The term autoinflammatory keratinization diseases (AIKDs) was recently proposed as a unifying concept for diseases characterized by inflammation in the epidermis and upper dermis which leads to hyperkeratosis, caused by genetic perturbations of the innate immune system. We present a case of a patient with hidradenitis suppurativa and porokeratosis, two AIKDs, followed by a review of these conditions as well as other AIKDs. This case was distinguished by hypertrophic porokeratoses involving cystic hair follicles, showing histopathologic features of both conditions within single biopsy specimens. The patient's course was additionally complicated by SCC arising within a porokeratosis. Our case demonstrates a rare overlap of two AIKDs, occurring not only within the same patient but also within the same lesions.

Acral lesions may represent the best/only skin lesions to biopsy in patients suspected to have dermatomyositis (DM). However, histopathologic features of acral DM skin lesions are poorly characterized.

Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous malignancy with neuroendocrine differentiation. Several molecular pathways have been implicated in MCC development and multiple cell-of-origin candidates have been proposed, including neural crest cells, which express acetylcholine receptors (AChRs). The role of nicotinic acetylcholine receptors (nAChRs) in MCC has not been explored. In this study, we investigated if MCC expresses nAChRs and if nAChR expression correlates with patient characteristics.

Pemetrexed is a chemotherapeutic, antimetabolite agent that has been used in oncology to treat diseases such as metastatic non-small cell lung cancer and unresectable malignant pleural mesothelioma. Pemetrexed use may result in pseudocellulitis, which presents as poorly demarcated patches or plaques with erythema, edema, warmth, and tenderness. These lesions can present unilaterally or bilaterally on the lower extremities. The histologic appearance includes vacuolar interface dermatitis, squamous metaplasia of eccrine coils and ducts, sparse mixed neutrophilic and lymphocytic interstitial inflammatory infiltrate, and widened subcutaneous fibrous septa with cystic fat degeneration. We present the case of a 58-year-old woman with non-small cell lung cancer and pemetrexed-induced pseudocellulitis with distinctive histological features. The clinical appearance of patients with this hypersensitivity condition may mimic cellulitis, emphasizing the importance of increased awareness and consideration of pseudocellulitis in the differential diagnosis of patients on chemotherapy to avoid unnecessary hospitalization and treatment.

Panniculitides are a group of inflammatory disorders of the subcutaneous fat that have been reported as a rare complication of both a serine threonine kinase BRAF inhibitor monotherapy and BRAF inhibition in combination with a mitogen activated protein kinase (MEK) inhibitor combination therapy used to treat metastatic melanoma. The cutaneous manifestations of BRAF and BRAF/MEK therapies have been well documented, but neutrophilic panniculitis remains a less common complication with fewer case reports. Physician awareness of this complication when following patients on similar targeted therapies can decrease delays in appropriate management. We report a case of one patient who developed neutrophilic panniculitis during treatment with the BRAF/MEK combination of dabrafenib and trametinib. We followed the patient from initial presentation in the emergency department to diagnosis to include pathology findings of the disease. In this case of neutrophilic panniculitis, the patient presented with a history of stage IIIa (pT2a N1a M0) cutaneous melanoma of the right flank and developed classic painful nodules on the lower legs and arms with associated fever within the first 2 weeks after initiating adjuvant melanoma targeted therapy. The biopsies showed a mixed, neutrophilic panniculitis, without overlying epidermal changes. Given the patient's clinical history, the biopsy was consistent with a BRAF inhibitor induced neutrophilic panniculitis. The panniculitis resolved with symptomatic care and the patient was maintained on the antitumor therapies.

Digital papillary adenocarcinoma (DPAC) is a rare but aggressive cutaneous malignant sweat gland neoplasm that occurs on acral sites. Despite its clinical significance, the cellular and genetic characteristics of DPAC remain incompletely understood.

This brief overview is inspired by seminal contributions by the late Dr. Martin C. Mihm, Jr. who provided a basis for recognition and better understanding of interactions between lymphocytes (tumor-infiltrating lymphocytes [TILs]) that home to and permeate cancers. In primary melanomas, this phenomenon may produce what Dr. Mihm called white depressed areas, prescient clues to what would fuel future attempts at harnessing anticancer immunity. The critical and sequential TIL attributes of antigenic stimulation, homing, and effector-target cell apoptotic injury herein are briefly reviewed in light of more recent advances in the field of immuno-oncology. The intent is to emphasize how fundamental clinical and histopathological observations, as forged by Dr. Mihm and his associates, have led to critically important prognostic paradigms as well as to translational insights that now have become transformative in the field of cancer immunotherapy.

The human body is composed mostly of water fortified by a variety of proteins, fats, carbohydrates, vitamins, minerals, and other nutrients, all organized into an elegant structurally complex and functionally efficient machine in which our consciousness resides. This heterogeneous assemblage of essential ingredients is enclosed in a container known as the integument, or simply, the skin. The container is as important as its contents; when itself devoid of structural and functional integrity, it will both leak as well as become infused with potentially harmful external agents. As we age, skin loses its integrity, and over time it is not unreasonable to conceive of the skin as becoming progressively "leaky." With this deterioration, skin becomes dry, scaly, accessible to microbes, pruritic, and inflamed, the latter setting up the potentially vicious cycle known as "inflammaging." One major example of the effects of chronological aging on the barrier function of skin involves depletion of filaggrin, a 37-kD histidine-rich protein which originates within keratohyaline granules of the epidermis. Some of the consequences of age-related filaggrin depletion may be inferred by experiments of nature known as ichthyosis vulgaris and atopic dermatitis (AD), the latter with atopy being the most common inflammatory disease worldwide. In AD, loss of function mutations in the FLG gene encoding for the filaggrin precursor, profilaggrin, are associated with skin that, as with aging, is also dry, scaly, accessible to microbes, pruritic and inflamed. In this mini-review, AD will be compared and contrasted with aging in terms of the consequences of deficient filaggrin barrier function. The goal is to enhance recognition that one of the most clinically symptomatic and visible signs of aging is a subtle yet ubiquitous form of "dermatitis" due to "leaky" skin, one that may be addressed therapeutically with smart combinatorial strategies that restore the molecular basis for skin barrier dysfunction.

Metastatic melanoma with unusual histopathology can be diagnostically challenging. One exceptionally rare cutaneous manifestation of metastases is blue-nevus-like metastatic melanoma (BNLMM). A 74-year-old male presented with a blue-gray lesion on his left helix in the same anatomical region of a previously resected lentigo maligna. Histopathological sections demonstrated an atypical biphasic proliferation of dendritic melanocytes with pigment incontinence and epidermal sparing, measuring > 0.05 mm in diameter. Although the majority of the cell population exhibited cytologic features consistent with a blue nevus, there was a subset of dendritic cells with irregular epithelioid contours and rare, typical dermal mitotic figures. Sections showed an increased Mart-1/Ki67 rate. Perineural and angiotropic involvement by the atypical melanocytes was identified. Immunohistochemical (IHC) stains for SOX-10, HMB45, and PRAME highlighted melanocytic proliferation. BAP-1 IHC was retained, and p16 IHC showed complete loss. No previous procedure site changes were present, indicating that the dendritic cell proliferation was separated from the primary invasive melanoma by normal dermis. The histopathological and immunohistochemical findings led to a diagnosis of microsatellite BNLMM. We report this case to highlight the importance of this rare entity and to avoid misdiagnosis of BNLMM, which would significantly impact patient prognosis, treatment, follow-up, and outcomes.

Melanomas show a wide spectrum of clinical, morphological, immunohistochemical, and molecular features, which can impact treatment and prognosis. Dedifferentiated and transdifferentiated melanomas (DTM) are defined as melanomas which have lost conventional melanocytic morphologic and immunohistochemical features, showing sarcomatous morphology and/or immunohistochemical staining of other cell lineages, and as such, can be mistaken for other entities such as collision tumors and undifferentiated spindle cell tumors. In this series, we highlight the utility of preferentially expressed antigen in melanomas (PRAME) in diagnosing undifferentiated/dedifferentiated melanomas. Case 1 is a lentigo maligna melanoma with dedifferentiation on the scalp of an 85-year-old. Case 2 is a desmoplastic melanoma with leiomyosarcomatous transdifferentiation on the cheek of an 80-year-old. Case 3 is a desmoplastic melanoma with rhabdomyosarcomatous transdifferentiation arising from the temple of an 88-year-old. In all cases, conventional melanocytic immunohistochemical markers were positive in the conventional melanoma and negative in the dedifferentiated/transdifferentiated areas. However, PRAME was positive in both the conventional and dedifferentiated areas with varying intensity. Although PRAME immunoreactivity can be seen in other malignant spindle cell tumors, this study highlights the potential utility of PRAME immunohistochemistry when considering a diagnosis of DTM.

Angiosarcoma is a rare and aggressive malignancy of endothelial cells with multiple subtypes. Foamy cell angiosarcoma is a rare variant in which endothelial cells demonstrate "foamy" cytoplasmic change. We present the case of a 59-year-old male who presented with progressive erythema and swelling of the midface and bilateral eyelids. Two biopsies obtained 3 months apart showed an infiltrate of foamy mononuclear cells in the deep dermis, resembling a xanthomatous histiocytic process. Clinical work-up for disorders including Erdheim-Chester disease, Langerhans cell histiocytosis, and necrobiotic xanthogranuloma was negative. Nine months later, a third set of biopsies was performed showing a similar infiltrate of foamy histiocyte-like cells within the deep dermis. However, there was also a dermal proliferation of irregular vascular spaces lined by atypical endothelial cells, diagnostic of angiosarcoma. Subsequent immunohistochemical stains demonstrated expression of CD31 and ERG within the foamy cells in both sets of biopsies, strongly suggesting endothelial lineage and supporting a diagnosis of foamy cell angiosarcoma. CD34 was negative. This case represents a very unusual presentation of angiosarcoma and a diagnostic conundrum. In cases such as these, especially when features of a vascular proliferation are absent, ERG appears to be the most useful marker for differentiating foamy cell angiosarcoma from histopathologic mimickers.

A 60-year-old male was admitted from the emergency department with extensive leg ulcers and polyarticular joint pain. Cryocrystalglobulinemia was diagnosed through positive cryoglobulin studies and characteristic histopathological findings. Treatment with bortezomib led to complete clinical resolution. Cryocrystalglobulinemia poses diagnostic and management challenges, highlighting the importance of interdisciplinary collaboration for optimal patient care.

Erythroderma is a dermatologic condition characterized by widespread red and scaly skin. The causes include, but are not limited to, psoriasis, eczema, drug eruptions, pityriasis rubra pilaris (PRP), and cutaneous T-cell lymphoma. Most of these are typified by Type 2 (e.g., eczema) or Type 17 (e.g., psoriasis) immune activation. However, since the clinicopathologic features of erythroderma can be nonspecific, assays that determine the underlying immune activation status are desirable.

Mpox (formerly known as monkeypox), a zoonotic disease caused by Monkeypox virus (MPXV), has become an international outbreak since May 2022. Mpox often presents with a mild systemic illness and a characteristic vesiculopustular skin eruption. In addition to molecular testing, histopathology of cutaneous lesions usually shows distinctive findings, such as epidermal necrosis, balloon degeneration, papillary dermal edema, and focal dermal necrosis, which have proven helpful in the diagnosis of mpox. Viral cytopathic changes with areas of multinucleation, smudging of the nuclei, and intracytoplasmic inclusions have also been described. Although useful, these features are relatively nonspecific. The use of a monoclonal antibody for immunohistochemical (IHC) staining of MPXV may be a useful tool in confirming mpox infection.

A 67-year-old male presented with plaques around the orbit and ecchymosis on the neck and back of hands for 2 years. Physical examination showed seborrheic-keratosis-like plaques around the orbit, ecchymosis on the neck and back of hands, as well as nail dystrophy. Serum λ light chain was positive. Histopathological examination demonstrated multiple keratinous cysts in the dermis and eosinophilic homogeneous material in the dermis, which was positive for Congo red with apple-green birefringence on polarized light. Kidney biopsy showed deposition of acellular eosinophilic material in the arteriole wall. Congo red staining was positive. A bone marrow biopsy revealed multiple myeloma. The diagnosis of primary systemic amyloidosis with multiple myeloma was made.

Spitz melanoma is extremely rare, and only a few cases of distant metastases have been reported. Herein, we describe a case of Spitz melanoma with multiple distant metastases. A 37-year-old woman presented with a 5.5-mm-diameter nodule on the right lower leg. She experienced multiple distant metastases, involving the lungs, liver, thyroid, stomach, ovary, bones, and skin, along with multiple lymph node metastases within 1 year. The patient succumbed to the disease 1 year and 6 months following the first excision. Histopathological examination revealed a dense distribution of large solid nests comprising large, atypical epithelioid melanocytes with abundant eosinophilic cytoplasm in the upper dermis. Diffuse PRAME and loss of p16 immunoexpression profiles were observed. Targeted DNA and Sanger sequencing revealed an in-frame MAD1L1(e16)::BRAF(e9) fusion in both primary tumor and metastatic subcutaneous lesion. A review of previously reported cases confirmed as Spitz melanoma with distant metastases (n = 7) revealed a broad age range (11-71 years, median 46 years), high mortality (5/7), frequent BRAF fusions (6/7), and recurrent TERT promotor mutations and CDKN2A/B deletions. This report adds valuable insights into our understanding of the clinical and genetic characteristics of Spitz melanoma with distant metastases.

Capicua transcriptional repressor (CIC)-rearranged sarcoma (CRS) is a rare and recently described tumor that most commonly affects patients between 15 and 30 years of age. It is an undifferentiated round cell malignancy, with a disease defining CIC fusion, with double homeobox 4 (DUX4) being the most common partner. Here, we report a 77-year-old woman who presented with a cutaneous thigh mass with a clinical morphology suggesting Merkel cell carcinoma. Immunohistochemically, there was positivity for INSM1 (extensive) and synaptophysin (patchy) and granular expression of neurofilament (extensive), CAM5.2, and CK20 (focal, nonspecific). The majority of the tumor showed histopathologic features within the range of what can be seen in Merkel cell carcinoma, but there were divergent features, including a myxoid zone with corded and stranded tumor cells and a Ewing-sarcoma-like zone with confluent concentric membranous CD99 expression. WT-1 was strongly expressed, prompting RNA-based next generation sequencing for gene fusions, which identified the CIC:DUX4 [t(19;4)(19q13.2;4q35.2)]. A novel IRAK3:HMGA2 fusion was also identified. This example of CRS simulated MCC clinically, histopathologically, and immunohistochemically and represents a likely underrecognized diagnostic pitfall.