Clifton R. White

Granulomatous variants of cutaneous T-cell lymphoma : the histopathology of granulomatous mycosis fungoides and granulomatous slack skin

Granulomatous mycosis fungoides is an unusual histologic variant of mycosis fungoides, a condition that is ordinarily indolent. Granulomatous slack skin, like granulomatous mycosis fungoides, shows epidermotropism, granulomatous inflammation, a clonal T-helper cell population, and progression to systemic lymphoma in some cases. Unlike granulomatous mycosis fungoides, it is characterized clinically by bulky, pendulous skin folds. The similarities between the two conditions prompted us to compare the histologic features. We reviewed 24 biopsies from 10 patients with granulomatous mycosis fungoides. These showed several distinct histologic patterns, including three cases that mimicked granuloma annulare. We also reviewed biopsy specimens from four patients with granulomatous slack skin. These specimens had a more stereotypic appearance, with permeation of the entire dermis and subcutis by lymphocytes, marked epidermotropism, and a more even distribution of granulomas and giant cells within the infiltrate. Biopsies of fully developed lesions of granulomatous slack skin showed elastolysis involving the full thickness of the dermis—a feature not seen in any of our granulomatous mycosis fungoides cases. Biopsy specimens from granulomatous mycosis fungoides and granulomatous slack skin may be mistaken for nonneoplastic granulomatous dermatitides, but they can usually be distinguished from these by the presence of epidermotropism or atypical lymphocytes. Because several of our patients with granulomatous mycosis fungoides died after courses of unremarkable length, it seems unlikely that the presence of granulomas is invariably correlated with a more benign course than nongranulomatous mycosis fungoides.

Evolution of B-cell Lymphoma from Pseudolymphoma A Multidisciplinary Approach Using Histology, Immunohistochemistry, and Southern Blot Analysis

Cutaneous B-cell lymphomas are rare neoplasms that can present as lesions involving solely the skin or develop in association with a systemic lymphoma. Histologically they are often difficult to differentiate from pseudolymphomas, and the use of immunohistochemistry may be necessary to correctly classify them. We report a study of multiple skin lesions in a patient who initially presented with multiple pseudolymphomas, apparently associated with an immune response to the dye of his tattoos. Over a period of 4 years his skin lesions evolved from histologically benign and immunologically polyclonal pseudolymphomas to a histologically malignant and immunologically monoclonal B-cell large cell lymphoma. Genotypic analysis with a probe for the heavy-chain immunoglobulin gene demonstrated the presence of clonal B-cell populations in all of the pseudolymphoma biopsy samples as well as in the subsequent lymphoma tissue samples, with a pattern of clonal bands suggestive of evolution of the B-cell clones. These findings suggest that the development of B-cell lymphoma in this patient was related to a persistent abnormal immune response to the chronic antigenic stimulus of the dye of the tattoo. The presence of clonal B-cell populations in pseudolymphoma by Southern blot analysis may be useful in predicting those patients who will subsequently develop overt lymphoma.

Identification of common polymorphisms in the coding sequence of the human MSH receptor (MCIR) with possible biological effects

The extension locus has been identified in many mammalian species as a gene that determines the relative amounts of eumelanin and phaeomelanin pigments in hair and skin. In at least three species, this locus has been demonstrated to encode the melanocyte‐stimulating hormone receptor (MC1‐R), and functionally variant alleles have been demonstrated to cause a broad range of pigmentation phenotypes. To test for MC1‐R allelic variation in man, genomic DNA was extracted from skin samples collected from patients with different skin types (I–VI), and eye and hair color. A PCR‐based approach was used to amplify the full‐length coding sequence of the MC1‐R and the resulting products were sequenced. Two polymorphic alleles were identified with single point mutations in the coding sequence: a valine‐to‐methionine substitution at position 92 (V92M), and an aspartic acid‐to‐glutamic acid substitution at position 84 (D84E). RFLP analysis demonstrated the presence of the V92M allele in 4 out of 60 (6.6%) of individuals examined, predominantly those with blue eyes and blond hair. This polymorphism was found in both heterozygous and homozygous states in individuals with type I skin. The D84E allele was found in one individual with skin type I; this person also has the V92 M allele and thus is a compound heterozygote.

Expression of vascular endothelial growth factor and its receptors in rosacea

Background: Rosacea is a common chronic disease of unclear pathogenesis, characterised by inflammation and vascular abnormalities of the facial skin and ocular surface. Recognising that vascular endothelial growth factor (VEGF) is vasoactive and has inflammatory activities, the expression of this molecule and its receptors, VEGF-R1 and VEGF-R2, in rosacea was investigated. Methods: Formalin-fixed, paraffin wax-embedded sections of skin obtained from 20 patients with rosacea were immunostained to detect expression of VEGF, VEGF-R1 and VEGF-R2, using an indirect methodology incorporating antigen retrieval. Adjacent sections were stained with haematoxylin and eosin. Results: Biopsy specimens were characterised by perivascular and perifollicular lymphohistiocytic infiltration and dilated vascular channels. In addition to keratinocyte and epithelial staining, which was also noted in normal skin, vascular endothelium frequently stained positive for VEGF-R1 (14/20, 70%) and VEGF-R2 (20/20, 100%), but infrequently for VEGF (2/20, 10%). In most specimens, infiltrating leucocytes, including lymphocytes, macrophages and plasma cells, expressed VEGF (17/20, 85%), VEGF-R1 (20/20, 100%) and VEGF-R2 (20/20, 100%). Conclusion: Expression of VEGF receptors, both by vascular endothelium and infiltrating mononuclear cells, is observed in rosacea. Although not expressed by endothelium, VEGF is present in epidermis and epithelium, and is expressed by infiltrating cells. VEGF receptor–ligand binding may contribute to the vascular changes and cellular infiltration that occurs in rosacea.

Amelanotic malignant melanoma.

Amelanotic malignant melanoma (AMM) often defies clinical diagnosis because of its wide range of clinical appearances and lack of pigmentation. Biopsy of AMM typically yields the correct diagnosis, although the histological findings, especially in metastatic lesions, occasionally may be confused with other malignancies. In cases histologically challenging, immunohistochemical techniques frequently provide diagnostic information. Multiple mechanisms to explain amelanosis have been suggested, all resulting in a single, common amelanotic phenotype. Appropriate studies to compare outcomes of amelanotic versus pigmented melanomas have not been performed. Treatment recommendations for AMM are identical to those for pigmented melanomas, although accurately defining clinical margins of the neoplasm often is challenging. Overall, a high index of suspicion and a low threshold to biopsy unusual clinical lesions ultimately may allow for earlier diagnosis and treatment of these frequently lethal malignancies.

Cutaneous acanthamoeba infection associated with leukocytoclastic vasculitis in an AIDS patient.

Cutaneous Acanthamoeba infection is a rare complication of immunocompromised individuals including those having acquired immunodeficiency syndrome (AIDS), who often have concurrent central nervous system involvement. Acanthamoeba typically involves the skin and central nervous system by disseminating from a primary focus in the lungs or sinuses. We report an unusual patient with AIDS who developed cutaneous infection with Acanthamoeba, apparently without CNS infection but with sinus involvement. Histologically, the purpuric lesions showed prominent leukocytoclastic vasculitis as well as myriads of organisms.

Chronic verrucous varicella-zoster virus infection in patients with the acquired immunodeficiency syndrome (AIDS). Histologic and molecular biologic findings.

Verrucous skin lesions have been attributed to various herpes viruses in immunosuppressed patients, including those with human immunodeficiency virus infection (HIV). We examined such lesions from six HIV-infected patients to determine the range of microscopic findings present and to establish which herpesviruses were present. Verrucous epidermal hyperplasia. pseudocarcinomatous hyperplasia, and massive hyperkeratosis correlate with the warty clinical appearance of the lesions. Herpetic cytopathic changes, including multinucleated epidermal giant cells, steel-gray nuclei, necrotic acantholytic keratinocytes, and Cowdry type A nuclear inclusions were seen most prominently in the dells between papillations and in adnexal epithelium. In two cases, increased numbers of spindled cells were seen in the dermis. Immunoperoxidase staining with anti-type IV collagen antibodies demonstrated that these findings were not those of Kaposis sarcoma, but represent a fibrotic reaction to the infection. Viral cultures of four of the cases demonstrated the presence of varicella-zoster virus, whose presence was detected by the polymerase chain reaction in paraffin-embedded lesional tissue from all six cases. Polymerase chain reaction did not show the presence of cytomegalovirus. herpes simplex, Epstein-Barr, or human papillomavirus. We conclude that these unusual verrucous lesions are a chronic manifestation of herpes zoster infection and that the reported presence of other agents in such lesions is probably coincidental.

Myxofibrosarcoma presenting in the skin: Clinicopathological features and differential diagnosis with cutaneous myxoid neoplasms

Myxofibrosarcoma (myxoid malignant fibrous histiocytoma) is one of the most common fibroblastic sarcomas in the older patient, where it can sometimes present with anatomically deceptive boundaries. Myxofibrosarcoma is now fully characterized as a distinctive and definable pathologic entity. Clinically there is a tendency for predominantly subcutaneous, multinodular, diffusely infiltrative growth, which may extend to the overlying dermis and present as a cutaneous lesion. Histologically myxofibrosarcoma comprises a spectrum ranging from hypocellular low-grade myxoid to high-grade pleomorphic sarcoma. We report herein 6 cases of myxofibrosarcoma each with dermatological presentation as a cutaneous nodule. The dermal component in each of the lesions was low- to intermediate-grade and predominantly myxoid resulting in confusion with benign myxoid neoplasms in small biopsy specimens. The purpose of this series is to focus the attention of workers in dermatology on a subject rarely discussed in dermatopathology literature: the cutaneous presentation of myxofibrosarcoma and the potential for clinical and histologic misinterpretation, as benign dermal lesions.

Juvenile xanthogranuloma: A clinical, histopathologic and immunohistochemical study

Juvenile xanthogranuloma (JXC) is a benign histiocylic proliferation of uncertain histogenesis which usually resolves spontaneously. Histopathologically, classic lesions are characterized by diffuse proliferations of foamy histiocytes, many of which may be multinucleated (Toulon cells), admixed with lymphocytes and eosinophils. Histologic variants of JXG, perhaps representing evolving lesions, may lack these typical histopathological features, showing diffuse infiltrates of non‐foamy mononuclear histiocytes without Toulon cells, posing problems in differentiation from other histiocylic or melanocylic proliferations. Immunohistochemically, JXG is characterized by variable expressions of several histiocytic markers as well as the absence of staining for SI00 protein. To assess better the spectrum of histopathological and immunohistochemical features of JXG, we studied nine cases of classic or histologic variant of JXG. The cases were evaluated by light microscopy and with an extensive battery of antibodies. All 9 cases, regardless of their light microscopic appearance, showed markedly positive staining with histiocytic markers including CD68, HAM56, cathepsin B and vimentin, but did not stain for S100 protein. Antibodies to factor XIIIa stained positively in 8 cases while staining for other markers was variable. Our results suggest that the histiocytes in JXG lesions have macrophagic differentiation, probably representing a reactive process to an unknown stimulus.

Pruritic dermatitis in asthmatic basenji-greyhound dogs: A model for human atopic dermatitis

A recurrent, nonseasonal pruritic dermatitis manifested as lichenified plaques and as inflammatory nodules and papules in each of fourteen basenji-greyhound (B-G) crossbreed dogs, all of which demonstrated both nonspecific and Ascaris-specific airway hyperreactivity, with changes in pulmonary mechanics of the same order as those seen in symptomatic human asthma. Other features analogous to human atopic disease included blunted cyclic adenosine monophosphate (cAMP) responsiveness to beta adrenergic agents and in vivo release of histamine and slow-reacting substance of anaphylaxis in response to antigen aerosol challenge. The dermatitis appears to be a manifestation of the atopic state in these dogs and may provide an animal model for the study of human atopic dermatitis.