Histopathologic PD-L1 Tumor Expression and Prognostic Significance in Nonmelanoma Skin Cancers: A Systematic Review.

ABSTRACT: PD-L1 and PD-1 inhibitors are being increasingly used to treat a variety of nonmelanoma skin cancers (NMSCs). This systematic review summarizes PD-L1 expression in NMSCs and determines its use for prognosis using targeted immunotherapy. A primary search of peer-reviewed English-language medical literature was conducted for studies on PD-L1 tumor expression in biopsied or excised NMSCs. Fifty-nine articles met criteria for inclusion. PD-L1 expression in advanced NMSCs ranged from 22%-89% for basal cell carcinomas, 42%-50% for Merkel cell carcinomas, and 26%-100% for squamous cell carcinomas. Study limitations included clone heterogeneity across studies, complicating comparison of PD-L1 expression. Differences were also noted in the selection of tumor reactivity threshold. We conclude that there is insufficient evidence to determine the prognostic significance of PD-L1 expression in NMSCs as a whole, but this remains a promising area. More investigation into the role of tumor PD-L1 as a biomarker for predicting clinical response to PD-L1 and PD-1 inhibitors in NMSCs is needed.

Programmed cell death 1 protein and programmed death-ligand 1 inhibitors in the treatment of nonmelanoma skin cancer: A systematic review.

BACKGROUND: Immunotherapy using programmed cell death 1 protein (PD-1) or programmed death-ligand 1 (PD-L1) inhibitors has been increasingly reported in a variety of nonmelanoma skin cancers (NMSCs). OBJECTIVE: To analyze the evidence of PD-1 and PD-L1 inhibitors in the treatment of NMSC. METHODS: A primary literature search was conducted with the PubMed, Cochrane Library, EMBASE, Web of Science, and CINAHL databases through October 28, 2018, to include studies on the use of PD-1 or PD-L1 inhibitors in patients for NMSC. Two reviewers independently performed study selection, data extraction, and critical appraisal. RESULTS: This systematic review included 51 articles. The most robust evidence was in the treatment of Merkel cell carcinoma and cutaneous squamous cell carcinomas, as supported by phase 1 and 2 clinical trials. Treatment of basal cell carcinoma, cutaneous sarcoma, sebaceous carcinoma, and malignant peripheral nerve sheath tumor also showed benefit with PD-1/PD-L1 inhibitors, but data are limited. There does not appear to be efficacy for PD-1/PD-L1 inhibitors in cutaneous lymphomas. LIMITATIONS: More investigation is needed to determine the efficacy, tumor responsiveness, and the safety profile of PD-1 and PD-L1 inhibitors in NMSC. CONCLUSION: PD-1 and PD-L1 inhibitors exhibit treatment efficacy in a variety of NMSCs.

Dietary and metabolic factors in the pathogenesis of hidradenitis suppurativa: a systematic review.

Hidradenitis suppurativa (HS) is a systemic recalcitrant inflammatory condition characterized by debilitating lesions with high morbidity. Its known association with obesity and smoking indicate correlation with other environmental factors, such as diet, suggesting a larger role for lifestyle modifications in disease treatment. This study seeks to assess the contribution of weight loss and dietary intake in HS management. A primary literature search was conducted using PubMed, Web of Science, and CINAHL in November 2018 to include association and intervention studies on the influence of diet and weight on HS. Twenty-five articles were included. Meta-analysis of nine case-control studies across Asia, Europe, and the United States showed that HS patients are four times more likely to be obese compared to the general population; random effects pooled odds ratio 4.022 (2.667-6.065), P < 0.001. Five articles assessed weight-loss interventions and revealed mixed findings. The remaining articles included three association studies on micronutrient levels, eight dietary intervention studies, and one article analyzing both micronutrient association and dietary intervention. Included articles in this systematic review reveal that low serum zinc and vitamin D levels are associated with increased lesion count in HS. Supplementation of zinc, vitamin D, vitamin B12, or exclusion of dairy or brewer's yeast can be effective in partial or complete lesion resolution. Reviewed data show that weight loss from bariatric surgery may lead to HS improvement but often results in more severe malnutrition that worsens or even leads to new onset HS post bariatric surgery. Future reporting is needed to conclusively determine the role of diet in HS.

Chondrodermatitis nodularis helicis in an adolescent boy: not just for old men.

Chondrodermatitis nodularis helicis (CNH) is a solitary, chronic, painful, often ulcerated lesion on the upper portion of the ear, mostly in older men. We present an unusual case of CNH in a 17-year-old adolescent boy who was a lifeguard. Correlation between clinical and histopathologic characteristics of CNH is outlined in the context of the existing literature to increase awareness of this condition in younger patients as well as to guide appropriate management and surveillance.

Matrical carcinoma with melanocytic hyperplasia mimicking nodular melanoma in an elderly Mexican male.

Matrical carcinoma with melanocytic hyperplasia (MCMH), previously referred to as malignant melanocytic matricoma, is a rare variant of the uncommon pilomatrical carcinoma, occurring most often on the head/neck and upper backs of middle-aged men. Nodular lesions may resemble pigmented basal cell carcinoma or melanoma clinically. We present a case of MCMH in a Hispanic patient with history of melanoma. Histopathological clues to appropriate diagnosis include basaloid cells, numerous atypical mitotic figures, matrical differentiation, shadow cells, strong diffuse nuclear and cytoplasmic expression of ß-catenin, and interspersed pigmented dendritic melanocytes.

Syringotropic Mycosis Fungoides: A Rare Form of Cutaneous T-cell Lymphoma Enabling a Histopathologic "Sigh of Relief".

Syringotropic mycosis fungoides (STMF) is a very rare variant of cutaneous T-cell lymphoma. It follows a much milder disease course than its clinically indistinguishable adnexal counterpart, folliculotropic mycosis fungoides (FMF). We report a case of a 36-year-old man who presented with erythematous, studded papules and plaques on the left upper extremity and right anterior thigh diagnosed as mycosis fungoides (MF) Stage 1A on initial superficial shave biopsy. Lesions recurred after initial improvement with narrow-band ultraviolet light therapy demonstrating a concentration of abnormal lymphocytes around eccrine sweat glands on repeat biopsy consistent with STMF. Although the deeper, periadnexal infiltrate found in both STMF and FMF confers increased resistance to skin-directed therapies effective in classic MF, these entities diverge with respect to their clinical behavior. Syringotropism is a marker for increased disease-specific survival, whereas even FMF carries a prognosis worse than conventional MF. Increased awareness among the dermatopathology community of the histopathologic distinction between STMF and FMF is essential to guide treatment type, duration, and intensity in adnexal disease.

Cutaneous Balamuthia mandrillaris infection as a precursor to Balamuthia amoebic encephalitis (BAE) in a healthy 84-year-old Californian.

Soil and freshwater-dwelling amoebae may opportunistically infect the skin and evoke a granulomatous dermatitis that camouflages their underlying morphology. Amoebic infestations are incredibly rare in the U.S., predominantly occurring in the young, elderly, and immunocompromised. Sadly, because diagnosis is difficult and unsuspected, most cases are diagnosed at autopsy. The following case is of a healthy 84-year-old man with a non-healing nodulo-ulcerative cutaneous lesion on his left forearm that appeared following a gardening injury. Lesional punch biopsies repeatedly showed non-specific granulomatous inflammation with no pathogens evident histologically or by culture. Histopathologic diagnosis was made five months after initial presentation via identification of amoebic trophozoite forms in tissue from a large excisional specimen. Anti-amoebic therapy was initiated immediately. The patient experienced mental status changes three days following lesion excision, with evidence of a cystic mass in the left medial parieto-occipital lobe by CT. Both intraoperative brain biopsies and cutaneous tissue samples tested positive for Balamuthia mandrillaris by indirect immunofluorescent antibody assay performed at the Centers for Disease Control. The patient achieved a full recovery on a triple antibiotic regimen. Clinical suspicion and thorough histopathologic analysis may determine the difference between survival and death for a patient presenting with a treatment-refractory localized granulomatous lesion.

Ischemic fasciitis: enhanced diagnostic resolution through clinical, histopathologic and radiologic correlation in 17 cases.

Ischemic fasciitis is a pseudosarcomatous nodule or mass resulting from sustained or repeated pressure and consequent ischemia of soft tissue. Fibrin and hemorrhage expand its hypocellular epicenter bordered by enlarged (atypical, ischemic) fibroblasts and reactive vascular prominence resulting in diagnostically important histologic zonation. Although classically in bedridden patients, ischemic fasciitis owing to posture-related intermittent pressure in ambulatory adults is not well characterized; there has not been a thorough review of its presentation in ambulatory patients in the dermatology/dermatopathology literature. This article reviews the clinical, pathologic and radiologic presentation of 17 cases of ischemic fasciitis diagnosed over a 14-year period. Eighty-six percent of the six cases submitted by non-dermatologists were limb girdle/trunk lesions averaging 6.7 cm in greatest diameter while 90% of the eleven lesions submitted by dermatologists were elbow and forearm lesions averaging 2.3 cm. In no case was the diagnosis anticipated pre-biopsy by clinician or radiologist. Dermatologists submitted the majority of cases. Because ischemic fasciitis may simulate soft tissue sarcoma clinically and histologically, diagnosis helps prevent overtreatment. Zonal histopathologic structure may be shown by any form of biopsy and should motivate correlation with available radiologic studies. Importantly, determining a history of postural pressure at the site confirms the histopathologic diagnosis and avoids unnecessary excision.

Mixed Pneumocystis and Cryptococcus cutaneous infection histologically mimicking xanthoma.

Cutaneous Pneumocystis jirovecii infection is rare. It is thought that the disease emerges from a latent infection delivered via hematogenous and/or lymphatic dissemination from a primary lung infection in immunocompromised individuals. A 32-year-old human immunodeficiency virus-positive male was admitted for headache and vomiting. He was diagnosed with meningitis due to Cryptococcus neoformans and sputum tested positive for Pneumocystis. Six months later, he presented with a slightly crusted yellowish brown plaque and 2 similar but smaller papules with telangiectasia near the right angle of the mouth. Biopsy of the area featured histiocytes expanded by foamy cytoplasm as in a xanthoma except that the vacuoles were coarser. Special stains ultimately demonstrated the characteristic disks of Pneumocystis accompanied by a minor component of budding yeasts (Cryptococcus) in the same fields. This case illustrates the utility of adequate special stains in recognizing a mixed cutaneous infection, particularly in human immunodeficiency virus-positive patients, when microscopy presents an odd xanthoma-like lesion.

Calcific periarthritis: more than a shoulder problem: a series of fifteen cases.

BACKGROUND: Calcific periarthritis, referring to a circumscribed juxta-articular deposit of minute non-birefringent mineral grains, is rarely the clinical diagnosis accompanying a pathologic specimen. Familiarity with the clinical, pathologic, and radiologic manifestations of calcific periarthritis, particularly when encountered adjacent to joints other than the shoulder, facilitates diagnosis and may obviate biopsy, avoid confusion with other entities, and speed appropriate treatment. METHODS: Pathologic specimens that fulfilled the criteria for a diagnosis of calcific periarthritis were prospectively collected. Clinical history and radiologic studies were acquired and analyzed. Well-controlled special stains were employed on two specimens with a neutrophilic infiltrate that excluded fungal and bacterial agents, as corroborated by microbiologic cultures showing no growth. RESULTS: Over a five-year period, fifteen patients between the ages of thirty-one and eighty-eight years (mean age, fifty-nine years) presented to various local healthcare providers for treatment of juxta-articular swelling that was subsequently determined to be calcific periarthritis. In seven patients, deposits were alongside a toe joint; in five, alongside a finger joint; and in three, involving the shoulder. The majority of the patients were female (73%). No patient had a documented recurrence of calcific periarthritis in follow-up periods ranging from eighteen to eighty-seven months (average forty-five months). CONCLUSIONS: Of twelve histologically verified cases of calcific periarthritis adjacent to joints other than the shoulder, in only one patient (toe) was the preoperative clinical diagnosis accurate, which signals the need for greater awareness of this entity as a differential diagnostic option.

Mucoepidermoid carcinoma of the parotid presenting as periauricular cystic nodules: a series of four cases.

Mucoepidermoid carcinoma is a relatively common neoplasm of the major and minor salivary glands that can secondarily involve skin. In the vicinity of the ear lobe, mimicry of a benign cyst, both clinically and histopathologically is a diagnostic pitfall to avoid. The clinical manifestations, diagnostic histopathology, and clinical course of mucoepidermoid carcinoma of the parotid gland presenting as a clinically benign periauricular cystic nodule in four patients ranging in age from 11 to 63 years, are analyzed in the present report. Illustrating the challenge of accurate diagnosis, three of the four cases were initially misinterpreted on biopsy as benign cystic lesions. Multiple biopsies displayed foamy histiocytes around mucinous extravasations into dermis that mimicked ruptured epithelial cysts in two cases before malignancy was ascertained. This series demonstrates the need to include parotid tumor in the differential diagnosis of odd periauricular cyst-like expansions and adenosquamous proliferations. Mucoepidermoid carcinoma in particular can explain indolent, infra-auricular 'mucinous cysts'. Familiarity with this syndrome should arouse suspicion of parotid carcinoma when a 'cyst' or nodule is located near the earlobe. Delay in diagnosis results in larger surgical procedures than are otherwise necessary.

Surfer's toe: trauma-induced idiopathic acro-osteolysis in the toes of a 46-year-old surfer: a case report.

Acquired acro-osteolysis (AOL) is defined as the resorption of bone from the tufts or shafts of the terminal phalanges. Acquired acro-osteolysis can manifest as a primary osteolysis syndrome and also appears in a number of disease states including rheumatologic disorders, neuropathic diseases, the result of prolonged exposure to polyvinyl chloride, and in rare cases, as a response to repeated mechanical stress. In this report, a 46-year-old surfer was evaluated for AOL as a complication of sports-related repetitive trauma to the right second and third toes. Radiography showed the bony tips of his right second and third toes had been eroded away. Acquired acro-osteolysis in the surfer's toes resulted from increased blood flow initiated to repair microdamage caused by repeated trauma to the distal ends of his second and third right toes due to the habitual dragging of the affected toes across a surfboard. The always initial lytic phase of bone repair was magnified by the increased arterial input to warm the extremities after prolonged exposure to cold. At 6-years' follow-up, the use of a protective bandage while surfing has permitted full regeneration of the affected toes.

Frontal sinus osteoma with osteoblastoma-like histology and associated intracranial pneumatocele.

Osteomas of the cranial sinuses are rare, benign bony tumors that can be complicated by the formation of an intracranial pneumatocele. If not treated promptly, a pneumatocele can lead to abscess formation, meningitis, or ventriculitis. In the present case, an intracerebral pneumatocele was formed when an 18 cm(3) osteoma breached the posterior wall of the frontal sinus creating a one-way valve through which air could enter the intracranial cavity. The patient presented after forceful sneezing with nonspecific symptoms of headache, nausea, and vomiting. CT demonstrated a frontal collection of loculated air with mass effect within the left cerebral hemisphere. A partly mineralized mass occupied the left superior nasal ethmoid sinus and left frontal sinus. Of interest pathologically in this case, the tumor had a substantial osteoblastoma-like component. Surgical repair involved frontal craniotomy to remove the osteoma and debride frontal sinus mucosa, plugging the frontal nasal ducts and sinus with fat and bone wax, and dural restoration using an underwater closed drainage system to vent intracranial air and stabilize the patient.

Large neglected ulcerated melanoma mimicking extramedullary plasmacytoma.

Amelanotic melanoma, a renowned impersonator, has taken on a new persona. A 63-year-old woman was seen in the emergency room with a chief complaint of back pain after a fall and was discovered to have a 15-cm fungating mottled gray mass independent of bone on the right elbow. Initial workup discovered lytic calvarial lesions, anemia (Hb 7; Hct 20%), and circulating plasma cells consistent with plasma cell myeloma. Biopsy of the elbow mass displayed sheets of plasmacytoid cells, some reactive for CD138. Flow cytometry revealed a substantial portion of the plasma cells in the tumor that were kappa restricted consistent with cutaneous plasmacytoma. The elbow mass was initially signed out as extramedullary involvement by her myeloma. Reevaluation of the mass after the patient experienced an explosive growth of multinodular jet black malignant melanoma on ipsilateral breast revealed MART-1 and S-100 reactivity of the majority of the cells. In retrospect, the elbow mass was a neglected primary amelanotic malignant melanoma with neoplastic plasma cells participating in its chronic inflammatory infiltrate.

Digital dermatofibromas--common lesion, uncommon location: a series of 26 cases and review of the literature.

Dermatofibroma (DF), also referred to as cutaneous fibrous histiocytoma (CFH), is a common tumor of the skin presenting as a firm nodule located predominantly on the limbs and shoulder and pelvic girdles that often extends into superficial subcutaneous tissue. This is a retrospective study of 26 DFs located on digits. All case slides were retrieved from saved files for diagnostic verification. One case was rejected after revision of the diagnosis to giant cell tumor of the tendon sheath. The 26 remaining cases constitute this reported series. Digital DFs affected 27 to 70 year-olds in a 2.25:1 male to female ratio. The most common clinical diagnosis submitted was "growth" or wart. In only 6 out of the 26 cases was the pre-biopsy diagnosis of DF ventured. Although lesional tissue went to dermal margins in 14 specimens, only one has been re-excised in follow up ranging from 2 months to 10 years. Because DFs can resemble several entities including leiomyosarcoma and dermatofibrosarcoma protuberans, a lack of familiarity with the occurrence of DF on the digits may result in more aggressive treatment than otherwise necessary. DF should be in the differential diagnosis of circumscribed, firm nodules presenting on the digits.

Cutaneous metastasis of osteosarcoma in the scalp.

As a primary malignant bone tumor, osteosarcoma is second only to chondrosarcoma. Although it commonly metastasizes and is aggressive in nature, it rarely colonizes the skin. This is a report of a 22-year-old male with osteosarcoma of the pelvis and metastasis to the lungs and chest wall who developed a clinically unsuspected solitary cutaneous metastasis in the scalp. Instead of the expected cyst, incisional biopsy disclosed a solid tan nodule of chondro-osseous sarcoma. Although rare, cutaneous metastases from osteosarcoma may appear in skin, especially the scalp, or in skin over the primary tumor. New skin lesions in a patient with a history of osteosarcoma warrant investigations including imaging and biopsy.

Plastic bag clip discovered in partial colectomy accompanying proposal for phylogenic plastic bag clip classification.

A plastic bag clip was incidentally found anchored in the mucosa of a partial colectomy specimen 2.6 cm proximal to a ruptured diverticulum for which the patient, a mentally retarded, diabetic, 58-year-old man, underwent surgery. Over 20 cases of accidental ingestion of plastic bag clips have been published. Known complications include small bowel perforation, obstruction, dysphagia, gastrointestinal bleeding and colonic impaction. Preoperative diagnosis of plastic clips lodged in the gastrointestinal tract is frustrated due to radiographic translucency. This occult threat could likely be prevented by the design of gastrointestinally safe, plastic-bag-sealing devices. Presented here is a morphologically based classification of bag clips as a possible guide for determining the most hazardous varieties and to aid further discussions of their impact on health.