Exclusive Cutaneous and Subcutaneous Sarcoidal Granulomatous Inflammation due to Immune Checkpoint Inhibitors: Report of Two Cases with Unusual Manifestations and Review of the Literature.

Recent emergence of immune checkpoint inhibitors (ICIs) has revolutionized the treatment of cancers and produced prolonged response by boosting the immune system against tumor cells. The primary target antigens are cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), a downregulator of T-cell activation, and programmed cell death-1 receptor (PD-1), a regulator of T-cell proliferation. This enhanced immune response can induce autoimmune adverse effects in many organs. Although skin toxicities are the most common, sarcoidal inflammation with exclusive cutaneous involvement is a rare occurrence with only 6 cases reported to date. We report 2 cases with unusual features. One patient is a female who was treated for metastatic renal cell carcinoma with combination of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1). She developed deep nodules showing sarcoidal dermatitis and panniculitis on histopathologic exam. The second patient is a male with melanoma of eyelid conjunctiva who was treated prophylactically with ipilimumab. He presented with papules/plaques confined to black tattoos, where the biopsy revealed sarcoidal dermatitis. By a comprehensive literature review, we intend to raise awareness about this potential skin side effect in the growing number of patients receiving targeted immunotherapies. It is crucial to have a high index of suspicion and perform timely biopsies to implement appropriate management strategies.

Neutrophilic Dermatosis of the Dorsal Hands: Report of a Case and Review of the Literature.

Neutrophilic dermatosis of the dorsal hands is an underrecognized entity, which is a distributional variant of Sweet's syndrome. It is often clinically misdiagnosed as an infectious process in overwhelming majority of the cases and the treatment is therefore delayed. Also, its association with underlying systemic and neoplastic disorders makes the need for an accurate diagnosis more crucial. We present a 45-year-old Caucasian woman who was initially diagnosed as having a hand infection with unsuccessful courses of antibiotic therapy. A later biopsy revealed a diffuse dermal infiltrate of neutrophils with leukocytoclasis, vasculopathic changes, and marked papillary dermal edema. Patient responded rapidly to oral prednisone treatment. By sharing a new case and comprehensive review of available published literature, we intend to raise awareness of this underreported entity and emphasize the role of timely biopsy of the lesions that will not only lead to an accurate diagnosis, but also avoid unnecessary antibiotic treatments, potentially aggressive management strategies such as surgical debridement or amputation, and referrals to wound care centers. More importantly, it will prompt a search to exclude any possible association, particularly hematopoietic malignancies.

Linear IgA Bullous Dermatosis: A Rare Clinicopathologic Entity with an Unusual Presentation.

Linear immunoglobulin A bullous dermatosis is a rare autoimmune mucocutaneous disorder caused by immunoglobulin A autoantibodies produced against several different antigens in the basement membrane zone. Clinically, it is characterized by tense vesicles or bullae, which on histopathological exam demonstrate subepidermal blister with a predominantly neutrophilic infiltrate. A smooth, linear pattern of immunoglobulin A deposition in the basement membrane zone on direct immunofluorescence is considered the gold standard for establishing a diagnosis. Treatment consists of dapsone or sulfapyridine. The authors report a 60-year-old woman who presented with pruritic erythematous patches and plaques on her trunk, back, and legs without blisters, who was diagnosed with eczema for several months with no response to prior treatments. A biopsy was performed, which was consistent with linear immunoglobulin A bullous dermatosis and later confirmed by direct immunofluorescence studies. The authors present this case to increase awareness of this rare disease, which could manifest in a nonclassical, nonblistering fashion.

Erythropoietic protoporphyria: a case report and literature review.

Erythropoietic protoporphyria is considered a rare disease overall, but in children is the most common form of porphyria, and certainly the most common type of erythropoietic porphyria. Despite this fact, erythropoietic protoporphyria is a disease that has been known to evade or at least delay diagnosis, leading to unnecessary suffering by the patient. Given the distress it may cause a patient and his or her family as well as the potential complications of this disease, the importance of maintaining a heightened awareness when presented with a child complaining of photosensitivity cannot be overstated. This case report will review the important clinical indicators, pathogenesis, histology, diagnosis, management, and treatment of this disease, so that affected children will no longer have to play "hide and seek" when diagnosed with this sun-sensitive disease.

Acute generalized exanthematous pustulosis: an enigmatic drug-induced reaction.

Acute generalized exanthematous pustulosis (AGEP) is a diffuse pustular disorder that is primarily drug induced and characterized by acute, extensive, small, nonfollicular, sterile pustules that usually begin in intertriginous folds with widespread edema and erythema. This article reports a case in which thalidomide, dexamethasone, or meloxicam may have been the etiologic agent to induce AGEP and the skin condition may have worsened with administration of additional medications during hospital admission. A good thorough medical history, including a drug history, along with clinicopathologic correlation is extremely important in a patient presenting with acute diffuse pustular lesions.

Cutaneous epithelioid angiosarcoma: a neoplasm with potential pitfalls in diagnosis.

Angiosarcoma (AS) is a rare neoplasm. Cutaneous AS is the most common form of AS. The epithelioid variant of the disease, however, is a rare entity. This subset can histologically mimic non-vascular neoplasms and impose serious challenges in reaching the correct diagnosis. We present five patients with cutaneous epithelioid angiosarcoma (EAS); in none, the clinical diagnosis included a vascular lesion. Three patients had history of breast conservation surgery with/without radiation therapy. Other patients had no previous radiation, and there was no lymphedema in any of the cases. The histopathological examination of the biopsy specimens by hematoxylin and eosin method was not suggestive of a malignant vascular neoplasm initially and the differential diagnoses included carcinoma, malignant melanoma and atypical lymphoid infiltrate. Only after performing immunohistochemical studies that included vascular markers, a definitive diagnosis was possible. Some cases showed unusual histopathological features. Cutaneous EAS is a rare variant of cutaneous AS that can mimic a variety of more common, non-vascular neoplasms, creating a major pitfall in the diagnosis. A careful and thorough histopathological examination and a high index of suspicion, along with appropriate immunohistochemical evaluation, can help reach a correct diagnosis and provide optimal patient care.

Acantholytic anaplastic Paget's disease.

Classic Paget's disease (PD) can be diagnosed relatively easily by histopathologic examination. 'Anaplastic' variant of this disease is a less-recognized subset that may pose as a diagnostic challenge and pitfall. We describe two cases who presented with scaly erythematous plaques on their nipple/areola. In the first patient, there was no palpable mass and imaging studies were negative. The second case presented with a lesion 5 years after a lumpectomy. Initial shave biopsies revealed histopathologic changes indistinguishable from Bowen's disease with no readily identifiable classic Paget's cells, associated with prominent superficial acantholysis. The neoplastic cells were negative for mucin, GCDFP-15, negative/minimally positive for CEA and strongly positive for CK7 markers. A high-grade ductal carcinoma in situ in the underlying breast was ultimately found in both cases. Anaplastic PD is a rare variant of this disease that histologically mimics Bowen's disease with an associated prominent superficial acantholysis. There is mucin, CEA and GCDFP-15 negativity with positive CK7 reaction. A high index of suspicion along with a complete immunohistochemical panel should be considered in evaluating any Bowenoid neoplasm of the breast skin, particularly in superficial skin shave biopsies along with negative imaging studies and no palpable mass clinically.

Mycetoma clinically masquerading as squamous cell carcinoma: case report and literature review.

Mycetoma is a chronic and progressive subcutaneous granulomatous infection characterized by painless swelling and tumefaction, draining sinus tracts, and purulent discharge. The term eumycetoma is used to describe an infection caused by fungi, while an actinomycetoma is used to describe an infection caused by filamentous bacteria. An accurate identification of the pathogen plays a vital role in the treatment plan as well as a positive outcome for the patient. In this report, we present an elderly white female with an initial presentation of mycetoma masquerading as a squamous cell carcinoma. We also review microbiology, diagnostic modalities, and treatment for mycetoma.

Primary carcinosarcoma of the ear: case report and review of the literature.

Primary carcinosarcoma is a very rare neoplasm comprising two intermingling malignant components-epithelial and mesenchymal. The authors report a new case of primary cutaneous carcinosarcoma involving the helix of the ear. Immunohistochemical analysis revealed epithelial components of both basal cell and squamous cell carcinomas with a partially ossified sarcomatous-like component.Cutaneous carcinosarcoma (CS) is a neoplasm with dual epithelial and mesenchymal malignant components. It is most commonly seen in elderly males on sun-exposed areas of the body.(1-2) The histogenesis of CS is currently under debate. Immunohistochemistry plays an integral part in the diagnosis of this rare biphasic neoplasm. After a review of the literature, the authors were able to find only four other reported cases of CS involving the ear.(1,3) They present the fifth case of primary cutaneous CS, which involved the helix of the ear.

Dermatofibrosarcoma protuberans: a case report and review of the literature.

Dermatofibrosarcoma protuberans (DFSP) is a rare, slow-growing fibrohistiocytic neoplasm that commonly favors young to middle-aged adults. It is most commonly seen on the trunk and frequently recurs locally after an incomplete excision, but distant metastasis is rare. Mohs micrographic surgery (MMS) is the treatment of choice for DFSP.

Primary mucinous carcinoma with direct histopathologic evidence of lymphatic invasion.

BACKGROUND: Primary mucinous carcinoma of the skin is a rare sweat gland neoplasm which occurs most commonly in the periorbital region. Although the tumor has a propensity for local recurrence and regional spread, distant metastases are rare. The standard treatment of primary mucinous carcinoma is wide local excision. Mohs micrographic surgery may also be utilized in cases where tissue conservation is of utmost concern. OBJECTIVE: We present a case of primary mucinous carcinoma arising in the scalp, which was treated with wide local excision. METHODS: A case report and literature review are presented. RESULTS: Histopathologic evaluation revealed a well-circumscribed neoplasm characterized by lobules and aggregates of epithelial cells embedded in abundant pools of mucin. In addition, small aggregates of neoplastic cells were found at a distance from the primary nodule, indicative of lymphatic invasion. CONCLUSION: Primary mucinous carcinoma has a high propensity for locoregional metastases and recurrence. To our knowledge, this is the first report demonstrating direct histopathologic evidence of lymphatic invasion which correlates with this tumor's biologic behavior.

Possible role of the bulge region in the pathogenesis of inflammatory scarring alopecia: lichen planopilaris as the prototype.

BACKGROUND: Lichen planopilaris (LPP) is the prototype of scarring alopecias that mainly target the infundibuloisthmic (bulge) region of hair follicle. Hair follicle stem cells have been shown to reside in the bulge. METHODS: We carried out this study to better define the possible pathogenetic role of the bulge in LPP. Thirty-five cases of LPP were studied. Multiple serial sections of biopsy specimens stained with hematoxylin and eosin, periodic acid Schiff-diastase, and Elastic van Gieson. The following immunostains were applied: CD3, CD4, CD8, CD1a, and Ki-67. Uninvolved follicles and normal scalp biopsy specimens served as normal controls. RESULTS: All cases showed a lichenoid lymphocytic infiltrate at the bulge region. The bulb area was spared. CD8(+) T cells were increased compared with CD4(+) T-cell population. Langerhans' cells were decreased. Proliferating stem cells, highlighted by Ki-67, showed a marked decrease in the bulge compared with uninvolved follicles. CONCLUSION: Our study supports the finding that in LPP, the inflammatory infiltrate mainly involves the bulge region, where the stem cells reside. Once this area is damaged, the hair loses its potential of regrowth with resulting scarring alopecia. This is in contrast with inflammatory non-scarring alopecias such as alopecia areata, where the bulb region is targeted, sparing the stem cells.

Infantile granular parakeratosis: recognition of two clinical patterns.

Granular parakeratosis is an acquired, idiopathic disorder of keratinization typified by retention hyperkeratosis. It usually occurs in women at intertriginous sites. There have been only 2 reports of infants with granular parakeratosis to our knowledge. We describe 3 additional infants with granular parakeratosis. We demonstrate that infantile granular parakeratosis exhibits 2 clinical patterns: bilateral linear plaques in the inguinal folds; and erythematous geometric plaques underlying pressure points from the diaper. A thick, flakelike scale is present in both forms and is characteristic. Diaper wearing appears to play an important role in the genesis of infantile granular parakeratosis but the mechanisms are unclear. Therapeutic responsiveness to topical agents is ambiguous, however, spontaneous clearance after months to 1 year appears to be the rule.

Early delayed-type hypersensitivity eosinophil infiltrates depend on T helper 2 cytokines and interferon-gamma via CXCR3 chemokines.

We investigated the role of T helper (Th)1- and Th2-type cytokines in delayed-type hypersensitivity to soluble protein antigens elicited early postimmunization. Mice were sensitized by intradermal injection without adjuvants, or subcutaneously with complete Freund's adjuvant, and subsequently ear challenged intradermally. As soon as day 3, antigen-specific eosinophil-rich responses were elicited in wild-type mice, but not in T-cell receptor-alpha-/- mice without adjuvant. Draining lymph node T cells stimulated with antigen secreted interleukin (IL)-4, IL-5 and interferon-gamma (IFN-gamma). IFN-gamma-dependent specific immunoglobulin G (IgG)2a and IL-4-dependent IgG1 were also generated. Delayed-type hypersensitivity ear swelling and local eosinophil recruitment were decreased in IL-5-/-, IL-4-/- and signal transducer and activator of transcription-6 (STAT-6)-/- mice, and with anti-IL-4 treatment of wild-type mice, suggesting Th2 mechanisms. Interestingly, responses were also decreased in IFN-gamma-/- mice, and IFN-gamma protein and the IFN-gamma-inducible CXC chemokine, IP-10, were present in 24-hr ear tissue extracts, suggesting Th1 effects. Finally, ear swelling, total histology and eosinophils were decreased in mice deficient in CXCR3, the chemokine receptor for IP-10. These results suggest that both a Th2-like (IL-5, IL-4 and STAT-6) and a Th1-like (IFN-gamma, IP-10, CXCR3) pathway contribute to eosinophil recruitment in early delayed-type hypersensitivity.

Verrucous plaque on the foot.

Amelanotic melanoma can present clinically in multiple ways, often mimicking benign processes. This makes diagnosis more difficult and often delays proper medical attention. This case report highlights the importance of having a high suspicion of melanoma in cases that do not behave clinically as expected.