no residual carcinoma cells. Amyloid deposition in MCC has been described in rare case reports. Our case was extraordinary in that there was only amyloid deposition and an associated granulomatous reaction, without identifiable MCC cells. This case demonstrates that amyloid deposition may be evidence of a prior MCC at the site of a prior procedure and may warrant careful evaluation for residual MCC.

Ibrutinib is a Bruton tyrosine kinase inhibitor used to treat many hematologic conditions, most commonly B-cell lymphomas and leukemias. Reportedly, skin rash is an adverse event in up to 27% of treated patients. Histopathologic description of these lesions is limited. We present two cases of ibrutinib-associated skin toxicities showing diverse histopathologic features. Case 1: A 72-year-old man was started on ibrutinib for chronic lymphocytic leukemia. Two months later, he developed multiple erythematous crusted papules on the chest, abdomen, and extremities. Biopsies revealed varied histopathology including poorly formed granulomatous dermatitis, epidermal necrosis, ulceration, and panniculitis. Ibrutinib was discontinued and his skin lesions resolved within 1 month. Case 2: A 48-year-old man received ibrutinib after failing standard therapy for primary central nervous system EBV positive diffuse large B-cell lymphoma. Two months after initiation of ibrutinib, he developed multiple firm, red, non-tender nodules on the forehead, buttock, and thigh. Biopsies revealed "pseudolymphoma"-like reaction with dense pandermal lymphohistiocytic inflammation and granulomas. His skin toxicity resolved without cessation of therapy. Awareness of the spectrum of histopathologic features that may be encountered in skin lesions of patients treated with ibrutinib, as illustrated by these two cases, will be critical for optimal patient management.

The development of immune checkpoint inhibitor (ICI) therapy with anti-CTLA-4 and anti-PD-1/L1 monoclonal antibodies has led to a paradigm shift in cancer therapy. ICI neoadjuvant therapy followed by surgery has become the standard of care for several advanced-stage cancers. The pathology associated with ICI therapy is vast and includes neoadjuvant-associated tissue reactions and activation of tertiary lymphoid structures (TLSs) at the site of the tumor bed and off-target immune-related adverse events (irAEs). TLSs are thought to recapitulate lymph node function and may act as localized immune machinery to mount an antitumor response. B cell activation in TLSs during neoadjuvant ICI therapy has been correlated with antitumor response. We report a patient with a history of sarcomatoid squamous cell carcinoma treated with neoadjuvant ICI cemiplimab who developed clonal expansion of B cells in the TLSs of the tumor bed. The TLSs morphologically mimicked a low-grade B cell lymphoma with plasmacytic differentiation. Awareness of clonal expansion of B cells in TLSs during neoadjuvant ICI therapy is critical to recognize a response to ICI therapy and to avoiding an incorrect diagnosis of low-grade B cell lymphoma. This article is protected by copyright. All rights reserved.

Langerhans cell sarcoma (LCS) is rare and aggressive; patients have an overall survival rate of less than 50%. We present a 62-year-old man with a history of superficial spreading melanoma of the upper back with sentinel lymph node metastasis, Langerhans cell histiocytosis, and LCS. The patient presented with erythematous papules and scaly areas on his face, neck, arms, chest, abdomen, and legs. A skin biopsy revealed a proliferation of large neoplastic cells involving the dermis and with epidermotropism. These cells had atypical bean-shaped nuclei, with ample cytoplasm and abundant mitotic figures including atypical forms. Immunohistochemical studies showed the tumor to be diffusely positive for CD1a, S100 protein, and langerin (CD207) and negative for melanocytic markers. Some tumor cells were positive for cyclin D1. A diagnosis of LCS involving the skin was established. The present study is a very unusual case of LCS showing epidermotropism. The patient's history of metastatic melanoma posed additional challenges for diagnosis, underlying the need of immunophenotyping in these cases. Consensus for optimal standard therapy has not been established in LCS, and thus, early recognition is important since these neoplasms tend to recur and metastasize. LCS in skin is discussed and published cases are comprehensively reviewed.

Immune checkpoint inhibitors (ICIs) for cancer treatment have revolutionized the field of medicine. However, an unintended but frequent consequence of ICI therapy is the development of cutaneous immune-related adverse events (irAEs), such as lichenoid dermatitis irAEs (LD-irAEs). The hypertrophic variant of LD-irAE may be a diagnostic challenge since it can mimic superficially invasive squamous cell carcinoma (SCC). A 79-year-old woman with metastatic melanoma who began treatment with an ICI-pembrolizumab-plus exportin-1 (XPO1) inhibitor presented after 1 month of therapy with symmetrical violaceous papules coalescing into plaques and with two nodules of the bilateral dorsal hands. Biopsy of the nodules revealed an actinic keratosis and atypical epidermal proliferation concerning for SCC. However, in the ensuing 3 weeks, the patient developed multiple new erythematous, violaceous, and scaly macules and papules, some coalescing into plaques on the extremities. Biopsies of these lesions revealed exuberant irregular epidermal hyperplasia with hypermaturation and lichenoid infiltrate concentrated at the base of the elongated, broadened rete ridges, consistent with hypertrophic LD-irAE. Treatment included topical fluocinonide ointment, intralesional triamcinolone injections and oral acitretin. Distinguishing hypertrophic LD-irAE and SCC can be challenging since both entities share histopathologic features; thus, correlation with clinical presentation is essential for diagnosis and optimal patient management.

Transforming growth factor-beta1 (TGF-β1) is expressed in normal epidermis. TGF-β1 potently inhibits keratinocyte proliferation and immunomodulatory properties, mainly by suppressing immune responses to self-antigens. Lichen planus (LP) is a form of dermatitis caused by cell-mediated immune dysfunction, but the exact pathogenic pathways are unknown, which poses therapeutic challenges. We report on a 68-year-old man who developed multiple pruritic, discrete, and well-demarcated, flat-topped red-purple papules and macules on the back and upper arms following 4 cycles of treatment with TGF-β receptor I (TGFBR-I) inhibitor, ly3200882, for metastatic chondrosarcoma. The biopsy showed hyperkeratosis, wedge-shaped hypergranulosis, elongation of the rete ridges, and a dense band-like lymphohistiocytic infiltrate admixed with colloid bodies and pigment incontinence, consistent with LP. Temporal correlation suggested that the TGFBR-I inhibitor might be a trigger. Treatment with topical clobetasol and oral metronidazole led to partial resolution of the lesions with postinflammatory hyperpigmentation. We believe this is the first reported case of LP related to TGFBR-I inhibitor therapy. This report expands the list of cutaneous adverse events associated with this novel class of targeted therapy. More importantly, this report supports emerging evidence that failure of TGF-β1 activation/signal transduction is an important mechanism in the pathogenesis of LP and suggests the TGF-β1 pathway as a potential therapeutic target in this disease.

BACKGROUND Cancer patients receiving antibodies abrogating immune checkpoint pathways may develop a diverse array of immune-related adverse events (irAEs), of which lichenoid dermatitis (LD) is the most common. The mechanism driving the emergence of these irAEs remain understudied, underscoring a critical need to determine the unique gene expression profiles and immune composition in LD-irAE. METHODS LD-irAE (n = 3) and benign lichenoid keratosis (BLK) control (n = 3) were profiled with NanoString nCounter PanCancer Immune Profiling Panel interrogating the mRNA levels of 770 genes. Immunohistochemical (IHC) studies (n = 14 samples) for CD14, CD16, T-Bet, Gata-3, and FoxP3 were further evaluated using Aperio digital image analysis. RESULTS The LD-irAE showed downregulation of 93 mRNA transcripts (P

Post-radiation vascular lesions are a rare complication most commonly seen in patients previously treated for breast cancer. The main two entities include angiosarcoma (AS), which are malignant tumors that have a poor prognosis, and atypical vascular lesions (AVL), which typically behave in a benign manner and only rarely progress to angiosarcoma. The overall incidence of these lesions is low, but it appears to be increasing. Histopathologic distinction of AVL and AS is essential due to different clinical outcomes and treatment. However, due to the occasional existence of overlapping clinical and histopathologic features, it may be sometimes difficult to render a definite diagnosis, particularly in small biopsies. Ancillary techniques are, in general, of little help for separating the borderland cases but, in some instances, immunohistochemical study (IHC) for Ki67 and IHC or fluorescence in situ hybridization analysis for MYC may help in the diagnosis of angiosarcoma. Herein we discuss the clinical characteristics, histopathologic features, management strategies, and outcome of these lesions, with special emphasis on their differential diagnosis.

Small-molecule inhibitors (nibs) have revolutionized cancer therapy with the emergence of clinically efficacious treatment for advanced-stage malignancies. Fibroblast growth factor receptor (FGFR) inhibitors have shown therapeutic efficacy in malignancies with molecular-genetic alterations in the FGFR/fibroblast growth factor pathway. In a phase 1 clinical trial, erdafitinib, a pan FGFR inhibitor, was well tolerated with a manageable toxicity profile. Hyperphosphatemia was a frequent adverse event in patients treated with erdafitinib; however, no serious complications were observed with this therapy. Here, we report the development of calcinosis cutis dermatologic toxicity in a patient with hyperphosphatemia while treated with a novel selective FGFR inhibitor, INCB 54828-101. Awareness of this form of dermatologic toxicity from an FGFR inhibitor will be important for close monitoring of serum levels of phosphate, FGF23, vitamin D, and calcitriol, the management of adverse serum chemistry with chelators, and treatment decisions to either reduce dose or withhold FGFR inhibitor.

Checkpoint inhibitors (CPIs) restore the function of effector immunocytes to target and destroy cancer cells. Immune-related adverse events (irAEs) are a consequence of immune reactivation, with unpredictable inflammatory response, loss of self-tolerance, and development of autoimmunity. Adverse events from CPIs that present as dermatologic toxicities have diverse clinical and histopathologic features. CPI-associated dermatologic toxicities may exhibit histopathologic features of lichenoid dermatitis, bullous pemphigoid, and granulomatous/sarcoid-like reactions. Suprabasal acantholytic dermatologic toxicities associated with CPIs are particularly rare but represent an emerging histopathologic pattern and include lichenoid dermatitis with suprabasal acantholysis/vesicle formation to Grover disease (transient acantholytic dermatosis). Here, we report two patients who developed suprabasal acantholytic dermatologic toxicities during CPI therapy. One patient exhibited a CPI-associated autoimmune blistering disease with paraneoplastic pemphigus (PNP)-like features restricted to histopathology and immunofluorescence, while the other patient had Grover-like lesions. A review of the literature revealed a spectrum of suprabasal acantholytic dermatologic toxicities associated CPIs that may present as lichenoid dermatitis with acantholysis/vesicle formation, Grover-like eruptions, and lesions with PNP-like features restricted to histopathology and immunofluorescence. It is important for clinicians and pathologists to recognize the types of dermatologic toxicities associated with CPIs to direct appropriate therapeutic strategies.

LL-37 is a naturally occurring 37-amino-acid peptide that is part of the innate immune system in human skin. Preclinical studies have showed that intra-tumoral injections of LL-37 stimulate the innate immune system by activation of plasmacytoid dendritic cells, which mediate tumor destruction. LL-37 intra-tumoral injections have been utilized in a phase 1 clinical trial for melanoma patients with cutaneous metastases. We report dermatologic toxicity in a 63-year-old woman with stage IIIC melanoma of the right calf and inguinal lymph nodes. She was previously treated with nivolumab and combination chemotherapy (cisplatin, vinblastine and dacarbazine) and subsequently treated with LL-37 injections upon progression of both prior regimens. She received a total of 8 weekly LL-37 injections, with interval clinical shrinkage of injected lesions. However, approximately 45 days after initiation of this therapy, she presented with multiple verrucous papules and a vesiculo-bullous lesion on the trunk and extremities. Clinically, most of these lesions were thought to be either squamous cell carcinoma or inflamed seborrheic keratosis. Histologically, 11 of the total 12 skin biopsies showed similar histopathologic features, with a prominent lichenoid inflammatory infiltrate admixed with eosinophils and an overlying atypical squamous epithelial proliferation with verrucous and keratoacanthoma-like features and varying degrees of keratinocytic atypia. Interestingly, a majority of the lesions did not show spongiosis (11/12). All lesions resolved within 2 months of cessation of LL-37 injection therapy. This case highlights adverse dermatological manifestations of LL-37 therapy, similar to the consequences of other novel therapies.

Immunotherapies targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death 1 (PD-1) receptor and its ligand (PD-L1) have showed significant therapeutic benefit in patients with clinically advanced solid malignancies, including melanoma. However, immune-related adverse events (irAE) are common, and novel dermatologic toxicities continue to emerge as more patients are treated with immunotherapy. Here we describe a patient treated with combination immunotherapy of ipilimumab and pembrolizumab, who developed asymptomatic erythematous patches on both legs. Histopathologic examination revealed a cutaneous interstitial granulomatous dermatitis. Notably, our patient did not require cessation of immunotherapy for these lesions, which subsequently remained stable, while the patient's melanoma remained controlled. This case expands the dermatologic toxicity profile of immune checkpoint blockade, as recognition of such toxicities is critical to optimal patient management.

Immunotherapies targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death 1 (PD-1) receptor and its ligand (PD-L1) have showed substantial therapeutic benefit in patients with clinically advanced solid malignancies. However, autoimmune toxicities are common and often significant adverse events with these agents. While rash and pruritus remain the most common cutaneous complications in treated patients, novel dermatologic toxicities related to immune checkpoint blockade continue to emerge as the number of patients exposed to immunotherapy increases. Here, we describe 2 patients treated with combination immunotherapy with ipilimumab and nivolumab who developed painful subcutaneous nodules. Although the findings were clinically concerning for disease recurrence, histopathologic examination of biopsies from the lesions revealed a subcutaneous mixed septal and lobular erythema nodosum-like panniculitis. Notably, neither patient received immunosuppressive therapy for these lesions, which subsequently remained stable, and both patients' cancer remained controlled. These cases show that the dermatologic toxicity profile of immune checkpoint blockade is diverse and continues to expand, and illustrates that recognition of such toxicities is critical to optimal patient management.

Chronic myelomonocytic leukemia (CMML) is a hematopoietic stem cell neoplasm exhibiting both myelodysplastic and myeloproliferative features. Cutaneous involvement by CMML is critical to recognize as it typically is a harbinger of disease progression and an increased incidence of transformation to acute myeloid leukemia. Cutaneous lesions of CMML exhibit heterogeneous histopathologic features that can be challenging to recognize as CMML. We describe a 67-year-old man with a 3-year history of CMML who had been managed on single-agent azacitidine with stable disease before developing splenomegaly and acute onset skin lesions. Examination of these skin lesions revealed a dense infiltrate of histiocytic cells morphologically resembling Langerhans type cells (lacking frank histopathologic atypia), and with the immunophenotype of an indeterminate cell histiocytosis (S100+ CD1a+ and langerin-). Given the history of CMML, next-generation sequencing studies were performed on the skin biopsy. These revealed a KRAS (p.G12R) mutation identical to that seen in the CMML 3 years prior, establishing a clonal relationship between the 2 processes. This case expands the spectrum for and underscores the protean nature of cutaneous involvement by CMML and underscores the importance of heightened vigilance when evaluating skin lesions of CMML patients.

Immunomodulatory drugs that leverages host immune mechanisms to destroy tumor cells have been met with great promise in the treatment of cancer. Immunotherapy, targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death 1 (PD-1) receptor and its ligand (PD-L1) have shown tremendous improvements in the survival of patients with advanced solid tumors. However, the development of dermatologic toxicity (DT) is a consequence to immunotherapy. Review of published reports of the DT to immunotherapy revealed patients receiving anti-CTCLA-4 antibody or anti-PD-1/PD-L1 antibody often develop a DT of any type and grade. In this article, of the 3825 patients who were treated with anti-PD-1 and of 556 patients receiving anti-PD-L1, DT of any type and grade were reported in 1474 (∼39%) and 95 (∼17%) of patients, respectively. The emergence of specific types of DT to immunotherapy is beginning to be recognized can be categorized into four groups: (a) inflammatory, (b) immunobullous, (c) alteration of keratinocytes and (d) alteration of melanocytes. Lichenoid dermatitis and bullous pemphigoid appear to be DT more associated with anti-PD-1/PD-L1 antibody. The DT profile in patients receiving immunotherapy is diverse, and early recognition of specific types of DT that clinicians may encounter is critical for optimal patient care

Extravascular migratory metastasis is a form of cancer metastasis in which tumor cells spread by tracking along the abluminal aspect of vessel walls without breaking the vascular endothelial lining or intraluminal invasion. This phenomenon has been extensively described in melanoma and is being increasingly recognized in other neoplasms. Various modalities of treatment, including radiation-, chemo-, targeted-, and immune- therapies may potentially induce angiotropic behavior in neoplastic cells. Although there is a risk for tumor recurrence and metastasis, angiotropism may be under-recognized and is rarely reported. Here, we report a case of recurrent poorly-differentiated acantholytic squamous cell carcinoma of the scalp with extensive perineural invasion, previously treated with multiple therapies. There was multifocal extravascular cuffing of neoplastic cells around and focally involving the walls of small to medium-caliber blood vessels within and surrounding the tumor, without obvious tumor intravasation. In addition, small subtle nests of neoplastic keratinocytes were noted along the abluminal aspect of a large-caliber deep dermal blood vessel in an en-face margin, away from the main tumor mass. Such involvement can be difficult to identify; and thus, may be missed particularly during intra-operative frozen section evaluation, leading to false-negative margins and is therefore, a diagnostic pitfall.

Anaplastic large cell lymphoma (ALCL) is an aggressive T-cell lymphoma characterized by strong and uniform expression of CD30. Brentuximab vedotin (BV), an anti-CD30 antibody-drug conjugate has been approved by the U.S. FDA for relapsed/refractory systemic ALCL and achieves improved outcomes. We report a 44-year-old African-American man who presented with lymphadenopathy, lip and chest nodules diagnosed as CD30+, ALK-negative ALCL. The patient was treated with BV upon recurrence. While on treatment, the patient developed new-onset nodules on the chest and back. Skin biopsy showed a diffuse dermal infiltrate of medium-to-large atypical lymphocytes with frequent mitosis and scattered eosinophils. Immunohistochemically, the atypical cells displayed the same immunophenotype as previous specimens (CD3+, CD4-/CD8-, CD56-, ALK- and TCR γ-), except for lack of CD30 expression which was attributed to BV treatment effect. The diagnosis was thought to be consistent with ALK-negative ALCL and the patient was continued on BV along with total skin electron beam radiation and the lesions cleared. The patient relapsed 2 months later with extensive disease and expired. In summary, this is the first report in the literature of loss of CD30 expression in ALCL after BV therapy. Awareness of this may prevent a mistaken diagnosis of a CD30-negative secondary T-cell lymphoma.

Disseminated histoplasmosis most commonly occurs in immunosuppressed individuals and involves the skin in approximately 6% of patients. Cutaneous histoplasmosis with an intraepithelial-predominant distribution has not been described. A 47-year-old man was admitted to our institution with fever and vancomycin-resistant enterococcal bacteremia. He had been diagnosed with T-cell prolymphocytic leukemia 4 years earlier and had undergone matched-unrelated-donor stem cell transplant 2 years earlier; on admission, he had relapsed disease. His medical history was significant for disseminated histoplasmosis 6 months before admission, controlled with multiple antifungal regimens. During this final hospitalization, the patient developed multiple 2-5 mm erythematous papules, a hemorrhagic crust across the chest, shoulders, forearms, dorsal aspect of the fingers, abdomen and thighs. Skin biopsy revealed clusters of oval yeast forms mostly confined to the cytoplasm of keratinocytes and within the stratum corneum; scattered organisms were present in the underlying superficial dermis without any significant associated inflammatory infiltrate. Special stains and immunohistochemical studies confirmed these to be Histoplasma organisms. We highlight this previously unrecognized pattern of cutaneous histoplasmosis to ensure its prompt recognition and appropriate antifungal therapy.

Monoclonal antibodies against the immune checkpoint programmed cell death receptor 1 (PD-1) improve the hosts' antitumor immune response and have showed tremendous promise in the treatment of advanced solid tumors and hematologic malignancies. Reports of serious autoimmune dermatologic toxicities from immune checkpoint blockade therapy, however, are emerging. We report our experience with five patients who presented with pruritic vesicles and blisters on the skin while treated with anti-PD-1 antibody immunotherapy with either nivolumab or pembrolizumab. Four of the patients' skin biopsies revealed subepidermal bullae with immunohistochemical study for type IV collagen labeling the floor of the blister cavity and direct immunofluorescence studies (in three of the four patients tested) decorated linear IgG and C3 immune deposits on the blister roof, diagnostic of bullous pemphigoid. One patient developed bullous erythema multiforme. All patients had partial or complete resolution of skin lesions following treatment with systemic corticosteroid and cessation of checkpoint blockade. Recognition and treatment of rare immune-related bullous dermatologic toxicities will become increasingly important as more patients are treated with effective and newer immune checkpoint blockade therapy.

Anaplastic thyroid carcinoma is a highly aggressive cancer accounting for 1-2% of thyroid malignancies. Cutaneous metastases from anaplastic thyroid carcinoma are exceedingly rare. We report a 65-year-old woman with anaplastic thyroid carcinoma (BRAF V600E mutation) who had lymph node metastases (pT4 N1b) treated by total thyroidectomy, postoperative radiotherapy, adjuvant chemotherapy (paclitaxel and pazopanib) and targeted therapy (vemurafenib). Nine months after initial diagnosis, radiographic studies revealed multiple pulmonary metastases. A dermatologic examination showed a solitary 1.2-cm chest nodule. Skin biopsy from this nodule revealed infiltrative dermal spindle cells arranged in poorly formed fascicles. Immunohistochemical studies demonstrated the tumor cells to be PAX-8 (+), pancytokeratin (+, focally), TTF-1 (-) and SOX-10 (-). Comparison with the patient's primary anaplastic thyroid carcinoma revealed focal areas of poorly differentiated spindle cells morphologically similar to the malignant spindle cells in the skin biopsy. Together, these findings confirmed the diagnosis of anaplastic thyroid carcinoma metastatic to skin. Cutaneous metastasis of anaplastic thyroid carcinoma composed exclusively of spindle cells broadens the histologic differential diagnosis of cutaneous spindle cell malignancies and presents further diagnostic challenges. PAX-8 may be useful in discerning the spindle cell component of anaplastic thyroid carcinoma from other spindle cell malignancies in the skin.

Background Indeterminate dendritic cell tumor is an extremely rare neoplastic proliferation of dendritic cells that share immunophenotypic features of Langerhans cells and macrophages but lack Birbeck granules and Langerin expression. Methods We report a 55-year-old female presenting with a leonine facies and generalized multiple confluent papules, nodules and plaques on neck, upper trunk, arms and thighs. Laboratory evaluations were performed including skin biopsies, peripheral blood flow cytometry and positron emission tomography-computed tomography. Results The lesional skin biopsy showed a dense dermal and perifollicular infiltrate composed of histiocytoid cells with nuclear grooves lacking dendritic processes in a background of lymphocytes. Eosinophils were absent. The histiocytoid cells were CD68+CD1a+Langerin- and only focally S100+. Special stains including GMS, Gram and Fite were all negative for infectious organisms. Although an initial diagnosis suggesting Langerhans cell histiocytosis was proposed due to CD1a positivity, a diagnosis of indeterminate dendritic cell tumor was finally rendered based on the histopathological findings and the lack of expression of Langerin. Conclusion This case illustrates the variegated clinical presentation of indeterminate cell tumor and the necessity of appropriate immunohistochemical workup for its diagnosis.

Background SMARCB1 (INI1/BAF47/SNF5) encodes a part of a multiprotein complex that regulates gene expression through chromatin remodeling. SMARCB1 expression is lost or downregulated in multiple human tumors, including epithelioid sarcoma, meningioma and rhabdoid tumors of the brain, soft tissue and kidney. Methods A 46-gene or 50-gene next-generation sequencing AmpliSeq Cancer Panel (Life Technologies; San Francisco, CA, USA) was applied to ∼1400 primary or metastatic melanoma tissues. Results We identified eight cases of melanoma harboring mutations in SMARCB1. Immunohistochemistry demonstrated preservation of SMARCB1 protein expression in all cases. SMARCB1 mutations occurred together with TP53 mutations in five of the eight cases, suggesting a functional relationship between these tumor suppressors in melanoma. Conclusions Because single-base substitutions in SMARCB1 occur in a small subset of melanomas and do not affect SMARCB1 protein expression, such mutations would only be discovered by sequencing approaches. Our findings highlight the potential for next-generation sequencing platforms to identify mutations unexpected for melanoma that may contribute to its oncogenic potential. Though rare, the identification of SMARCB1 mutations adds to the growing literature regarding the role of epigenetic control mechanisms in melanoma progression and therapeutic resistance and provide a rationale for strategies targeting such alterations (via chromatin remodeling agents) in clinical trials.

Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma that most commonly arises on the head and neck of elderly Caucasian men.1 Clinically, the tumors present as firm, rapidly growing, painless violaceous nodules with a smooth surface. Recurrence and metastasis occur frequently.2, 3 Up to 25% of tumors may recur, and approximately 80% of patients may develop metastases through the course of their disease 4Ultraviolet radiation, immunosuppression, and Merkel cell polyomavirus (MCV) appear to have etiologic roles in MCC 5The clinicopathologic parameters of MCC that portend poor prognosis include male sex, age greater than 55 years, location on the head and neck, tumor size greater than 2.0 cm, infiltrative growth pattern, vascular invasion, and high mitotic count.4, 6, 7 However, more recently, primary tumor size failed to correlate with lymph node metastasis.8-10 Tumor biomarker expression of p63 and survivin have been shown to correlate with poor prognosis, whereas P-cadherin expression has been associated with prolonged recurrence-free survival.11, 12 Mitotic biomarker analyses in MCC have not been thoroughly evaluated. Mitotic figure count is an important microscopic parameter in tumor classification and prognosis in several human malignancies, including MCC. Chromatin condensation during the G2/M phase of the cell cycle is an essential component of mitosis. An important regulator of chromatin condensation is posttranslational modification of histones. PHH3 (Ser 10) and H3KT (H3K79me3T80ph) are histone modifications in mitosis that share similar, strict temporal regulation: both appear in G2 thru M phases of the cell cycle. Neither is present in other phases of the cell cycle and neither is present in apoptotic cells. PHH3 has been shown to facilitate immunodetection of mitotic figures (evaluation of mitotic figure count) in several tumors (e.g., melanoma, astrocytomas, prostate cancer), and mitotic count combined with the number of G2+ tumor nuclei detected with H3KT identified a subset of primary invasive melanomas with risk of metastasis. 13, 14,15, 16 However, the prognostic utility of mitotic histone markers in MCC has not been well characterized. We compared the immunodetection of mitotic figures and G2+ tumor nuclei with anti-PHH3 and anti-H3KT along with the proliferative marker Ki-67 in MCC and correlated these findings with clinical outcome.

Primary cutaneous T-cell lymphomas (CTCL) comprise a heterogeneous group of neoplasms with diverse clinical behavior. Mycosis fungoides (MF) is the most common type of CTCL. Immunophenotypical shift during progression of the disease is a rare event and its significance is unknown. We present three primary CTCL cases that showed an immunophenotypical shift and poor prognosis. Conventional hematoxylin/eosin and immunohistochemical-stained sections were examined in all the cases. Molecular analysis for rearrangement of the T-cell receptor (TCR) gene was performed in two cases. One case was classified as MF, while the other two lacked epidermotropism, and were considered primary cutaneous peripheral T-cell lymphoma (PTCL), NOS. Two cases were CD3+/CD4+ and one case was CD3+/CD8+ at diagnosis. The first two patients suffered many relapses and eventually, new CTCL lesions with a CD3+/CD8+ phenotype were observed. Both cases revealed identical clonal TCR rearrangements on the initial and late lesions, supporting the interpretation of a single clonal proliferation with different phenotypes. The third case progressed with skin recurrences and pulmonary lesions with a predominant CD3+/CD4+/CD8- phenotype. All cases manifested poor prognosis and two patients died of lymphoma. Immunophenotypical shift between CD4 and CD8 in CTCL seems to be a rare phenomenon that may be associated with disease progression.

Background Cutaneous CD8(+) CD30(+) lymphoproliferative lesions are difficult to classify and encompass entities that follow a benign course to overt lymphoma. In order to identify histopathologic criteria for lesions in this spectrum, a series of such cases was reviewed. Methods Twenty-eight biopsies from 27 patients with CD8(+) CD30(+) cutaneous lymphoid proliferations were evaluated. Results Seventeen cases were classified as lymphomatoid papulosis (LyP) 'type D', eight as cutaneous anaplastic large cell lymphoma (C-ALCL) and two as CD8(+) mycosis fungoides (MF) with CD30 expression. Features of LyP included spongiosis and/or parakeratosis (90%), epidermotropism by large lymphocytes (90%), with (80%) or without (10%) small lymphocytes; wedge-shaped infiltrate (70%) with perivascular (100%) and interstitial (80%) pattern; and relative uniformity of CD30(+) large atypical cells (90%). C-ALCL was characterized by ulceration (63%), epidermotropism restricted to small lymphocytes (100%), marked density (63%) and pleomorphism (62%) of CD30(+) large atypical cells, and at least focal extension of infiltrate to subcutaneous tissue (88%). CD8(+) CD30(+) MF had vacuolar interface change and a lichenoid pattern (100%). Conclusions We concur with previous authors that distinction of CD8(+) LyP from lymphoma in its differential diagnosis is difficult based on histopathology alone. Nonetheless, we propose that certain histopathologic clues may be helpful in this differential diagnosis.

Immunomodulatory drugs that leverages host immune mechanisms to destroy tumor cells have been met with great promise in the treatment of cancer. Immunotherapy, targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death 1 (PD-1) receptor and its ligand (PD-L1) have shown tremendous improvements in the survival of patients with advanced solid tumors. However, the development of dermatologic toxicity (DT) is a consequence to immunotherapy. Review of published reports of the DT to immunotherapy revealed patients receiving anti-CTCLA-4 antibody or anti-PD-1/PD-L1 antibody often develop a DT of any type and grade. In this article, of the 3825 patients who were treated with anti-PD-1 and of 556 patients receiving anti-PD-L1, DT of any type and grade were reported in 1474 (∼39%) and 95 (∼17%) of patients, respectively. The emergence of specific types of DT to immunotherapy is beginning to be recognized can be categorized into four groups: (a) inflammatory, (b) immunobullous, (c) alteration of keratinocytes and (d) alteration of melanocytes. Lichenoid dermatitis and bullous pemphigoid appear to be DT more associated with anti-PD-1/PD-L1 antibody. The DT profile in patients receiving immunotherapy is diverse, and early recognition of specific types of DT that clinicians may encounter is critical for optimal patient care.

Background The p27(KIP1) and p57(KIP2) proteins belong to the CIP/KIP family of cyclin-dependent kinase inhibitors involved in the growth arrest and cellular senescence. High levels of p27(KIP1) unexpectedly have been detected in invasive malignant melanomas (MM), whereas the role of p57(KIP2) in melanocytic lesions is unknown. We therefore chose to study the expression of p27(KIP1) and p57(KIP2) in melanocytic neoplasms. Design The expression of p27(KIP1) and p57(KIP2) were examined by immunohistochemistry in 40 melanocytic neoplasms and by Western blot analysis in cultured human melanocytes. Results Expression of both nuclear p27(KIP1) and p57(KIP2) (> 10% of cells with nuclear labeling) was observed in most cases with non-proliferating melanocytes (8/10, benign nevi and 9/10 DN, dysplastic nevi), but in only a few cases containing proliferating melanocytes (3/11 RN, recurrent nevi and 2/9 MM, melanoma) (p Conclusion The difference in expression patterns of p27(KIP1) and p57(KIP2) in proliferating and senescent melanocytes suggests the interplay between these proteins may play a functional role in melanocytic tumorigenesis.

Anaplastic thyroid carcinoma is a highly aggressive cancer accounting for 1-2% of thyroid malignancies. Cutaneous metastases from anaplastic thyroid carcinoma are exceedingly rare. We report a 65-year-old woman with anaplastic thyroid carcinoma (BRAF V600E mutation) who had lymph node metastases (pT4 N1b) treated by total thyroidectomy, postoperative radiotherapy, adjuvant chemotherapy (paclitaxel and pazopanib) and targeted therapy (vemurafenib). Nine months after initial diagnosis, radiographic studies revealed multiple pulmonary metastases. A dermatologic examination showed a solitary 1.2-cm chest nodule. Skin biopsy from this nodule revealed infiltrative dermal spindle cells arranged in poorly formed fascicles. Immunohistochemical studies demonstrated the tumor cells to be PAX-8 (+), pancytokeratin (+, focally), TTF-1 (-) and SOX-10 (-). Comparison with the patient's primary anaplastic thyroid carcinoma revealed focal areas of poorly differentiated spindle cells morphologically similar to the malignant spindle cells in the skin biopsy. Together, these findings confirmed the diagnosis of anaplastic thyroid carcinoma metastatic to skin. Cutaneous metastasis of anaplastic thyroid carcinoma composed exclusively of spindle cells broadens the histologic differential diagnosis of cutaneous spindle cell malignancies and presents further diagnostic challenges. PAX-8 may be useful in discerning the spindle cell component of anaplastic thyroid carcinoma from other spindle cell malignancies in the skin.

SMARCB1 (INI1/BAF47/SNF5) encodes a part of a multiprotein complex that regulates gene expression through chromatin remodeling. SMARCB1 expression is lost or downregulated in multiple human tumors, including epithelioid sarcoma, meningioma and rhabdoid tumors of the brain, soft tissue and kidney.A 46-gene or 50-gene next-generation sequencing AmpliSeq Cancer Panel (Life Technologies; San Francisco, CA, USA) was applied to ∼1400 primary or metastatic melanoma tissues.We identified eight cases of melanoma harboring mutations in SMARCB1. Immunohistochemistry demonstrated preservation of SMARCB1 protein expression in all cases. SMARCB1 mutations occurred together with TP53 mutations in five of the eight cases, suggesting a functional relationship between these tumor suppressors in melanoma.Because single-base substitutions in SMARCB1 occur in a small subset of melanomas and do not affect SMARCB1 protein expression, such mutations would only be discovered by sequencing approaches. Our findings highlight the potential for next-generation sequencing platforms to identify mutations unexpected for melanoma that may contribute to its oncogenic potential. Though rare, the identification of SMARCB1 mutations adds to the growing literature regarding the role of epigenetic control mechanisms in melanoma progression and therapeutic resistance and provide a rationale for strategies targeting such alterations (via chromatin remodeling agents) in clinical trials.

Immunodeficiency-related lymphoproliferative disorders (IR-LPD) may occur in the setting of immunosuppressive therapy with methotrexate and TNF-α antagonists. As far as we are aware, this is the first report of an Epstein-Barr virus-associated B-cell lymphoproliferative disorder, secondary to methotrexate therapy in a patient with mycosis fungoides/Sézary syndrome.

Indeterminate dendritic cell tumor is an extremely rare neoplastic proliferation of dendritic cells that share immunophenotypic features of Langerhans cells and macrophages but lack Birbeck granules and Langerin expression.We report a 55-year-old female presenting with a leonine facies and generalized multiple confluent papules, nodules and plaques on neck, upper trunk, arms and thighs. Laboratory evaluations were performed including skin biopsies, peripheral blood flow cytometry and positron emission tomography-computed tomography.The lesional skin biopsy showed a dense dermal and perifollicular infiltrate composed of histiocytoid cells with nuclear grooves lacking dendritic processes in a background of lymphocytes. Eosinophils were absent. The histiocytoid cells were CD68+CD1a+Langerin- and only focally S100+. Special stains including GMS, Gram and Fite were all negative for infectious organisms. Although an initial diagnosis suggesting Langerhans cell histiocytosis was proposed due to CD1a positivity, a diagnosis of indeterminate dendritic cell tumor was finally rendered based on the histopathological findings and the lack of expression of Langerin.This case illustrates the variegated clinical presentation of indeterminate cell tumor and the necessity of appropriate immunohistochemical workup for its diagnosis.

Extramammary Paget disease (EMPD) is an uncommon tumor that presents in apocrine-rich skin as an irregular, pruritic plaque. Histopathologically, EMPD consists of an intraepidermal proliferation of atypical epithelioid cells. Rarely, the tumor cells contain intracytoplasmic melanin pigment, and the lesion clinically and histopathologically can mimic a melanocytic proliferation.A 51-year-old female with a history of breast carcinoma presented with a pigmented patch on her right thigh of 6 months duration. The clinical impression was an atypical melanocytic nevus. Histopathologic examination revealed an intraepidermal proliferation of epithelioid cells along the dermal-epidermal junction with pagetoid migration. The tumor cells exhibited increased cytoplasm containing conspicuous melanin pigment and enlarged oval-irregular nuclei. Immunohistochemical studies showed the tumor cells to be strongly and diffusely positive for cytokeratin 8/18, cytokeratin 7 and p63; focally and weakly positive for epithelial membrane antigen (EMA), but negative for cytokeratin 5/6, Cam5.2, carcinoembryonic antigen (CEA), human melanoma black 45 (HMB-45), tyrosinase and Sox-10, supporting the diagnosis of pigmented EMPD. The lesion was subsequently excised, and the patient is free of disease after 24 months.We present this unusual case of pigmented EMPD arising on the thigh to draw attention to the entity and to underscore the potentially misleading clinical, histopathologic and immunophenotypic features that mimic other cutaneous intraepidermal lesions.

Primary cutaneous T-cell lymphomas (CTCL) comprise a heterogeneous group of neoplasms with diverse clinical behavior. Mycosis fungoides (MF) is the most common type of CTCL. Immunophenotypical shift during progression of the disease is a rare event and its significance is unknown. We present three primary CTCL cases that showed an immunophenotypical shift and poor prognosis. Conventional hematoxylin/eosin and immunohistochemical-stained sections were examined in all the cases. Molecular analysis for rearrangement of the T-cell receptor (TCR) gene was performed in two cases. One case was classified as MF, while the other two lacked epidermotropism, and were considered primary cutaneous peripheral T-cell lymphoma (PTCL), NOS. Two cases were CD3+/CD4+ and one case was CD3+/CD8+ at diagnosis. The first two patients suffered many relapses and eventually, new CTCL lesions with a CD3+/CD8+ phenotype were observed. Both cases revealed identical clonal TCR rearrangements on the initial and late lesions, supporting the interpretation of a single clonal proliferation with different phenotypes. The third case progressed with skin recurrences and pulmonary lesions with a predominant CD3+/CD4+/CD8− phenotype. All cases manifested poor prognosis and two patients died of lymphoma. Immunophenotypical shift between CD4 and CD8 in CTCL seems to be a rare phenomenon that may be associated with disease progression.

Cutaneous CD8(+) CD30(+) lymphoproliferative lesions are difficult to classify and encompass entities that follow a benign course to overt lymphoma. In order to identify histopathologic criteria for lesions in this spectrum, a series of such cases was reviewed.Twenty-eight biopsies from 27 patients with CD8(+) CD30(+) cutaneous lymphoid proliferations were evaluated.Seventeen cases were classified as lymphomatoid papulosis (LyP) 'type D', eight as cutaneous anaplastic large cell lymphoma (C-ALCL) and two as CD8(+) mycosis fungoides (MF) with CD30 expression. Features of LyP included spongiosis and/or parakeratosis (90%), epidermotropism by large lymphocytes (90%), with (80%) or without (10%) small lymphocytes; wedge-shaped infiltrate (70%) with perivascular (100%) and interstitial (80%) pattern; and relative uniformity of CD30(+) large atypical cells (90%). C-ALCL was characterized by ulceration (63%), epidermotropism restricted to small lymphocytes (100%), marked density (63%) and pleomorphism (62%) of CD30(+) large atypical cells, and at least focal extension of infiltrate to subcutaneous tissue (88%). CD8(+) CD30(+) MF had vacuolar interface change and a lichenoid pattern (100%).We concur with previous authors that distinction of CD8(+) LyP from lymphoma in its differential diagnosis is difficult based on histopathology alone. Nonetheless, we propose that certain histopathologic clues may be helpful in this differential diagnosis.

The histopathologic distinction between benign and malignant cutaneous keratinocytic proliferations can pose a difficult diagnostic challenge - often with important clinical implications. Activating transcription factor 3 (ATF3) has emerged as a potential biomarker which may aid in the segregation of these lesions, and we hypothesize that ATF3 expression may be a specific marker of cutaneous squamous cell carcinoma (SCC). Using immunohistochemistry, we characterized ATF3 expression in a series of 126 cutaneous epithelial proliferations, including SCC (n = 27), basal cell carcinomas (BCC, n = 59), seborrheic keratoses with atypia (SK, n = 16), hyperplastic actinic keratoses (AK, n = 12) and prurigo nodularis cases (PN, n = 12). We showed strong, nuclear and/or nucleolar expression of ATF3 in a statistically significant number of cases of SCC compared to BCC, SK and PN. We conclude that ATF3 expression is a surrogate of malignancy (or pre-malignancy) in keratinocytic epithelial proliferations and thus helps distinguish SCC from other cutaneous epithelial neoplasms.

Cutaneous epithelioid angiomatous nodule (CEAN) is a rare vascular proliferation that develops on the trunk and extremities. The lesion arises over weeks to months and affects both sexes without age predilection. Histologically, CEAN is characterized by a circumscribed proliferation of epithelioid endothelial cells in the superficial dermis with a background of lymphocytes, plasma cells and eosinophils. The epithelioid cells are positive for CD31, CD34 and/or D2-40. We report a case of CEAN that had remained stable for more than 30 years on the chest wall of a woman with a history of breast cancer. The lesional cells were epithelioid in appearance and positive for estrogen receptor (ER), raising suspicion for breast carcinoma. However, the cells were positive for CD31, CD34, D2-40 and EMA (epithelial membrane antigen); they were negative for cytokeratins, carcinoembryonic antigen (CEA), CD1a, gross cystic disease fluid protein (GCDFP-15), S-100, a melanocytic cocktail, HHV-8 and progesterone receptor. The histologic and immunohistochemical features, including a low proliferation index (10% by Ki-67), helped to distinguish this lesion from carcinoma and other vascular lesions. This is the most comprehensive immunohistochemical profile reported for CEAN to date and the first time that ER expression has been described.