Validation of epidermal AMBRA1 and loricrin (AMBLor) as a prognostic biomarker for nonulcerated American Joint Committee on Cancer stage I/II cutaneous melanoma.

BACKGROUND: Combined expression of the autophagy-regulatory protein AMBRA1 (activating molecule in Beclin1-regulated autophagy) and the terminal differentiation marker loricrin in the peritumoral epidermis of stage I melanomas can identify tumour subsets at low risk of -metastasis. OBJECTIVES: To validate the combined expression of peritumoral AMBRA1 and loricrin (AMBLor) as a prognostic biomarker able to identify both stage I and II melanomas at low risk of tumour recurrence. METHODS: Automated immunohistochemistry was used to analyse peritumoral AMBRA1 and loricrin expression in geographically distinct discovery (n = 540) and validation (n = 300) cohorts of nonulcerated American Joint Committee on Cancer (AJCC) stage I and II melanomas. AMBLor status was correlated with clinical outcomes in the discovery and validation cohorts separately and combined. RESULTS: Analysis of AMBLor in the discovery cohort revealed a recurrence-free survival (RFS) rate of 95.5% in the AMBLor low-risk group vs. 81.7% in the AMBLor at-risk group (multivariate log-rank, P < 0.001) and a negative predictive value (NPV) of 96.0%. In the validation cohort, AMBLor analysis revealed a RFS rate of 97.6% in the AMBLor low-risk group vs. 78.3% in the at-risk group (multivariate log-rank, P < 0.001) and a NPV of 97.6%. In a multivariate model considering AMBLor, Breslow thickness, age and sex, analysis of the combined discovery and validation cohorts showed that the estimated effect of AMBLor was statistically significant, with a hazard ratio of 3.469 (95% confidence interval 1.403-8.580, P = 0.007) and an overall NPV of 96.5%. CONCLUSIONS: These data provide further evidence validating AMBLor as a prognostic biomarker to identify nonulcerated AJCC stage I and II melanoma tumours at low risk of disease recurrence.

Sebaceous carcinoma epidemiology, associated malignancies and Lynch/Muir-Torre syndrome screening in England from 2008 to 2018.

BACKGROUND: Sebaceous carcinomas (SC) may be associated with the cancer predisposition syndrome Muir-Torre/Lynch syndrome (MTS/LS), identifiable by SC mismatch repair (MMR) screening; however, there is limited data on MMR status of SC. OBJECTIVE: To describe the epidemiology of SC, copresentation of other cancers, and population level frequency of MMR screening in SC. METHODS: A population-based retrospective cohort study of SC patients in the National Cancer Registration and Analysis Service in England. RESULTS: This study included 1077 SC cases (739 extraocular, 338 periocular). Age-standardized incidence rates (ASIR) were higher in men compared with women, 2.74 (95% CI, 2.52-9.69) per 1,000,000 person-years for men versus 1.47 person-years (95% CI, 1.4-1.62) for women. Of the patients, 19% (210/1077) developed at least one MTS/LS-associated malignancy. MMR immunohistochemical screening was performed in only 20% (220/1077) of SC tumors; of these, 32% (70/219) of tumors were MMR deficient. LIMITATIONS: Retrospective design. CONCLUSIONS: Incorporation of MMR screening into clinical practice guidelines for the management of SC will increase the opportunity for MTS/LS diagnoses, with implications for cancer surveillance, chemoprevention with aspirin, and immunotherapy treatment targeted to MTS/LS cancers.

Melanocytic matricoma: A report of three cases, review of the literature, and suggestion of a new terminology.

Melanocytic matricoma is a rare, biphasic adnexal tumor. It typically presents as a pigmented papule on the sun-damaged skin of elderly patients. Histopathology shows a dermal nodule composed of basaloid cells, ghost cells, and deeply pigmented dendritic melanocytes. The basaloid cells are usually positive for ß-catenin and these tumors show overlapping histopathological and molecular features with pilomatricoma. Here, we review the literature on melanocytic matricoma and present three new cases. We suggest different terminology to reflect the overlapping features with pilomatricoma that recognizes that melanocytic matricoma is likely to be a variant of pilomatricoma associated with melanocytic hyperplasia. Although melanocytic matricoma is usually considered benign, malignant transformation has been reported. This highlights the need for increased awareness of this entity.

An incidental finding of an asymptomatic intraneural glomus tumor: A case report and review of the literature.

Glomus tumors are rare, soft-tissue neoplasms arising from the thermoregulatory neuromyoarterial glomus bodies. They are commonly observed in the extremities and typically present with symptoms of cold hypersensitivity, pain and localized tenderness. Intraneural glomus tumors (INGTs) are even rarer. Here we review the literature on INGT and present an unusual case of an asymptomatic INGT, found incidentally within the excision specimen of a spiradenocarcinoma that arose near the natal cleft. Interestingly, this had not been identified on magnetic resonance imaging (MRI) used to investigate the spiradenocarcinoma. Although glomus tumors are usually considered benign, malignant transformation has been reported, highlighting the need for reporting pathologists and treating clinicians to be aware of this entity.

A case of metastatic non-neural granular cell tumor in a 13-year-old girl.

Conventional granular cell tumor represents a mesenchymal neoplasm observed in a variety of locations and is now believed to be of Schwann cell origin. Granular cell change has also been observed in a variety of different tumors, but recently described in the skin has been a distinct entity termed non-neural granular cell tumor, which lacks expression of S100 protein and is of uncertain histogenesis. This tumor typically displays a greater degree of nuclear atypia and mitotic activity than conventional granular cell tumor but appears to behave in a relatively benign fashion, as only two previous instances of lymph node metastasis have been documented. Herein, we report a case of non-neural granular cell tumor arising on the back of a 13-year-old girl, and later axillary lymph node metastasis with extracapsular extension was observed.

Serum tumor necrosis factor-alpha level in hepatitis E virus-related acute viral hepatitis and fulminant hepatic failure in pregnant women.

AIM: The host response in hepatitis E virus (HEV)-related liver disease of pregnant women is unclear. This study was carried out to evaluate the serum concentration of tumor necrosis factor (TNF)-α in HEV-related acute viral hepatitis (AVH) and fulminant hepatic failure (FHF) in pregnant women in relation to pregnancy outcome. METHODS: The study included 262 pregnant and 158 non-pregnant women with jaundice. There were 160 healthy asymptomatic pregnant women and 124 healthy asymptomatic non-pregnant women as controls. The jaundiced patients were classified as AVH or FHF. Serum TNF-α level was assayed by commercially available enzyme-linked immunoassay kits. RESULTS: A significantly higher level of TNF-α was observed in HEV-infected pregnant women than non-HEV pregnant women (P < 0.001). TNF-α level was significantly higher in AVH and FHF of HEV-infected pregnant women compared with AVH and FHF of HEV infected non-pregnant women (P = 0.036 and P = 0.010, respectively). The HEV-infected pregnant FHF expired group had significantly higher levels of TNF-α than the non-pregnant FHF expired group (P = 0.025). TNF-α levels were significantly higher in AVH of HEV-infected pregnant women than healthy pregnant controls (P < 0.001). Higher TNF-α levels were observed in HEV-infected women having preterm delivery and low birthweight newborns compared with non-HEV and healthy pregnant women. CONCLUSION: Higher serum concentration of TNF-α observed in HEV infected AVH and FHF pregnant cases shows that pregnancy with HEV infection increases TNF-α secretion. TNF-α may be an important factor in the outcomes of pregnancy due to HEV infection.

Developmental cell programs are co-opted in inflammatory skin disease.

The skin confers biophysical and immunological protection through a complex cellular network established early in embryonic development. We profiled the transcriptomes of more than 500,000 single cells from developing human fetal skin, healthy adult skin, and adult skin with atopic dermatitis and psoriasis. We leveraged these datasets to compare cell states across development, homeostasis, and disease. Our analysis revealed an enrichment of innate immune cells in skin during the first trimester and clonal expansion of disease-associated lymphocytes in atopic dermatitis and psoriasis. We uncovered and validated in situ a reemergence of prenatal vascular endothelial cell and macrophage cellular programs in atopic dermatitis and psoriasis lesional skin. These data illustrate the dynamism of cutaneous immunity and provide opportunities for targeting pathological developmental programs in inflammatory skin diseases.

Evaluation of Patient and Parent Satisfaction After Orthodontic Treatment/Orthognathic Surgery for Cleft Lip and Palate Deformity.

OBJECTIVES: The objectives of this study were to evaluate the satisfaction of patients, parents, and individuals other than health professionals (neighbors or relatives), regarding the quality of care, and to evaluate the patients general care, facial appearance, dental changes, and psychological assessment by social outlook and emotional quotient. MATERIALS AND METHODS: Sixty patients with cleft lip and palate reporting to a dental institution were divided into two age groups, 0-15 years (G1) and 15-30 years (G2), their parents (P1 and P2) and a group comprising their neighbour's or relatives (T1 and T2) were also divided according to G1 and G2. To evaluate their satisfaction toward the treatment received, three separate questionnaires were given to the three groups and their responses were subjected to statistical analysis. RESULTS: The results showed that majority of patients (74%) and their parents (60%) were satisfied with the orthodontic treatment they received to align the teeth. But they were not satisfied with the appearance of lip (61.6% and 56.6%), nose (60% and 53.3%), and speech (62%). This study showed that cleft-affected individuals were teased mainly for speech (60%) followed by lip and teeth. Sixty percent of the patients admitted that their self-confidence was quite affected because of cleft and 36.6% expressed that their school/college results have been affected. CONCLUSION: Majority of cleft lip and palate patients as well as their parents were satisfied with their child's dental appearance; they were unsatisfied with the appearance of nose, lip, smile, and speech.

Epigenetic modifiers DNMT3A and BCOR are recurrently mutated in CYLD cutaneous syndrome.

Patients with CYLD cutaneous syndrome (CCS; syn. Brooke-Spiegler syndrome) carry germline mutations in the tumor suppressor CYLD and develop multiple skin tumors with diverse histophenotypes. Here, we comprehensively profile the genomic landscape of 42 benign and malignant tumors across 13 individuals from four multigenerational families and discover recurrent mutations in epigenetic modifiers DNMT3A and BCOR in 29% of benign tumors. Multi-level and microdissected sampling strikingly reveal that many clones with different DNMT3A mutations exist in these benign tumors, suggesting that intra-tumor heterogeneity is common. Integrated genomic, methylation and transcriptomic profiling in selected tumors suggest that isoform-specific DNMT3A2 mutations are associated with dysregulated methylation. Phylogenetic and mutational signature analyses confirm cylindroma pulmonary metastases from primary skin tumors. These findings contribute to existing paradigms of cutaneous tumorigenesis and metastasis.

Targeting Tropomyosin Receptor Kinase in Cutaneous CYLD Defective Tumors With Pegcantratinib: The TRAC Randomized Clinical Trial.

Importance: There are no medical interventions for the orphan disease CYLD cutaneous syndrome (CCS). Transcriptomic profiling of CCS skin tumors previously highlighted tropomyosin receptor kinases (TRKs) as candidate therapeutic targets. Objective: To investigate if topical targeting of TRK with an existing topical TRK inhibitor, pegcantratinib, 0.5% (wt/wt), is safe and efficacious in CCS. Design, Setting, and Participants: A phase 1b open-label safety study, followed by a phase 2a within-patient randomized (by tumor), double-blind, placebo-controlled trial (the Tropomyosin Receptor Antagonism in Cylindromatosis [TRAC] trial). The setting was a single-center trial based at a tertiary dermatogenetics referral center for CCS (Royal Victoria Infirmary, Newcastle, United Kingdom). Patients who had germline mutations in CYLD or who satisfied clinical diagnostic criteria for CCS were recruited between March 1, 2015, and July 1, 2016. Interventions: In phase 1b, patients with CCS applied pegcantratinib for 4 weeks to a single skin tumor. In phase 2a, allocation of tumors was to either receive active treatment on the right side and placebo on the left side (arm A) or active treatment on the left side and placebo on the right side (arm B). Patients were eligible if they had 10 small skin tumors, with 5 matched lesions on each body side; patients were randomized to receive active treatment (pegcantratinib) to one body side and placebo to the other side once daily for 12 weeks. Main Outcomes and Measures: The primary outcome measure was the number of tumors meeting the criteria for response in a prespecified critical number of pegcantratinib-treated tumors. Secondary clinical outcome measures included an assessment for safety of application, pain in early tumors, and compliance with the trial protocol. Results: In phase 1b, 8 female patients with a median age of 60 years (age range, 41-80 years) were recruited and completed the study. None of the participants experienced any adverse treatment site reactions. Three patients reported reduced pain in treated tumors. In phase 2a (15 patients [13 female; median age, 51 years], with 150 tumors), 2 tumors treated with pegcantratinib achieved the primary outcome measure of response compared with 6 tumors treated with placebo. The primary prespecified number of responses was not met. The incidence of adverse events was low. Conclusions and Relevance: In this study, pegcantratinib, 0.5% (wt/wt), applied once daily appeared to be well tolerated and to penetrate the tumor tissue; however, the low tumor drug concentrations demonstrated are likely to account for the lack of response. Dose-escalation studies to assess the maximal tolerated dose may be beneficial in future studies of CCS. Trial Registration: isrctn.org Identifier: ISRCTN75715723.

Frequency of primary solid malignant neoplasms in both sexes, as seen in our practice.

BACKGROUND: To determine the frequency of various histologic types of primary solid malignant neoplasms in males and females, in our practice, in a large series of surgical biopsies. METHODS: A retrospective study of 20,000 consecutive surgical biopsies in the section of Histopathology, Aga Khan University Hospital (AKU), Karachi, in 2004. RESULTS: Squamous cell carcinoma of oral cavity was the commonest malignant neoplasm in males followed by diffuse Large B cell, Non-Hodgkin's lymphoma and Prostatic adenocarcinoma. In females, infiltrating Ductal carcinoma of the breast was overwhelmingly the commonest malignant neoplasm followed by Squamous cell carcinoma of the oral cavity and esophagus. CONCLUSION: Out of 20,000 biopsies, there were 4616 (23.08%) malignant neoplsms. Carcinoma of oral cavity is very common in our population in both sexes.

Mixed epithelial and stromal tumour of kidney.

Mixed epithelial and stromal tumour of kidney is a recently described, rare entity and includes cases previously termed as cystic hamartoma of renal pelvis and adult mesoblastic nephroma. We report a case of 36 years old female who presented with a history of recurrent loose stools for 5 years. During ultrasound abdomen, a solid right renal mass was incidentally found in upper pole of right kidney. On gross examination it was a 3.5 cm diameter mass which was microscopically composed of both epithelial and stromal components in the form of cystically dilated tubules and fascicles of spindle shaped cells. These cells stained positive for alpha smooth muscle actin, desmin, progesterone receptors and negative for estrogen receptors.

Fine needle aspiration cytology of thyroid nodule: diagnostic accuracy and pitfalls.

BACKGROUND: To evaluate the utility of FNAC in patients with Thyroid Nodule. METHODS: Records of all patients treated surgically for thyroid nodule(s) at Aga Khan University Hospital from January 2000 to December 2004 were reviewed. The patients who had pre operative FNAC as first line of the evaluation and the final post operative histopathology report available were included in the study. RESULTS: 125 patients (90 female 35 male) had thyroid surgery. The cytological diagnosis was made according to following categories: Benign, Follicular lesion, Malignant and Inadequate sampling. Among 63 "Benign cases", 57 were benign and 6 turned out to be malignant. Among 44 cases from "Follicular group", 31 were benign and 13 were malignant. Out of 15 patients from "Malignant" group, 14 were malignant and 1 was benign. Among three patients from the "Inadequate sampling group", 2 turned out to be benign and one was malignant. The overall results showed a sensitivity of 98%, specificity of 70%, and positive predictive value of 91%, negative predictive value of 93% and diagnostic accuracy of 91%. CONCLUSION: We conclude that FNAC is an invaluable and minimally invasive procedure for pre operative assessment of patients with a thyroid nodule in our setting as well. FNAC has high sensitivity in picking up malignancy in thyroid and also has high diagnostic accuracy in the evaluation of thyroid nodules.

Heterotopic glial tissue in tonsil: a case report.

We describe a six month old boy with a mass in the left tonsil. It was present since birth and was enlarging progressively. It was completely excised. Histopathology showed a choristoma of neural origin composed of glial cells--astrocytes in a fibrillary background, and a choroid plexus. Immunohistochemistry confirmed the findings.

Sarcoidosis presenting with hypercalcaemia following withdrawal of long-term immunosuppression in renal transplantation.

Long-term immunosuppression, including corticosteroids, is a hallmark of renal transplantation. We describe a patient who had a failed transplant after 15 years, subsequent graft nephrectomy and withdrawal of his immunosuppression therapy including prednisolone. Within months of complete cessation of prednisolone, he developed hypercalcaemia and subsequent systemic symptoms including ocular, respiratory and dermatological. A skin biopsy demonstrated non-caseating granulomatous lesion and a diagnosis of sarcoidosis was confirmed. Re-commencement with prednisolone resulted in complete resolution of clinical and biochemical features of sarcoidosis. Sarcoidosis is unlikely to present in the immunosuppressed patient. This case highlights that unexplained hypercalcaemia at the time of withdrawal of immunosuppression, including corticosteroids, may be a feature of sarcoidosis.

Pyoderma gangrenosum: a rare cause of breast ulceration.

Breast ulceration is an alarming sign for clinicians and places a significant physical and psychological burden on the patient. We report a rare presentation of pyoderma gangrenosum of the breast in a patient known to have ulcerative colitis but no active underlying disease process and no history of breast tissue trauma. This case report with literature review highlights the importance of considering pyoderma gangrenosum as a differential diagnosis in breast ulcers.