Joshua Weaver

Quantitative analysis of eosinophils in acute graft-versus-host disease compared with drug hypersensitivity reactions.

Acute graft-versus-host disease (aGVHD), if not detected and treated early, is a common cause of morbidity and mortality. Drug hypersensitivity reactions (DHRs), the most frequent clinical and histopathological mimickers of early aGVHD, are often still distinguished from aGVHD by the presence of eosinophils within the inflammatory infiltrate on skin biopsy. Distinguishing these entities is important because the delay of appropriate treatment of aGVHD may lead to advanced stages of the disease process with a poor prognosis. To determine whether the existence or amount of eosinophilic infiltrate could be used to differentiate these entities, we employed a quantitative method of analyzing eosinophils in skin biopsies of rashes from patients with aGVHD and DHR. Eosinophils were counted in 50 high-power fields (HPFs) in skin biopsies of patients with clinical grade ≥2 aGVHD (+aGVHD), with clinical grade <2 aGVHD (−aGVHD), and those with clinical DHR (+DHR). The average number of eosinophils per 10 HPFs (ave. eos/10 HPFs) increased throughout each group. The ave. eos/10 HPFs in +DHR was significantly different from both aGVHD groups (P < 0.001). The specificity to completely rule out aGVHD did not reach 100% until 16.0 ave. eos/10 HPFs was observed. There is a significant difference between the numbers of eosinophils found in differentiating DHR from aGVHD, but a very high number (>16.0 ave. eos/10 HPFs) is necessary to rule out aGVHD completely. Therefore, a quantitative analysis of eosinophils in all biopsies to rule out aGVHD would be of limited value and should only be considered in those biopsies with significant eosinophilia.

Grover Disease (Transient Acantholytic Dermatosis)

Grover disease, also known as transient acantholytic dermatosis, is a papulovesicular rash of the upper trunk, generally among older white males; it is usually pruritic but temporary. Grover disease is characterized by 4 different acantholytic histologic patterns, and it has been associated with numerous disorders, including hematologic malignancies. Follow-up and treatment are often difficult to evaluate secondary to the spontaneous remittance and occasional fluctuant course of the disease. Our objective will be to discuss the diagnostic considerations of Grover disease and focus on the postulated pathogenesis, including concurrent disorders and the role of the pathologist in examining skin biopsies of this nonhereditary vesicobullous disorder. Although recognized as a common condition, Grover diseases pathogenesis still remains unknown. Because Grover disease has been associated frequently with other dermatologic and nondermatologic skin conditions, inspection for other pathologic processes within the skin biopsy is essential to rule out other concomitant disorders, including hematopoietic malignancies.

Non-mycosis fungoides cutaneous T-cell lymphoma: reclassification according to the WHO-EORTC classification.

Background: Non‐mycosis fungoides (non‐MF) primary cutaneous T‐cell lymphomas (PCTCL) are heterogeneous and divided into subgroups by the World Health Organization‐European Organization for Research and Treatment of Cancer (WHO‐EORTC) classification of cutaneous lymphomas. We report the first North American series to examine the applicability of the classification, compare our findings with the predominant European literature and confirm the significance of separation into the indolent and aggressive groups.

Simple non-staining method to demonstrate urate crystals in formalin-fixed, paraffin-embedded skin biopsies.

Background:  Gouty tophi classically occur as nodules over joints and the helix. The ideal fixative for preservation of gout crystals has traditionally been alcohol because the crystals are formalin and water soluble. However, most biopsies are submitted in formalin fixative, which results in dissolution of urate crystals leaving behind a non‐specific pale amorphous area. Although complex staining methods to show urate crystals in tissue have been described, the present study elucidates a simple non‐staining method utilizing a thick unstained coverslipped microscopy slide that allows detection and confirmation of birefringence of urate crystals in formalin‐fixed, paraffin‐embedded tissue.

CD4+/CD56+ hematodermic neoplasm (blastic NK‐cell lymphoma)

CD41/CD561 hematodermic neoplasm (CD4/ CD56 HN) is an aggressive hematopoietic malignancy, which has a predilection for the skin and consists of lineage-negativeCD41 andCD561 blastlike cells (Fig. 1). Since originally being described in 1994, CD4/CD56 HN, has undergone a plethora of name changes chronicling the evolution of our understanding of this neoplasm. The term blastic natural killer (NK)-cell lymphoma, agreed upon in the 2001 World Health Organization classification of tumors of hematopoietic and lymphoid tissue, was based on the distinct cytology and suggested an NKcell origin because of its CD56 expression. In 1999, the French Study Group on cutaneous lymphomas suggested agranular CD41/CD561 hematodermic neoplasm’ as a descriptive term because of its uncertain lineage. Other more recent studies from the non-dermatopathology literature, seven of which will be briefly discussed herein, have examined the potential cell of origin and through functional, immunohistochemical and molecular studies have suggested a plasmacytoid dendritic cell (pDC) derivation. They provide evidence that CD4/CD56 HN is a distinct entity that could more appropriately be termed pDC leukemia/lymphoma’. pDCs, which used to be called plasmacytoid monocytes, are mononuclear plasmacytoid cells normally found clustered in the T-cell-rich interfollicular areas of lymphoid tissue and are thought to be a first-line of defense against certain pathogens in the innate immune system. The oldest two articles further examine and define the function of the pDC. Although the in vivo function of pDCs remains hypothetical, one in vitro functional study has shown that stimulated pDCs differentiate into cells exhibiting features of dendritic cells. The CD41/ CD11c2/CD32 pDCs were isolated from tonsils, rescued fromnormal rapid apoptosis by interleukin-3, and exposed to CD40 ligand resulting in differentiation into dendritic cells. The resultant cells expressed myeloid antigens and had the ability to uptake soluble antigens and phagocytose particles. In addition, another functional study found that pDCs are a main source of a-interferon. pDCs were isolated from peripheral blood and stimulated to proliferate and differentiate. Exposure to viral pathogens showed more interferon production in the immature pDCs. These functional studies suggest that the pDC is a distinct cell type that functions as interferon producers in their precursor state while acting as antigen presenters upon terminal differentiation to a mature dendritic cell. CD4/CD56 HN frequently manifests in skin before leukemic involvement is evident; therefore, appropriate markers need to be identified that can be used to distinguish CD4/CD56 HN from their morphologic mimickers in paraffin-embedded skin biopsies. Cutaneous extramedullarymyeloid sarcoma (leukemia cutis) is the most notable mimic of CD4/ CD56 HN both histologically and immunophenotypically because cases of cutaneous acute myelomonocytic/monocytic leukemia (c-AML) can express the lineage non-specificmarkers CD4 andCD56. Several new immunohistochemical markers may be useful adjunctive tools in differentiating difficult cases of CD4/CD56 HN from c-AML. The next five more recent publications attempt to discover these new immunohistochemical andmolecular adjunctive tools to help distinguish and clearly separate CD4/CD56 HN from its potential mimickers. CD123 (IL3Ra), a marker for pDCs, was used to examine a small series of CD4/CD56 HN and isolated normal pDCs. High expression of CD123 was identified on all 14 cases of CD4/CD56 HN and all isolated normal pDCs, further supporting the theory that CD4/CD56 HN line of differentiation is the enigmatic pDCs. The specificity of CD123 was verified by examining a variety of controls including potential clinicopathologic mimickers such as acute and chronic myeloid and myelomonocytic leukemias. Only 2 of 30 of the control cases expressed CD123 including one c-AML and one chronic myelomonocytic leukemia involving the skin. Another study compared the expression of two markers previously discovered on normal pDCs in 26 cases of CD4/ CD56 HN and 18 cases of c-AML. The first marker,

Fibroblastic connective tissue nevus

Fibroblastic connective tissue nevus (FCTN) is a newly recognized, benign cutaneous mesenchymal lesion of fibroblasts/myofibroblastic lineage, which expands the classification of connective tissue nevi. We present three cases of FCTN and discuss significant clinical, morphologic and immunophenotypic overlap with dermatomyofibroma. Our cases were from young women, aged 32, 24 and 10, and presented as 1.2 and 1 cm nodules on the posterior neck and right upper flank, respectively while presenting as a linear plaque of the right posterior thigh in the latter case. The lesions showed a poorly circumscribed proliferation of hypercellular spindle cells arranged in short to longer intersecting fascicles entrapping adnexal structures. Superficial adipose tissue was also entrapped in one case. The spindle cells had fibroblastic features with pale eosinophilic cytoplasmic extensions and inconspicuous nucleoli. The spindle cells were positive for CD34 in two cases. One case was negative for CD34, smooth muscle actin (SMA), desmin and S100. The overall features were consistent with a diagnosis of FCTN. In two cases, we further elucidated the fibroblastic differentiation of the spindle cells in FCTN with electron microscopy, which has not been previously described.

The utility of using immunohistochemistry in the differentiation of metastatic, cutaneous clear cell renal cell carcinoma and clear cell hidradenoma

Clear cell hidradenoma and cutaneous clear cell renal cell carcinoma (CCRCC) overlap morphologically. The distinction may be difficult in a patient with a history of CCRCC, presenting with a cutaneous nodule, potentially leading to an erroneous diagnosis. We investigated the usefulness of napsin A and paired box gene 8 (PAX‐8) with previously studied markers epithelial membrane antigen (EMA), carcinoembryonic antigen (CEA), vimentin and cluster of differentiation marker 10 (CD10) in differentiating CCRCC from hidradenoma.

Psoriasiform Rash in a Toddler.

A 13-month-old boy presented with a 5-week history of worsening rash involving the face, groin, and extensor surfaces of the extremities, which failed topical steroid treatment. The patient was otherwise healthy and developing normally. He was never breastfed. Physical examination revealed periorificial crusted patches on the face, erythematous scaly plaques on the extensor aspects of the extremities (Figures 1 and 2; Figure 2 available at www.jpeds.com), and diffuse involvement of the perineum, genital, and perianal areas. Shave biopsy (Figures 3 and 4; available at www.jpeds. com) demonstrated findings consistent with nutritional deficiency dermatitis. Laboratory studies revealed low serum zinc and alkaline phosphatase levels. The patient’s rash cleared within days of initiating zinc sulfate supplementation. Insurance refused to cover genetic testing. Acrodermatitis enteropathica (AE) is a potentially life threatening, autosomal recessive form of zinc deficiency caused by mutations in the SLC39A4 gene that encodes a metal ion transporter. This leads to malabsorption of zinc across intestinal mucosa. AE presents upon weaning from breastfeeding. Premature infants, due to their higher zinc re-