Cytokeratin 17 is highly sensitive in discriminating cutaneous lymphadenoma (a distinct trichoblastoma variant) from basal cell carcinoma.

BACKGROUND: Cutaneous lymphadenoma (CL) is rare neoplasm that clinically and histologically resembles basal cell carcinoma (BCC). CL, composed of dermal basaloid epithelial islands with prominent admixed lymphocytes, characteristically contains cytokeratin 20 (CK20)-positive Merkel cells (MCs). However, CK20 may be of limited use because of low MC density in small samples. CK17 is expressed diffusely throughout BCC. We investigated the discriminatory utility of CK17 and CK20 in CL and BCC. METHODS: A retrospective clinicopathological review of 11 cases of CL and 14 BCC was performed. CK20-positive MCs within basaloid tumor lobules and CK17 immunohistochemical staining and pattern of expression were recorded. RESULTS: Intratumoral CK20-positive MCs were identified in 4/11 CL cases (36.4%) and 0/14 BCC cases (p = 0.012, sensitivity = 0.36). CK17 showed diffuse positive staining in all 14 BCC cases. CK17 showed a distinct patchy and peripheral rim staining in basaloid islands of 10/11 CL cases (p < 0.001, sensitivity = 0.91); one case showed patchy staining throughout tumor lobules. CONCLUSIONS: In cases with a differential diagnosis of CL and BCC, CK20 staining of intratumoral MCs has a high positive predictive value for CL but is of low sensitivity. The pattern of CK17 expression is a highly sensitive marker for distinguishing CL from BCC in small samples.

Cutaneous squamous cell carcinoma progression is associated with decreased GATA-3 immunohistochemical staining.

BACKGROUND: The GATA family of transcription factors is an essential regulator of cellular proliferation and differentiation. In the skin, GATA-3 is critical for epidermal stratification and maintenance of barrier function. A role for GATA-3 in the development of human cutaneous squamous cell carcinoma (SCC) is not known. Here, we investigated GATA-3 immunohistochemical staining in premalignant and invasive cutaneous SCC from sun-exposed and sun-protected skin. METHODS: GATA-3 immunohistochemistry was performed on actinic keratoses (AK) (n = 19), in situ squamous cell carcinomas with actinic [SCCIS (A)] (n = 9) or bowenoid features [SCCIS (B)] (n = 17), well-, moderately and poorly differentiated SCC (n = 36), Bowenoid papulosis of the perineum (n = 15) and penile SCC (pSCC) (n = 10). RESULTS: We found that GATA-3 immunohistochemical staining is progressively lost in sun-exposed skin as neoplasia progresses from pre-cancerous AK to SCCIS (A), and ultimately, to SCC, which shows near absent GATA-3 staining. This reduction in GATA-3 staining is independent of histological grade in SCC. Only slight down-regulation of GATA-3 was seen in all cases of SCCIS (B) and Bowenoid papulosis, while near absent GATA-3 expression was seen in pSCC. CONCLUSION: We propose that decreased GATA-3 immunohistochemical staining is associated with cutaneous SCC progression on both sun-exposed and sun-protected sites.

Cutaneous Squamous Cell Carcinomas of the Lower Extremities Show Distinct Clinical and Pathologic Features.

Cutaneous squamous cell carcinomas mainly affect older, predominantly male patients. Most are due to chronic ultraviolet exposure, and associated with actinic keratoses. On the lower extremities, they occur more commonly in women. However, data on these tumors as a distinct group are scarce. We evaluated 61 squamous cell carcinomas of the lower extremities. Overall, 69% of patients were female. Mean age was 75 years. More than 90% of tumors were well differentiated, 3% showed perineural invasion, and none lymphovascular invasion. In all, 63.9% showed evidence of severe chronic sun damage. Associated actinic keratoses were identified in only 13% of cases. By contrast, 80% were associated with distinctive basal epidermal proliferations with a retiform growth pattern. These proliferations were evaluated immunohistochemically for keratinocyte stem cell markers, p53 and Notch1 in 15 cases. All cases were positive for cytokeratin 14, p53, and Notch1 (with variable intensity in the latter 2), and predominantly negative for cytokeratin 19. Interestingly, basal retiform proliferations were positive for cytokeratin 15 in 66% of cases. Fifteen head and neck squamous cell carcinomas were evaluated in comparison. Those lacked associated basal retiform proliferations except in 1 case. In contrast, 87% were associated with actinic keratoses and 100% with severe chronic sun damage. Actinic keratoses associated with head and neck tumors showed cytokeratin 15 staining only in 7% of cases (P = .003 compared with cytokeratin 15 in basal retiform proliferations associated with leg carcinomas). These findings support the hypothesis that lower extremity squamous cell carcinomas are distinct and may exhibit a pathogenesis less reliant on actinic damage.

Atypical propylthiouracil-induced ANCA-positive vasculitis: report of a case with unusual clinical and histopathologic findings.

The side effects of propylthiouracil, including cytopenia and vasculitis, are well established.  We present an interesting case in which cytopenia and cutaneous vasculopathy occurred concomitantly in a critically ill patient.  The patient was initially treated for suspected infection until dermatologic and rheumatologic workup revealed ANCA-positivity and vasculopathy on histopathology, most consistent with an atypical presentation of ANCA-positive vasculitis.  Upon initiation of immunosuppressive therapy, the patient's condition rapidly improved emphasizing the importance of early recognition of this condition.

Comparison of resident and glaucoma faculty practice patterns in the care of open-angle glaucoma.

BACKGROUND: Previous studies suggest there are large variations in adherence of ophthalmologists with the American Academy of Ophthalmology's Preferred Practice Patterns (PPPs). The purpose of this study was to compare rates of compliance with glaucoma care guidelines between resident and glaucoma faculty physicians at a single institution. METHODS: Charts of resident continuity clinic or glaucoma faculty patients with primary open angle glaucoma (POAG), ocular hypertension (OHTN), or suspicion of glaucoma were reviewed during the 2005-6 academic year. Performance within care measures specified by the 2005 PPP guidelines was compared between resident and faculty physicians using univariate and multivariable logistic regression models. RESULTS: 112 resident and 100 faculty charts were reviewed. The mean compliance rate for all 7 care measures for resident physicians was significantly lower than that of faculty physicians (78% vs. 96%, p < 0.001). As compared to glaucoma faculty, resident physicians were less likely to have documented 6 of the 7 individual care measures (p ≤ 0.001 for all); the exception was optic nerve (ON) description. In multivariable analyses, resident patients were more likely to have at least one undocumented care measure than faculty patients (OR = 10.1, 95% CI = 5.1 to 20.0, p < 0.001). Among resident patients, undocumented care measures were more common among patients with poorer visual acuity (VA) in the better eye. CONCLUSIONS: Though unmeasured differences in clinic structure and patient characteristics may have partially contributed to poorer resident performance, residents were more likely than faculty to omit PPP care measures and significantly underperformed faculty in global assessment of glaucoma care. Resident education should focus on integration of PPPs into residency training and monitoring of resident compliance with evidence-based guidelines.

Basaloid Carcinoma of the Breast Mimicking Cutaneous Basaloid Neoplasms.

Basaloid carcinoma of the breast (BCB) is a rare, triple-negative aggressive primary breast tumor that can closely mimic cutaneous basal cell carcinoma (BCC), neuroendocrine tumors, adnexal neoplasms, and other primary breast tumors. Accurate diagnosis of this tumor is critical for appropriate clinical management. We add to the literature 2 female patients with BCB presenting with a nipple mass. Histopathologic findings from both patients showed dermal nests and cords of atypical basaloid cells with epidermal involvement, closely resembling cutaneous BCC. A panel of immunohistochemical stains, including the novel use of CK17, is essential for differentiating BCB from mimickers. BCB is a rare primary breast tumor that follows an aggressive clinical course and closely mimics many basaloid neoplasms, including cutaneous BCC clinicopathologically. Increased awareness of BCB among dermatologists and dermatopathologists is critical for accurate diagnosis and patient care.

Human NKG2E is expressed and forms an intracytoplasmic complex with CD94 and DAP12.

The NKG2 family of NK receptors includes activating and inhibitory members. With the exception of the homodimer-forming NKG2D, NKG2 receptors recognize the nonclassical MHC class I molecule HLA-E, and they can be subdivided into two groups: those that associate with and signal through DAP12 to activate cells, and those that contain an ITIM motif to promote inhibition. The function of NKG2 family member NKG2E is unclear in humans, and its surface expression has never been conclusively established, largely because there is no Ab that binds specifically to NKG2E. Seeking to determine a role for this molecule, we chose to investigate its expression and ability to form complexes with intracellular signaling molecules. We found that NKG2E was capable of associating with CD94 and DAP12 but that the complex was retained intracellularly at the endoplasmic reticulum instead of being expressed on cell surfaces, and that this localization was dependent on a sequence of hydrophobic amino acids in the extracellular domain of NKG2E. Because this particular sequence has emerged and been conserved selectively among higher order primates evolutionarily, this observation raises the intriguing possibility that NKG2E may function as an intracellular protein.

Risk factors for adverse consequences of low intraocular pressure after trabeculectomy.

PURPOSE: To determine the risk factors for low intraocular pressure (IOP) and its detrimental consequences after trabeculectomy. PATIENTS AND METHODS: We performed a retrospective chart review of consecutive patients aged 12 years and above undergoing trabeculectomy alone by 1 of 2 surgeons between May 2000 and October 2008 at the Wilmer Institute. RESULTS: Among 753 eyes of 596 patients, 112 eyes (14.9%) of 103 patients had an IOP of ≤5 mm Hg at ≥3 months postoperatively (late low IOP). Physical signs related to low IOP occurred in 61 eyes of 58 patients, and 40 eyes of 37 patients had revision surgery for low IOP. Physical signs of low IOP included 34 eyes with choroidal detachment or shallow anterior chamber, 10 with hypotony maculopathy, and 7 with both. Compared with 187 control eyes of 165 patients, risk factors for late low IOP included: surgeon 2 (P=0.0003), left eyes (P=0.03), and secondary glaucoma (P=0.05). Physical signs of low IOP were more common in phakic eyes (P=0.03), whereas need for revision surgery was associated with younger age (P=0.01). The presence of hypotony maculopathy significantly decreased the risk of choroidal detachment/shallow anterior chamber (P=0.003). Hypotony maculopathy was associated with younger age (P=0.02). CONCLUSIONS: Late low IOP was more common with techniques used by 1 of 2 surgeons and in eyes with secondary glaucoma. Clinical signs of low IOP were more common in phakic eyes. Younger age was a risk factor for hypotony maculopathy. Hypotony maculopathy and choroidal detachment tend to occur in different eyes.

Ras, Raf, and MAP kinase in melanoma.

A growing understanding of the biology and molecular mechanisms of melanoma has led to the identification of a number of driver mutations for this aggressive tumor. The most common mutations affect signaling of the Ras/Raf/MAPK (mitogen-activated protein kinase) pathway. This review will focus on mutations in genes encoding proteins that play a role in the MAPK pathway and that have been implicated in melanoma biology, such as BRAF, NRAS, and MEK (MAPK kinase), and detail the current understanding of their role in melanoma progression from a molecular biology perspective. Furthermore, this review will also consider some additional mutations in genes such as KIT, GNAQ, and GNA11, which can be seen in certain subtypes of melanoma and whose gene products interact with the MAPK pathway. In addition, the association of these molecular changes with clinical and classical histopathologic characteristics of melanoma will be outlined and their role in diagnosis of melanocytic lesions discussed. Finally, a basic overview of the current targeted therapy landscape, as far as relevant to the pathologist, will be provided.

High levels of phosphatase and tensin homolog expression are associated with tumor progression, tumor recurrence, and systemic metastases in pT1 urothelial carcinoma of the bladder: a tissue microarray study of 156 patients treated by transurethral resection.

OBJECTIVE: To evaluate immunohistochemical expression of phosphatase and tensin homolog (PTEN) and mammalian target of rapamycin (mTOR) pathway members in pT1 urothelial carcinomas treated by transurethral resection and to determine if immunohistochemistry can be used to predict prognosis. METHODS: Formalin-fixed, paraffin-embedded tissue samples from 156 patients with pT1 urothelial carcinoma treated by transurethral resection were used to build 5 tissue microarrays. Tissue microarray sections were stained for PTEN, phosphorylated (phos)-AKT, phos-mTOR, phos-S6, eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1), and phos-4EBP1. Patients were monitored after initial treatment (mean, 22.5; median, 16; range, 3-108 months) to detect tumor recurrence, tumor progression, or systemic metastases. RESULTS: During follow-up, 101 patients (65%) showed tumor recurrence, 57 showed tumor progression (37%), and 18 showed systemic metastases (12%). Patients with ≥2 lesions at the initial workup had higher proportions and higher hazard ratios of tumor recurrence, tumor progression, and systemic metastases. Complete loss of PTEN expression was observed in 6 patients (4%), and >80% of the mTOR pathway members showed at least focal positivity. Proportions of tumors with higher levels of PTEN immunohistochemical expression were higher in patients with tumor recurrence (P=.001), tumor progression (P=.05), and systemic metastases (P=.001). Proportions of tumors with lower phos-S6 and low phos-4EBP1 levels were higher in patients with tumor recurrence (P≤.05). Proportions were similar for the remaining biomarkers. CONCLUSION: Higher levels of PTEN immunohistochemical expression were associated with higher rates of tumor recurrence, tumor progression, and systemic metastases in patients with pT1 urothelial carcinomas treated by transurethral resection.

Comparison of limbus-based and fornix-based trabeculectomy: success, bleb-related complications, and bleb morphology.

PURPOSE: To compare the success and complications of trabeculectomy performed with limbus-based and fornix-based conjunctival approaches. DESIGN: Retrospective case series with some prospective data collection. PARTICIPANTS: Consecutive patients undergoing trabeculectomy by 2 surgeons between May 2000 and October 2008. INTERVENTION: We performed limbus-based operations during the first 4 years and fornix-based operations during the last 4 years. We collected data by chart review and by examination at the most recent visit. For each follow-up visit, we defined success as undergoing no further glaucoma procedure and achieving one of our intraocular pressure (IOP) criteria. We used Kaplan-Meier survival analysis, Cox proportional hazards models, and generalized estimating equation (GEE) analysis. During 2009, 439 trabeculectomy sites of 347 patients were quantitatively assessed by the Indiana bleb grading system. MAIN OUTCOME MEASURES: (1) Success rate of trabeculectomy, as determined by the achievement of each of our different IOP goals, with or without IOP-lowering medications; and (2) incidence of surgical complications. RESULTS: During the 4 years after surgery, the success rates of limbus-based and fornix-based trabeculectomy were not statistically different for any of our IOP criteria. Blebs after limbus-based surgery were more likely to be graded as higher and to be avascular (GEE model, both P < 0.0001). Four percent of eyes experienced late-onset bleb leaks within 4 years after both limbus- and fornix-based operations; however, limbus-based cases developed bleb leaks significantly later than did fornix-based cases (2.1 vs. 1.0 years; P=0.002, GEE model). Late bleb-associated infection during the first 4 years after surgery occurred more often in limbus-based operations, although statistical significance was borderline (P=0.054, Cox model). Symptomatic hypotony during all available follow-up was more common with fornix-based operations (P=0.01, GEE model). Eyes undergoing the fornix-based operation had a greater risk of cataract surgery in the 4-year period after surgery (P=0.02, Cox model), and fornix-based cases requiring cataract surgery had the operation earlier than limbus-based cases (P=0.002, GEE model). CONCLUSIONS: Success rates are similar between limbus-based and fornix-based trabeculectomy. Limbus-based procedures produce higher, more avascular blebs, with a greater risk of infection. Fornix-based procedures have more symptomatic hypotony and more and earlier cataract development.

Outcomes and bleb-related complications of trabeculectomy.

PURPOSE: To determine rates of success and complications of trabeculectomy surgery. DESIGN: Case series. PARTICIPANTS: Consecutive patients undergoing trabeculectomy by 2 surgeons between May 2000 and October 2008. INTERVENTION: By using the Wilmer Institute's billing database, we identified all patients at least 12 years of age coded as having undergone trabeculectomy between May 2000 and October 2008 by 1 of 2 glaucoma surgeons and whose surgery was not combined with another operation. From the chart, we abstracted demographic information on the patients and clinical characteristics of the eyes. The Kaplan-Meier product-limit method and Cox proportional hazard models were used to look at success rates and characteristics associated with inadequate intraocular pressure (IOP) reduction. Complications were tabulated. MAIN OUTCOME MEASURES: (1) Success rate of trabeculectomy, as determined by the achievement of each of 4 different IOP goals, with or without IOP-lowering medications; and (2) incidence of surgical complications. RESULTS: During the study period, 797 eyes of 634 persons underwent trabeculectomy without concurrent surgery. The success rates 4 years after surgery, with or without the use of IOP-lowering eye drops, were 70%, 72%, 60%, and 44%, for achievement of target IOP, ≤18 mmHg and ≥20% IOP reduction, ≤15 mmHg and ≥25% reduction, and ≤12 mmHg and ≥30% reduction, respectively. Increased chance of success was associated with European-derived race; use of mitomycin C (MMC); higher concentrations of MMC, when used; and higher preoperative IOP. Age and previous intraocular surgery were not associated with surgical success. Complications included worsening lens opacity in 242 of 443 phakic eyes (55%), loss of ≥3 lines of acuity (Snellen) in 161 eyes (21%), surgery for bleb-related problems in 70 eyes (8.8%), and infection occurring >6 weeks after surgery in 27 eyes (3.4%). A total of 101 eyes of 94 patients had at least 1 subsequent operation for inadequate IOP control. CONCLUSIONS: Trabeculectomy surgery performed by 2 experienced glaucoma specialists achieved target IOP at 4 years in 70% of those operated and was associated with progressive cataract and small risks of bleb-related complications. These results are comparable to those reported in smaller series.

Cytosolic PLA2 is required for CTL-mediated immunopathology of celiac disease via NKG2D and IL-15.

IL-15 and NKG2D promote autoimmunity and celiac disease by arming cytotoxic T lymphocytes (CTLs) to cause tissue destruction. However, the downstream signaling events underlying these functional properties remain unclear. Here, we identify cytosolic phospholipase A(2) (cPLA(2)) as a central molecule in NKG2D-mediated cytolysis in CTLs. Furthermore, we report that NKG2D induces, upon recognition of MIC(+) target cells, the release of arachidonic acid (AA) by CTLs to promote tissue inflammation in association with target killing. Interestingly, IL-15, which licenses NKG2D-mediated lymphokine killer activity in CTLs, cooperates with NKG2D to induce cPLA(2) activation and AA release. Finally, cPLA(2) activation in intraepithelial CTLs of celiac patients provides an in vivo pathophysiological dimension to cPLA(2) activation in CTLs. These results reveal an unrecognized link between NKG2D and tissue inflammation, which may underlie the emerging role of NKG2D in various immunopathological conditions and define new therapeutic targets.