Employing immunohistochemical staining to labial minor salivary gland biopsies from patients with Sjogren's syndrome increases diagnostic certainty.

BACKGROUND: Sjogren's syndrome (SjS) is an autoimmune disease characterized clinically by dry eyes and dry mouth, and histopathologically by lymphocytic infiltrates in the salivary glands. Labial minor salivary gland biopsy (MSGB) is a major diagnostic test for SjS, deemed positive by a focus score of ≥1, meaning that ≥50 lymphocytes were found in 4 mm2 tissue on hematoxylin and eosin (H&E)-stained slides. The diagnosis can be challenging, and the above diagnostic criteria has low and variable sensitivity. METHODS: We performed a retrospective study on MSGBs done for possible SjS. We compared the percent of MSGBs which met the histologic criteria by H&E stain alone and that with the addition of CD45, CD3, and CD20 immunohistochemical (IHC) staining for these patients. A total of 45 cases with complete data were analyzed. RESULTS: Thirty-five of the 45 patients had the diagnosis of Sjogren's syndrome (SjS+) based on ACR criteria. However, based on H&E staining alone, only 22/35 cases (63%) met the histologic criteria. After adding IHC staining with CD45, CD3, and CD20 to MSGBs of SjS + patients, 29/35 (83%) cases met the histological criteria for SjS. All MSGBs from patients without SjS had no significant lymphocyte infiltrate on either H&E or IHC stains. CONCLUSIONS: Immunohistochemical better identifies lymphocytic infiltrates in MSGB and increases diagnostic certainty. Due to high cost, their use should be restricted to cases where there is high clinical suspicion of SjS and negative H&E evaluation alone, or if the diagnosis is uncertain.

Sweet syndrome with perifollicular involvement because of koebnerization from facial hair plucking.

Sweet syndrome (SS), also known as acute febrile neutrophilic dermatosis, is an uncommon skin eruption characterized by fever, leukocytosis, and tender erythematous papules, nodules, and plaques. Histopathologically, SS lesions are characterized by marked superficial papillary edema with a dense neutrophilic infiltrate. SS is known to demonstrate both the Koebner phenomenon and pathergy. The majority of reported cases of these phenomena occur following significant cutaneous injury (e.g., biopsies, burns) rather than minor trauma such as pressure and friction. Here, we present the first known reported case of SS koebnerization secondary to minor grooming-related hair plucking. In addition, this is also the first reported case to our knowledge of SS with perifollicular involvement on histopathology.

Verruciform xanthoma in recessive dystrophic epidermolysis bullosa and keratitis-ichthyosis-deafness syndrome: Report of two cases and a review of the literature.

Verruciform xanthoma is a benign, wart-like lesion that can clinically mimic squamous cell carcinoma. We describe two teenage patients with severe genodermatoses, recessive dystrophic epidermolysis bullosa (RDEB), and keratitis-ichthyosis-deafness (KID) syndrome, respectively, each found to have plaques suspicious for malignancy, later demonstrated on histopathologic examination to be verruciform xanthoma. We discuss the connection between these severe genodermatoses and the suspected pathophysiology of verruciform xanthoma. In addition, we highlight the importance of recognizing verruciform xanthoma as a clinical mimicker of squamous cell carcinoma, for which patients with RDEB and KID syndrome are at increased risk.

Common BRAF(V600E)-directed pathway mediates widespread epigenetic silencing in colorectal cancer and melanoma.

During cancer development, it is well established that many genes, including tumor suppressor genes, are hypermethylated and transcriptionally repressed, a phenomenon referred to as epigenetic silencing. In general, the factors involved in, and the mechanistic basis of, epigenetic silencing during cancer development are not well understood. We have recently described an epigenetic silencing pathway, directed by the oncogenic B-Raf proto-oncogene (BRAF) variant BRAF(V600E), that mediates widespread epigenetic silencing in colorectal cancer (CRC). Notably, the BRAF(V600E) mutation is also present in 50-70% of melanomas. Here, we show that the same pathway we identified in CRC also directs epigenetic silencing of a similar set of genes in BRAF-positive melanoma. In both CRC and melanoma, BRAF(V600E) promotes epigenetic silencing through up-regulation of v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog G (MAFG), a transcriptional repressor with sequence-specific DNA-binding activity. The elevated concentration of MAFG drives DNA binding on the promoter. Promoter-bound MAFG recruits a set of corepressors that includes its heterodimeric partner BTB and CNC homology 1, basic leucine zipper transcription factor 1 (BACH1), the chromatin remodeling factor chromodomain helicase DNA-binding protein 8 (CHD8), and the DNA methyltransferase DNMT3B, resulting in hypermethylation and transcriptional silencing. Our results reveal a common BRAF(V600E)-directed transcriptional regulatory pathway that mediates epigenetic silencing in unrelated solid tumors and provide strong support for an instructive model of oncoprotein-directed epigenetic silencing.

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.

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.

The Value of Direct Immunofluorescence on Proteinase-Digested Formalin-Fixed Paraffin-Embedded Skin Biopsies.

Direct immunofluorescence (DIF) on frozen tissue (DIF-F) is the method of choice for the identification of immune deposits present in skin and other tissues. DIF can also be performed on formalin-fixed paraffin-embedded tissue (DIF-P) after antigen retrieval with proteases and has proven to be of value in renal pathology. However, its utility in skin biopsies has not been fully examined. In this study, we performed DIF-P on 60 skin biopsies that comprised of bullous pemphigoid (n = 18), pemphigoid gestationis (n = 1), pemphigus (n = 7), linear IgA disease (n = 7), vasculitis (n = 20), lupus erythematosus (n = 3), and dermatitis herpetiformis (n = 4) cases. We compared the results of DIF-P with those of DIF-F from the same patients. The diagnostic features were found in 15 of 19 (79%) pemphigoid (bullous pemphigoid and pemphigoid gestationis), 3 of 7 (43%) pemphigus, 3 of 7 (43%) linear IgA disease, 14 of 20 (70%) vasculitis, 1 of 3 (33%) lupus erythematosus, and none (0%) of the dermatitis herpetiformis cases tested. Overall, DIF-P is less sensitive than DIF-F but seems to be a valuable technique that could aid in the diagnosis of vasculitides, immunobullous, and connective tissue disorders when fresh tissue is unavailable.

Tumoral PD-L1 expression in desmoplastic melanoma is associated with depth of invasion, tumor-infiltrating CD8 cytotoxic lymphocytes and the mixed cytomorphological variant.

Recently, patients with metastatic desmoplastic melanoma (DM) have been shown to respond more favorably to anti-PD1/PD-L1 therapy than other melanoma subtypes. Given this, we evaluated PD-L1/2 expression in primary DM samples and correlated these with subtype, CD8+ lymphocyte status, histopathological prognosticators, and select genetic alterations. Eighty-six (36 mixed DM, 50 pure DM) archival annotated samples met inclusion criteria and were immunohistochemically semiquantitatively evaluated. Per established criteria, for PD-L1/L2, cases with ⩾5% tumoral expression, and for CD8, cases with a predominantly peri/intratumoral CD8+ infiltrate were scored positive. Univariate analysis (chi-square and Wilcoxon) identified potential confounders and a nested case-control study was accomplished using multiple logistic regression. For PD-L1, 49% of cases were positive and 71% of cases with thickness >4 mm were positive; PD-L1 expression differed by median depth (3.29 mm, interquartile range=3.58 mm for PD-L1 positives vs 1.75 mm, interquartile range=2.04 mm for PD-L1 negatives, P=0.0002) and was linearly associated with increasing depth of invasion (P=0.0003). PD-L1-positive cases were more likely to display CD8+ lymphocytes (60 vs 28% P=0.0047).The presence of CD8+ lymphocytes correlated significantly with depth of invasion >1 mm (P=0.022). On multivariate analysis, PD-L1 was 6.14 × more likely to be expressed in mixed DM than pure DM (P=0.0131), CD8+ staining was 6.22 × more likely in PD-L1 positive cases than in PD-L1 negative (P=0.0118), and tumor depth was associated with greater odds of PD-L1 expression (OR=1.61, P=0.0181). PD-L2 expression was observed in 48% of cases but did not correlate with any variables. Correlation of tumoral PD-L1 with increased depth and CD8+ lymphocytes implicates the tumoral immune microenvironment with advancing disease in DM. Enhanced tumoral PD-L1 expression in the mixed cytomorphological variant provides an insight into the differential pathogenesis of the subtypes and suggests that these patients are likely better candidates for anti-PD/PD-L1 therapy.

Pregnancy-associated morphea: a case report and literature review.

Morphea, also known as localized scleroderma, is arare fibrosing disorder of the skin, the pathogenesisof which is incompletely understood. It is thought,however, to involve interplay of genetic dispositionand triggering environmental factors, such asinfections and autoimmunity. Pregnancy as a potentialtrigger has only been reported in four cases. Herein,we present a patient who developed morphea of thebreasts during pregnancy, which rapidly resolvedwith a normal delivery. Our patient was distinct fromsome of the reported patients because her conditionwas tightly correlated with her pregnancy, as judgingby rapid resolution after delivery. In addition, therewas no apparent infection, history of autoimmunity,or development of autoimmunity during or afterpregnancy. Although the pathogenesis of pregnancyassociatedmorphea is largely unknown, we exploredpotential mechanisms of this condition, which mayinvolve mechanical injury, "microchimerism," andshifts in intrapartum hormones, such as TGF-ß.

Lichen planus pigmentosus in a blaschkoid distribution.

Lichen planus pigmentosus is a pigmentary disorder of unknown etiology, with diffuse hyperpigmentation of sun-exposed areas, more commonly seen in some ethnic and racial groups. We report an unusual case of lichen planus pigmentosus in a 40-year-old man with Fizpatrick type III skin that was present in a blaschkoid distribution on the trunk, a distribution that has been rarely reported. This unique presentation of lichen planus pigmentosus may contribute to better understanding of the etiology, as the blaschkoid distribution may reflect underlying cutaneous mosaicism that renders those cells more susceptible to an insult that results in lichen planus pigmentosus. This disorder should be considered in the differential diagnosis of macular hyperpigmentation, especially in those from more commonly affected ethnic and racial groups, even when the distribution is atypical and in the absence of history of sun exposure.

Ki-67, p53, and p16 expression, and G691S RET polymorphism in desmoplastic melanoma (DM): A clinicopathologic analysis of predictors of outcome.

BACKGROUND: The prognostic role Ki-67, p53, and p16 immunostains and RET (rearranged during transfection) polymorphism in desmoplastic melanoma has not been evaluated. OBJECTIVE: We sought to identify potential prognostic markers. METHODS: We performed Ki-67, p53, and p16 immunostains on 66 desmoplastic melanomas, and sequenced RET G691 polymorphism and recurrent mutations of 17 cancer genes in 55 and 20 cases, respectively. RESULTS: Recurrence and metastasis were documented in 11 of 66 (17%) and 26 of 66 (39%) patients, respectively. Death was noted in 25 of 55 (45%) patients. Ki-67 expression (≥10%, 43%) correlated with male gender (P = .009), ulceration (P = .002), and Breslow depth (P = .009). p53 Expression (≥50%, 28%) correlated with male gender (P = .002) and head and neck location (P = .0228). Using Kaplan-Meier plots, Ki-67 expression (P = .0425) and mitosis (P = .00295) correlated with overall survival, whereas vascular invasion (P = .0292) correlated with disease progression. There was a significant correlation between Ki-67 and p53 expression (P = .003). RET polymorphism was present in 10 of 46 (22%) cases and inversely correlated with Breslow depth (P = .024). LIMITATION: Our study is small and lacks power to perform a multivariate analysis. CONCLUSION: Although Ki-67 expression correlated with overall survival, additional studies are needed to determine whether Ki-67 would be an independent prognostic marker in addition to the current routine histopathologic assessment.

Unusual Cutaneous Metastasis of Uterine Carcinosarcoma: A Case Report and Review of the Literature.

Cutaneous metastasis of uterine cancer is rare and is often associated with late-stage disease. Most uterine malignancies are endometrial adenocarcinomas, but a small subset is uterine carcinosarcoma, also known as malignant mixed Mullerian tumors. Uterine carcinosarcomas are highly aggressive tumors with an average 5-year survival rate of 26%-34%. Metastases most commonly occur in the abdominal wall, lung, and bone. Cutaneous metastasis is exceedingly rare and may pose a diagnostic challenge. The authors report a 57-year-old woman with multiple subcutaneous nodules on the face and trunk. A biopsy revealed similar morphology and staining characteristics as the sarcomatous component of the primary uterine carcinosarcoma. Histopathological features and immunophenotypical characteristics of the metastatic tumor are detailed in comparison with the original tumor. A review of the literature is also provided.

Complete Spontaneous Regression of Merkel Cell Carcinoma After Biopsy: A Case Report and Review of the Literature.

Merkel cell carcinoma (MCC) is a rare primary cutaneous neuroendocrine tumor that typically occurs on the head and neck of the elderly and follows an aggressive clinical course. Merkel cell polyomavirus (MCPyV) has been identified in up to 80% of cases and has been shown to participate in MCC tumorigenesis. Complete spontaneous regression of MCC has been rarely reported in the literature. We describe a case of a 79-year-old man that presented with a rapidly growing, 3-cm mass on the left jaw. An incisional biopsy revealed MCC. Additional health issues were discovered in the preoperative workup of this patient which delayed treatment. One month after the biopsy, the lesion showed clinical regression in the absence of treatment. Wide excision of the biopsy site with sentinel lymph node dissection revealed no evidence of MCC 2 months later. The tumor cells in the patient's biopsy specimen were negative for MCPyV by polymerase chain reaction and immunohistochemistry (CM2B4 antibody, Santa Cruz, CA). The exact mechanism for complete spontaneous regression in MCC is unknown. To our knowledge, only 2 previous studies evaluated the presence of MCPyV by polymerase chain reaction in MCC with spontaneous regression. Whether the presence or absence of MCPyV correlates with spontaneous regression warrants further investigation.

Neurotrophin receptors and perineural invasion in desmoplastic melanoma.

BACKGROUND: Perineural invasion (PNI) in desmoplastic melanoma is associated with increased local recurrence and reduced disease-free survival. The biological mechanisms underlying PNI remain unclear although several lines of evidence implicate neurotrophins and their receptors. OBJECTIVES: We investigated the expression of p75NGFR and TrkA, and the presence of functional RET polymorphism (RETp) as they relate to PNI in desmoplastic melanoma. METHODS: In all, 43 cases of desmoplastic melanoma were immunohistochemically evaluated for TrkA and p75NGFR expression and RETp was detected by direct DNA sequencing. RESULTS: PNI was present in 67% of cases. On univariate analysis, p75NGFR was associated with PNI (expression detected in 79% of PNI-positive cases compared with 36% of PNI-negative cases, P = .005), increased Breslow depth (P = .007), and greater Clark level (P = .01). RETp was noted in 28% of cases but was not significantly associated with PNI (P = .27) or other histopathologic variables. TrkA expression was absent in all cases. PNI was associated with increased Breslow depth and Clark level (P = .01 and P = .009, respectively). Controlling for the association between p75NGFR and depth, p75NGFR remained associated with an increased propensity for PNI (odds ratio 4.68, P = .04). LIMITATIONS: The sample size was limited. CONCLUSION: In desmoplastic melanoma, p75NGFR expression is significantly associated with PNI and a more locally aggressive phenotype.

Nodular amyloidosis derived from keratinocytes: an unusual type of primary localized cutaneous nodular amyloidosis.

Primary, localized cutaneous amyloidosis includes macular, lichen, and nodular (tumefactive) types in which the amyloid deposits are limited to the dermis without systemic involvement. The material in lichen and macular amyloidosis is derived from epidermal keratinocytes [keratinocyte-derived amyloid (AK)], whereas that in nodular amyloidosis is derived from immunoglobulin light-chains amyloid (AL). Primary, localized cutaneous nodular amyloidosis (PLCNA) is a form of primary, localized cutaneous amyloidosis that has been associated with a risk of progression to systemic amyloidosis. We report an unusual case of nodular AK-type amyloid deposited in the dermis of the feet. The patient is a 60-year-old woman with asymptomatic verrucoid-like lesions present around the medial and lateral aspects of the bilateral heels for 1-2 years. A biopsy showed massive deposition of eosinophilic amorphous material in the papillary and reticular dermis. The material stained positive for Congo red with apple-green birefringence on polarized light. It was also positive for pan-cytokeratin and negative for kappa and lambda light-chain immunostains. An extensive workup was negative for systemic involvement. Lipid chromatography tandem mass spectrometry confirmed that the deposition was AK-type amyloid. We believe that this is the first case of PLCNA with AK deposition. This entity should be included in the differential diagnosis of PLCNA so that an extensive systemic workup may be avoided.

Dystrophic epidermolysis bullosa associated with amniotic band syndrome.

Amniotic band syndrome (ABS) is a term used to describe congenital anomalies that result from the entrapment of a fetus in fibrous bands. We describe two male infants born with features of dystrophic epidermolysis bullosa (DEB) and ABS. These cases add to the few previous reports of simultaneous DEB and ABS. Abnormal type VII collagen in anchoring structures of the amniotic epithelium is a proposed mechanism for loose amniotic bands that entangle the fetus, with an abnormality in the gene that encodes for type VII collagen.