John Andrew Carlson

Localized lymphedema (elephantiasis): a case series and review of the literature

Background:  Lymphedema typically affects a whole limb. Rarely, lymphedema can present as a circumscribed plaque or an isolated skin tumor.

Role of TRPM in melanocytes and melanoma

Transient receptor potential (TRP) cation channel superfamily plays important roles in variety cellular processes including polymodal cellular sensing, cell adhesion, cell polarity, proliferation, differentiation and apoptosis. One of its subfamilies are TRPM channels. mRNA expression of its founding member, TRPM1 (melastatin), correlates with terminal melanocytic differentiation and loss of its expression has been identified as an important diagnostic and prognostic marker for primary cutaneous melanoma. Because TRPM1 gene codes two transcripts: TRPM1 channel protein in its exons and miR‐211 in one of its introns, we propose a dual role for TRPM1 gene where the loss of TRPM1 channel protein is an excellent marker of melanoma aggressiveness, while the expression of miR‐211 is linked to the tumor suppressor function of TRPM1. In addition, three other members of this subfamily, TRPM 2, 7 and 8 are implicated in the regulation of melanocytic behaviour. TRPM2 is capable of inducing melanoma apoptosis and necrosis. TRPM7 can be a protector and detoxifier in both melanocytes and melanoma cells. TRPM8 can mediate agonist‐induced melanoma cell death. Therefore, we propose that TRPM1, TRPM2, TRPM7 and TRPM8 play crucial roles in melanocyte physiology and melanoma oncology and are excellent diagnostic markers and theraputic targets.

Chromogenic in situ hybridization analysis of melastatin mRNA expression in melanomas from American Joint Committee on Cancer stage I and II patients with recurrent melanoma

Objective:  To determine whether loss of melastatin (MLSN) is a universal phenomenon in American Joint Committee on Cancer (AJCC) stage I and II melanoma patients who experienced recurrence.

Skin tumors with matrical differentiation: lessons from hair keratins, beta-catenin and PHLDA-1 expression.

Pilomatricomas are tumors that emulate the differentiation of matrix cells of the hair follicle, showing cortical differentiation, with sequential expression of K35 and K31 keratins. Beta‐catenin gene is frequently mutated in pilomatricoma, leading to beta‐catenin nuclear accumulation, and to downstream expression of LEF1. Skin matrical tumors other than pilomatricoma are very rare, and comprise purely matrical tumors and focally matrical tumors. We aimed at studying cortical differentiation, beta‐catenin pathway and expression of the follicular stem‐cell marker PHLDA1 in a series of matrical tumors other than pilomatricoma.

The Evolution of Osseous Metaplasia in Localized Cutaneous Nephrogenic Systemic Fibrosis: A Case Report

Gadolinium (Gd) is associated with nephrogenic systemic fibrosis (NSF), a severe disorder mimicking scleroderma with involvement of the skin, lungs, heart, liver, and muscles. There is strong evidence that specific Gd-containing contrast agents (GCCAs) used in magnetic resonance imaging can cause NSF when administered to patients with chronic kidney disease. We present the 8-year history of cutaneous NSF with osseous metaplasia that occurred in a 56-year-old man with dialysis-dependent renal failure who was exposed to GCCA [gadopentate dimeglumine (Magnevist; Bayer Schering Pharma AG, Pittsburgh, PA)]. Three months after exposure to GCCA, he developed pruritic, pigmented patches that slowly coalesced and darkened over 8 years. Although not recognized at onset, skin biopsy showed typical histology of NSF affecting the entire dermis: CD34+/procollagen I+ spindle cells associated with fibrosis. Biopsy performed 6 years later showed superficial scar-like fibrosis that was CD34/procollagen I− and had numerous elastocollagenous balls (refractile elastic fibers surrounded by coarse collagen). Biopsy 7 years later showed the superimposition of osseous metaplasia on elastocollagenous balls. Both of these later biopsies had typical NSF histology affecting the deep dermis and subcutis. Over time, there was progressive diminishment of CD34+ and procollagen I+ cells and an increase in FXIIIa+ and CD68+ cells. Scanning electron microscopy and energy-dispersive x-ray spectroscopy showed Gd deposits in all areas of typical NSF histology but not in the regions of scar-like fibrosis, elastocollagenous balls, or osseous metaplasia. We suspect that the later changes may represent a late, involuting stage of NSF.

Neutrophilic myositis as a manifestation of celiac disease: a case report

A 42-year-old white man presented with recurrent attacks of muscle pain and swelling. Clinically, he looked like he had severe pyogenic infection. He failed to respond to multiple courses of wide-spectrum antibiotics. Repeated cultures from muscle lesions and from the blood were negative. Hospital course was very hectic and life threatening at times. Upon further questioning, the patient gave a history of frequent loose-bowel movements for many years. A duodenal biopsy with villous blunting and positive antiglidin antibodies confirmed the diagnosis of celiac disease. The patient had complete recovery and remained in remission on a gluten-free diet.

Delayed onset of the Jarisch-Herxheimer reaction in doxycycline-treated disease: a case report and review of its histopathology and implications for pathogenesis.

Abstract:The Jarisch–Herxheimer reaction (JHR) is a transient inflammatory syndrome triggered hours after the start of antibiotic treatment of spirochete infections, namely syphilis. Clinically, JHR manifests as an abrupt onset of constitutional symptoms and exacerbation of cutaneous lesions that resolve without intervention. JHRs pathogenesis is unclear and it is histopathologically rarely reported. Herein, the authors report a 47-year-old woman, with solitary erythema migrans and positive Lyme disease serology, who presented for medical care 14 days after commencement of doxycycline therapy. She complained of malaise, facial flushing, gingival erythema, and acquisition of additional plaques characterized by swelling, increased erythema, pruritus, and exfoliative scale. Punch biopsies demonstrated subacute to chronic spongiotic psoriasiform reaction patterns with a superficial lymphocytic infiltrate. By Borrelia-specific immunohistochemistry, spirochetes were found in the deep dermis, unassociated with inflammation, and focally in the upper spinous layer, associated with spongiosis. Borrelia burgdorferi DNA was detected by nested polymerase chain reaction. Doxycycline was discontinued, and symptoms and signs resolved within a few days. Liberation of endotoxin-like materials (eg, lipoproteins) from degenerating spirochetes and concomitant cytokine production is the suspected cause of JHR and supported by the finding of lesional spirochetes. Alternatively, a reversal reaction with a delayed-type hypersensitivity reaction is also a plausible cause based on spirochetes found in the lymphocytic spongiotic dermatitis.

Primary cutaneous marginal zone lymphoma associated with juxta-articular fibrotic nodules in a teenager.

Primary cutaneous marginal zone lymphoma (PCMZL) has rarely been reported in teenagers and is occasionally associated with Borrelia burgdorferi infection. Juxta‐articular fibrotic nodules represent a unique, localized fibrosing response to spirochete infections, namely Borreliosis. Herein, we report a 15‐year‐old healthy boy who presented with a 4‐year history of progressive acquisition of asymptomatic, erythematous nodules, ≤3 cm, beginning with his right forearm (3), then right arm (1) and lastly his right inner thigh (1). Biopsy showed PCMZL in three of five samples, and inflamed, fibrotic nodules, near the elbow in two. The bottom heavy lymphomatous nodules consisted of mostly small CD20+ CD43+ lymphocytes, some with plasmacytoid features. Mature plasma cells were lambda light chain restricted by in situ hybridization. The juxta‐articular fibrotic nodules were located in the deep dermis and subcutis, had peripheral plasma cell‐rich infiltrates, and showed nodular sclerosis (morphea profunda‐like) in one, and lamellar and angiocentric sclerosis in the other reminiscent of quiescent lesions of chronic localized fibrosing leukocytoclastic vasculitis. Immunohistochemistry for B. burgdorferi revealed rare positive organisms; however, polymerase chain reaction (PCR) and serology were negative for B. burgdorferi as were serologic and/or PCR assays for Bartonella henselae, Ba. quintana, Ehrlichia chaffeensis, Treponema pallidum, Helicobacter pylori and Babesia microti. No evidence of extracutaneous disease was found by the review of systems and imaging studies. A 4‐week trial of doxycycline therapy failed, whereas intralesional (IL) corticosteroid therapy induced rapid regression of his nodules. After two local recurrences, also treated with IL corticosteroids, he is well, without cutaneous disease, 20 months later. A literature review of 19 pediatric cases PCMZL reveals a similar natural history as adult PCMZL. Despite negative serology and PCR for B. burgdorferi, the occurrence of ipsilateral juxta‐articular fibrotic nodules, positive B. burgdorferi immunohistochemistry and rapid response to IL corticosteroids implicate the presence of a replicative or non‐replicative infectious (spirochetal) antigen in the initiation and promotion of this teenagers PCMZL.

Alpha-interferon secreting blastic plasmacytoid dendritic cells neoplasm: a case report with histological, molecular genetics and long-term tumor cells culture studies.

Abstract: We report a new case of blastic plasmacytoid dendritic cell neoplasm (BPDCN) with extensive immunophenoptyping, genotyping (karyotype, array-comparative genomic hybridization, and fluorescent in situ hybridization), and long-term tumor cells culture. BPDCN is a very rare and aggressive disease clinically characterized by a skin revealing localization more or less rapidly disseminating to the bone marrow and other organs with or without and leukemia. The disease was initially phenotypically characterized by the expression of both CD4 and CD56 antigens, whereas lymphoid and myeloid lineage antigens were negative. A phenotypic link with alpha-interferon (IFN-I)-producing plasmacytoid dendritic cells was demonstrated. The data collected in this case report provide additional biological and genotypical data on tumor cells of BPDCN. This study confirms the capability of tumor cells to secrete IFN-I, demonstrated by biological IFN-I activity of cultured cells and immunohistochemical expression of Mx-1 protein. Although a common genetic profile involving chromosomes 5, 6, 9, 12, 13, and 15 has been identified, no specific genetic marker has been demonstrated that is specific to BPDCN. The demonstration of ETV6 gene deletion in this case deserves further investigations as a putative BPDCN marker.

Delay in diagnosis: trauma- and coinfection-related cutaneous leishmaniasis because of Leishmania guyanensis infection.

Trauma can trigger the onset of some lesions of cutaneous leishmaniasis (CL). In this study, we present the case of a 65‐year‐old man who developed persistent, ulcerative, nodular lymphangiitis at the site of elbow abrasions from a fall during a trip to northeastern Brazil. Skin and lymph node biopsy showed tuberculoid granulomatous inflammation and Grocott‐methamine silver‐positive yeast forms consistent with Sporothrix and Staphylococcus lugdunensis was identified from tissue culture. Antibacterial and antifungal treatment produced short‐term healing. Crusted papules recurred at the sites of injury 3 months later and persisted despite therapy. After 15 months, two punch biopsies showed scarring and granulomatous inflammation; cultures and histochemical stains were negative for microorganisms. Because of refractory disease, multiple polymerase chain reaction (PCR) assays for infectious agents on DNA extracted from the biopsy specimens were performed, and Leishmania guyanensis was detected in all specimens. The patient refused pentavalent antimonial therapy and elected for excision of the CL lesions. After 2 years of follow up, he is without disease. CL should be considered in the differential diagnosis in patients who present with ulcerative, nodular lymphangiitis; have a history of travel to endemic regions; and describe a traumatic insult to the affected region. PCR methods for infectious agents increase the sensitivity and specificity of detecting causative agents in these patients who are negative by routine methods. In some, leishmaniasis may be an occult infection whose presence is heralded by trauma. Coinfection, by altering the immune response, may have facilitated the clinical acquisition of CL.