Lyndon D. Su

Scleromyxoedema-like cutaneous diseases in renal-dialysis patients

15 renal dialysis patients have been identified with a skin condition characterised by thickening and hardening of the skin of the extremities and an increase in dermal fibroblast-like cells associated with collagen remodelling and mucin deposition. The disease closely resembles scleromyxoedema, yet has significant enough clinical and histopathological differences to warrant its designation as a new clinicopathological entity.

Nephrogenic fibrosing dermopathy.

This report details the histopathologic findings in a unique fibrosing disorder that recently emerged among patients with renal disease. The affected patients were initially identified among recipients of renal transplants at a single institution, but later cases at other centers were identified, and included patients receiving renal dialysis for a variety of different kidney diseases. The cutaneous changes consisted largely of indurated plaques and papules on the extremities and trunk. Systemic findings seen in scleromyxedema, which the condition resembles in some respects, were absent. By routine microscopy, the findings range from a very subtle proliferation of dermal fibroblasts in early lesions, to a florid proliferation of fibroblasts and dendritic cells in fully developed cases. Thick collagen bundles with surrounding clefts are a prominent finding, and a variable increase in dermal mucin and elastic fibers was usually evident with special stains. CD-34 positive dermal dendrocytes were floridly abundant, with dendritic processes aligned with elastic fibers and around collagen bundles in a dense network. Factor XIIIa and CD-68 positive mono-and multinucleated cells are also present in increased numbers. Electron microscopy highlighted increased elastic fibers closely apposed to dendritic cell processes. The entire dermis was commonly involved, with increased spindle cells, collagen, mucin, and elastic fibers extending through the subcutis along the septa of fatty lobules. In some instances, the process resembled a sarcoma on histopathologic examination. The recent emergence of this condition and the apparent clustering of cases in specific dialysis centers initially suggested a possible infectious and/or toxic agent. To date, however, no such agent has been identified. We propose the term “nephrogenic fibrosing dermopathy (NFD)” until a specific cause can be identified.

Anti-oncogenic role of the endoplasmic reticulum differentially activated by mutations in the MAPK pathway

Dysfunction of the endoplasmic reticulum (ER) has been reported in a variety of human pathologies, including cancer. However, the contribution of the ER to the early stages of normal cell transformation is largely unknown. Using primary human melanocytes and biopsies of human naevi (moles), we show that the extent of ER stress induced by cellular oncogenes may define the mechanism of activation of premature senescence. Specifically, we found that oncogenic forms of HRAS (HRASG12V) but not its downstream target BRAF (BRAFV600E), engaged a rapid cell-cycle arrest that was associated with massive vacuolization and expansion of the ER. However, neither p53, p16INK4a nor classical senescence markers – such as foci of heterochromatin or DNA damage – were able to account for the specific response of melanocytes to HRASG12V. Instead, HRASG12V-driven senescence was mediated by the ER-associated unfolded protein response (UPR). The impact of HRAS on the UPR was selective, as it was poorly induced by activated NRAS (more frequently mutated in melanoma than HRAS). These results argue against premature senescence as a converging mechanism of response to activating oncogenes and support a direct role of the ER as a gatekeeper of tumour control.

Nephrogenic fibrosing dermopathy: a novel cutaneous fibrosing disorder in patients with renal failure

BACKGROUND Nephrogenic fibrosing dermopathy is a newly recognized cutaneous fibrosing disorder marked by the acute onset of induration involving the upper and lower limbs in patients with acute or chronic renal failure. The etiology, pathogenesis, associated clinical conditions (other than renal failure), and ultimate course have not been defined in the few cases studied. Presently, there is no effective treatment, and the condition persists in most patients. METHODS Clinical and histopathologic data on 13 patients from our institution with the diagnosis of nephrogenic fibrosing dermopathy were reviewed. Several clinical and laboratory parameters were examined to see if any were consistently associated with the disease. Biopsy specimens were analyzed to determine if there was a pattern to the evolution of fibrosis in these patients. RESULTS All 13 patients had renal failure before disease onset: 8 were undergoing chronic hemodialysis, 2 were undergoing chronic peritoneal dialysis, and 3 with acute renal failure had never undergone dialysis before the development of dermopathy. Most patients had other serious underlying medical conditions. Many patients were taking erythropoietin, cyclosporine, or both before the onset of disease. In transplant patients, no histocompatibility antigens were found to be associated with the disease. There were various laboratory abnormalities, but none were consistently associated with the condition. In skin biopsy specimens taken 7 to 180 days after disease onset, there were histopathologic changes suggestive of a tissue reaction to injury, as well as the development of smooth muscle actin-positive myofibroblasts. CONCLUSION Nephrogenic fibrosing dermopathy is a novel cutaneous fibrosing disorder that is distinguished from other sclerosing or fibrosing skin disorders by distinctive clinical and histopathologic findings occurring in the setting of renal failure. There were no additional clinical risk factors or laboratory findings common to the 13 patients studied, other than renal failure. The resemblance to a tissue injury reaction and the presence of myofibroblasts in the tissue specimens suggest that fibrogenic cytokines may be involved in the evolution of the disease.

Nephrogenic Systemic Fibrosis: A Report of 29 Cases

OBJECTIVE The purpose of this study was to determine the incidence of nephrogenic systemic fibrosis and its relation to renal failure and the administration of gadolinium-based contrast material at an academic medical center. MATERIALS AND METHODS A dermatopathology database was searched to identify patients in whom nephrogenic systemic fibrosis was diagnosed. The medical records of these patients were reviewed. Renal function concurrent with any administration of gadolinium-based contrast material was assessed, as was patient outcome. A database of patients undergoing long-term dialysis was reviewed separately to determine how many had received gadolinium and the frequency of nephrogenic systemic fibrosis among these patients. RESULTS Twenty-nine patients were found to have had nephrogenic systemic fibrosis between November 15, 1999, and December 31, 2006. It was known that gadolinium-based contrast material had been administered to 25 of these patients before diagnosis. All 29 patients had compromised renal function (27 had chronic renal failure, and two had acute renal failure). Determination of the temporal relation between gadolinium-based contrast administration and symptom onset often was difficult. Only eight patients had severe morbidity. Nephrogenic systemic fibrosis developed in 12 (2.9%) of 414 patients undergoing long-term dialysis who received gadolinium-based contrast material. CONCLUSION We confirm the strong association between nephrogenic systemic fibrosis and gadolinium-based contrast administration. Although the use of high doses of gadolinium and the occurrence of chronic renal failure have been implicated in other reports, several of our patients received standard doses of gadolinium, and two had transient acute renal failure before diagnosis. Most patients had mild or moderate symptoms. Nephrogenic systemic fibrosis developed in 2.9% of patients undergoing long-term dialysis who received gadolinium-based contrast material but in none of the long-term dialysis patients who did not receive gadolinium-based contrast material.

CD117 (KIT receptor) expression in Merkel cell carcinoma

The KIT receptor tyrosine kinase (CD117 antigen) is found in a variety of normal tissue cell types and in several malignant tumors, including acute myeloid leukemia. We recently encountered two tumors initially suspected as acute myeloid leukemia cutis and expressing CD117 that showed punctate positivity for cytokeratin 20 diagnostic for Merkel cell carcinoma. We evaluated 20 additional cases of MCC and found that 21 of 22 tumors (95%) expressed CD117. Intensity of CD117 expression did not appear to correlate with aggressive behavior. While the function of the KIT receptor in MCC is not known, its pathogenic role in other malignant neoplasms suggests the possibility of a similar role in MCC.

BRAF and NRAS mutations in spitzoid melanocytic lesions

BRAF mutations are common events in a variety of melanocytic nevi and primary cutaneous melanomas. We have previously found BRAF mutations in 82% of nevi, consisting of congenital, common acquired and dysplastic types, and 33% of primary cutaneous melanomas other than the spitzoid type, similar to other published reports. A small number of studies have evaluated Spitz nevi and have failed to detect any lesions possessing a BRAF mutation. Only one study included categories of atypical Spitz nevus and borderline lesions suspected to be spitzoid melanomas, along with classic Spitz nevi and spitzoid melanomas. We examined a spectrum of spitzoid lesions that included 48 Spitz nevi, some with atypical features, seven atypical (borderline) Spitz tumors, and 13 spitzoid melanomas. BRAF mutations were detected in 12 of 68 spitzoid lesions, of which two were spitzoid melanomas and 10 were Spitz nevi. Five of the 10 Spitz nevi with BRAF mutations were altered by more than usual cytologic atypia and/or architectural atypia overlapping with dysplastic nevi, or irritation/inflammation; one desmoplastic Spitz nevus had a BRAF mutation. These results indicate that a small subset of Spitz nevi, some with atypical histologic features, possess BRAF mutations. Therefore, the BRAF mutational status does not separate all Spitz nevi from spitzoid melanomas and non-Spitz types of melanocytic proliferations, contrary to previous reports.

Expression of polycomb group protein EZH2 in nevi and melanoma.

Background:  Enhancer of zeste homolog 2 (EZH2), a polycomb group protein that regulates the cell cycle, has recently been implicated in the progression of several human cancers. We sought to determine the pattern of EZH2 expression in benign and malignant melanocytic tumors to see if EZH2 might play a role in melanoma pathogenesis and progression.

Antibody to S100a6 protein is a sensitive immunohistochemical marker for neurothekeoma

Background: Neurothekeoma is a benign tumor of putative peripheral nerve sheath origin. It occurs in a myxoid (classic) variant, cellular variant, and intermediate (mixed) variant. Cellular neurothekeoma (CNT) usually involves the head and neck or extremities of young patients. Histologically, CNT can be confused with melanocytic and fibrohistiocytic lesions. An immunohistochemical antibody panel is often necessary to confirm the histological impression and exclude melanocytic and/or fibrohistiocytic lesions.

Interstitial mycosis fungoides, a variant of mycosis fungoides resembling granuloma annulare and inflammatory morphea *

Background: Interstitial mycosis fungoides (IMF) is a rare variant of mycosis fungoides that resembles the interstitial form of granuloma annulare and inflammatory morphea. IMF has received little attention in the literature.