Gene Expression Profiling in the Skin Reveals Strong Similarities between Subacute and Chronic Cutaneous Lupus that Are Distinct from Lupus Nephritis.

Subacute cutaneous lupus erythematosus and chronic cutaneous lupus erythematosus are represented in the majority of cutaneous lupus subtypes, each of which has variable implications for systemic manifestations such as lupus nephritis. On dermatologic examination, subacute cutaneous lupus erythematosus and chronic cutaneous lupus erythematosus are distinct. However, it is often difficult to diagnose the subtype from histology alone. Our study utilized whole-genome microarray expression analysis on human skin samples of subacute cutaneous lupus erythematosus, on human skin samples of chronic cutaneous lupus erythematosus, and on healthy controls, along with analysis on human samples of lupus nephritis and normal kidney tissue to compare cutaneous lupus subtypes with each other as well as with lupus nephritis. The data revealed that cutaneous lupus subtypes were distinct from healthy control skin, with gene expression predominantly characterized by upregulation of IFN-1 and T-cell chemotactic genes. However, the cutaneous lupus subtypes were very similar to one another; comparative analyses revealed few statistically significant differences in gene expression. There were also distinct differences between the gene signatures of cutaneous lupus and lupus nephritis. Cutaneous lupus samples revealed gene signatures demonstrating a prominent inflammatory component that may suggest the skin as an early site of initiation of lupus pathogenesis, whereas lupus nephritis reflected the recruitment and activation of M2 macrophages and a wound healing signature.

YAP/TAZ Activation Drives Uveal Melanoma Initiation and Progression.

Uveal melanoma (UM), the most common ocular malignancy, is characterized by GNAQ/11 mutations. Hippo/YAP and Ras/mitogen-activated protein kinase (MAPK) emerge as two important signaling pathways downstream of G protein alpha subunits of the Q class (GαQ/11)-mediated transformation, although whether and how they contribute to UM genesis in vivo remain unclear. Here, we adapt an adeno-associated virus (AAV)-based ocular injection method to directly deliver Cre recombinase into the mouse uveal tract and demonstrate that Lats1/2 kinases suppress UM formation specifically in uveal melanocytes. We find that genetic activation of YAP, but not Kras, is sufficient to initiate UM. We show that YAP/TAZ activation induced by Lats1/2 deletion cooperates with Kras to promote UM progression via downstream transcriptional reinforcement. Furthermore, dual inhibition of YAP/TAZ and Ras/MAPK synergizes to suppress oncogenic growth of human UM cells. Our data highlight the functional significance of Lats-YAP/TAZ in UM initiation and progression in vivo and suggest combination inhibition of YAP/TAZ and Ras/MAPK as a new therapeutic strategy for UM.

Distinguishing between irritated seborrheic keratosis and squamous cell carcinoma in situ using BCL-2 and IMP3 immunohistochemistry.

BACKGROUND: Distinguishing an irritated seborrheic keratosis (ISK) from a squamous cell carcinoma in situ (SCCIS) can occasionally be challenging, both histologically and clinically. The purpose of this study was to determine if an immunohistochemical profile of select markers can aid in differentiating these two entities. METHODS: We randomly selected and stained 103 ISK and 111 SCCIS for EGFR, IMP3, and BCL-2. IMP3 staining was scored as negative or 0 (0% positive), 1+ (1%-25% positive), 2+ (26%-50% positive), and 3+ (>50% positive). BCL-2 and EGFR were graded as either positive or negative. RESULTS: Sixty five out of 103 (63%) ISKs were positive for BCL-2, none (0%) were positive for IMP3, and 18 (18%) were positive for EGFR. Fifteen out of 111 (14%) SCCISs were positive for BCL-2, 26 (23%) were positive for IMP3, and 27 (24%) were positive for EGFR. BCL-2 was moderately sensitive (63%) and specific (87%) in identifying ISK. IMP3 was specific (100%) but not sensitive (23%) for SCCIS. CONCLUSION: Our findings indicate that the combination of IMP3 and BCL-2 may be of diagnostic utility in distinguishing between ISK and SCCIS in daily clinical practice. EGFR immunohistochemistry did not appear to be useful in this setting.

Emperipolesis and S100 expression may be seen in cutaneous xanthogranulomas: A multi-institutional observation.

Cutaneous Rosai-Dorfman disease (RDD) can be difficult to distinguish from other non-Langerhans cell histiocytoses, particularly xanthogranuloma (XG). Pathologists use S100 immunoreactivity, abundant plasma cells, and the presence of emperipolesis to distinguish RDD from XG. However, S100 expression has been reported in XG and, in practice, we have occasionally observed emperipolesis in cases that were otherwise clinically and pathologically consistent with XG. We present 10 cases of XG with emperipolesis and variable S100 immunoreactivity. Histologically, 7 cases were most in keeping with XG, and a histologic differential of XG versus RDD was raised in the remaining 3 cases. All 10 cases were clinically consistent with XG. Notably, none of these cases showed abundant plasma cells. Nine cases showed variable S100 immunostaining, ranging from focal/weak expression, to focal/strong, diffuse/moderate, and diffuse/strong expression. Histiocytes in all cases were CD68 positive and CD1a negative. We conclude that emperipolesis and S100 expression in a skin biopsy cannot reliably distinguish XG from cutaneous manifestations of RDD. Clinical correlations are essential, as are histologic clues to a diagnosis of classic XG that include an abundance of foamy mononuclear cells, Touton giant cells, and an absence of pale-stained histiocytes, abundant plasma cells, fibrosis, or vascular proliferation.

Indolent, waxing and waning cutaneous presentation of HTLV-1-associated adult T-cell leukemia/lymphoma in an HIV-1-positive patient.

We present an unusual case of human T-cell leukemia-lymphoma virus type 1 (HTLV-1)-associated adult T-cell leukemia/lymphoma in an human immunodeficiency virus (HIV) patient who presented with non-diffuse, papular, waxing and waning cutaneous eruptions. The patient is a 61-year-old Haitian male with history of HIV on highly active antiretroviral therapy (HAART) who presented with multiple painful pink papules on his distal fingers and back for more than a year with a waxing and waning course. Skin biopsy demonstrated a CD4+, CD25+, CD8- lymphocytic proliferation with a clonal T-cell receptor gene rearrangement. Peripheral blood demonstrated lymphocytosis with a CD4:CD8 ratio greater than 20:1 and an identical T-cell receptor (TCR) clone as that in the biopsy. HTLV-1 antibodies and PCR testing for HTLV virus were positive. Retrospective review of CBCs during the past 8 years demonstrated chronic lymphocytosis with a sharp increase in absolute CD4 counts corresponding to the onset of rash. The patient lacked systemic symptoms after 6 months follow-up.

A Private Investigation: Radiologic-Pathologic Correlation of Testicular Tumors.

To review the classification of testicular tumors, describe the sonographic and pathologic features of each tumor type, and discuss the mimics, diagnostic pitfalls, and management of testicular tumors. Method consists of pictorial review. We review sonographic and pathologic findings of several testicular tumors and tumorlike entities. Although ultrasound is the first-line imaging modality to differentiate between intratesticular and extratesticular location of an intrascrotal mass, it is not specific for intratesticular lesion characterization. Therefore, correlation with histology sampling is often necessary.

Malignant melanoma within squamous cell carcinoma and basal cell carcinoma: is it a combined or collision tumor?--a case report and review of the literature.

We report a case of a very unusual combined and collision basosquamous melanocytic malignant tumor on the chest of an 84-year-old man. To our knowledge, this is the first case report describing this entity. We attempt to address the diagnostic challenge and the clinical and histological characteristics of these rare neoplasms with a review of the English literature to further categorize and summarize what has been previously reported about these extraordinary tumors.

Primary cutaneous langerhans cell sarcoma: a report of four cases and review of the literature.

Langerhans cell sarcoma (LCS) is a rare but potentially life-threatening neoplastic condition. The diagnosis of LCS requires morphological and immunophenotypic characterization to distinguish it from other epithelioid-appearing malignancies. Four cases of LCS were encountered in the consultative practices of 2 of the authors. The patients ranged in age from 54 to 88 years of age. In 2 of the cases the patients had a history of acute myelogenous leukemia with eruptions occurring after initiation of decitabine. One patient died within 3 months of presenting with the skin eruption, whereas the other patient is in remission. In the other 2 patients, there was no antecedent history; the presentation was in the context of a solitary nodule. One patient declined treatment and died of disseminated metastatic disease. The other patient had complete excision with no evidence of recurrent or metastatic disease. In all cases, the biopsies showed a sheet-like growth of large atypical epithelioid cells. Phenotypic studies revealed positivity for CD4, CD1a, and S100 in all and variable staining for langerin, lysozyme, CD83, CD31, and CD14. Cutaneous LCS represents a terminally differentiated myeloid tumor with a variable but potentially aggressive clinical course. It may be related to a common stem cell defect given the association with acute leukemia. The morphology ranges from atypical appearing Langerhans cell to a high-grade large cell epithelioid malignancy mimicking amelanotic nodular melanoma.

Recurrent and metastatic primary cutaneous mucinous carcinoma after excision and Mohs micrographic surgery.

Primary cutaneous mucinous carcinoma is a neoplasm of sweat gland origin. Optimal management guidelines have not been established for this rare tumor. It is treated most commonly by traditional excision and more recently by Mohs micrographic surgery in an effort to decrease its recurrence rate. We report a case of primary cutaneous mucinous carcinoma with multiple recurrences and metastases following 3 excisions and 2 Mohs procedures, highlighting the potential difficulty in treating this cancer and suggesting the need for a more effective treatment approach.

Skin biopsy for inflammatory and common neoplastic skin diseases: optimum time, best location and preferred techniques. A critical review.

The diagnosis of skin diseases, particularly inflammatory dermatoses, is based primarily on clinical information. Pathologic examination of the biopsied specimen often serves as a complementary or confirmative part of the diagnosis. However, the clinical diagnosis of skin diseases may be challenging, as the clinical information and appearance of skin lesions invariably overlap. Evidence for a correct diagnosis may be lacking without histopathologic examination of skin biopsies. It is well known that the histologic diagnosis of inflammatory and other skin diseases requires clinicopathologic correlation, and there is evolution of skin lesions into different stages as the diseases progress. Other factors important for accurate dermatopathologic diagnosis are optimum time, best location and preferred techniques of skin biopsy. In searching for available information concerning when, where and how to take skin biopsies, it is noted that there are only limited practical guidelines currently available. We present this review article in hopes that our collective dermatopathologic and dermatologic experience can provide a quick reference for accurate diagnosis and proper management of skin diseases.

Familial cutaneous collagenoma.

A 41-year-old woman presented to our dermatology clinic in February 2005 with a chief complaint of numerous flesh-colored nodules on her back and abdomen. She initially noticed the lesions at age 17 years. The plaques had increased in size and number over time, but remained asymptomatic. The patient reported multiple similar lesions on a maternal uncle and a cousin. Her family history was also notable for cardiomyopathy, resulting in the death of her mother. The patient's past medical history was notable for poorly controlled type I diabetes, currently managed with an insulin pump; and coronary artery disease. The patient had undergone multiple cardiac procedures before the age of 40 years, including quadruple coronary artery bypass grafting surgery and placement of 9 cardiac stents. Her ejection fraction on cardiac catheterization in November 2004 was 65% with no wall motion abnormalities. On physical examination, numerous spongy, discrete, flesh-colored plaques and nodules were seen concentrated across the upper part of her back between the scapulae as well as underneath the breasts and across the flanks (Figure 1). All lesions were asymptomatic. Prior workup of this patient had included plain films of the long bones and hands, which were within normal limits. A biopsy from lesional skin on the back highlighted by trichome stain showed an increased number of markedly thickened and eosinophilic dermal collagen bundles compared with adjacent normal skin. Immunohistochemical studies with anticollagen type I and type III antibodies confirmed that the increased collagen material consisted of type I collagen fibers, which is the same type of collagen found in normal dermis. The elastic fibers, highlighted by Verhoeff-van Gieson stain (Figure 2), were diminished and haphazardly arranged. No increased cellular component or inflammatory infiltrate was observed. These findings were consistent with a collagenoma. Further analysis of the lesional tissue by electron microscopy revealed that the ultrastructural appearance of the collagen fibers, including arrangement and diameters, were not significantly different from that of the normal tissue (Figure 3).

Localized nephrogenic fibrosing dermopathy: Aberrant dermal repairing?

Nephrogenic fibrosing dermopathy (NFD) has emerged as a clinicopathologic entity since 2000 and was recently renamed nephrogenic systemic fibrosis. The cause and pathogenesis remain uncertain. The classic clinical presentation is diffuse thickening and hardening of the skin that occurs in patients with renal insufficiency, with or without systemic involvement. We report a patient with renal failure who presented to our dermatology clinic with a localized plaque on the left forearm along the vein that was traumatized during the infusion of erythropoietin. Histologic examination revealed a dermal proliferation of CD34(+) fibrocytes with collagen fibers and interstitial mucin accumulation, features characteristic for NFD. We conclude that NFD may present as a localized, scarlike plaque after trauma and exhibit overlapping histopathologic features resembling cicatrix and other dermal reparative/regenerative processes. NFD may, in fact, be a disorder of aberrant extracellular matrix remodeling in patients with renal insufficiency. This is a single case observation with discussion of literature and attempted hypothesis on pathogenesis. No experimental evidence is provided.

T-cell prolymphocytic leukemia: an aggressive T cell malignancy with frequent cutaneous tropism.

BACKGROUND: T-cell prolymphocytic leukemia (T-PLL), formerly categorized as T-cell chronic lymphocytic leukemia, is a rare and aggressive hematologic malignancy. Although the skin is characteristically involved, it is not a well-recognized entity in the dermatologic literature. METHODS: Six cases of cutaneous T-PLL are presented from a clinical, light microscopic, and phenotypic perspective. RESULTS: The patient population comprised 2 women and 4 men, with a mean age of 69.8 years. The disease was associated in all with skin involvement with facial preference; edema, purpura, and lesional symmetry were characteristic. The skin biopsies demonstrated a largely non-epidermotropic angiocentric lymphocytic infiltrate with accompanying hemorrhage. The cells showed irregular- to reniform-shaped nuclei with small nucleoli and eosinophilic rims of cytoplasm. Phenotypic studies revealed three prevailing profiles: CD4 dominant in 4, CD8 dominant in one, and co-expression of CD4 and CD8 in one. CD3 loss was seen in one case. All expressed T-cell leukemia 1 (TCL-1) and CD7; cutaneous lymphocyte antigen expression was discernible in a dot-like perinuclear array. All cases tested excluding one expressed TCL-1 and CD52. In two cases tested, T-cell receptor beta rearrangements were observed. Cytogenetic studies demonstrated a paracentromeric chromosome 14 inversion. Polysomy 8 and MYC amplification was seen in one case, manifesting an aggressive clinical course. Four patients died from their disease within 18 months of diagnosis. LIMITATIONS: Cytogenetic MYC amplification, FISH, and TCR beta studies were conducted on each of 2 cases, respectively, due to limitations of tissue block samples and/or peripheral blood. cMYC translocation studies were conducted on 3 of the 6 cases, again due to limitations imposed by the tissue samples on the cases. The last case was recently diagnosed and, therefore, long-term follow-up is not possible. CONCLUSION: T-PLL is a distinctive post-thymic T-cell malignancy with frequent cutaneous tropism. A diagnosis is possible in almost all cases based on characteristic clinical, light microscopic, phenotypic, and cytogenetic features. While a chromosome 14 inversion is highly characteristic, additional inherent cytogenetic differences, such as trisomy 8 with CMYC over-amplification, may account for some case to case variation in clinical course.

De novo intraepidermal epithelioid melanocytic dysplasia as a marker of the atypical mole phenotype -- a clinical and pathological study of 75 patients.

BACKGROUND: We encountered a distinctive pattern of dysplastic intraepidermal melanocytic proliferation, which defies classification as a dysplastic melanocytic nevus, but in which the morphologic features fall short of a diagnosis of melanoma in situ. We designate such lesions as de novo intraepidermal epithelioid melanocytic dysplasia. METHODS: From 75 patients, 82 skin biopsies were encountered that showed this distinctive morphology. Hematoxylin- and eosin-stained histologic sections were studied and the features were correlated with personal and family histories of dysplastic nevi and melanoma. RESULTS: The diagnosis of de novo melanocytic dysplasia was made in 27 male patients and 48 female patients (mean age: 44 years). The histologic hallmark was a pagetoid (single-cell) array of moderately to severely atypical epithelioid melanocytes within the epidermis. Seventy-three lesions were located on sun-exposed skin and nine on sun-protected skin. In 41 patients, there was an atypical mole phenotype, whereas 20 patients had a prior or subsequent diagnosis of melanoma with five of 16 patients questioned revealing a family history of melanoma. CONCLUSIONS: De novo intraepidermal epithelioid melanocytic dysplasia is a distinct entity associated with an atypical mole phenotype and a personal and/or family history of melanoma.