Current concepts in the diagnosis and pathobiology of intraepithelial neoplasia: A review by organ system.

Answer questions and earn CME/CNE In this report, a team of surgical pathologists has provided a review of intraepithelial neoplasia in a host of (but not all) anatomic sites of interest to colleagues in various medical specialties, namely, uterine cervix, ovary, breast, lung, head and neck, skin, prostate, bladder, pancreas, and esophagus. There is more experience with more readily accessible sites (such as the uterine cervix and skin) than with other anatomic sites, and the lack of uniform terminology, together with divergent biology in various sites, makes it difficult to paint a unifying, relevant portrait. The authors' aim was to provide a framework from which to move forward as we care for patients with such precancerous lesions. CA Cancer J Clin 2016;66:408-436. © 2016 American Cancer Society.

Poroid Hidradenocarcinoma of the Ankle: Case Report of a Rare Malignant Cutaneous Adnexal Neoplasm.

Soft-tissue masses on the anterior ankle result from a broad range of underlying processes, often presenting a diagnostic challenge. Appropriate treatment of these tumors can be determined by using a combination of patient history, interpretation of pathologic findings, physical examination, and radiographic appearance. We present a case of an exceptionally rare malignant cutaneous adnexal tumor, highlighting the importance of adherence to fundamental biopsy principles for diagnosing and managing musculoskeletal lesions.

Treatment of human polyomavirus-7-associated rash and pruritus with topical cidofovir in a lung transplant patient: Case report and literature review.

Human polyomavirus-7-associated rash and pruritus (PVARP) is a chronic superficial viral skin infection, which primarily impacts immunocompromised individuals. We report on a case of PVARP in a lung transplant recipient. Our patient developed symptoms 13 years after being on his immunosuppressive regimen, with an insidious course of progressive gray lichenification with marked islands of sparing and quality of life-altering pruritus. Treatment for PVARP is not established; however, topical cidofovir combined with immunomodulation may offer sustained therapeutic benefit.

Melanoma subtypes demonstrate distinct PD-L1 expression profiles.

PD-L1 expression in the tumor immune microenvironment is recognized as both a prognostic and predictive biomarker in patients with cutaneous melanoma, a finding closely related to its adaptive (IFN-γ-mediated) mechanism of expression. Approximately 35% of cutaneous melanomas express PD-L1, however, the expression patterns, levels, and prevalence in rarer melanoma subtypes are not well described. We performed immunohistochemistry for PD-L1 and CD8 on 200 formalin-fixed paraffin-embedded specimens from patients with acral (n=16), mucosal (n=36), uveal (n=103), and chronic sun-damaged (CSD) (n=45) melanomas (24 lentigo maligna, 13 'mixed' desmoplastic, and 8 'pure' desmoplastic melanomas). CD8+ tumor-infiltrating lymphocyte (TIL) densities were characterized as mild, moderate, or severe, and their geographic association with PD-L1 expression was evaluated. Discrete lymphoid aggregates, the presence of a spindle cell morphology, and the relationship of these features with PD-L1 expression were assessed. PD-L1 expression was observed in 31% of acral melanomas, 44% of mucosal melanomas, 10% of uveal melanomas, and 62% of CSD melanomas (P<0.0001). Compared to our previously characterized cohort of cutaneous melanomas, the proportion of PD-L1(+) tumors was lower in uveal (P=0.0002) and higher in CSD (P=0.0073) melanomas, while PD-L1 expression in the acral and mucosal subtypes was on par. PD-L1 expression in all subtypes correlated with a moderate-severe grade of CD8+ TIL (all, P<0.003), supporting an adaptive mechanism of expression induced during the host antitumor response. The tumor microenvironments observed in CSD melanomas segregated by whether they were the pure desmoplastic subtype, which showed lower levels of PD-L1 expression when compared to other CSD melanomas (P=0.047). The presence of lymphoid aggregates was not associated with the level of PD-L1 expression, while PD-L1(+) cases with spindle cell morphology demonstrated higher levels of PD-L1 than those with a nested phenotype (P<0.0001). Our findings may underpin the reported clinical response rates for anti-PD-1 monotherapy, which vary by subtype.

Sox10 is expressed in primary melanocytic neoplasms of various histologies but not in fibrohistiocytic proliferations and histiocytoses.

BACKGROUND: Sox10 is a transcription factor associated with neural crest development. Its expression has been reported in melanocytes and peripheral nerve sheath cells and their associated tumors. OBJECTIVE: To assess Sox10 sensitivity in benign and malignant melanocytic neoplasms of various histologic subtypes and to discern the specificity of Sox10 in distinguishing between melanocytic neoplasms and fibrohistiocytic and histiocytic mimickers. METHODS: Sox10 expression was examined by immunohistochemistry in 145 cases of formalin-fixed paraffin-embedded tissue, including benign and malignant melanocytic lesions of various histologies and stages (n = 83), fibrohistiocytic and histiocytic lesions (n = 33), and peripheral nerve sheath tumors (n = 19), among others (n = 10). RESULTS: Immunoreactivity with Sox10 was observed in 100% (83/83) of benign and malignant melanocytic lesions of various subtypes, as well as in 100% (19/19) of benign and malignant peripheral nerve sheath lesions. Among the fibrohistiocytic proliferations and histiocytoses examined, Sox10 was negative in all cases (0/33). Sox10 expression did not vary by histologic subtype in nevi or melanoma; however, both the percentage of tumor nuclei demonstrating Sox10 expression and the intensity of expression were inversely correlated with malignant potential (nevi, melanoma in situ, invasive and metastatic melanoma) (P < .001, P = .016, respectively). Malignant peripheral nerve sheath tumors also showed decreased mean Sox10 expression and decreased intensity of expression when compared with benign counterparts (P < .001, P = .021, respectively). LIMITATIONS: This is a retrospective study with 145 cases included. CONCLUSIONS: Sox10 is a highly sensitive marker for melanocytic proliferations and may be useful diagnostically when the differential diagnosis includes fibrohistiocytic and histiocytic proliferations demonstrating S100 expression.

Can ultrasound be used as the primary screening modality for the localization of parathyroid disease prior to surgery for primary hyperparathyroidism? A review of 440 cases.

BACKGROUND/AIMS: Sestamibi scintigraphy and neck ultrasonography have both been proposed as screening modalities for the detection of abnormal parathyroid glands in patients with primary hyperparathyroidism. As a result, many surgeons use both techniques prior to surgery. The goal of this study was to independently evaluate both ultrasound and sestamibi as single-modality preoperative screening tools for primary hyperparathyroidism. METHODS: A retrospective review of consecutive patients who underwent surgery for primary hyperparathyroidism from January 1999 to December 2009. Imaging results were compared to surgical findings. RESULTS: 440 patients were found to meet inclusion criteria. Sensitivities for correct localization of a single parathyroid adenoma for sestamibi versus ultrasound were: 83% (95% CI 78-86) versus 72% (95% CI 67-76). Ultrasound operator had no influence on sensitivity, and ultrasound identified nodular thyroid disease in 31% of patients. CONCLUSION: Ultrasonography alone can be used as the primary screening modality in patients with primary hyperparathyroidism. Ultrasound sensitivity is conserved despite operator variability, and identifies concomitant thyroid pathology.

Lichen planus following tetanus-diphtheria-acellular pertussis vaccination: A case report and review of the literature.

Lichen planus is an inflammatory dermatosis with a prevalence of approximately 1%. Recent meta-analyses show that patients with hepatitis C virus have a 2.5- to 4.5-fold increased risk of developing lichen planus. Lichen planus has also followed vaccinations and has specifically been attributed to the hepatitis B vaccine, the influenza vaccine, and the tetanus-diphtheria-acellular pertussis vaccine. We describe a case of lichen planus in a hepatitis C virus-infected African American male occurring in temporal association with the administration of the tetanus-diphtheria-acellular pertussis vaccine. The patient's presentation was clinically consistent with lichen planus and confirmed by biopsy. It is likely that many cases of vaccine-induced lichen planus have gone unpublished or unrecognized. In areas with high prevalence of hepatitis C virus infection, we may expect to see more cases of vaccine-induced lichen planus especially in light of the updated Centers for Disease Control and Prevention tetanus-diphtheria-acellular pertussis vaccination recommendations. This case serves to educate healthcare providers about vaccine-induced lichen planus and, in particular, the need to counsel hepatitis C virus-infected patients about a potential risk of developing lichen planus following vaccination. We also reflect on current theories suggesting the T-cell-mediated pathogenesis of lichen planus and the role that hepatitis C virus and toxoid or protein vaccines may play in initiating the disease.

Multidimensional, quantitative assessment of PD-1/PD-L1 expression in patients with Merkel cell carcinoma and association with response to pembrolizumab.

BACKGROUND: We recently reported a 56% objective response rate in patients with advanced Merkel cell carcinoma (MCC) receiving pembrolizumab. However, a biomarker predicting clinical response was not identified. METHODS: Pretreatment FFPE tumor specimens (n = 26) were stained for CD8, PD-L1, and PD-1 by immunohistochemistry/immunofluorescence (IHC/IF), and the density and distribution of positive cells was quantified to determine the associations with anti-PD-1 response. Multiplex IF was used to test a separate cohort of MCC archival specimens (n = 16), to identify cell types expressing PD-1. RESULTS: Tumors from patients who responded to anti-PD-1 showed higher densities of PD-1+ and PD-L1+ cells when compared to non-responders (median cells/mm2, 70.7 vs. 6.7, p = 0.03; and 855.4 vs. 245.0, p = 0.02, respectively). There was no significant association of CD8+ cell density with clinical response. Quantification of PD-1+ cells located within 20 µm of a PD-L1+ cell showed that PD-1/PD-L1 proximity was associated with clinical response (p = 0.03), but CD8/PD-L1 proximity was not. CD4+ and CD8+ cells in the TME expressed similar amounts of PD-1. CONCLUSIONS: While the binomial presence or absence of PD-L1 expression in the TME was not sufficient to predict response to anti-PD-1 in patients with MCC, we show that quantitative assessments of PD-1+ and PD-L1+ cell densities as well as the geographic interactions between these two cell populations correlate with clinical response. Cell types expressing PD-1 in the TME include CD8+ T-cells, CD4+ T-cells, Tregs, and CD20+ B-cells, supporting the notion that multiple cell types may potentiate tumor regression following PD-1 blockade.

Cutaneous Eruptions in Patients Receiving Immune Checkpoint Blockade: Clinicopathologic Analysis of the Nonlichenoid Histologic Pattern.

Cutaneous eruptions are among the most common immune-related adverse events (irAEs) associated with anti-programmed cell death protein 1/programmed cell death ligand 1 therapy, and are often clinically and histologically characterized as lichenoid. Nonlichenoid patterns may also occur and are likely to be encountered by surgical pathologists, given the increasing clinical use of these agents. The purpose of this study is to describe the histopathologic features of nonlichenoid cutaneous irAEs from patients receiving anti-programmed cell death protein 1/programmed cell death ligand 1 therapies for a variety of underlying advanced malignancies. Sixteen patients with 17 biopsied eruptions were included from 2 academic institutions with extensive experience administering and monitoring responses to immune checkpoint blockade as well as treating the potential side effects. Eruptions occurred a median of 10 days (range, 1 d to 11.4 mo) after treatment initiation. Nearly half of specimens demonstrated either a psoriasiform/spongiotic or an urticarial-type reaction pattern on histologic review. Patterns consistent with Grover disease, bullous pemphigoid, and granulomatous dermatitis were also observed. Nearly two-thirds of patients required systemic corticosteroids for treatment of the cutaneous irAE, and 19% of patients discontinued immunotherapy due to their skin eruptions. 75% of patients showed an objective antitumor response. The diverse array of nonlichenoid cutaneous irAE presented here should reflect and inform the scope of histologic patterns encountered by the practicing surgical pathologist. Such eruptions are seen in patients with a variety of underlying tumor types, many of whom ultimately demonstrate a favorable response to immune checkpoint blockade.

Atypical Hidradenoma Mimicking Primary Mammary Carcinoma on Breast Fine-Needle Aspiration: A Case Report with Long-Term Follow-Up.

BACKGROUND: Fine-needle aspiration (FNA) is well-established as an accurate technique for the diagnosis of palpable breast masses. While the differential diagnosis of such lesions usually focuses on benign or malignant mammary proliferations, a subset of breast neoplasms arises from skin and soft tissue. Skin adnexal neoplasms such as hidradenoma can pose a particular pitfall on breast FNA cytology (FNAC) as epithelial proliferations that are not of ductal or lobular origin. CASE: A 59-year-old female presented with a superficial breast mass. FNAC revealed a hypercellular lesion with marked nuclear atypia that was highly suspicious for carcinoma. However, at partial mastectomy, the histological features of the tumor were consistent with atypical hidradenoma. Negativity for estrogen receptor (ER) and progesterone receptor (PR) confirmed the diagnosis. Eighteen years later, the patient remains free of recurrence or metastasis. CONCLUSIONS: This report offers the first description of findings of atypical hidradenoma on FNAC. In the breast, its high cellularity and nuclear atypia can mimic a primary mammary carcinoma on FNAC. Although breast and skin adnexal tumors show a immunohistochemical overlap, negative ER and PR stains in a low-grade tumor can suggest a nonmammary lesion. Skin adnexal neoplasms should be considered in the differential diagnosis of superficial breast tumors.

Fusion of aortic valve commissures in patients supported by a continuous axial flow left ventricular assist device.

BACKGROUND: Left ventricular assist devices (LVADs) are an important therapy for selected individuals with advanced heart failure unable to wait for a suitable donor for transplantation. Pulsatile LVADs are associated with commissural fusion of the aortic valve, yet little is known about this association with newer generation continuous axial flow LVADs. METHODS: We retrospectively reviewed pathologic samples from 9 patients enrolled in the HeartMate II Bridge to Transplantation Trial. Echocardiograms at 1, 6 and 12 months after device placement were evaluated for aortic valve opening and aortic insufficiency. At the time of transplantation, explanted hearts were examined for gross pathologic valvular abnormalities and histologic analysis. RESULTS: All but 1 explant had evidence of commissural fusion of the native aortic valve leaflets. Over time there was a decreasing prevalence of aortic valve opening and an increasing prevalence of mild to moderate aortic insufficiency independent of pump speed. All patients had improvements in their functional status and were successfully bridged to orthotopic heart transplantation. CONCLUSIONS: Commissural fusion of the native aortic valve leaflets occurs frequently with an increasing prevalence of aortic insufficiency during continuous flow LVAD support. With the potential broader use of non-pulsatile LVADs and the prospect of using LVADs as means to assist in myocardial recovery, special attention should be given to evaluating aortic valve function during LVAD support.

Extensive cardiac allograft vasculitis and concurrent fat necrosis 6 years after orthotopic heart transplantation.

Coronary artery vasculitis has been described as a rare lesion in the spectrum of transplant vasculopathy or as an extension of severe acute cellular rejection. We describe a patient, 6 years after orthotopic cardiac transplantation, who developed rapid heart failure and died despite aggressive treatment, minimal cardiac rejection (ISHLT Grade 1R), and no known transplant vasculopathy. Autopsy showed a diffuse and essentially complete necrotizing vasculitis of the entire coronary vasculature involving small, medium and large vessels, with extensive fat necrosis within the pericardial space. Macrophages of the M2 phenotype were found lining the major coronary vascular lumens and infiltrating their walls. The presence of the M2 macrophage phenotype supports transplant vasculitis as part of the chronic transplant vasculopathy continuum.