Basaloid/follicular hyperplasia overlying connective tissue/mesenchymal hamartomas simulating basal cell carcinomas.

BACKGROUND: Basaloid hyperplasia has been described overlying dermatofibromas as well as in the epidermis overlying nevus sebaceus. Although the morphology of these areas may resemble that of basal cell carcinoma (BCC), in the majority of cases aggressive behavior of the proliferation is not seen. In fact, the basaloid proliferation often shows follicular differentiation and may be stimulated and maintained by its relationship with the underlying stromal cells. OBJECTIVE: We wanted to determine whether immunohistochemical staining for antibodies, which may suggest differences in pathogenesis, were different in basaloid hyperplasia overlying connective tissue/mesenchymal hamartomas and BCC. METHODS: We report 3 cases of connective tissue/mesenchymal hamartomas with overlying basaloid hyperplasia, in which the areas of the basaloid proliferation showed follicular differentiation. Immunohistochemical stains included Ber-EP4, PCNA, Ki-67, Bcl-2, p53, SM-Actin, CD31, factor XIIIa, KP-1, and CD34. RESULTS: There was a diffuse positive reaction for Ber-EP4 in all specimens and there was increased nuclear staining for PCNA and Ki-67. There was focal cytoplasmic staining for Bcl-2 in the areas of basaloid hyperplasia. Immunohistochemical staining for p53 showed only scattered positive cells except in a small focus in the areas of basaloid hyperplasia. The connective tissue component of all lesions showed diffuse staining for CD34 surrounding areas of basaloid hyperplasia in the mesenchymal component as well as in abundant S-100(+) nerves. CONCLUSION: The areas of basaloid hyperplasia in these hamartomas exhibited an immature phenotype similar to that seen in both BCCs and follicular tumors; however, the patterns of proliferation markers, p53, Bcl-2, and the surrounding stromal cell markers were similar to those of benign follicular tumors. Thus the staining pattern for this group of antibodies suggests that areas of basaloid hyperplasia are not BCC.

Rapid onset of cutaneous squamous cell carcinoma in patients with rheumatoid arthritis after starting tumor necrosis factor alpha receptor IgG1-Fc fusion complex therapy.

Tumor necrosis factor alpha (TNF-alpha) is now believed to be a major contributor to the pathogenesis of the synovitis and joint destruction in rheumatoid arthritis. Etanercept is a recombinant human TNF-alpha receptor Fc fusion protein consisting of a dimer of the extracellular portion of two p75 TNF-alpha receptors fused to the Fc portion of human IgG1. Etanercept produces significant dose-dependent improvements in disease activity. We describe 7 patients who experienced 1 or more squamous cell carcinomas that showed rapid growth and arose over a 2- to 4-month period of etanercept therapy. Soluble TNF-alpha receptor therapy through inhibition of a T(H)1 cytokine pattern and inhibition of the direct and indirect cytotoxic effects of TNF-alpha may initially decrease mechanisms for controlling subclinical tumors and may contribute to the histologic features seen within these tumors. However, prolonged TNF-alpha inhibition may have some antitumor effects.

Telomerase activity in Kaposi's sarcoma, squamous cell carcinoma, and basal cell carcinoma.

Patients with acquired immune deficiency syndrome (AIDS) often develop Kaposi's sarcoma (KS), an unusual skin tumor. The malignant nature of KS has long been disputed. Telomerase activity that maintains telomere length and ensures chromosomal stability, a frequently appearing marker in human malignancies, has been proposed to play a critical role in supporting continued cell growth, hence formation of tumors. We examined telomerase activity in tissue extracts from 22 KS, 10 squamous cell carcinoma (SCC), and 22 basal cell carcinoma (BCC) using the telomeric repeat amplification protocol (TRAP). All of the tumor tissues were previously cryopreserved at -80 degrees C. In this study, all tumor samples tested were positive for telomerase activity. Consistent with the presence of the enzyme activity, the skin tumors had relatively long telomeres. Inhibitors in the tissue extracts of some samples needed to be diluted or extracted by phenol before the enzyme activity was detected in the TRAP assay. All KS as well as two other skin carcinoma samples revealed positive telomerase activity. Our finding supports telomerase's role in tumor cell immortality and suggests the true neoplastic nature of KS.

The clinical and histologic spectrum of cutaneous fibrous perineuriomas.

Cutaneous fibrous perineuriomas (CFPs) and the closely related sclerotic perineuriomas are recently reported tumors. We present nine additional cases of CFPs. All tumors were small nodules on the extremities; however, they were not limited to a distal acral location as previously reported. In addition to tabulation of the histologic features, we performed a battery of immunohistochemical stains, including S-100 protein, CD34, cytokeratin, epithelial membrane antigen (EMA), KP-1, and collagen type IV. Histologically, these tumors presented with sharp circumscription of their deep aspect, as previously reported, or were not circumscribed on any side. The cells ranged from plump and spindled with one or more nuclei to thin, elongated, spindled cells with slender nuclei. A variably fibrotic stromal matrix surrounded these components. Immunohistochemical staining showed EMA-positive staining of the cellular component, with collagen type IV-positive staining surrounding the cells. The tumor cells were negative for S-100 protein, factor XIIIa, CD34, cytokeratin, and KP-1. The tumors reported here add to the clinical and histopathologic spectrum of CFPs.

Peroxisomal proliferator-activated ligand therapy for HIV lipodystrophy.

Lipodystrophies associated with HIV disease have been reported in recent years and have included a general redistribution of fat with more central fat and increased dorsocervical fat. These lipodystrophies are commonly associated with hyperlipidemia and in some cases with insulin resistant diabetes. Although a similar redistribution of fat is seen in hypercortisolism, in general, serum and urinary cortisol levels are normal in these HIV-positive patients. However cortisol/dehydroepaindrosterone (DHEA) ratios are increased in HIV disease and may result in a relative hypercortisolism. Seven HIV-positive male patients on multidrug antiviral therapy including HIV protease inhibitors had developed increased central and dorsocervical fat over 1 year. All patients had increased serum lipids and three had insulin resistant diabetes. Four patients were treated initially with DHEA 100-200 mg/day, with addition of a cyclo-oxygenase (COX) inhibitor (indomethacin 100 mg/day) and three others were treated from the onset with a combination of DHEA 200 mg/day and a COX inhibitor (indomethacin 100 mg/day or naprosyn 1000 mg/day). All patients reported moderation or normalization of their serum lipids and some moderation of blood sugars while on DHEA alone. More marked improvement in blood sugar and noticeable decreases in the dorsocervical fat; however, occurred only with addition a COX inhibitor. Both DHEA and COX inhibitors have a number of mechanisms of action; among these is their role as a peroxisome proliferator-activator receptor ligand. Dysregulation of peroxisome function is associated with the spectrum of biochemical changes seen within these HIV associated lipodystrophies. Use of HIV protease inhibitors is reported in the majority of patients with these lipodystrophies, and protease inhibitors may accentuate the underlying peroxisome dysregulation. Supplementation with DHEA and a COX inhibitor may improve peroxisomal function.

Smoldering HTLV-1-induced T-cell lymphoma localized within the skin; a radiation-resistant tumor.

BACKGROUND: Human T-cell lymphotrophic virus type 1 (HTLV-1)-induced lymphoproliferative disease occurs in approximately 3-5% of people in endemic areas who have been HTLV-1 positive for decades. Lymphoproliferative disease may present as four subtypes, including an acute adult T-cell leukemia/lymphoma (ATLL), an aggressive HTLV-1 lymphoma, chronic ATLL, and smoldering ATLL. MATERIALS AND METHODS: A 72-year-old HTLV-1+ Haitian woman presented with a 2-year history of a cutaneous eruption localized to the right arm. The eruption had evolved into multinodular lesions over the past 6-7 months. Peripheral blood and cutaneous biopsy specimens were evaluated. Immunohistochemical studies for lymphoid markers were performed on the cutaneous biopsy material, and polymerase chain reaction (PCR) and Southern blot assay were evaluated for the presence and integration of HTLV-1 within the genome. RESULTS: The biopsy specimen showed a pleomorphic T-cell infiltrate with epidermotrophism, and an immunohistochemical phenotype showing CD3+, CD4+, CD8-, CD25, CD30-, HLDA-DR+ cells. PCR and Southern blot assay evaluation showed a single clonal integration of HTLV-1 provirus within a monoclonal tumor cell population. The patient had no abnormal lymphoid forms on peripheral smear at presentation, and no evidence of other organ involvement. CONCLUSIONS: Smoldering HTLV-1-induced lymphoma is uncommon even in endemic areas. In previously reported cases, the smoldering variant was accompanied by abnormal forms in the peripheral blood and/or by other signs of systemic disease. This case illustrates that smoldering disease may be localized to the skin with no detected morphologic abnormalities on peripheral smear.

Generalized essential telangiectasia in a patient with Graves' disease: should the spectrum of autoimmune diseases associated with generalized telangiectasia be expanded?

Generalized essential telangiectasia (GET), as originally described, is not associated with any underlying disease. Although patients with GET lack the typical periungual telangiectases associated with autoimmune collagen vascular diseases, these patients may have an underlying autoimmune process. We present a patient with a history of Graves' disease and low-titer anti-nuclear antibodies, who developed rapidly progressive generalized telangiectases. The gender and age of the majority of patients with GET fit well within the demographics of most autoimmune diseases. The documented occurrence of an autoimmune disease in several of the limited number of patients previously diagnosed with GET provides additional evidence that GET may be associated with an underlying autoimmune disease.

Glial heterotopia in the subcutaneous tissue overlying T-12.

Heterotopic glial nodules occur most commonly in the head and neck area, and are theorized to arise following abnormalities in the development of the facial and skull bone plates. However, in spite of the fact that some of these lesions are associated with communication with the central nervous system (CNS), the lack of a meningeal component, argues against simple herniation and separation of brain tissue through a defect in the skull. We present an infant with a nodule directly over the spine present in the T-12 region with no skin abnormalities. Magnetic resonance imaging (MRI) and computerized axial tomography (CT) showed no spinal abnormalities with an overlying fibrotic soft tissue mass. The patient had no other associated clinical findings. Histologic findings showed a cellular component arising within the reticular dermis with a deep circumscribed margin. The nodule contained irregularly shaped cells containing abundant cytoplasm and indistinct cellular margins with bland nuclei. These cells were clustered around and between a fibro-mucinous stroma. Immunohistochemical stains showed positive staining for S-100 protein, vimentin, GFAP, NSE, and CD57, and negative staining for Ki-67, CD34, Neurofilament protein, cytokeratin, and EMA. The spindle cells showed positive staining for CD34 and vimentin. The clinical and histologic features and immunohistochemical profiles are used to separate this lesion from the closely related, ependymal rests, ependymomas, and primary cutaneous chorodomas.

Infiltrative glomus tumor arising from a benign glomus tumor: a distinctive immunohistochemical pattern in the infiltrative component.

Malignant glomus tumors (MGT) are rare. Although metastatic MGT has been reported, most MGT have only been locally aggressive, some with multiple local recurrences. We report an additional case of an infiltrative glomus tumor. In addition to the pattern of immunohistochemical staining for alpha-smooth muscle actin (SM-actin) previously described, we performed immunohistochemical stains for Ki-67 and CD34. The infiltrative component of the glomus tumor showed variably decreased staining with SM-actin and occasional tumor cells showed nuclear staining with Ki-67. CD34 staining occurred in stromal cells forming the pseudocapsule in the benign component of this tumor and in other benign glomus tumors. The infiltrative component showed increased CD34 stromal cells. Although Ki-67 staining showed only an occasional proliferative cell, the immunohistochemical staining pattern of CD34 and SM-actin raise the possibility that the infiltrative component of this tumor may have differences in the degree of differentiation from the circumscribed part and that local factors could support its spread from a conventional benign glomus tumor.

Micrococcus folliculitis in HIV-1 disease.

Organisms with little pathogenic potential in immunocompetent hosts may produce disease in HIV-1 + patients. We describe three HIV-1 + patients in late disease who presented with pruritic papules with central ulceration over the face and arms. In all the patients the eruptions had been present for months, and the patients did not develop sepsis. Biopsy specimens in all the patients showed large Gram-positive cocci, forming tetrads. Colony morphology, catalase positivity and coagulase negativity, and resistance to nitrofurantoin were used to separate micrococci from staphylococci. Micrococcus species are usually considered normal inhabitants of the skin; however, in patients with HIV-1 disease, Micrococcus species can produce localized cutaneous infections.

Immunohistochemical staining for Ber-EP4, p53, proliferating cell nuclear antigen, Ki-67, bcl-2, CD34, and factor XIIIa in nevus sebaceus.

Increased expression of p53 has been found in the majority of basal cell carcinomas (BCCs). The pattern and intensity of this staining, as well as staining for proliferation antigens, seems to correlate with behavior of histologic subtypes of BCC. Nevus sebaceus (NS) is considered a hamartoma. Multiple epithelial neoplasms do arise in NS, and, rarely, they show an aggressive biologic behavior. Significant numbers of these neoplasms, however, have areas of basaloid hyperplasia that are often reported as BCC. Although morphologically similar to BCC, the mechanism underlying the development of these areas has not been investigated, so we sought to evaluate the expression of Ber-EP4, p53, proliferating cell nuclear antigen, Ki-67, bcl-2, Factor XIIIa, and CD34 in areas showing basaloid hyperplasia, arising in NS. We performed immunohistochemical stains for Ber-EP4, p53, proliferating cell nuclear antigen, Ki-67, bcl-2, Factor XIIIa, and CD34 on seven cases of NS with areas of basaloid hyperplasia. All of the eight cases of NS showed diffuse positive membrane staining for Ber-EP4 and negative nuclear staining for p53. Proliferating cell nuclear antigen and Ki-67 staining was only slightly increased in the areas of basaloid hyperplasia, compared with the surrounding epidermis and with areas of the epidermis peripheral to the hamartomatous proliferation, and bcl-2 was only focally positive. Factor XIIIa-positive cells and CD34-positive vascular endothelial cells were increased within the subjacent dermis, a pattern suggestive of follicular differentiation. Our findings suggest that even though areas of basaloid hyperplasia in NS are morphologically similar to BCC, they are induced by different stimulatory and molecular mechanisms. These different mechanisms result in expression of immunohistochemical markers more characteristic of benign follicular tumors than of BCC.

Kaposi's sarcoma in women: A clinicopathologic study.

BACKGROUND: Although all epidemiologic subsets of Kaposi's sarcoma (KS) (i.e., sporadic, endemic, epidemic, and iatrogenic) have an association with human herpes virus 8 (HHV8), these subsets occur in patient populations with distinctive clinical features. To a variable degree men outnumber women in all subsets. OBJECTIVE: A retrospective study of women with histologically proven cutaneous KS was undertaken to determine the clinical and histopathologic features, as well as any associations. METHODS: Two hundred and fifty cases of cutaneous KS in women from 1975 to 1993 were reviewed. RESULTS: Of the patients, 80% were more than 60 years of age, and of the patients less than 60 years old, 28 were from areas of the world with endemic KS. All HIV+ patients but one were from areas of endemic KS. Two patients were renal transplant patients. Sixty-four percent of the patients had single lesions and 21% recurrent lesions. Twelve patients had, or were known to develop, internal involvement, and in six patients the cause of death was KS. All but four cases histologically showed areas of solid proliferations of tumour cells consistent with plaque or tumour stage. An angiosarcoma-like histologic pattern appeared to be associated with more aggressive epidemiologic subsets. High mitotic rates were rarely seen and did not correlate with aggressive epidemiologic subsets. CONCLUSION: Kaposi's sarcoma in women is diagnosed almost exclusively in plaque or tumour stage. The majority of women within our study fit within the epidemiologic subset of sporadic KS.

Advanced laboratory techniques at the Armed Forces Institute of Pathology applicable to diagnosis and research in dermatology.

The Armed Forces Institute of Pathology (AFIP) is well known for providing expert pathology in many specialties and educational courses for civilian and military personnel. Some of the departments at the AFIP have also developed expertise in various advanced laboratory techniques for diagnosis and research that are applicable to dermatology and are not available at most medical centers.

Eosinophilic globules in spindle cell and epithelioid cell nevi: composition and possible origin.

The presence of eosinophilic globules has been described as a helpful sign for the histologic differentiation of Spitz's nevus from malignant melanoma. The origin of these bodies is not clear, and they have been likened to Civatte or colloid bodies of lichen planus. This would suggest that they might originate from degenerating keratinocytes or melanocytes or both. These eosinophilic globules and the colloid bodies of lichen planus have been reported to be similar in that they both stain positively for type IV collagen and laminin. These previous reports have failed to include, or have not emphasized, the staining for keratin that separates these two bodies. We stained 10 spindle cell and epithelial cell (S&E) nevi for S-100 protein, keratin, vimentin, type IV collagen, and laminin. In all 10 cases of S&E nevi, the eosinophilic globules showed a positive reaction for type IV collagen and laminin and a negative reaction for keratin, S100 protein, and vimentin, unlike the colloid bodies of lichen planus, which showed a negative reaction for type IV collagen and laminin and also a strong positive reaction for keratin. These results suggest that the eosinophilic globules of Spitz's nevi are basement membrane material, perhaps synthesized by either basal cells, melanocytes or both, and are not degenerated basal cells or melanocytes.

The spectrum of neurocristic cutaneous hamartoma: clinicopathologic and immunohistochemical study of three cases.

Neurocristic cutaneous hamartomas result from aberrant development of the neuromesenchyme. Thus, the elements within these tumors reflect the spectrum of differentiation that results from migration of neural crest-derived cells. We present three cases, in addition to routine hematoxylin-eosin staining, a battery of immunohistochemical staining, including S-100 protein, HMB-45, EMA, CD34, and neurofilament-protein stains, was performed on each specimen. A dermal melanocytic component was the dominant feature of two of these lesions, while neurosusenticular and neuromesenchymal components dominated in one tumor. Both tumors that developed on the scalp showed effects on the overlying epidermis and/or on adnexal development. The melanocytic component was positive for S-100 protein and HMB-45. The surrounding stroma showed tactoid bodies and increased CD34 staining. Neurocristic cutaneous hamartomas represent dysplastic development of neural crest-derived cells. Although melanocytic cells have been previously reported to be the dominant cell population, neurosusentacular and neuromesenchymal cells also may be the principal component. In cephalic areas, the neuromesenchyme may not only be an important component of the tumor, but may also effect the development of the overlying epithelium and adnexal structures. Although none of these cases presents evidence of malignant transformation, identification of these tumors could be important if malignant transformation results in the development of tumors with a distinctive biologic behavior.

Lichenoid/Interface cutaneous eruptions to IVIg with the primary infusion may be related to the re-regulation of anti-idiotype network.

BACKGROUND: Intravenous immunoglobulin (IVIg) has been used in recent years to treat an increasing number of autoimmune diseases to decrease cytokine secretion and to neutralize toxins, in addition to the therapy of immunodeficiency disorders. In addition to angioedema-like hypersensitivity eruptions, there have been reports of eczematous, purpuric, petechial/purpuric, and vasculitic reactions to IVIg; however, there has been only one previous report of a case in which the patient developed a lichenoid dermatitis after infusion of IVIg. OBSERVATIONS: We present two patients with chronic inflammatory, demyelinating polyneuropathy, who after the first course of IVIg developed a folliculocentric interface/lichenoid eruption that cleared without therapy or with topical steroids. The eruption did not recur with subsequent IVIg infusions in either patient. CONCLUSIONS: The multiple diverse effects of IVIg on the immune system, and the re-regulation of the anti-idiotype network with repeat IVIg infusions, may explain why this eruption occurred with the initial infusion of IVIg and not with repeated infusions.

Sensitivity of cross-reacting antihuman antibodies in formalin-fixed porcine skin: including antibodies to proliferation antigens and cytokeratins with specificity in the skin.

Although no animal is a perfect skin model for the study of toxicological and therapeutic agents, structurally the pig may be superior to even non-human primates. Because our work involves effects of toxicological and therapeutic agents on the skin, we wanted to identify stains which may prove useful as well as determine cross-reactivity of some newer antihuman antibodies. We performed a battery of formalin-fixed skin from weanling pigs and minipigs. The battery of antibodies included LCA, CD3, OPD-4, CD34, UCHL-1, L-26, KP-1, MAC-387, Factor XIIIa, Leu-7, S-100 protein, HMB-45, GFAP, synaptophysin, neurofilament protein, ubiquitin, vimentin, type IV collagen, laminin, fibronectin, Factor VIII related antigen, Desmin-M, smooth muscle actin, cytokeratin 7, cytokeratin 20, AEI/AE3, CAM 5.2, EMA, GCDFP, Ki-67, and PCNA. Immunohistochemical stains for CD3, Leu-7, S-100 protein, type IV collagen, laminin, Factor VIII related antigen, GFAP, synaptophysin, neurofilament protein, ubiquitin, smooth muscle actin, vimentin, Desmin-M, cytokeratin 7, cytokeratin 20, AE1/AE3, CAM 5.2, Ki-67 and PCNA showed consistent cross-reactivity. In formalin-fixed tissue, only antibodies to lymphoreticular cells showed poor cross-reactivity. A high percentage of the remaining antibodies did show good cross-reactivity but with some interesting similarities and differences in specificity.