A territory wide follow-up of primary and secondary extramammary Paget disease of two decades - effects of local disease on survival.

Introduction Extramammary Paget disease (EMPD) is an uncommon malignant cutaneous neoplasm that are divided into primary and secondary forms. In this multicenter study, histologically proven cases of primary and secondary EMPD were reviewed for clinical outcomes with subgroup analysis for secondary EMPD. Methodology Cases of EMPD were identified from pathology report of the involved institutions over a period of over two decades. Cases of secondary EMPD were identified review of case notes, radiology, and pathology reports. Clinicopathological and outcome data were retrieved for statistical analysis. Results A total of 109 cases were retrieved, including 19 cases of secondary EMPD, most commonly associated with colorectal (n=6), anal (n=5) and prostatic carcinomas (n=3). A difference was observed between older age and secondary (versus primary) EMPD (p=0.016), but no differences were seen in other clinico-demographical parameters. Male sex (p=0.018), age over 60 years old (p=0.004) and involvement of margins (resectable) (p=0.018) were associated with shorter OS. For DSS, involvement of margins (p=0.009) was an adverse predictor. Secondary EMPD had a shorter DSS than primary EMPD (p=0.005). Multivariable analysis confirmed all above associations (p<0.05). In subgroup analysis for secondary EMPD, margin involvement remained associated with shorter OS (p = 0.007) and DSS (p = 0.003). Conclusions Secondary EMPD is associated with poorer outcomes. Margin involvement is strong and independent indicator of shorter OS and DSS, including secondary EMPD. Resectability is a strong predictor of favorable outcome and excision with clear margins should be attempted when surgically feasible.

Digital Image Comparison of Cellular Yield in Bronchial Brushing: Pre- and Post-Biopsy Lavage Cytology.

INTRODUCTION: Bronchoscopy is a useful diagnostic tool capable of performing core biopsy, forceps biopsy, bronchoalveolar lavage, and bronchial brushing. This study compares the cellularity of bronchial cytology including pre- and post-biopsy lavage by digital image analysis, aiming to increase diagnostic and tumor yield by optimizing the sequence and combination of bronchial biopsy and cytology. METHODS: Alveolar macrophage, bronchial epithelium, and tumor cell cellularity from liquid-based cytology preparations of bronchial brushing and pre-biopsy and post-biopsy bronchoalveolar lavage were annotated on digitized whole-slide images and compared. Secondary analysis on the relationship of tumor cell and non-lesional cell yield was performed. RESULTS: Overall, 118 cytology specimens from 43 patients were retrieved in total. Bronchial epithelium count was higher in pre-biopsy than post-biopsy lavage (p < 0.01) but not for alveolar macrophages nor tumor cell (p > 0.05). Tumor cell count was higher for bronchial brushing cytology samples than lavage (p = 0.018). The alveolar macrophage count was higher in post-biopsy lavage than bronchial brushing (p = 0.033); otherwise, brushing showed consistently higher bronchial epithelium and tumor cell counts. There were 33 false negative (tumor cell absent) specimens, and the combination of bronchial brushing and pre-biopsy lavage yielded the lowest false negative cases. Correlation between bronchial epithelium and alveolar macrophage counts with tumor cell count was weak (correlation coefficient = -0.168-0.203) except for post-biopsy lavage (correlation coefficient = 0.412-0.479, p < 0.05). CONCLUSION: Bronchial brushing yields a greater amount of tumor cell than lavage, and timing lavage before or after core biopsy does not affect tumor cell yield. Combining bronchial brushing and pre-biopsy lavage results in the lowest false negative rate.

PRAME expression in genital melanocytic lesions - Potential diagnostic pitfall of intermediate expression in atypical genital nevi.

INTRODUCTION: The Preferentially Expressed Antigen in Melanoma (PRAME) immunostain has seen significant diagnostic use in confirming malignancy for melanocytic lesions. However, the expression of PRAME in genital melanocytic lesions have not been reported. In this study, PRAME staining was performed on a cohort of genital melanocytic lesions, aiming to investigate the diagnostic role of PRAME in genital melanocytic lesions and its expression in atypical genital nevi. METHODOLOGY: A cohort including genital invasive melanoma, melanoma-in-situ, atypical genital nevus (AGN), compound nevus, intradermal nevus, blue nevus, lentigo and melanosis was retrieved with histology reviewed and PRAME immunostaining performed. RESULTS: A total of 66 cases were reviewed. The average proportion expression of PRAME were 56.75 % and 57.43 % for invasive melanoma and melanoma-in-situ, with average H-scores of 153.5/300 and 163.14/300 respectively, which were greater than AGN (3.25 %, 7.75/300, p<0.001), compound/intradermal nevi, lentigo/melanosis, and background junctional melanocytes (<1 %, <1/300, p<0.001). The different cutoffs of PRAME expression, the sensitivity and specificity were 65.22 % and 100 % (>100/300); 69.57 % and 95.83 % (>10/300); and 82.61 % and 93.75 % (≥1/300) respectively. Low level PRAME expression was seen in half of the cases of AGN (n=2/4, 50 %), and at low cutoffs (>10/300 and ≥1/300) unable to differentiate invasive melanoma from AGN (p>0.05). CONCLUSIONS: For genital melanocytic lesions, PRAME immunostain shows high specificity at strong and diffuse staining. AGN not uncommonly display low level expression. Focal and/or weak PRAME expression should not be considered as an absolute indication of malignancy, and comprehensive histological assessment remains the key to accurate diagnosis of melanocytic lesions.

Increased histological severity and chronicity of interface inflammation in anti-MDA5 dermatomyositis-A comparative dermatopathological analysis.

Anti-melanoma differentiation-associated gene 5 (MDA5) dermatomyositis is characterized by serological detection of anti-MDA5 antibody and rapidly progressive interstitial lung disease. In this study, the largest cohort of skin biopsies to date of anti-MDA5 dermatomyositis was reviewed and compared with cases of dermatomyositis with negative serology. Findings contribute to the histological diagnosis and evaluation of the severity of cutaneous inflammation in anti-MDA5 dermatomyositis. Skin biopsies collected over a 7-year period from individuals with clinically and histologically confirmed dermatomyositis with anti-MDA5 serology were reviewed. A total of 46 cases with 17 anti-MDA5 positive cases were retrieved. Patients with positive antibody were younger (53.7 vs. 60.6 years, p = .013). No differences in epidermal changes (p > .05) were observed. Pertaining to interface changes, anti-MDA5 dermatomyositis showed a higher degree of pigmentary incontinence (p = .014), suggesting increased and sustained cutaneous inflammation. Periodic acid-Schiff (PAS) stain demonstrated a greater degree of basement membrane thickening (p = .045). Other parameters, including dermal inflammation, dermal mucin deposition and vasculitic/vasculopathic features did not show statistical difference between anti-MDA5 positive and negative dermatomyositis (p > .05). Findings suggest increased cutaneous inflammation for anti-MDA5 dermatomyositis. In skin biopsies, marked pigmentary incontinence or basement membrane thickening should raise suspicion of anti-MDA5 dermatomyositis.

A rare presentation of pemphigus vegetans as an isolated vegetative lesion-Review of histopathological clues and treatment effects in multiple biopsy specimens.

BACKGROUND: Pemphigus is a group of immunobullous dermatoses characterized by the presence of autoantibodies directed against adhesion molecules of keratinocytes, with pemphigus vegetans being the rarest form, accounting for 1%-2% of all cases of pemphigus. Pemphigus vegetans is characterized by verrucous vegetative lesions in addition to vesiculobullous lesions. METHODS: We report a rare case of pemphigus vegetans presenting as an isolated vegetative lesion in the groin 3 months prior to the development of blisters. Owing to the atypical presentation, multiple biopsies were performed before and after corticosteroid treatment. RESULTS: Comparing the histopathology of pre-treatment and post-treatment biopsy specimens, the resolution of intraepidermal microabscesses, and reduction in intraepidermal and dermal inflammatory infiltrates, spongiosis and interface change, attributable to treatment, were noted. However, direct immunofluorescence showed persistent intracellular intraepidermal deposition of IgG and C3 2 weeks into treatment, despite near-complete resolution of blisters on clinical examination. Clinical regression of the vegetative lesion was noted only after 6 weeks into corticosteroid treatment, while histopathological evidence of treatment was apparent at the second week. CONCLUSION: The current case illustrates the importance of a liberal use of immunofluorescence studies in establishing the uncommon yet significant diagnosis of pemphigus vegetans, particularly for vegetative lesions that are persistent, in the intertriginous areas and/or in the setting of concurrent cutaneous or mucosal symptoms.

Metastatic lung carcinoma in thyroid aspirates: A case series and literature review illustrating diagnostic challenges.

BACKGROUND: Papillary thyroid carcinoma (PTC) is the most common primary malignant thyroid neoplasm and malignant diagnosis in thyroid aspirates. Metastatic adenocarcinoma of the lung is an under-recognised mimicker which overlaps cytomorphologically and immunocytochemically with PTC. This case series reviews thyroid aspirates of metastatic lung carcinomas, aiming to address the similarities and methods of differentiating this entity from PTC. METHODS: Thyroid aspirates of metastatic lung carcinomas were obtained by a computerised search. Clinico-cytological features and ancillary test results were reviewed. A literature review was performed for published cases of metastatic lung carcinomas in thyroid aspirates. RESULTS: A total of 14 cases were found, including nine adenocarcinomas, three TTF1-positive non-small cell lung carcinomas (NSCLCs), one small cell carcinoma and one squamous cell carcinoma. The adenocarcinomas and TTF1-positive NSCLCs displayed PTC-like features including papillae/papillary-like fronds (n = 6/12, 50%), nuclear grooves (n = 5/12, 41.7%) and inclusions (n = 1/12, 8.3%), chromatin clearing (n = 3/12, 25%), calcifications (n = 3/12, 25%) and multinucleated giant cells (n = 2/12, 16.7%). Useful distinguishing features observed were prominent nucleoli, coarse chromatin, mitosis, and necrosis. TTF-1 immunocytochemistry was positive in most cases (n = 5/6, 83.3%), while PAX8 and thyroglobulin were consistently negative. EGFR exon 19 deletion was detected on cell block preparation in a single case, corresponding to its lung primary. The literature search yielded 84 cases of metastatic malignancies, with lung carcinomas comprising of 3.6%-33.3% in case series of metastatic malignancies. CONCLUSION: Metastatic adenocarcinoma of lung and PTC share significant cytomorphological and immunocytochemical similarities. A high degree of caution, meticulous clinico-cytological assessment and prudent use of ancillary techniques is necessary to avoid potential misdiagnosis.

The role of cytokeratin 7/20 coordination revisited-Machine learning identifies improved interpretative algorithms for cell block immunohistochemistry in aspirates of metastatic carcinoma.

BACKGROUND: Fine-needle aspiration (FNA) is a robust diagnostic technique often used for tissue diagnosis of metastatic carcinoma. For interpretation of FNA cytology, cell block immunohistochemistry (IHC) and clinicocytologic parameters are indispensable. In this review of a large cohort, the current report: 1) describes clinicocytologic parameters and immunoprofiles of aspirates of metastatic carcinoma, 2) compares the predictivity of immunostains and classical approaches for IHC interpretation, and 3) describes machine learning-based algorithms for IHC interpretation. METHODS: Aspirates of metastatic carcinoma that had IHC performed were retrieved. Clinicocytologic parameters, IHC results, the corresponding primary site, and histologic diagnoses were recorded. By using machine learning, decision trees for predicting the primary site were generated, their performance was compared with 2 human-designed algorithms, and the primary site was suggested in the historical diagnosis. RESULTS: In total, 1145 cases were identified. The 6 most populated groups were selected for machine learning and predictive analysis. With IHC input, the decision tree achieved a concordance rate of 94.5% and overall accuracy of 83.6%, which improved to 95.3% and 85.8%, respectively, when clinical data were incorporated and exceeded the human-designed IHC algorithms (P < .001). The historical diagnosis was more accurate unless indeterminate diagnoses were regarded as discordant (P < .001). CDX2 and TTF-1 immunostains had the highest weight in model accuracy, occupied the root of the decision trees, scored higher as features of importance, and outperformed the predictive power of cytokeratins 7 and 20. CONCLUSIONS: Cytokeratins 7 and 20 may be superseded in immunostaining panels, including organ-specific immunostains such as CDX2 and TTF-1. Machine learning generates algorithms that surpasses human-designed algorithms but is inferior to expert assessment integrating clinical and cytologic assessment.

Long-Term Survival and Clinicopathological Implications of DNA Mismatch Repair Status in Endometrioid Endometrial Cancers in Hong Kong Chinese Women.

To investigate the role of DNA mismatch repair status (MMR) in survival of endometrioid endometrial cancer in Hong Kong Chinese women and its correlation to clinical prognostic factors, 238 patients with endometrioid endometrial cancer were included. Tumor MMR status was evaluated by immunohistochemistry. Clinical characteristics and survival were determined. Association of MMR with survival and clinicopathological parameters were assessed. MMR deficiency (dMMR) was found in 43 cases (16.5%). dMMR was associated with poor prognostic factors including older age, higher stage, higher grade, larger tumor size and more radiotherapy usage. Long-term survival was worse in dMMR compared to the MMR proficient group. The dMMR group had more deaths, shorter disease-specific survival (DSS), shorter disease-free survival (DFS), less 10-year DSS, less 10-year DFS, and more recurrence. The 5-year DSS and 5-year DFS in the dMMR group only showed a trend of worse survival but did not reach statistical significance. In conclusion, dMMR is present in a significant number of endometrioid endometrial cancers patients and is associated with poorer clinicopathological factors and survival parameters in the long run. dMMR should be considered in the risk stratification of endometrial cancer to guide adjuvant therapy and individualisation for longer follow up plan.

Increased co-expression of PSMA2 and GLP-1 receptor in cervical cancer models in type 2 diabetes attenuated by Exendin-4: A translational case-control study.

BACKGROUND: Type 2 diabetes (T2D) increases the risk of many types of cancer. Dysregulation of proteasome-related protein degradation leads to tumorigenesis, while Exendin-4, a glucagon-like peptide 1 receptor (GLP-1R) agonist, possesses anti-cancer effects. METHODS: We explored the co-expression of proteasome alpha 2 subunit (PSMA2) and GLP-1R in the Cancer Genome Atlas (TCGA) database and human cervical cancer specimens, supplemented by in vivo and in vitro studies using multiple cervical cancer cell lines. FINDINGS: PSMA2 expression was increased in 12 cancer types in TCGA database and cervical cancer specimens from patients with T2D (T2D vs non-T2D: 3.22 (95% confidence interval CI: 1.38, 5.05) vs 1.00 (0.66, 1.34) fold change, P = 0.01). psma2-shRNA decreased cell proliferation in vitro, and tumour volume and Ki67 expression in vivo. Exendin-4 decreased psma2 expression, tumour volume and Ki67 expression in vivo. There was no change in GLP-1R expression in 12 cancer types in TCGA database. However, GLP-1R expression (T2D vs non-T2D: 5.49 (3.0, 8.1) vs 1.00 (0.5, 1.5) fold change, P < 0.001) was increased and positively correlated with PSMA2 expression in T2D-related (r = 0.68)  but not in non-T2D-related cervical cancer specimens. This correlation was corroborated by in vitro experiments where silencing glp-1r decreased psma2 expression. Exendin-4 attenuated phospho-p65 and -IκB expression in the NF-κB pathway. INTERPRETATION: PSMA2 and GLP-1R expression in T2D-related cervical cancer specimens was increased and positively correlated, suggesting hyperglycaemia might promote cancer growth by increasing PSMA2 expression which could be attenuated by Exendin-4. FUNDING: This project was supported by Postdoctoral Fellowship Scheme, Direct Grant, Diabetes Research and Education Fund from the Chinese University of Hong Kong (CUHK).

Trichoblastic Carcinosarcoma Arising From the Vagina: A Case Report With Comprehensive Immunophenotypic Analysis.

A 54-year-old woman presented with abdominal pain. Magnetic resonance imaging revealed an upper vaginal mass with no pelvic side wall involvement, nodal, or distant metastasis. Radical hysterectomy was performed. Histology showed trichoblastic carcinoma with hair follicle structures and malignant sarcomatous and carcinomatous components. Hair follicular differentiation was confirmed by positivity to hair follicle markers (Bcl-2, TLE1, CD56/NCAM, and TDAG51) and presence of CD10-positive trichogenic stroma. The tumor involved the vaginal muscularis only (FIGO [International Federation of Gynecology and Obstetrics] stage I) and was excised with clear margins. The patient remained disease free at 3-month follow-up. This is the first case of cutaneous-type carcinosarcoma reported in the vagina, highlighting the difference in histology, immunophenotype, and behavior compared with gynecologic carcinosarcomas.