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The overlap of Erdheim-Chester disease (ECD) and Langerhans cell histiocytosis (LCH) is more common than it was generally accepted. Both diseases seem to be linked by a mutation in oncogenic BRAFV600E, probably an early event which occurs in bone marrow progenitor cells. In this article are described the clinical and histological findings in 2 cases of ECD-LCH overlap syndrome bearing the BRAFV600E mutation in both ECD and LCH lesions in bone and skin. In one case, lesions of ECD and LCH were situated directly site-to-site in the same bone section leading to the assumption of a common myeloid precursor cell for these diseases. Furthermore, we focus on the histopathological diagnostic criteria of cutaneous involvement in ECD. Lesional tissue shows a dermal infiltrate of lipidized CD68, CD163, CD1a, and langerin histiocytes admixed with Touton giant cells-a xanthogranulomatous phenotype. Often, this pattern of histopathology requires correlation with patterns of systemic involvement to differentiate ECD from other xanthogranulomatous infiltrates. This endeavor is of major importance to determine early diagnosis and treatment, because ECD often shows a poor prognosis compared with its differential diagnoses. Finally, adults who suffer from LCH and develop xanthogranulomatous infiltrates should always be screened for ECD-LCH overlap syndrome.

Comprehensive genomic profiling of clinical samples by next-generation sequencing (NGS) can identify one or more therapy targets for the treatment of metastatic melanoma (MM) with a single diagnostic test.NGS was performed on hybridization-captured, adaptor ligation-based libraries using DNA extracted from 4 formalin-fixed paraffin-embedded sections cut at 10 microns from 30 MM cases. The exons of 182 cancer-related genes were fully sequenced using the Illumina HiSeq 2000 at an average sequencing depth of 1098X and evaluated for genomic alterations (GAs) including point mutations, insertions, deletions, copy number alterations, and select gene fusions/rearrangements. Clinically relevant GAs (CRGAs) were defined as those identifying commercially available targeted therapeutics or therapies in registered clinical trials.The 30 American Joint Committee on Cancer Stage IV MM included 17 (57%) male and 13 (43%) female patients with a mean age of 59.5 years (range 41-83 years). All MM samples had at least 1 GA, and an average of 2.7 GA/sample (range 1-7) was identified. The mean number of GA did not differ based on age or sex; however, on average, significantly more GAs were identified in amelanotic and poorly differentiated MM. GAs were most commonly identified in BRAF (12 cases, 40%), CDKN2A (6 cases, 20%), NF1 (8 cases, 26.7%), and NRAS (6 cases, 20%). CRGAs were identified in all patients, and represented 77% of the GA (64/83) detected. The median and mean CRGAs per tumor were 2 and 2.1, respectively (range 1-7).Comprehensive genomic profiling of MM, using a single diagnostic test, uncovers an unexpectedly high number of CRGA that would not be identified by standard of care testing. Moreover, NGS has the potential to influence therapy selection and can direct patients to enter relevant clinical trials evaluating promising targeted therapies.

PURPOSE Acne agminata has only been rarely reported in the ocular adnexa. This study was undertaken to identify histopathological, clinical, and management features of this disorder. METHODS A computerized database was utilized to identify cases of ocular adnexal acne agminata. Via chart review and light microscopy, clinical and histopathologic aspects of this dermatosis were collected, and statistical analyses were performed. RESULTS Twelve cases (5 males, 7 females, mean age = 50.5 years) of clinically and histopathologically confirmed ocular adnexal acne agminata were identified. The main variant of granuloma was sarcoidal in 6 cases (50%) and tuberculoid in 5 cases (41.7%), although 9 specimens (75%) displayed greater than 1 variant of granuloma. In addition, specimens demonstrated varying degrees of fibrosis (8 cases, 66.7%), necrosis (6 cases, 50%), spongiosis (5 cases, 41.7%), and perifollicular inflammation (6 cases, 50%). All specimens showed signs of lymphstasis-lymphangiectasis. At a minimum of 6-month postprocedure interval, all patients experienced complete relief of their symptoms and did not experience recurrence. CONCLUSIONS This study represents the largest cohort of ocular adnexal acne agminata, and revealed a spectrum of granulomatous subtypes, including coexistence of different granuloma subtypes within the same specimen. Lymphangiectases is a hallmark of this disorder, and varying features of tissue reaction are typical features of acne agminata. All of these cases were successfully cured by surgical resection of lesions without recurrence at last follow-up, and this modality should be considered the standard of care in the management of this problem.

Onycholysis, separation of the nail plate from the nail bed, is etiologically classified as primary (idiopathic) or secondary (eg, caused by psoriasis, squamous cell carcinoma). Repetitive microtrauma plays a role in idiopathic onycholysis and also facilitates human papillomavirus (HPV) infection. Herein, we report a case of persistent primary onycholysis associated with repetitive trauma and infection by a multiplicity of Beta-papillomavirus (Beta-PV) genotypes. An otherwise healthy 27-year-old woman presented with a 6-year history of onycholysis of the halluces and right second toe. Her occupation required wearing steel-toed boots. Fungal cultures were negative and antifungal therapy was ineffective. Punch biopsy of the hallux nail bed revealed epidermal hyperplasia, acanthosis, hypergranulosis, hyperkeratosis, and regions of koilocytosis without significant inflammation. This histopathology implicated chronic irritation and HPV infection. Immunohistochemistry demonstrated productive HPV infection. Nested PCR using degenerate consensus primers revealed infection with 5 known and 1 novel Beta-PV genotypes (HPV 5, HPV 8, HPV 20, HPV 23, HPV 37, and FA25). The histopathology of primary onycholysis is unknown. Based on the aforementioned, we propose that repetitive microtrauma caused by wearing steel-toed boots promoted onycholysis and HPV infection, the latter of which, altered the differentiation of nail bed epithelium, preventing adhesion of nail plate to the nail bed. Lastly, the presence of oncogenic Beta-PV genotypes (ie, HPV 5, 8, and 20) implicates a risk for subungual squamous cell carcinoma, particularly if the nail remains symptomatic and persistently irritated.

Pigmented lesions in the anogenital area encompass a wide variety of disorders including squamous intraepithelial neoplasia. The authors sought to explore the mechanism(s) underlying clinically pigmented squamous intraepithelial neoplasia in the anogenital area. A light-microscopic and immunohistochemical study of 64 lesional specimens from 45 patients (32 women, 13 men; age range, 23-73 years) with pigmented lesions in the anogenital area was performed. Histopathologically, 63 (98%) specimens showed melanin incontinence into the superficial dermis beneath the dysplastic epithelium. A focal or total loss of basilar hyperpigmentation was detected in 30 (48%) and 13 (20%) of lesions, respectively. In 17 (27%) cases, absence of basal layer hyperpigmentation was accompanied by a subepithelial lichenoid infiltrate. Melanin within the upper part of dysplastic areas were seen in 63 cases (98%), whereas dendritic melanocytes colonization, mild in all but 1 specimen case, was observed in 53 (83%) cases. All cases proved to be the usual type of squamous intraepithelial neoplasia; no single case of the simplex (differentiated) variant was present. The main mechanisms of pigmented squamous intraepithelial neoplasia of the anogenital area include melanin incontinence and occurrence of melanin in dysplastic keratinocytes. Colonization of the dysplastic epithelium by dendritic melanocytes seems to contribute, but it is rarely a prominent feature.

ObjectiveTo describe the clinical and pathologic features of women undergoing labioplasty for labia minora hypertrophy (LH) and to determine whether localized lymphedema plays a role in its pathogenesis.Materials and MethodsA retrospective case series of consecutive cases of labioplasties pe

Purpose To delineate signals by which the vascular abnormalities inherent to ocular rosacea arise and to correlate these signals with elements of the innate immune system. Methods Experimental study. Immunohistochemical staining was performed for a variety of vascular markers and for toll-like receptor-4 on eyelid biopsies taken from patients with ocular rosacea and normal controls. Statistical comparisons were then performed between the 2 groups. Results Immunohistochemical staining for CD31 and integrin-β-3 did not demonstrate any statistically significant differences between eyelids from patients with ocular rosacea and normal controls. Cutaneous biopsies from ocular rosacea patients demonstrated statistically significant enrichments of intercellular adhesion molecule-1 and CD105 among arterioles, whereas there were no statistically significant differences in the venules between normal controls and ocular rosacea patients. The correlation between the number of toll-like receptor-4-positive cells and each vascular marker was statistically significant. Conclusions Cutaneous biopsies of the eyelid did not demonstrate an increase in the total number of blood vessels. However, the vascular abnormalities that are typical of ocular rosacea represent activated, inflamed vessels, and these phenomena may be mediated by intercellular adhesion molecule and CD105. Furthermore, the strong correlations between toll-like receptor-4 and each vascular marker suggest that the innate immune system may govern the cutaneous effects of ocular rosacea. Intercellular adhesion molecule, CD105, and toll-like receptor-4 may represent important therapeutic targets in the management of this disease.

Chronic papillomatous dermatitis (CPD) is a stoma site complication due to chronic irritant contact dermatitis. Papillomatosis can also arise in the setting of human papillomavirus (HPV) infection or chronic lymphedema (elephantiasis). Herein, we report the case of a 57-year-old female who presented with a papillomatous growth surrounding a loop ileostomy suspected to be recurrent ovarian serous carcinoma. Excisional biopsy demonstrated nevus sebaceous (NS)-like organoid hyperplasia with koilocytes overlying a dermal scar that exhibited lymphangiectases. Polymerase chain reaction and sequencing for HPV DNA detected HPV 16. In situ hybridization for high-risk HPV DNA showed punctate nuclear pattern in the keratinocytes populating the NS-like hyperplasia indicating integrated HPV 16 DNA. No recurrence has been observed 11 months postexcision. Reports of CPD have documented a spectrum of reactive epidermal hyperplasias including pseudoepitheliomatous, verrucous, papillomatous, syringofibroadenomatous, and rudimentary follicular hyperplasias. HPV DNA has been detected in 3 of 4 CDP cases tested to date and in authentic NS. We postulate that localized lymphedema secondary to scarring coupled with chronic epidermal irritation and inflammation allowed for latent HPV infection to manifest as CPD with NS-like cutaneous hyperplasia.

Pathologically, Whipple disease (WD) is characterized by the accumulation of myriad macrophages parasitized by Tropheryma whipplei (TW) bacilli denoted by periodic acid-Schiff (PAS) positivity. These PAS+ macrophages are typically found in the duodenum associated with lymphangiectasia. Recently, we reported the presence of PAS+ macrophages and free TW in erythema nodosum leprosum (ENL)-like lesions and normal skin in a patient with WD who suffered from the immune reconstitution inflammatory syndrome (IRIS). We extend that report by describing the clinical and pathologic findings over 5 years of follow-up. First, the IRIS gradually diminished and abated over 18-month time. Second, at no point did WD recur, and all duodenal and skin biopsies tested by polymerase chain reaction were negative for TW DNA. Third, PAS+ macrophages were identified in 26 of 27 skin biopsies (96%) and decreased along with free TW over time. Fourth, ENL-like lesions had significantly greater numbers of PAS+ macrophages than normal skin. Moreover, normal abdominal skin (region of ENL-like lesions) had greater PAS+ counts than arm skin (not a site of IRIS). Last, lymphangiectases, a histologic sign of lymphostasis, was found in all skin biopsies. Overall, these findings implicate bacillary burden as a factor in the immune tolerance to live TW in active WD and the initiation of ENL-like nodules against dead/nonreplicative TW in treated WD. In addition, poor lymphatic drainage is likely responsible for the gradual clearance of TW from the skin and the impaired delayed-type hypersensitivity reaction (absence of activated macrophages) against TW found in WD, presumptively due to reduced/absent immune cell trafficking necessary for lymphocyte-macrophage interactions and induction of adaptive immunity.

Intratarsal keratinous cyst of the meibomian gland is a recently described entity that recurs if not completely excised. Herein, we report 2 cases and discuss their diagnosis and management: (1) A 57-year-old man with a recurrent mass of the upper eyelid treated with incision and drainage as a chalazion for more than 5 years and (2) An 85-year-old man presented with a slow growing nodule of the upper eyelid. Exploration via the eyelid crease approach revealed cysts fixed to the tarsus that were completely excised with a portion of the anterior tarsus. Histologically, these cysts exhibited a keratinizing squamous epithelium without a granular layer (trichilemmal keratinization), were lined by an eosinophilic undulating cuticle, contain string-like keratin debris, and had a fibrous wall without sebaceous lobules. All epithelial components strongly expressed high-molecular weight keratins, whereas the lining, cuticle, and keratin contents strongly expressed carcinoembryonic antigen. No recurrence has occurred 7 and 12 months postoperatively. The location and clinicopathologic findings of intratarsal keratinous cysts distinguish it from sebaceous tumors, steatocystoma simplex, epidermoid cyst, and dermoid cyst. However, like steatocystomas, intratarsal keratinous cysts exhibit a sebaceous duct phenotype. The anterior lid crease approach with partial tarsectomy seems to be an effective treatment.

Multiple familial trichoepitheliomas (MFT) constitute an autosomally inherited syndrome possibly related to Brooke-Spiegler syndrome (BSS). Although some early studies suggested a role for the PTCH gene on chromosome 9q22.3 in the etiopathogenesis of MFT, recent studies of occasional patients with the MFT clinical phenotype identified mutations in the CYLD gene on chromosome 16q12-q13, a gene responsible for BSS. A systematic investigation of PTCH and CYLD mutations in patients with MFT has never been performed. Our main objective was to collect a reasonably large series of patients with MFT to (1) study the clinicopathological spectrum of the disease, (2) determine whether the PTCH gene is implicated in the pathogenesis of MFT, and if so (3) determine the relative frequency of CYLD and PTCH mutations, (4) establish if there may be any possible genotype-phenotype correlations, and (5) study the spectrum of somatic mutations. Clinical analysis including family histories, histopathological investigations, and molecular genetic studies were performed. There were 9 female and 7 male patients ranging in age from 11 to 63 years. They presented with multiple, small, discrete and sometimes confluent, skin-colored to pink, asymptomatic nodules preferentially located on the face, being especially prominent and confluent in the nasolabial folds and inner aspects of the eyebrows. A total of 66 conventional trichoepitheliomas (TEs) were studied microscopically. Aside from typical features of TE, some also exhibited variant morphological patterns including areas reminiscent of other benign adnexal neoplasms and melanocytic hyperplasia. In none of the 9 patients tested was a germline mutation of the PTCH gene identified. Germline CYLD mutations were detected in 6 of 13 patients tested (identical in 2 unrelated patients) including 2 novel mutations, whereas the remaining 7 individuals showed wild-type alleles. Two patients with germline wild-type CYLD showed, however, a somatic mutation in the gene (1 duplication, 1 substitution mutation). Neither CYLD nor PTCH germline mutations were found in the 5 patients in whom both genes were analyzed. MFT seems to be a phenotypic variant of BSS. The PTCH gene is rarely, if ever, involved in the pathogenesis of MFT. Absence of a germline mutation of the CYLD gene in cases harboring a somatic mutation may be explained by large deletions in the gene or by mutation in intronic sequences or in the promoter region. Considering our 5 patients with no mutation in either gene, the final possibility is that another, as yet undescribed gene (neither CYLD nor PTCH) is implicated in the pathogenesis of some patients with MFT.

We describe a 45-year-old woman with atopic dermatitis who presented with a progressive, papular eruption over her anterior lower legs that began 30 years earlier. Biopsy with polymerase chain reaction analysis revealed lichenified plane warts harboring human papillomavirus 38 DNA. No signs or family history of epidermodysplasia verruciformis existed. Local trauma from shaving, barrier dysfunction, and decreased cell immunity and interferon production associated with atopic dermatitis are likely responsible for this presentation of lower leg verrucosis.

Background Carcinoma-associated calcifications (Ca(2+)) are a common phenomenon. In the skin, basal cell carcinomas (BCC) can be associated with Ca(2+). Objective To examine the prevalence, characteristics, and clinicopathologic correlations of BCC associated with Ca(2+). Material and methods Eighty-three BCC with Ca(2+) were retrieved, 27 (11.1%) of which were identified from a review of 243 consecutive BCC. Ca(2+) were classified into 4 types: type 1, Ca(2+) within BCC epithelium; type 2, Ca(2+) in BCC keratocysts; type 3, BCC tumor necrosis with Ca(2+); and type 4, free Ca(2+) adjacent to BCC. Clinical and pathologic features were assessed and compared with BCC without Ca(2+). Expression of hair-associated proteins (hair keratins (K31, K32, and K35) and matrical transcription factors (LEF1, HOXC13, and β-catenin) were examined in a subset of BCC with Ca(2+) and compared with matched controls without Ca(2+). Results Compared with BCC without Ca(2+), BCC with Ca(2+) were significantly more likely to show a nodular keratinizing phenotype with keratocyst formation, background solar elastosis, active regression, and areas of tumor necrosis (all P ≤ 0.03). Comparing all BCC, high-risk BCC (mostly infiltrative) had significantly higher frequency of Ca(2+) than low-risk (mostly nodular) BCC (44% vs. 25%; P = 0.009). The median and mean number of Ca(2+) deposits per specimen were 2 and 3 ± 4, range 1-30. In decreasing frequency, type 2 Ca(2+) (58%), type 4 (53%), type 3 (14%), and type 1 (10%) were found. In 9 cases (11%), type 2 and type 4 Ca(2+) were linearly arranged, ostensibly after a follicular or eccrine duct tract. In 5 cases (6%), initial histologic sections showed type 4 dermal Ca(2+) without evidence of BCC; level sections revealed BCC in the adjacent tissue. Neither BCC with nor BCC without Ca(2+) showed evidence of matrical differentiation by immunophenotypic analysis. Conclusions A minority of BCC exhibits Ca(2+) that are associated with BCC-related keratin and/or necrosis. Like other follicular-derived tumors (trichilemmal cyst, pilomatricoma, and trichoepithelioma), BCC produce keratins that are ostensibly predisposed to calcification but are not related to matrical differentiation (mature hair keratin formation). Either due to transtumor elimination or due to tumor regression, Ca(2+) are frequently found free in solar elastotic or fibrotic dermis: a histologic clue in sun-damaged skin to the presence of BCC in the surrounding dermis.

Hydroa vacciniforme (HV) is a rare, blistering, childhood photodermatosis that heals with smallpox-like scars, is associated with latent Epstein-Barr virus (EBV) infection, and spontaneously resolves by early adulthood. Cytotoxic T cells are suspected to mediate the histologic hallmark of HV-dense, perivascular, lymphocytic infiltrates and reticular degeneration and necrosis of the epidermis. We report a case of 13-year-old white girl with EBV-associated HV, whose lesional skin harbored a predominate CD6 + , CD123 + infiltrate of plasmacytoid monocytes (PMs). Other significant pathologic attributes included abundant non-neutrophilic nuclear debris, necrosis of adnexal structures, lymphocytic vasculitis, and clusters of CD30 + cells. PMs produce large amounts of type I interferon during viral infection, which induces apoptosis of some cell types and promotes the survival of others. This antiviral response can explain these aforementioned pathologic findings representing wide spread cell death and lymphoid proliferation, as well as eventual resolution of HV with time, via elimination of latent EBV-infected cells. The destruction of adnexal structures can account for the depressed circinate scars characteristic of HV The validity of this proposed mechanism must be evaluated by first examining the prevalence and number of PMs in future case series of HV.

Volar melanotic macules are asymptomatic, tan-brown to brownish-black macules found on the palms, fingers, soles, and/or toes of dark-skinned individuals and are infrequently reported in light-skinned individuals. Herein, we report the acquisition of multiple, brownish-black volar digital macules in a 63-year-old white woman and avid gardener that were noted after the onset of pruritic, chronic hand dermatitis over a 10-month period. She was healthy without any medical conditions or medications. No family history of intestinal polyposis or mucosal melanosis existed. At presentation, she had less than 20 brownish-black, 2- to 10-mm irregular macules over the volar aspect of the thumbs and index fingers, left greater than right hand, associated with erythema, scale, and a negative potassium hydroxide examination. In addition, she had melanotic macules of her lips, buccal mucosa, and conjuctiva. No nail or anogenital macules were found. Biopsy demonstrated a region of epidermal hyperplasia, hyperkeratosis, and interface dermatitis associated with melanophages and sparse lymphocytic infiltrate. Melanin staining revealed diffuse pan-epidermal hypermelanization, dermal melanin, and dendritic melanocytes, which expressed HMB-45. After 1-year follow-up and treatment with topical corticosteroid, the volar macules have faded to tan brown. Based on the location, avocation, and coexisting mucosal melanotic macules, an irritant phytodermatitis with postinflammatory hyperpigmentation was diagnosed in the setting of Laugier-Hunziker syndrome-a disorder denoted by macular hyperpigmentation of nail, volar, and/or mucosal surfaces in healthy adults. Volar melanotic macules can also complicate 5-flourouracil therapy, tinea pedis, and other inflammatory disorders; be associated with acral melanomas; or represent a cutaneous manifestation of systemic disease such as Addison disease, Peutz-Jegher syndrome, Leopard syndrome, Carney syndrome, AIDS, and neurofibromatosis.

Recently described macular arteritis presents as asymptomatic hyperpigmented macules, runs a chronic, indolent course, and shows lymphocytic arteritis at various stages of evolution ranging from fibrinoid necrosis to endarteritis obliterans. Herein, we present another case that was clinically suspected to be unilateral plantar pompholyx. A 47-year-old male presented with a 2-month history of persistent, reticulated, asymptomatic, nonblanching erythematous and brawny macules, and scattered, slightly scaly papules over the plantar instep of his left foot. Two punch biopsies extending to the subcutis revealed healed arteritis (endarteritis obliterans with fragmented elastic lamina) in the subcutis in one biopsy and purpura and hemosiderin deposition surrounding small subcutaneous arterioles and venules in the second. Additional histologic features included lymphocytic eccrine hidradenitis and chronic spongiotic dermatitis. Extensive laboratory work did not reveal evidence of systemic disease. Despite topical corticosteroid therapy, he has had persistent, asymptomatic disease after 6 months follow-up. The differential diagnoses considered included pigmented purpuric dermatitis, perniosis (chilblains), plantar eccrine hidradenitis, Buerger disease, livedo vasculopathy, and cutaneous polyarteritis nodosa. Cutaneous polyarteritis nodosa also runs a benign course and is denoted by muscular vessel vasculitis, which can resolve with retiform hyperpigmentation. Based on these overlapping clinical-pathologic features, macular arteritis might represent a latent, non-nodule forming chronic variant of cutaneous polyarteritis nodosa.

Vulvovaginal melanomas are rare and their etiology is unknown. Genital mucosal human papillomavirus (HPV) 16 has been identified in both cutaneous and mucosal melanoma, suggesting that it might play a role in the pathogenesis or progression of melanoma. In this study, we investigated the prevalence of HPV DNA by using a broad spectrum of degenerate and type-specific primers for genital-mucosal, epidermodysplasia verruciformis-associated (EV), and cutaneous HPV types in 6 vulvar and 3 vaginal melanomas. The patients were mostly postmenopausal women (8/9), had a mean age of 67 years (range, 44-85 years), and had mucosal lentiginous (7) or nodular (2) melanomas. In the adjacent skin/mucosa, mucosal melanosis was found in 5, lichen sclerosus or a lichenoid mucositis in 4, and blue nevi in 2 women. With nested polymerase chain reaction techniques followed by direct sequencing, HPV DNA was identified in 6 of 9 (67%) melanomas; these were either cutaneous (HPV 3) (4/9) or epidermodysplasia verruciformis-associated types (HPV 38, Z95969, AJ00151) (4/9). Epidermodysplasia verruciformis-associated HPV (type 15) was found solely in 1/10 (10%) normal vulvar controls. Genital-mucosal HPV types were not detected either by degenerate nested polymerase chain reaction or type-specific probes for HPV 16. We propose that the above findings are not coincidental but may represent a molecular record of HPV involvement in pathogenesis or progression of melanoma, which is consistent with the strong but poorly defined association of cutaneous HPV types with nonmelanoma skin cancers. The theory that HPV may act as a cofactor in melanoma development deserves further clinical and experimental investigations.

Most biopsies of cutaneous vasculitis will exhibit a small vessel neutrophilic vasculitis [leukocytoclastic vasculitis (LCV)] that is associated with immune complexes on direct immunofluorescence examination or, less commonly, antineutrophilic cytoplasmic antibodies (ANCA) by indirect immunofluorescence testing. Is in uncommon for skin biopsy to reveal solely a neutrophilic arteritis signifying the presence of cutaneous polyarteritis nodosa or, if accompanied by significant lobular panniculitis, nodular vasculitis/erythema induratum. In other cases, cutaneous vascular damage (fibrinoid necrosis, muscular vessel wall disruption, or endarteritis obliterans) will be mediated by a nonneutrophilic inflammatory infiltrate. Eosinophilic vasculitis can be a primary (idiopathic) process that overlaps with hypereosinophilic syndrome, or it can be a secondary vasculitis associated with connective tissue disease or parasite infestation. Authentic cutaneous granulomatous vasculitis (versus vasculitis with extravascular granulomas) can represent a cutaneous manifestation of giant cell arteritis, an eruption secondary to systemic disease such as Crohn's disease or sarcoidosis, or a localized disorder, often a post-herpes zoster (HZ) phenomenon. Lymphocytic vasculitis is a histologic reaction pattern that correlates with broad clinical differential diagnosis, which includes connective tissue disease - mostly systemic lupus erythematosus (SLE), endothelial infection by Rickettsia and viruses, idiopathic lichenoid dermatoses such as perniosis or ulcerative necrotic Mucha-Habermann disease, and angiocentric cutaneous T-cell lymphomas. Skin biopsy extending into the subcutis, identifying the dominant inflammatory cell and caliber of vessels affected, extravascular histologic clues such as presence of lichenoid dermatitis or panniculitis, and correlation with clinical data allows for accurate diagnosis of these uncommon vasculitic entities.

Neoplastic progression is characterized in part by escape from immune surveillance and formation of growth-permissive stroma. Basal cell carcinoma (BCC) can be subclassified into low- and high-risk types for local recurrence. To determine whether these types of BCC correlate with alterations in local host immune response and stroma and whether these changes follow stepwise histologic progression from low- to high-risk subtypes, we assessed the clinicopathologic features in 175 consecutive primary (nonrecurrent) BCC excision specimens. BCCs exhibited a significantly higher frequency of mixed rather than homogeneous growth patterns (76% vs. 24%, P=0.0001). Nodular (84%) was the most common pattern identified followed by superficial (77%), infiltrative (27%), morpheic (5%) and micronodular patterns (4%). Only superficial (12% of all BCC) and nodular (12%) patterns were identified in BCC with a homogeneous histologic phenotype. Micronodular and infiltrative-morpheic patterns were not identified together in mixed patterned BCCs, and these high-risk types were contiguous with nodular BCC. Superficial predominant BCC (major growth pattern) was significantly associated with trunk and extremity location (76%) and skin without solar elastosis (82%), whereas BCC harboring a nodular growth pattern component was significantly associated with a head and neck location (63%) and the presence of adjacent solar elastosis (all P< or =0.03). Significant correlations were identified for BCC subtypes with inflammatory and stromal alterations: superficial BCC with old regression and moderate to dense peritumoral lymphocytic infiltrates; high-risk types correlated with active regression; infiltrative and morpheic BCC with fibrosing tumor stroma; and micronodular BCC with loss of both host inflammatory and stromal tumor responses. Evaluating the theoretical histologic stepwise model of BCC progression (superficial-to-nodular-to-micronodular, or superficial-to-nodular-to-infiltrative-to-morpheic BCC types) revealed significant linear correlations with host response and alterations of tumor stroma (r=0.54, P=0.0001). BCC exhibit distinct epithelial-stromal-inflammatory patterns that correlate with BCC subtype and tumor progression. This ostensible pathway of diminishing host response and gain of permissive tissue environment highlights neoplastic evolution from low to high risk for local recurrence of BCC and implicates a histologic continuum reflecting dynamic host-BCC interactions.

Post herpes zoster (HZ) reactions have been associated with panoply of neoplastic, inflammatory, and fibro-inflammatory cutaneous disorders. Varicella zoster virus (VZV) DNA has not been identified in most of these reports. After an episode of HZ, a healthy, active 90-year-old female developed ulcerative nodules in the affected trigeminal V1 dermatome and the contra-lateral trigeminal region over a 1-year period. Excision and/or biopsy of all these lesions showed similar pathologic changes that consisted of herpetic folliculitis, adjacent dense mixed nodular lymphocytic infiltrates with germinal centers (cutaneous lymphoid hyperplasia (CLH)), and in the deeper excision specimens, an obliterative vasculitis of a vessel with smooth muscle in its wall. Immunophenotype analysis revealed a mixed, predominate T- and B-cell population without loss of pan-T cell antigens or aberrant expression by B cells of T-cell antigens. Polymerase chain reaction for herpetic DNA was positive for VZV DNA. Lymphocyte gene rearrangement analysis revealed 2 distinct, anatomically and chronologically, monoclonal B-cell populations and a monoclonal T-cell population in one nodule. Treatment with valacyclovir has lead to almost complete resolution of her cutaneous nodules after 6 months of therapy. In this case, it can be surmised that persistence of VZV infection and lack of effective cell-mediated immunity lead to development of both immunopathology (vasculitis) and excessive lymphoid cell proliferation (CLH).

Blue nevi are benign dermal melanocytic proliferations that can sometimes share overlapping microscopic features with melanoma. We used comparative genomic hybridization to analyze three groups of dermal melanocytic proliferations. Group 1 consisted of 10 cellular blue nevi and 1 deep penetrating nevus, none of which showed chromosomal aberrations. Group 2 consisted of 11 lesions that were histopathologically ambiguous. Three of these lesions demonstrated chromosomal aberrations (three or fewer per lesion). Group 3 consisted of seven histopathologically malignant lesions, each showing three or more chromosomal aberrations. Moderate to severe cytologic atypia and a mitotic rate of three or more mitoses per 10 high power fields were present in six of eight (75%) lesions that had at least three chromosomal aberrations but were absent in 15 of 20 (75%) lesions without chromosomal aberrations. Necrosis was present in four of the 29 (13%) lesions, with every lesion with necrosis demonstrating three or more genomic abnormalities. In conclusion, histopathologically unequivocally benign or malignant dermal melanocytic proliferations show nonoverlapping patterns of chromosomal aberrations. Ambiguous lesions can be separated into lesions with and without chromosomal aberrations. Future studies with clinical follow-up are necessary to determine which aberrations are most informative for classification of these lesions.

Oncogenic human papillomavirus (HPV) types such as HPV 16 are known to play a crucial role in the development of anogenital carcinomas. The etiology of anogenital malignant melanoma is unknown. We report two case of vulvar malignant melanoma in which multiple HPV types including HPV 16 and putative novel HPV types (alb-1, alb-2, alb-7, and alb-10) were identified by degenerated nested polymerase chain techniques (polymerase chain reaction) in both the malignant melanoma and surrounding skin. One melanoma was associated with lichen sclerosus, and the other, with melanoma in situ and pigmented vulvar squamous papillomatosis. These melanomas harbored HPV types alb-7, and HPV 16 as well as alb-1, respectively. HPV types 16, 20, 21, 36, alb-2, and AJ001060 were detected in vulvar skin affected by lichen sclerosus. Vulvar squamous papillomatosis harbored HPV types 28 and alb-10. HPV 16 was physically integrated into the host genome in lichen sclerosus skin and possibly in the melanoma associated with pigmented vulvar squamous papillomatosis. Twenty-two percent (4 of 18) of normal control specimens from skin tumor excisions were found to harbor HPV DNA (HPV types 3, 54, and alb-7); none of these control samples harbored multiple HPV DNA. These findings of multiple HPV DNA and integrated HPV 16 in skin associated with vulvar malignant melanoma indicate that HPV may play a role in the development of vulvar malignant melanoma. The role of HPV could be either direct through infection of melanocytes or indirect as a cofactor with free radicals in chronic fibroinflammatory vulvar disorders such as lichen sclerosus.

A 71-year-old white woman sought treatment for poroma of the right lower eyelid. Excisional biopsy was performed, and the specimen had histologic features consistent with poroma. One year after excision, there has been no recurrence of the lesion. Clinicians should be aware that poroma can occur in regions other than the hands and feet.

This report details the gross and histopathologic findings of an unusual complex choristoma at the lateral canthus. Although this lesion displays elements of hair follicle nevus, bulbar dermoid, epibulbar osseous choristoma, and accessory tragus, it does not fit neatly in any of these categories. We propose that this lesion is the result of faulty migration of pluripotential cells during embryogenesis.

A healthy 13-year-old female presented with a 5-month history of an enlarging red-brown, firm lower eyelid mass associated with loss of eyelashes. An excisional biopsy revealed a well-circumscribed nodule composed of coalescing nests of epithelioid cells, rare multinucleated cells, and vacuolated macrophages and spindle cells. Additional studies revealed a positive vimentin and alpha(1)-antitrypsin, and negative S100 protein and Factor XIIIa immunophenotype. This constellation of clinicopathologic features is diagnostic of solitary reticulohistiocytoma, but also shows overlap with xanthogranuloma, a common childhood histiocytosis. Reticulohistiocytoma should be considered in the differential diagnosis of eyelid tumors and has the potential for local recurrence. Diffuse cutaneous reticulohistiocytosis or multicentric reticulohistiocytosis should be considered if similar cutaneous lesions with or without symptoms of arthritis are present, respectively.

A 58-year-old man who had his left eye enucleated at the age of 26 after sustaining ocular trauma presented secondary to an inability to tolerate his prosthesis. Examination revealed upper and lower eyelid cicatricial entropion with areas of symblephara and conjunctival scarring causing forniceal shortening. No areas suspicious for malignancy were noted. Surgical correction was performed, and a segment of the conjunctiva sent for pathology revealed squamous cell carcinoma in situ. Map biopsies of the conjunctiva were subsequently performed, with no further areas of malignancy identified. The patient has been followed with close clinical surveillance, with no evidence of any recurrent suspicious areas within the conjunctiva. This case report confirms that squamous cell carcinoma in situ may occur in an anophthalmic socket and be managed conservatively, reserving the need for orbital exenteration for more invasive disease.