Jag Bhawan

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.

Cathepsin K in Melanoma Invasion

Cathepsin K (catK) is a lysosomal cysteine protease with strong collagenolytic activity that mediates bone resorption in osteoclasts. Recently, catK expression has been reported in skin and lung fibroblasts, which suggests a role in maintaining homeostasis of the extracellular matrix outside of bone. Matrix degradation is a pivotal step in tumor invasion and metastasis. As other proteases, in particular matrix metalloproteinases and some cathepsins, but not catK, have been described to mediate melanoma invasion, we studied catK in melanoma. Immunostaining revealed strong catK expression in most primary melanomas and all cutaneous melanoma metastases. Melanocytic nevi also demonstrated catK expression, but it was less intense than in melanomas. Melanoma lines express both the pro- and the active form of catK and internalize extracellular collagen into lysosomes. Inhibition of catK greatly reduced melanoma cell invasion through Matrigel basement membrane matrix and increased detection of internalized collagen. We suggest that catK may play an important role in melanoma invasion and metastasis by mediating intracellular degradation of matrix proteins after phagocytosis. Clinical use of catK inhibitors, a class of medication currently in clinical trials for the treatment of osteoporosis, may be a promising avenue for the treatment of melanoma.

Elastic fibers in scar tissue

The capacity of the skin to be stretched and to return to its resting position is correlated to the quantity and to the quality of the elastic fiber network. Although elastic fibers have been demonstrated in scars, the time course of their appearance in scars and their role in scar elasticity has not been elucidated. A study was therefore undertaken to evaluate the elastic fiber network in scars.

Morphea-like Tattoo Reaction

Tattoo reactions are histologically diverse. In general, dermal changes predominate, although epidermal changes such as acanthosis or spongiosis can also be seen. The chronic inflammatory cell infiltrate can be nodular, lichenoid, or granulomatous. Occasionally, the dermal infiltrate may be so dense as to suggest a diagnosis of cutaneous lymphoma. We report an unusual tattoo reaction that mimicked morphea histologically.

Expression and regulation of cathepsin K in skin fibroblasts

Abstract:u2002 Cathepsin K (catK) is a lysosomal cysteine protease with strong collagenolytic activity well known to mediate bone resorption in osteoclasts. Recently, catK has also been reported to be expressed in other tissues. In the dermis, it is expressed only under certain circumstances such as scarring or inflammation. We therefore investigated the expression and regulation of this protease in dermal fibroblasts using immunoblotting and immunostaining. Cultured skin fibroblasts were found to strongly express catK in lysosomes. Internalization of collagen I and IV to lysosomes of fibroblasts indicates a role of catK in intracellular collagen degradation after endocytosis, a process that is different from the metalloproteinase‐mediated collagen degradation in the extracellular space. In fibroblasts, interleukin‐1α and cellular confluence upregulate catK expression and transforming growth factor‐β1 inhibits confluence‐induced catK upregulation in skin fibroblasts. RANKL (ligand of receptor activator of NF‐κB) did not alter catK expression. These regulators of catK expression are likely to play a role in the as‐needed upregulation in certain skin conditions, where the prominent matrix‐degrading properties of catK are thought to require tight regulation to maintain the homeostasis of the extracellular matrix.

Intracellular Degradation of Elastin by Cathepsin K in Skin Fibroblasts— A Possible Role in Photoaging

Solar elastosis is observed in the dermis of photoaged skin and is characterized by an accumulation of abnormal elastin in the extracellular space. Several proteases that degrade elastin in the extracellular space have been implicated in its formation. The lysosomal protease cathepsin K (catK) has recently been described to be highly expressed in skin fibroblasts under certain pathologic conditions. As cat K is one of the most potent mammalian elastases, we hypothesized that catK‐mediated intracellular elastin degradation may play a role in the formation of solar elastosis. Immunostaining of cultured skin fibroblasts incubated with labeled elastin demonstrated internalization of extracellular elastin to lysosomes and its degradation by catK. Induction of catK expression in fibroblasts was observed both in vitro and in vivo after exposure to longwave UVA. In contrast to fibroblasts from young donors, cells from old donors failed to activate catK in response to UVA. These data suggest a role of intracellular elastin degradation by catK in the formation of solar elastosis. We propose that an age‐related decline in catK activity, in particular after UV exposure, may promote the formation of actinic elastosis through a decline of orderly intracellular elastin degradation and subsequent accumulation of elastin in the extracellular space.

Sclerotic bodies in nephrogenic systemic fibrosis : a new histopathologic finding

Nephrogenic systemic fibrosis (NSF – known previously as nephrogenic fibrosing dermopathy) is a systemic disorder observed exclusively in patients with a history of kidney disease associated with renal failure. Reported histopathologic findings of NSF include spindle‐shaped fibroblast‐like cells with fibrosis, thickened collagen bundles with surrounding spindled and epithelioid cells, increased number of elastic fibers, sparse inflammatory infiltrate and increased stromal mucin. Two populations of multinucleated giant cells (Factor XIIIa and CD68 positive) have also been observed. We observed the presence of sclerotic bodies with entrapped elastic fibers in two cases of NSF, which we interpreted to be collagenous in nature, a finding not previously reported. These bodies should not be confused with osseous metaplasia previously seen in association with NSF, which show lacunae and cells within the osseous bodies that may or may not be calcified. We did not observe lacunae or cells within the sclerotic bodies in our cases. Furthermore, the sclerotic bodies in our cases stained blue on Masson trichrome, whereas previous investigators observed the osseous metaplasia to be red. We suggest that sclerotic bodies may be an additional clue to the diagnosis of NSF.

Continuous therapy followed by a maintenance therapy regimen with a triple combination cream for melasma

BACKGROUNDnMelasma is often recalcitrant to treatment. Triple combination (TC) cream is an effective and approved treatment for melasma.nnnOBJECTIVEnWe sought to determine the efficacy and safety of continuous therapy followed by a maintenance treatment regimen during a period of 24 weeks with a TC cream containing hydroquinone 4%, tretinoin 0.05%, and fluocinolone acetonide 0.01%.nnnMETHODSnSeventy patients with melasma were treated with a TC cream daily for 12 weeks, after which, if clear or almost clear, they applied the cream twice per week for 12 more weeks. For patients who were not clear or almost clear after 12 weeks, daily treatment was continued.nnnRESULTSnIn all, 25 patients completing the study per protocol were treated daily for 24 weeks (cohort A); 6 patients were treated daily for 12 weeks followed by 12 weeks of maintenance therapy (cohort B); and 21 patients were treated daily for 12 weeks, relapsed during the maintenance phase, and returned to daily dosing (cohort C). Pigmentation was significantly reduced at weeks 12 and 24 and global melasma severity improved at week 24 in cohorts A and C compared with baseline. Adverse events occurred in 53% of patients and were primarily mild in severity.nnnLIMITATIONSnThis was an open-label trial.nnnCONCLUSIONnAbout half of patients treated with a TC cream for melasma were able to begin maintenance therapy twice per week after 12 weeks; however, relapses occurred in most of these patients, requiring resumption of daily therapy. The cream is safe in the treatment of moderate to severe melasma for up to 24 weeks when used intermittently or continuously. Significant reductions in melasma severity scores were seen at weeks 12 and 24 when compared with baseline scores in all evaluable study groups.

Isolated dyskeratotic acanthoma. A variant of isolated epidermolytic acanthoma.

Disorders affecting the maturation of the epidermis are regarded as incidental findings in normal skin and otherwise unrelated benign lesions. These include epidermolytic hyperkeratosis, focal acantholytic dyskeratosis, and pagetoid dyskeratosis. The former two entities also occur as primary pathologic lesions. We report a hyperkeratotic lesion with a specific histologic pattern consisting of dyskeratotic cells throughout the epidermis and a parakeratotic horn, with large, rounded cells at all levels of the stratum corneum. Because we believe it to be a variant of the solitary, acquired lesions characterized by abnormal epidermal maturation, such as epidermolytic acanthomas, we suggest the term dyskeratotic acanthoma for this lesion.

HIV-Associated Vitiligo Totalis with Minimal Repigmentation and Alopecia Areata Diffusa During Immune-Reconstitution

Background: Cutaneous findings in the setting of HIV infection encompass a broad spectrum of diseases. Only few cases of vitiligo or alopecia areata have been described in HIV/AIDS patients and it remains unclear whether there is a causal relationship between HIV/AIDS and these two conditions. Observations: Our patient initially presented with diffuse generalized pruritic hypo- and depigmented macules and patches. She was diagnosed with advanced HIV/AIDS at that time. There was progression to vitiligo totalis followed by partial repigmentation and generalized alopecia areata diffusa with immune-reconstitution. Conclusions: This is, to our knowledge, the first case of rapidly progressing vitiligo totalis in a patient with advanced HIV/AIDS. We conclude that this, together with the observation of repigmentation during immune-reconstitution, sug- gests a causal relation between vitiligo and HIV/AIDS. The different time course of the also observed alopecia areata dif- fusa, with first manifestation during immune-reconstitution, may be due to differences in the immune-pathogenesis be- tween vitiligo and alopecia areata.