Onychocytic Matricoma: A Clinical, Dermoscopic, and Pathological Analysis of 14 Cases.

ABSTRACT: Onychocytic matricoma (OCM) is a benign neoplasm of the nail matrix. Only 18 cases of this tumor have been reported in the literature to date. We retrospectively analyzed the clinical features of 14 patients with OCM. The most common clinical feature was longitudinal xanthopachyonychia (n = 9), followed by longitudinal leukopachyonychia (=3) and longitudinal pachymelanonychia (n = 2). The most common clinical findings identified following dermoscopy and analysis at high magnification of classical photographs were free-edge thickening of the nail plate without pitting (n = 14), longitudinal ridging (n = 7), round white clods (n = 7), white dots (n = 7), and filiform hemorrhages (n = 7), followed by oval and linear white clods (n = 5), fuzzy lateral border (n = 5), and red-purple blood clods (n = 3). Nail clipping histopathology showed a thickened nail plate with multiple, small, round-to-oval spaces. The tumor expressed immunopositivity for LEF-1. Dermoscopy of the nail plate and nail clipping histology provides useful information with regards to the differential diagnosis with subungual squamous cell carcinoma and nail melanoma. Ex vivo-in vivo correlation facilitates a better dermoscopic assessment of this unique underrecognized disease. However, the differential diagnosis between OCM and onychocytic carcinoma requires biopsy of the tumor. LEF-1 as an onychogenic marker can be used to resolve the differential diagnosis between OCM and subungual longitudinal acanthoma/seborrheic keratosis.

Digital Papillary Adenocarcinoma in Nonacral Skin: Clinicopathologic and Genetic Characterization of 5 Cases.

Digital papillary adenocarcinoma (DPA) is a rare sweat gland neoplasm that has exceptionally been reported outside acral locations. Recently, human papillomavirus 42 was identified as the main oncogenic driver of DPA. Herein, we report 5 tumors arising in extra-acral locations predominantly in the female anogenital skin. Four patients were female and 1 patient was male. The mean age at the diagnosis time was 65 years (range: 55 to 82 y). Tumors were located on the vulva (n=3), perianal area (n=1), and forearm (n=1). Histologically, all tumors were lobular and mainly solid and composed of sheets of cells with rare focal papillae and frequent glandular structures in a "back-to-back" pattern and lined by atypical basophilic cells. Immunohistochemistry showed diffuse positivity for SOX10. Epithelial membrane antigen and carcinoembryonic antigen highlighted the luminal cells and staining for p63 and p40 revealed a consistent and continuous myoepithelial component around glandular structures. Follow-up was available in 3 cases (mean duration: 12 mo [range: 8 to 16 mo]). One patient developed local recurrence and 1 experienced regional lymph node metastases. HPV Capture Next-generation sequencing revealed the presence of the HPV42 genome in all samples. Viral reads distributions were compatible in the 5 cases with an episomal nature of the viral genome, with a recurrent deletion in the E1 and/or E2 open reading frames. In conclusion, this study demonstrates that digital DPA may rarely present in nonacral locations mainly in the female anogenital area, usually with a more solid pattern as compared with those cases presenting on the digits and it is also associated with HPV42.

Onychomatricoma: a clinicopathological, immunohistochemical, and molecular study of 10 cases highlighting recurrent RB1 deletion and the potential diagnostic value of LEF-1.

AIMS: Onychomatricoma (OM), an uncommon benign fibroepithelial neoplasm of the nail unit, is sometimes diagnostically challenging for clinicians and pathologists. OM consistently expresses CD34, but no specific immunohistohemical markers or recurrent genetic alterations have been identified to date. Recent studies have suggested that Wnt signalling is a key molecular characteristic of OM. METHODS AND RESULTS: Ten cases were analysed: four classical OM including two with pleomorphic cells; two superficial acral fibromyxoma-like variants of OM; three micropapilliferum variants of OM including one with pleomorphic cells; and one proliferating variant of OM. Immunohistochemically, the spindle cells were positive with CD34 (n = 10) and CD99 (n = 1), with focal reactivity for CD10 (n = 5). The epithelial component of the tumours expressed immunopositivity for LEF-1. Using array comparative genomic hybridization (aCGH), we demonstrated that all OM, including its variants that were tested (n = 8), harboured a few copy number alterations with losses of whole or part of chromosome 13 including the RB1 gene (n = 8) and chromosome 16 (n = 6). CONCLUSION: We report a recurrent loss of RB1 (13q) as a possible driver molecular event in OM indicating a relationship between OM and other lesions of the spectrum of the so-called '13q/RB1' family of tumours. We did not identify a role for the Wnt/beta-catenin signalling pathway, as has been proposed in a recent study. LEF-1 could be a potential sensitive and specific marker of OM and should be used in the differential diagnosis between OM, superficial acral fibromyxoma, and the CD34-positive fibrosing family of tumours.

Sentinel lymph node biopsy alone in the management of early cervical carcinoma.

OBJECTIVE: Sentinel lymph node (SLN) biopsy aims to assess lymph node status with reduced surgical morbidity. The aim of the study was to determine the accuracy and safety of SLN biopsy in the management of early cervical carcinoma using a double technique (technetium-99m (Tc-99m) nanocolloid and methylene blue dye injection). METHODS: This was a 10-year study from January 2009 to January 2019 that recruited 103 consecutive women undergoing surgery for early cervical carcinoma, FIGO 2009 stage IA1 (grade 3, and grade 2 with lymphovascular space invasion) to IB1 (<2 cm), at the West Kent Gynaecological Oncology Centre, Maidstone, UK. All patients were given the choice of pelvic node dissection and SLN mapping or SLN only. All patients elected to undergo SLN only. In total 97 patients had SLN mapping performed laparoscopically. We used the combined method (Tc-99m nanocolloid and/or methylene blue dye). All SLN routinely underwent ultrastaging. RESULTS: At least one SLN was detected in all 103 patients, using at least one of the combined methods (Tc-99m nanocolloid or blue dye). Bilaterally SLN were removed in 85/103 women with an 83% bilateral detection rate. The median SLN count was 2.3 (range 1-6) nodes. Of 103 patients, 7 (6.7%) patients had lymph node involvement. There were no pelvic or para-aortic lymph node recurrences with a median follow-up of 53 (range 8-120) months. The specificity and negative predictive value of a negative SLN was 100%. None of our 103 patients reported lower extremity lymphedema. CONCLUSION: In carefully selected patients with early cervical carcinoma, SLN biopsy alone appears to be a safe method for lymph node assessment of women undergoing surgical staging. Ultrastaging is an essential part of histologic examination of SLN.

Cancer-associated fibroblasts in renal cell carcinoma: implication in prognosis and resistance to anti-angiogenic therapy.

OBJECTIVES: To investigate the role of cancer-associated fibroblasts (CAFs) in clear cell renal cell carcinoma (ccRCC) with respect to tumour aggressiveness, metastasis development, and resistance to anti-angiogenic therapy (vascular endothelial growth factor receptor-tyrosine kinase inhibitors [VEGFR-TKI]). PATIENTS AND METHODS: Our study involved tissue samples from three distinct and independent cohorts of patients with ccRCC. The presence of CAFs and tumour lymphangiogenesis was investigated, respectively, by transcriptional signatures and then correlated with tumour development and prognosis. The effect of these CAFs on tumour cell migration and VEGFR-TKI resistance was analysed on co-cultures of ccRCC cells with CAFs. RESULTS: Results from our cohorts and from in silico investigations showed that VEGFR-TKI significantly increase the number of CAFs in tumours. In the same populations of patients with ccRCC, the proportion of intra-tumoral CAFs correlated to shorter disease-free and overall survival. The presence of CAFs was also correlated with lymphangiogenesis and lymph node metastasis. CAFs increased the migration and decreased the VEGFR-TKI-dependent cytotoxic effect of tumour cells. CONCLUSIONS: Our results show that VEGFR-TKI promote the development of CAFs, and CAFs favour tumour aggressiveness, metastatic dissemination, and resistance to treatment in ccRCC. CAFs could represent a new therapeutic target to fight resistance to treatment of ccRCC. Targeting CAF and immunotherapies combination are emerging as efficient treatments in many types of solid tumours. Our results highlight their relevance in ccRCC.

Adult Granulosa Cell Tumor With High-grade Transformation: Report of a Series With FOXL2 Mutation Analysis.

Adult granulosa cell tumor (AGCT) is a low-grade malignant neoplasm with a significant propensity for late recurrence and metastasis. Almost all AGCTs are composed of cells with bland nuclear features and even when these tumors recur or metastasize, the nuclear features are almost always low-grade. We report 5 cases of AGCT in patients aged 37 to 88 years composed of areas of typical AGCT with low-grade morphology admixed with areas of high-grade morphology, with marked nuclear atypia, often with bizarre multinucleate cells and high mitotic activity; this is the first reported series of high-grade transformation in AGCTs. The high-grade areas often morphologically closely resembled juvenile granulosa cell tumor with abundant eosinophilic cytoplasm, significant mitotic activity, and intermediate sized follicles. Four cases were FIGO stage IA at diagnosis and 1 was stage IIIC with omental involvement. FOXL2 mutation analysis of both the morphologically low-grade and high-grade areas in 4 of 5 cases confirmed the presence of missense point mutation, c.402C>G, p.(Cys134Trp), providing conclusive evidence that the high-grade component represents transformation of typical AGCT rather than the coexistence of another sex cord-stromal tumor, such as juvenile granulosa cell tumor, which has been suggested for such neoplasms. In 3 of 4 cases where immunohistochemistry was undertaken, there was a striking difference between the p53 staining in the low-grade and high-grade components with wild-type staining in the former and diffuse mutation-type immunoreactivity in the latter, suggesting that TP53 mutation is likely to play a role in high-grade transformation. TP53 mutation analysis covering exons 4 to 10 was undertaken in 4 cases and TP53 mutations were identified in the high-grade component of 2 of the cases. In 1 case, there was diffuse block-type p16 staining in the high-grade component. Follow-up in the 4 stage IA neoplasms revealed no evidence of tumor recurrence in 3 (6 to 9 mo follow-up) while the other patient developed mediastinal, peritoneal, and pulmonary metastasis 17 months after diagnosis. High-grade transformation is uncommon in AGCTs and given that one of our cases was advanced stage at diagnosis, another exhibited widespread metastasis within a short period and there have been occasional case reports of aggressive behavior in AGCTs with high-grade transformation, this event may herald an aggressive clinical course.

Cervical Squamous Carcinomas With Prominent Acantholysis and Areas Resembling Breast Lobular Carcinoma: An Aggressive Form of Dedifferentation.

There have been occasional reports of primary cervical adenocarcinoma with areas of dedifferentiation resulting in morphologic mimicry of breast lobular carcinoma. We describe 4 cases of primary cervical squamous carcinoma with prominent acantholysis (3 cases), areas resembling breast lobular carcinoma (3 cases) or both (2 cases). All 4 tumors showed positivity with p63 and CK5/6 and 3 of 4 exhibited block-type immunoreactivity with p16. Two of the 4 cases contained high-risk human papillomavirus (types 16 and 18) on molecular testing; of the 2 cases which were human papillomavirus negative, 1 exhibited patchy nonblock immunoreactivity with p16. All cases exhibited some degree of loss of E-cadherin membranous staining in the areas of acantholysis and foci resembling breast lobular carcinoma. Three of 4 patients had extracervical spread at diagnosis; the fourth patient developed extracervical recurrence on follow-up. The initial FIGO stages were IB1, IIB (2 cases) and IVB. The 2 patients whose neoplasms were human papillomavirus negative developed distant metastases (supraclavicular, meningeal, and lung) during the course of their disease; the same 2 patients died of disease at periods of 4 mo and 1 yr after diagnosis. Cervical squamous carcinomas with acantholytic features and areas resembling breast lobular carcinoma are an unusual morphologic variant of squamous carcinoma. We consider the acantholysis and mimicry of breast lobular carcinoma to be part of a spectrum of morphologic changes, possibly related to loss of E-cadherin. These features can be regarded as a form of dedifferentiation which indicates a potential for aggressive behavior.

A randomized trial examining the effects of Conjoint Behavioral Consultation in rural schools: Student outcomes and the mediating role of the teacher-parent relationship.

The results of a large-scale randomized controlled trial of Conjoint Behavioral Consultation (CBC) on student outcomes and teacher-parent relationships in rural schools are presented. CBC is an indirect service delivery model that addresses concerns shared by teachers and parents about students. In the present study, the intervention was aimed at promoting positive school-related social-behavioral skills and strengthening teacher-parent relationships in rural schools. Participants were 267 students in grades K-3, their parents, and 152 teachers in 45 Midwest rural schools. Results revealed that, on average, improvement among students whose parents and teachers experienced CBC significantly outpaced that of control students in their teacher-reported school problems and observational measures of their inappropriate (off-task and motor activity) and appropriate (on-task and social interactions) classroom behavior. In addition, teacher responses indicated significantly different rates of improvement in their relationship with parents in favor of the CBC group. Finally, the teacher-parent relationship was found to partially mediate effects of CBC on several student outcomes. Unique contributions of this study, implications of findings for rural students, study limitations and suggestions for future research are discussed.

Acquired Localized Longitudinal Pachyonychia and Onychomatrical Tumors: A Comparative Study to Onychomatricomas (5 Cases) and Onychocytic Matricomas (4 Cases).

BACKGROUND: Besides onychomatricoma (OM), which shows a clinical band pattern of nail plate thickening, 2 new onychomatrical tumors with this clinical feature have recently been described: onychocytic matricoma (OCM) and in situ onychocytic carcinoma. OBJECTIVE: The purpose of this study was to present 4 cases of OCMs and compare their clinical and histopathologic characteristics with usual OMs. METHODS: We studied 4 cases of OCMs with nail clipping in 3 cases and an extensive immunohistochemical study for hair-related keratins and epithelial keratins. Nail clipping of OCMs was compared with the distal nail plate of 5 cases of OMs. RESULTS: All cases showed an acquired localized longitudinal band pattern of a thickened nail plate with yellow discoloration in 2 cases and a black streak in 2 cases. All cases showed a V-shaped keratogenous epithelial tumor with a papillomatous pattern of growth. The nail plate was thickened with small holes in a honeycomb pattern. In contrast, the 5 OMs showed the classical pattern of a panonychoma fibropapilliferum. The nail plate showed large cavities in a honeycomb pattern. CONCLUSIONS: This case series raises awareness of the clinical value of longitudinal pachyonychia coupled with nail clipping in the early detection of onychomatrical tumors as generic diagnosis with a limited differential diagnosis and a simple therapeutic approach. Nail clipping could be an aid in the surgical planning of onychomatrical tumor. A diagnosis of a benign growth could be suggested when the average dimensions of cavities are superior to 0.15 mm sparing the patient from an excisional procedure with its risk of subsequent permanent nail dystrophy. In contrast, nail clipping with a honeycomb pattern of minute cavities with average dimension inferior to 0.10 mm should prompt a biopsy of the distal matrix to rule out a malignant lesion.

Spatio-temporal genetic heterogeneity of CTNNB1 mutations in sporadic desmoid type fibromatosis lesions.

Desmoid type fibromatosis (DT) is a rare lesion of unclear pathogenesis that most often presents a mutation of the (ß-catenin) gene. The natural history and clinical evolution are highly variable between patients and to date there is no consensus on optimal therapy. We report two cases of a patient with multiple DT lesions. Molecular investigations performed in both patients on multiple tumors at different anatomical sites revealed non-identical CTNNB1 mutations. The first patient was a 39-year-old man with a history of recurrent DT. In two of the DT lesions, three different mutations were found in codons 41 and 45, respectively. The lesions showed marked inflammatory features, characterized by IgG4 positive lymphoplasmacytic infiltrates and a foreign body reaction, which increased in intensity over time. The patient was eventually treated with a COX-2 inhibitor and the remaining mass was stabilized. In the two DT lesions of the second patient, CTNNB1 mutations S45P and T41A were found. The presence of different mutations in multiple focally recurrent sporadic DT lesions indicates that they do not have a clonal relationship. Our data suggest that a CTNNB1 mutation is a necessary event probably by providing a selective growth advantage. An IgG4 host antigen response is discussed as a potential predisposing factor for one of the patients.

Location of Sentinel Lymph Node in Cervical Carcinoma and Factors Associated With Unilateral Detection.

OBJECTIVE: The aims of this study were to assess locality of the sentinel lymph node (SLN) in cervical carcinoma and examine factors affecting bilateral SLN detection. METHODS: This was a retrospective review of SLN data (anatomical location, count and laterality) in patients with early-stage cervical cancer (International Federation of Gynecology and Obstetrics stage IA1 with lymphovascular space invasion to stage IIA) using intraoperative gamma probe and blue dye. The preoperative single-photon emission computed tomography with computed tomography was used to detect laterality, number of the SLNs, and rare locations. Patients were treated between January 2005 to January 2015 at the West Kent Gynaecological Oncology Centre, Maidstone Hospital, Maidstone, United Kingdom. RESULTS: A total of 132 women were investigated. The most common SLN location was the external iliac (38.6%) followed by obturator (25.3%) and internal iliac (23.6%) regions. A small percentage was identified in presacral (1.4%) and para-aortic regions (0.7%). Older age (P = 0.01) and an elevated body mass index (P = 0.03) were associated with decreased SLN count by preoperative single-photon emission computed tomography with computed tomography, and only age affected SLN count by gamma probe (P = 0.01). Initial surgery, large loop excision of the transformation zone, or cone biopsy of the cervix had no effect on SLN count. There was no difference observed in bilateral detection with respect to surgical approach (open: n = 48/laparoscopic: n = 84). However, older age was independently associated with a decrease in bilateral SLN detection (P = 0.003). In these patients who underwent unilateral full pelvic lymphadenectomy, all the nonsentinel nodes were negative. CONCLUSIONS: The majority of SLNs were located in the external iliac, obturator, and internal iliac regions. Both older age and an elevated body mass index were associated with a reduced SLN count. Unilateral detection of SLN was independently associated with older age, which may be due to sclerosis in the lymphatic vessels or reduced perfusion in the pelvis in these women. If no SLN is detected on one side, the consensus is to perform a full pelvic lymphadenectomy on that side of the pelvis.

Examining the validity of the Homework Performance Questionnaire: Multi-informant assessment in elementary and middle school.

Methods for measuring homework performance have been limited primarily to parent reports of homework deficits. The Homework Performance Questionnaire (HPQ) was developed to assess the homework functioning of students in Grades 1 to 8 from the perspective of both teachers and parents. The purpose of this study was to examine the factorial validity of teacher and parent versions of this scale, and to evaluate gender and grade-level differences in factor scores. The HPQ was administered in 4 states from varying regions of the United States. The validation sample consisted of students (n = 511) for whom both parent and teacher ratings were obtained (52% female, mean of 9.5 years of age, 79% non-Hispanic, and 78% White). The cross-validation sample included 1,450 parent ratings and 166 teacher ratings with similar demographic characteristics. The results of confirmatory factor analyses demonstrated that the best-fitting model for teachers was a bifactor solution including a general factor and 2 orthogonal factors, referring to student self-regulation and competence. The best-fitting model for parents was also a bifactor solution, including a general factor and 3 orthogonal factors, referring to student self-regulation, student competence, and teacher support of homework. Gender differences were identified for the general and self-regulation factors of both versions. Overall, the findings provide strong support for the HPQ as a multi-informant, multidimensional measure of homework performance that has utility for the assessment of elementary and middle school students.

Charging of gold/metal oxide/gold nanocapacitors in a scanning electron microscope.

Triangular parallel-plate nanocapacitors were fabricated by a combination of microsphere lithography and physical vapor deposition. The devices were comprised of a 20 nm layer of dielectric material sandwiched between two 20 nm layers of gold. Dielectric materials with a range of relative permittivities were investigated. Charging of the capacitors was probed in a scanning electron microscope (SEM) by monitoring the change in brightness of the images of the devices as a function of time. The time constants, RC, associated with the charging of the capacitors, were extracted from the SEM grayscale data. The resulting average RC values were 248 ± 27 s for SiO2, 70 ± 8 s for Al2O3, 113 ± 80 s for ZnO and 125 ± 13 s for HfO2. These values are consistent with the anticipated RC values based on the resistivities and permittivities of the materials used in the devices and importantly, were measured without the need to attach any wires or leads.

Adult granulosa cell tumour-like areas occurring in ovarian epithelial neoplasms: report of a case series with investigation of FOXL2 mutation status.

AIMS: To look for FOXL2 mutation in rare ovarian epithelial lesions showing stromal components with morphological features of adult granulosa cell tumour (AGCT). METHODS AND RESULTS: We report the 402C→G FOXL2 mutation status in five epithelial ovarian lesions in women aged 45-77 years showing stromal proliferations that were morphologically indistinguishable from AGCT. The lesions were mucinous cystadenoma, mixed epithelial cystadenoma, endometriotic cyst, mucinous borderline tumour (intestinal type), and mucinous carcinoma. In one case, the AGCT component formed a discrete nodule, and in the others it was distributed within the septa and cyst walls. FOXL2 mutation was present in two cases and absent in three cases. One mutation-positive case showed an AGCT nodule abutting a mucinous borderline tumour, interpreted as a collision tumour. The other positive case had an AGCT component within the septa of a mucinous carcinoma, and both components are likely to be neoplastic. In the three cases without FOXL2 mutation, the stromal component most likely represents a non-neoplastic AGCT-like proliferation. CONCLUSIONS: Areas typical of AGCT are rarely associated with epithelial ovarian lesions. These are heterogeneous and likely to be truly neoplastic in only a subset of cases. FOXL2 mutation testing may be useful in confirming a true neoplastic AGCT component.

Acute kidney injury following crizotinib administration for non-small-cell lung carcinoma.

A case of locally advanced non-small-cell lung carcinoma (NSCLC) was inadequately controlled with cisplatin, bevacizumab and pemetrexed chemotherapy. Following identification of a mutation of the echinoderm microtubule-associated protein like 4-anaplastic lymphoma kinase (EML4-ALK) gene, crizotinib was then administered as targeted treatment. Kidney function was normal at diagnosis and during the first line therapy. The administration of crizotinib coincided on two occasions with a conspicuous rise in the serum creatinine level. Urinary protein over creatinine ratio was 0.31 g/g with 22% albumin and macroscopic hematuria. A kidney biopsy was performed at the time of the second episode of renal impairment which showed acute tubular necrosis (ATN) indicating recent renal injury together with a mononuclear cell infiltrate consistent with ongoing repair related to a previous insult. The renal lesions were closely related temporally to crizotinib administration, supporting a causative role for crizotinib in the acute renal injury and this phenomenon has not previously been described.

EGFR mutation status in brain metastases of non-small cell lung carcinoma.

Brain metastases are a frequent and grave complication of non-small cell lung carcinoma (NSCLC). The prognosis is generally poor, despite standard therapy based on surgery and radiotherapy. A degree of understanding of the molecular basis of tumors has led to the development of targeted agents with promising initial findings for the treatment of NSCLC. EGFR mutations have been identified which are associated with significant sensitivity to EGFR tyrosine kinase inhibitors (TKI) and correlate with improved outcome in patients with NSCLC who are treated with these agents. The adoption of treatment tailored to the genetic make-up of individual tumors could lead to substantial therapeutic improvements, and such targeted therapy might be considered as a therapeutic option for brain metastases in the future. We review current knowledge about EGFR mutation status in the specific context of brain metastasis: its association with the response of brain metastases to TKI, its prevalence in brain metastases, and the correlation between mutation status in metastases as compared to the corresponding primary lung carcinoma.