Cutaneous late-phase response to allergen. Mediator release and inflammatory cell infiltration.

To better define the inflammatory infiltrates and kinetics of mediator release during the cutaneous late-phase reaction (LPR), we examined skin biopsies at 8 h, and skin chamber cell counts and mediator release for 12 h after antigen challenge. Compared with the control sites, the antigen-stimulated biopsy sites contained 14 times as many basophils (P less than 0.01) and six times as many eosinophils (P less than 0.001) with one to two fold more mononuclear cells (P less than 0.03) and neutrophils (P less than or equal to 0.01). Similar changes were found in the skin chambers. Although there were neutrophils in the control chamber, they were only twice as numerous in the antigen challenged site (P less than 0.01). Eosinophils were 35-fold (P less than or equal to 0.03) more prevalent in the antigen chamber than the control chamber for hours 8-12 and basophils were noted starting in the eighth hour and were 20-fold (P less than or equal to 0.03) more concentrated in the antigen chamber during the next 4 h. The mononuclear cells were not significantly different between antigen and control blisters. With respect to inflammatory mediators, there was an initial peak of histamine (13.2 +/- 2.9 ng/ml) in the blister fluid at 1 h. The level then fell to approximately 2 ng/ml, followed by a secondary rise starting at the eighth hour and increasing to 9.8 +/- 2.8 ng/ml by the twelfth hour. This secondary increase in histamine correlated significantly (r = 0.81, P less than 0.05) with the observed influx of basophils. PGD2 in the blister fluid rose to 371+/-25 pg/ml during the first 4 h and then slowly decreased to half this level during the last 4 h. Thus, the cutaneous LPR has been shown to manifest a secondary increase in histamine levels and a markedly specific increase in eosinophils and basophils with mediator release apparently being derived from the latter cells.

Generalized papular pruritic eruption in African patients with human immunodeficiency virus infection.

Of 284 patients hospitalized with HIV infection, 52 (18%) presented with a generalized pruritic papular eruption. No significant association between this eruption and other HIV manifestations or any opportunistic infection was found. Fifty-three of 61 (87%) consecutive African patients referred for a generalized papular pruritic eruption of unknown etiology of at least 1 month's duration were HIV seropositive, including 15 (65%) of 23 in good general condition. Thirty-seven (95%) of 38 patients with this eruption and severe weight loss (greater than 10% of normal body weight) were seropositive. The initial skin lesions were small, firm, intensely pruritic papules which released a small drop of clear fluid when scratched. Scratched papules became later hyperpigmented macules. Lesions were symmetrically distributed over the body and were most frequently found on the extensor surfaces of the arm, the dorsal surface of the hands, the inferior part of the legs, the ankles and the dorsum of the feet. Histologic examination showed a non-specific inflammatory reaction. Thirty-three (51%) patients reported that the skin eruption was their initial disease manifestation. In African patients, the presence of an unexplained generalized pruritic papular eruption is highly indicative of HIV infection.

Neonatal lupus erythematosus: new serologic findings.

A child with neonatal lupus was evaluated and found to possess serum anti Ro(SSA) antibodies. The cutaneous lesions and anti Ro(SSA) antibodies disappeared during the next 5 mo. The infant's mother was asymptomatic but possessed anti Ro(SSA) and anti La(SSB) antibodies.

Calciphylaxis is associated with hyperphosphatemia and increased osteopontin expression by vascular smooth muscle cells.

Calciphylaxis or calcific uremic arteriolopathy (CUA) is a fatal disease in dialysis patients due to calcification of cutaneous blood vessels. The pathogenesis has been attributed to elevated parathyroid hormone (PTH). However, recent studies evaluating vascular calcification in nondialysis patients have found that the smooth muscle cells play an active role, including production of the bone matrix protein osteopontin. To examine the involvement of various clinical parameters and smooth muscle cells of CUA, we performed a case-control analysis comparing 10 CUA patients with our current dialysis patients. Available histologic sections were immunostained for osteopontin, markers of smooth muscle cells, endothelial cells, and macrophages. Compared with our current dialysis population, patients with CUA were more likely to be obese, white, and female (P < 0.02). Comparison of laboratory values found CUA patients with lower serum albumin, greater serum phosphorus, and greater calcium X phosphorus product (P < 0.01). In contrast, there was no difference in the concentration of PTH or calcium between the 2 groups. Immunostaining of calcified blood vessels showed that all calcified vessels stained positive for osteopontin, whereas all the noncalcifed vessels showed no osteopontin localization. Staining for smooth muscle alpha-actin decreased in the medial layer with calcification, with cells appearing to be sloughed off, leading to near occlusion of the vessel lumen. Our case-control study demonstrates that hyperphosphatemia and an elevated calcium X phosphorus product is associated with CUA. Histologic examination suggests that the calcification is associated with increased expression of osteopontin by smooth muscle cells.

Atypical melanocytic nevi of the genital type with a discussion of reciprocal parenchymal-stromal interactions in the biology of neoplasia.

UNLABELLED: Melanocytic lesions of the genital area, especially those on the vulva, may present great difficulty in histological interpretation. A histological diagnosis of malignant melanoma was made in more than one third of 56 genital area melanocytic lesions submitted in consultation to the authors. The median age of the patients with these lesions was 25 years. This article is a clinicopathological study of these lesions and distinguishes them from malignant melanoma. The stroma of the lesions of the genital area was different from the stroma seen in the dysplastic nevi and melanoma. The differences in the stromal form in the diverse lesions is useful in diagnosis and is of profound biological significance. The stroma in the reported lesions and in some lesions of melanocytic neoplasia is described in detail, and its biological significance is discussed. Three sets of cases are used in this comparative study to delineate the clinicopathological nature and the biology of the genital nevi. The 56 cases submitted in consultation constitute the primary series of our work (The Clark Cutaneous Pathology Laboratory Series). These are compared with a series of cases from the Pigmented Lesion Group of the University of Pennsylvania and Pathology Services, Inc, and another series of cases from the Genetic Epidemiology Branch of the National Cancer Institute. The two series used for comparative study contain approximately the same number of cases of dysplastic nevi and malignant melanoma as there are atypical melanocytic nevi of the genital type in the primary series. The total number of cases was studied by comparison of their attributes in a relational database. The clinical data of the primary series was acquired through the use of a questionnaire completed by the contributors. The 56 cases presented two distinctive pathological pictures. One of these is termed atypical melanocytic nevi of the genital type (AMNGT), whereas dysplastic nevi (DN) formed the second of the two pathological pictures. There were 36 AMNGT and 14 DN. The remaining six cases were common nevi without atypia or ill-defined melanocytic hyperplasias. The lesions of AMNGT are usually located on the vulva, but they are seen on the perineum and, rarely, on the mons pubis and in the axilla. Lesions similar to AMNGT have been seen uncommonly on the male genitalia. The stromal patterns were distinctive and related to specific melanocytic lesions. An unclassified (unclass) or nonspecific stromal pattern was associated with AMNGT; a pattern of regression with differentiation (diff-regress) dominated the stroma of common dermal nevi; concentric eosinophilic fibroplasia (cef) and lamellar fibroplasia (lf) were present in dysplastic nevi; fibroplasia with a plaquelike lymphocytic infiltrate (fl) and diffuse eosinophilic fibroplasia (def) were noted in radial growth phase melanoma; and fibroplasia with angiogenesis (fa) or an absence of evidence for parenchymal stromal reciprocal interactions (nopsi) marked thick or deeply invasive vertical growth phase melanomas. Recommendations for management of the lesions are suggested. CONCLUSIONS: One kind of atypical melanocytic proliferation in the genital area forms a distinctive clinicopathological entity that can be distinguished from melanoma and dysplastic nevi, the AMNGT. Such lesions are more common on the labia minora or the mucosa of the clitoral region than they are on the labia majora. The other common atypical melanocytic proliferation of this area is a dysplastic nevus, which is much more common on the labia majora than on the labia minora. The reciprocal interactions between parenchyma and stroma are discussed as homeostatic processes, a continually functioning template maintaining tissue, organ, and organismal form and function. The progressive disorganization of this template in neoplasia is illustrated and is considered to be a cardinal element in the biology of neoplasia.

Histopathologic diagnosis of pityriasis lichenoides et varioliformis acuta and its clinical correlation.

To assess the specificity of the histopathologic features in the diagnosis of pityriasis lichenoides et varioliformis acuta (PLEVA), we reviewed the clinical manifestations and courses of 42 patients for whom this diagnosis was suggested in the pathology report. The histologic diagnosis of PLEVA was clinically substantiated in 16 of these 42 cases. Of the 26 cases in which PLEVA was erroneously diagnosed histologically, the correct clinical diagnosis was suggested before biopsies were done in 21 instances. In the five remaining cases, both the prebiopsy clinical diagnosis and the pathologic diagnosis proved to be incorrect. Pityriasis rosea, insect bites, and eczematous dermatitis accounted for the majority of the cases that histologically mimicked PLEVA. The constellation of histologic findings described in PLEVA (presence of intraepidermal lymphocytes and erythrocytes, dermal hemorrhage, and so-called lymphocytic vasculitis) is not specific and may be seen in a variety of dermatologic disorders.

Cytomegalovirus is predictably present in perineal ulcers from immunosuppressed patients.

We examined five consecutive skin biopsy specimens taken from perineal ulcers on immunosuppressed patients. Examination of hematoxylin-eosin-stained sections in conjunction with immunohistochemistry using monoclonal antibodies to early and late viral antigens resulted in identification of cytomegalovirus in all specimens. Cells containing cytomegalovirus were present in the ulcer base and papillary dermis. Herpes simplex virus was identified in three of five specimens. This series demonstrates that cytomegalovirus is predictably present in perineal ulcers from immunocompromised patients, but does not establish this virus as the cause of the ulcers.

Pemphigus foliaceus resembling eruptive seborrheic keratoses.

A 78-year-old man had an acute eruption of lesions that clinically resembled seborrheic keratoses. Microscopic examination of the lesions indicated acantholysis and dyskeratosis primarily in the granular layer. The patient's serum contained antibodies to intercellular substance. Direct immunofluorescence microscopy of a lesion demonstrated immunoglobulin deposition in the intercellular areas. Treatment with oral prednisone produced rapid resolution of the lesions. Patients in whom eruptive seborrheic keratoses (Leser-Trélat sign) develop should have histological examination of their lesions to rule out the diagnosis of pemphigus foliaceus.

Histologic comparison of autologous graft-vs-host reaction and cutaneous eruption of lymphocyte recovery.

BACKGROUND AND DESIGN: The cutaneous eruptions due to allogeneic graft-vs-host disease, autologous graft-vs-host disease, and lymphocyte recovery occur in the setting of peripheral leukocyte reconstitution after marrow aplasia. Since the eruptions of lymphocyte recovery (ELR) and autologous graft-vs-host disease develop in the presence of histocompatibility, we question whether reliable histologic differentiation is possible. To this end, we performed a retrospective, blind analysis of 38 skin biopsy specimens obtained from patients who received autologous marrow transplants or intensive chemotherapy alone for various malignant neoplasms. RESULTS: In 31% of the cases, we were unable to distinguish between an ELR and a grade 2 graft-vs-host reaction. In 40% of the ELR specimens, a significant number of dyskeratotic keratinocytes were present, leading to the false interpretation of a grade 2 graft-vs-host reaction. Satellite cell necrosis was observed in both groups. The patterns of dyskeratotic keratinocytes were similar; one ELR specimen displayed prominent follicular involvement. Most ELR specimens were consistent with grade 1 graft-vs-host reaction changes. CONCLUSIONS: These findings indicate that the presence of dyskeratotic keratinocytes is not specific for a graft-vs-host reaction and that cutaneous eruptions after autologous marrow transplantation are best considered an ELR.

Characterization of the dermal infiltrate in human immunodeficiency virus-infected patients with psoriasis.

We investigated the dermal inflammatory cell infiltrates of psoriatic lesions from nine human immunodeficiency virus-infected patients and nine age-, sex-, and site-matched control specimens. The study was retrospective and observer blinded. T lymphocytes were quantitated using UCHL-1, a pan-T-cell monoclonal antibody, and plasma cell number was estimated in hematoxylin-eosin-stained sections. Differences in both variables reached statistical significance. There were fewer T cells and the number of plasma cells was significantly higher in specimens from the human immunodeficiency virus-positive individuals in comparison with control specimens. As plasma cells are readily identified on hematoxylin-eosin-stained sections, their presence in skin biopsy specimens from psoriatic leisons should arouse suspicion of human immunodeficiency virus infection. The depletion of helper/inducer T lymphocytes by the human immunodeficiency virus may promote the presence of plasma cells in cutaneous inflammatory infiltrates.

Graft-versus-host reaction. Cutaneous manifestations following bone marrow transplantation.

The distinctive cutaneous changes that occur in both the acute and chronic forms of the graft-vs-host reaction (GVHR) are described in two living patients in whom the GVHR developed after bone marrow transplantation for aplastic anemia. In the skin, the mild form of the acute GVHR is recognized as a subtle macular erythema, and the severe form appears as erythematous papules and violaceous macules with scale. Skin biopsy specimens in both of the acute forms show vacuolar alterations of the epidermal basal-cell layer with a perivenular infiltrate of lymphocytes. The chronic GVHR evolves from generalized scaling to diffuse areas of aclerotic and atrophic skin with a curious reticulated hyperpigmentation, ulcerations, and alopecia. Histopathologic study shows collagenization of the dermis that can be correlated with the clinical sclerodermoid changes. Owing to its visibility, the skin offers a unique opportunity for the early recognition of the GVHR.

Induction of acantholysis in organ explant culture by penicillamine and captopril.

Pemphigus is an autoimmune disease proved to be mediated by IgG autoantibodies. Skin lesions clinically and histologically identical to pemphigus may occur in patients receiving penicillamine and captopril, but some of these patients lack circulating or tissue-bound autoantibodies. Therefore, we examined the ability of these drugs to produce acantholysis directly in organ explant culture. Human skin explants were prepared from split-thickness graft skin from adults and from neonatal foreskins. Explants were cultured in media containing 0.1 to 200 mmol/L of penicillamine or captopril; parallel drug-free control cultures were also prepared. Acantholysis occurred in all split-thickness graft skin cultures incubated for 72 hours with at least 20 mmol/L of penicillamine and at 24 to 48 hours in those incubated with at least 10 mmol/L of captopril. Acantholysis occurred less frequently in foreskin cultures, being present in 1 (8%) of 12 of those exposed to at least 20 mmol/L of penicillamine and 3 (12%) of 25 of those exposed to at least 10 mmol/L of captopril. None of the parallel drug-free control cultures developed acantholysis. Subcorneal acantholysis, resembling that seen in pemphigus foliaceus, and suprabasilar acantholysis, resembling that seen in pemphigus vulgaris, were induced in vitro. Our results indicate that both drugs can act as ligands and produce acantholysis in organ explant culture in the absence of autoantibody. This ligand-induced acantholysis may also be responsible for induction of the disease in vivo in those patients who lack demonstrable autoantibodies.

Thiazide diuretic therapy and chronic photosensitivity.

Chronic photosensitivity associated with hydrochlorothiazide ingestion occurred in four patients. These patients developed a debilitating photosensitivity that persisted for months to years even after they stopped taking the diuretic. Their age range was 44 to 66 years. Phototesting with ultraviolet B (UV-B) and ultraviolet A (UV-A) radiation revealed decreased minimal erythemal doses for one or both wave bands in all patients tested. Histologic examination of skin biopsy specimens from the patients' UV-B and UV-A test sites and lesional skin revealed an acute eczematous dermatitis. Treatment with methoxsalen and UV-A radiation successfully cleared the photosensitive eruption in the patients.

Papulovesicular light eruption. A defined subset of polymorphous light eruption.

A distinctive photodermatitis is seen commonly in tourists visiting Hawaii. Analysis of 150 cases revealed that the eruption is acute in onset following exposure to sunlight, is confined to exposed areas, and mainly affects young to middle-aged white women. The clinical presentation is remarkably uniform, consisting of papules, papulovesicles, or vesicles. These findings are consistent with a diagnosis of polymorphous light eruption (PMLE) and the histologic picture supports this diagnosis. Other clinical variants of PMLE were not seen in our patients, however, which suggests that this condition is more monomorphous than polymorphous. We suggest papulovesicular light eruption as a suitable name for this common and distinctive subset of PMLE.

Histologic evaluation of preauricular and postauricular human skin after high-energy, short-pulse carbon dioxide laser.

BACKGROUND: Despite its growing use in dermatalogic surgery, the effects of high-energy, short-pulse carbon dioxide laser on human skin have not been well documented. OBJECTIVES: To study the histologic effects of this high-energy, short-pulse CO2 laser on human skin and to compare these changes with the effects of standard chemexfoliation procedures. OBSERVATIONS: Twenty-four hours after laser administration, there was extensive epidermal necrosis and coagulative change in the superficial papillary dermis. With increasing doses of laser energy, there was a statistically significant increase in the depth of dermal wounding (P<.001 for days 1 and 3, F-test). Reepithelialization occurred in most specimens by day 3. By day 90, most specimens showed a subepidermal dermal repair zone consisting of compact new collagen fibers overlying collagen with evidence of solar elastosis. CONCLUSION: This high-energy, short-pulse CO2 laser produces morphologic changes similar to those seen with medium-depth chemical peels. This laser can ablate skin precisely and bloodlessly with little interference in the wound healing process, suggesting that it may serve as an alternative treatment for photoaged skin.

Intravenous administration of recombinant human granulocyte-macrophage colony-stimulating factor causes a cutaneous eruption.

The intravenous administration of recombinant human granulocyte-macrophage colony-stimulating factor to three patients with leukemia who were receiving marrow aplasia-inducing chemotherapy resulted in the development of wide-spread erythematous macules and papules. The course of the eruption paralleled the time of infusion of the granulocyte-macrophage colony-stimulating factor. Skin biopsy specimens taken from two of the eruptions displayed characteristic changes consisting of a variable mixture of granulocytes and lymphocytes, increased number and size of dermal macrophages, mild to moderate epidermal exocytosis, intercellular edema, and rare dyskeratotic keratinocytes. Immunophenotypic analysis of one specimen was notable for keratinocyte intercellular adhesion molecule-1 expression. Administration of the recombinant human cytokine in pharmacologic doses is postulated to induce changes in the immunologic status of the skin, resulting in the expression of a cutaneous eruption.

Acute graft-vs-host disease. Development following autologous and syngeneic bone marrow transplantation.

Graft-vs-host disease (GVHD) is a frequent complication of allogeneic bone marrow transplantation but has been infrequently reported following autologous or syngeneic bone marrow transplantation. Ninety-six autologous and 19 syngeneic marrow transplants were performed at our institution between July 1977 and March 1984. We report acute cutaneous GVHD occurring in seven patients who received autologous marrow and two patients who received marrow from an identical twin. All nine patients had clinically detectable eruptions and had skin biopsy specimens with histologic changes of grade 2 acute GVHD. Although most cases were mild and self-limiting, four patients required systemic corticosteroids to treat their disease. Thus, acute cutaneous GVHD was seen in approximately 8% of patients receiving autologous or syngeneic bone marrow transplants at our institution.

Recurrent palmoplantar hidradenitis in children.

BACKGROUND: There are several reports of tender, erythematous plantar nodules occurring in pediatric patients. Despite similar morphological features, the histologic findings in these lesions have been quite diverse. A new entity called idiopathic plantar hidradenitis (also termed neutrophilic eccrine hidradenitis in children), which is characterized by tender, red nodules on the feet and unique histopathologic features, was recently described. OBSERVATIONS: We describe two children with these unusual cutaneous lesions and histopathologic findings and compare them with patients with idiopathic plantar hidradenitis. Our patients, in contrast to those with idiopathic plantar hidradenitis, had involvement of the palms as well as the soles. Both children had self-limited recurrent lesions; in one child, the lesions were associated with low-grade fever. Biopsy specimen findings in both cases demonstrated dense neutrophilic infiltrates localized to the eccrine units. CONCLUSIONS: Our patients had clinical and histologic findings similar to those recently reported as idiopathic plantar hidradenitis (neutrophilic eccrine hidradenitis in children). Because palms and soles can be affected and the lesions typically recur, we suggest that this condition be referred to as recurrent palmoplantar hidradenitis.

Observations and proposed mechanism of N,N',N''-triethylenethiophosphoramide (thiotepa)-induced hyperpigmentation.

After receiving N,N',N''-triethylenethiophosphoramide (thiotepa) and cyclophosphamide intravenously, five women with metastatic adenocarcinoma of the breast developed a patterned hyperpigmentation confined to skin occluded by adhesive-containing materials. Determinations of thiotepa concentrations in occluded and nonoccluded skin, plasma, bandage with adhesive, and gauze containing sweat were performed. The results suggest that this alkylating agent is excreted onto the skin surface in sweat, accumulates beneath adhesive-containing bandages and electrocardiogram pads, and exerts a local toxic effect resulting in hyperpigmentation.

The utility of submitting fibroepithelial polyps for histological examination.

BACKGROUND: The fibroepithelial polyp (FEP) is a common cutaneous lesion that is often removed for medical or cosmetic reasons. We examined the utility of submitting clinically diagnosed FEPs for routine microscopic examination. DESIGN: We reviewed 11500 consecutive cutaneous pathology reports. Materials submitted with the clinical diagnosis of FEP or a synonym were reviewed and the histopathologic slides were examined. A comparison group of specimens submitted with the clinical diagnosis of melanocytic nevus was reviewed. SETTING: The biopsy reports were generated at a regional non-hospital-based dermatopathology laboratory providing service to physicians (dermatologists and nondermatologists) practicing ambulatory medicine predominantly within a 4-state region (Ind, Ky, Tenn, and WVa). RESULTS: Of 1335 clinical specimens submitted as FEPs, there were 5 malignant tumors. In the comparison group of 697 clinically diagnosed melanocytic nevi, there were 6 malignant tumors. In comparison with clinically diagnosed melanocytic nevi, the likelihood that a lesion clinically diagnosed as FEP would be a malignant tumor on histological examination is very low (relative risk, 0.4). None of the lesions clinically diagnosed as FEPs by dermatologists proved to be malignant. CONCLUSIONS: Our data suggest there is an extremely low prevalence of malignancy in lesions clinically diagnosed as FEPs. We conclude that cutaneous lesions diagnosed as typical FEPs by dermatologists need not be submitted for microscopic examination.