Severe Atypia Research Articles

Mural Intracholecystic Neoplasms Arising in Adenomyomatous Nodules of the Gallbladder: An Analysis of 19 Examples of a Clinicopathologically Distinct Entity.

Intracholecystic neoplasms (ICNs) (pyloric gland adenomas and intracholecystic papillary neoplasms, collectively also called intracholecystic papillary/tubular neoplasms) form multifocal, extensive proliferations on the gallbladder mucosa and have a high propensity for invasion (>50%). In this study, 19 examples of a poorly characterized phenomenon, mural papillary mucinous lesions that arise in adenomyomatous nodules and form localized ICNs, were analyzed. Two of these were identified in 1750 consecutive cholecystectomies reviewed specifically for this purpose, placing its incidence at 0.1%. Median age was 68 years. Unlike other gallbladder lesions, these were slightly more common in men (female/male=0.8), and 55% had documented cholelithiasis. All were characterized by a compact multilocular, demarcated, cystic lesion with papillary proliferations and mucinous epithelial lining. The lesions' architecture, distribution, location, and typical size were suggestive of evolution from an underlying adenomyomatous nodule. All had gastric/endocervical-like mucinous epithelium, but 5 also had a focal intestinal-like epithelium. Cytologic atypia was graded as 1 to 3 and defined as 1A: mucinous, without cytoarchitectural atypia (n=3), 1B: mild (n=7), 2: moderate (n=2), and 3: severe atypia (n=7, 3 of which also had invasive carcinoma, 16%). Background gallbladder mucosal involvement was absent in all but 2 cases, both of which had multifocal papillary mucosal nodules. In conclusion, these cases highlight a distinct clinicopathologic entity, that is, mural ICNs arising in adenomyomatous nodules, which, by essentially sparing the "main" mucosa, not displaying "field-effect/defect" phenomenon, and only rarely (16%) showing carcinomatous transformation, are analogous to pancreatic branch duct intraductal papillary mucinous neoplasms.

Should "suspicious for high-grade urothelial carcinoma" and "positive for high-grade urothelial carcinoma" remain separate categories?

The Paris System (TPS) for Reporting Urinary Cytology aims to standardize urine cytology reporting. Per TPS, the diagnosis of "suspicious for high-grade urothelial carcinoma (SHGUC)" is applied in cases that have few urothelial cells with severe atypia but are quantitatively insufficient for a diagnosis of "high-grade urothelial carcinoma (HGUC)." In our study, we compared the diagnostic accuracy and risk of malignancy (ROM) of these 2 categories to assess whether they could be combined in clinical practice to perhaps improve overall interobserver variability. All urine specimens with a diagnosis of either SHGUC or HGUC from January 2016 to July 2019 were retrieved from the pathology database of 2 large academic institutions. Only cases with follow-up biopsies within 6 months were included. One hundred eighty-nine cases met the study criteria. Of these, 122 had a cytologic diagnosis of SHGUC, and 67 had a diagnosis of HGUC. Ninety-five (78%) cases from the SHGUC group and 64 (96%) cases from the HGUC group had biopsy-proven HGUC. The majority of cases with discordance had a history of treatment with either intravesical bacillus Calmette-Guérin or mitomycin. The difference in the rate of biopsy-proven HGUC between the SHGUC category and the HGUC category (95/122 vs 64/67, respectively) was statistically significant (P < .001). The difference in ROM between SHGUC and HGUC was statistically significant in our study cohort. Intravesical chemotherapy was frequently observed in negative biopsy cases in both groups. Our preliminary findings suggest that the 2 TPS categories should remain separate.

MALIGNANT MUCINOUS MYOEPITHELIOMA: A CASE REPORT

A 42-year-old female presented with asymptomatic fibrous submucosal mass that arose approximately 4 years earlier, in the left lower labial mucosa, measuring 40 mm. Aspiration showed a mucosanguinolent content. Histopathologic analysis of the incisional biopsy revealed glandular epithelial neoplasia characterized by proliferation of nests of cells in a fibrous connective tissue with areas of hyalinization. Signet ring cells, PAS-positive mucosal cells, and areas of mucus deposition were observed. Neoplastic cells presented severe cellular atypia. Immunohistochemistry was positive for p63, CK14, and CK7 and negative for SMA and S100. Ki-67 rate was 15.75%, confirming the diagnosis of malignant mucinous myoepithelioma. A head and neck surgeon performed the surgical resection of the tumor. No recurrence was observed after 5 months. Malignant mucinous myoepithelioma is a rare lesion that exhibits microscopic similarities with different entities, including other mucous-producing carcinomas, which makes its diagnosis a challenge. Support: CAPES, FAPEMIG.

Characterization of TP53-wildtype tubo-ovarian high-grade serous carcinomas: rare exceptions to the binary classification of ovarian serous carcinoma.

While TP53 mutation is widely considered to be a defining feature of tubo-ovarian high-grade serous carcinoma (HGSC), rare TP53-mutation-negative cases have been reported. To gain further insight into this rare subset, a retrospective review was conducted on 25 TP53-wildtype tubo-ovarian HGSCs, constituting 2.5% of 987 HGSCs profiled by the MSK-IMPACT sequencing platform. Consistent with serous differentiation, positive staining for Pax8 and WT1 was present in virtually all TP53-wildtype HGSCs. Other characteristic features of HGSC, such as serous tubal intraepithelial carcinoma, or genetic alterations of CCNE1 and BRCA1/2 were identified in these tumors, furthering supporting their classification as bona fide HGSC, despite lacking TP53 mutations. Overall, the level of chromosomal instability of TP53-wildtype HGSCs was intermediate between low-grade serous carcinoma (LGSC) and TP53-mutated HGSC. Morphologic assessment by observers blinded to mutation status revealed a significant subset of tumors with Grade 2 nuclear atypia (which exceeds the degree of atypia allowed for LGSC, but less than typically encountered for HGSC) combined with micropapillary features (6/19, 32%, chemotherapy-naive TP53-wildtype HGSCs compared to 0/21, 0%, TP53-mutated HGSCs; p = 0.007). Some TP53-wildtype HGSCs harbored driver mutations in KRAS (n = 3), BRAF (n = 1) or NRAS (n = 2). Overall, 10 (40%) cases had "LGSC-like" morphology (i.e., Grade 2 nuclear atypia and micropapillary features) and/or RAS/RAF mutation, and most of these showed a wildtype p53 pattern of expression by immunohistochemistry (7/9, 78%). The remaining TP53-wildtype HGSCs (n = 15, 60%) exhibited severe nuclear atypia (Grade 3) and were morphologically indistinguishable from conventional TP53-mutated HGSC. Despite lacking genetic alterations of TP53, these "usual HGSC-like" tumors often showed evidence of p53 dysfunction, including downregulation of expression ('null' or equivocal p53 staining in 9/14, 64%) or MDM2 amplification (n = 2). Our results support the existence of TP53-wildtype HGSCs, which comprise a heterogeneous group of tumors which may arise via distinct pathogenic mechanisms.

Abstract B01: Validation of a novel cytologic biomarker for urothelial carcinoma

Abstract Introduction: Cytology and cystoscopy have limited sensitivity and specificity for the diagnosis of urothelial carcinoma (UC), due to inflammatory atypia, sampling errors, and other clinicopathologic factors that may obscure test results. Therefore, there remains a clinical need to identify biomarkers to improve the diagnostic accuracy to detect UC. Keratin 17 (K17) is an embryologic cytokeratin that functions as an oncoprotein to promote the degradation of tumor suppressors that drive tumorigenesis. Published work from our group established that K17 is highly expressed in UC and confirmed specificity for UC by immunohistochemical localization of K17 in tissue biopsies of both low-grade and high-grade UCs (Babu et al., Mod Pathol, 2018). Objective: The objective of the current study was to develop an immunocytochemical (ICC) assay to determine K17 is a sensitive and specific biomarker to enhance diagnostic accuracy for UC in urine cytology. Methods: 80 ThinPrep CytoLyt-fixed urine specimens, collected at Stony Brook Medicine in 2018, including 39 with a clinicopathologic diagnosis of UC based on current cytologic diagnosis, and/or a history of biopsy confirmed UC within one year (+/-) of urine cytology specimen collection. K17 ICC was performed by indirect immunoperoxidase methods and K17 test results were scored based on the detection of immunoreactive urothelial cells and not on an assessment of cytologic atypia. The sensitivity and specificity of urine K17 ICC for detection of urothelial neoplasia was calculated by comparison of ICC test results with the cytologic diagnosis and/or the histologic diagnosis of positive cystoscopic biopsy specimens (papillary urothelial neoplasm of low malignant potential [PUNLMP, n=1] or greater). Samples that had no history of abnormal urine cytologic or biopsy diagnosis were categorized as negative for urothelial neoplasia. Results: Relative to the final clinicopathologic diagnosis of UC (n=38) or PUNLMP (n=1), K17 ICC had a sensitivity of 100% (95% CI: 91-100%) and specificity of 90% (95% CI: 77-96%). The positive predictive value was 90% (95% Cl: 78-96%) and the negative predictive value was 100% (95% Cl: 90-100%). Comparing ICC test results to cytologic and biopsy diagnoses, K17 ICC was positive in 9/23 (39%) cases with negative urine cytology. Of these 9 cases, 4 cases had biopsy confirmed UC. K17 ICC was positive in 4/11 (36%) of cases with inflammatory/reactive changes. Of these 4 cases, 3 had biopsy-confirmed UC. K17 ICC was positive in 14/30 (46%) of cases with mild atypia. Of these 14 cases, 12 had biopsy-confirmed UC and 1 had PUNLMP. K17 ICC was positive in 16/16 (100%) of cases with moderate atypia (n=8), severe atypia (n=3), or UC (n=5), all with biopsy-confirmed UC. Conclusions: K17 ICC is a novel and highly sensitive and specific diagnostic test for underlying biopsy-confirmed UC among samples with inflammatory/reactive changes, cytologic atypia, or positive urine cytology. Thus, the K17 test could serve as an adjunct to guide the clinical management of UC cases. Citation Format: Sruthi Babu, Lucia Roa-Peña, Ina Chan, Nam W. Kim, Sholeh Jahanfard, Luisa F. Escobar-Hoyos, Kenneth R. Shroyer. Validation of a novel cytologic biomarker for urothelial carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr B01.

Utility of fine needle aspiration cytology (FNAC) in diagnosis of papillary lesions of the breast

Background: Diagnosis of lesions of the breast using Cytological screening is difficult. Understanding the common cytological features of papillary lesions of the breast can be useful for the diagnosis. Aims and objectives:To determine the utility of Fine Needle Aspiration Cytology (FNAC) in the diagnosis of papillary lesions of the breast Materials and methods: A retrospective study was performed from January 2010 to December 2015 in the cytology section, Department of Pathology of a tertiary care and referral hospital including patients diagnosed as papillary lesion on FNAC. Eight four cases were found (includes 44 cases which had histopathology follow-up, 36 cases which didn’t had follow-up), 4 cases were removed because of non-availability of slides. Thus, a total of 44 breast aspirates and their corresponding histology were reviewed. All the observations were done on total 44 cases. Results:Papillary Neoplasms on FNAC (n= 33): 13 cases (29.54%) were histologically confirmed as papillary neoplasms. All 13 cases (100%) showed true papillae with fibrovascular cores. 76% showed presence of columnar cells. 4 were benign and 9 malignant. Dyscohesion and severe atypia was only seen in malignant neoplasms. 20 cases were non papillary lesion on histopathology. Out of the 20 cases, 11 cases (55%) were infiltrating duct carcinoma (IDC), 4 were fibroadenomas (FA), 3 fibrocystic disease and one each was ductal carcinoma in situ (DCIS) and lobular carcinoma. Presence of papillaroid fragments and columnar cells was the most common cause for false positive diagnosis. Papillary Neoplasms Not Suspected Cytologically (n=11): In 5 cases cellularity was scanty and unsatisfactory for opinion. Missing fibrovascular cores in the aspirate was the cause of false negative diagnosis. The overall incidence of false positive was 25% and false negative was 13.75%. Sensitivity of FNAC to diagnose papillary lesions was 54.1%.Conclusion: Cytodiagnosis of papillary lesions is challenging and identification of true fibrovascular cores is essential for accurate diagnosis.

A novel risk score to predict early and late recurrence in solitary fibrous tumour.

Solitary fibrous tumours (SFTs) are rare mesenchymal neoplasms with recurrence rates of 10-30%. Current risk stratification systems for extrameningeal SFTs are based on cohorts with limited follow-up and are not suitable for prediction of late recurrences. In this study we aimed to develop a prognostic model accounting for both early and late recurrences using a relatively large patient cohort with long-term follow-up. Clinicopathological factors were analysed in a cohort of 100 extrameningeal, STAT6-positive SFTs. Median follow-up for overall survival (OS) and recurrence-free interval (RFi) were 121 and 84months, respectively. Disease relapse occurred in 31% of patients and median time to recurrence was 63months. In univariate analysis mitotic count, necrosis, male gender and presence of severe atypia and pleomorphism were associated with inferior RFi. Mitotic count, necrosis and male gender were independent predictors of recurrence in multivariate analysis. Previously published risk models were also statistically associated with RFi in our cohort, but failed to reliably identify low-risk patients due to poor prediction of late recurrences. A novel risk score based on mitotic count, necrosis and gender was able to stratify patients into low-, intermediate- and high-risk groups for both early and late recurrences. In this cohort of patients with extrameningeal SFT and long-term follow-up mitotic count, necrosis and gender were independent prognostic markers of recurrence. We propose a novel risk score based on these factors and accounting for late recurrences, which should be validated in external cohorts with sufficient follow-up time.

Post-operative complications following feminizing genitoplasty in moderate to severe genital atypia: Results from a multicenter, observational prospective cohort study

Disorders/differences of sex development (DSD) are congenital conditions in which there is atypical chromosomal, gonadal and/or phenotypic sex. While there remains controversy around the traditionally binary concept of sex, most patients with DSD are reared either male or female depending on their genetic sex, gonadal sex, genital phenotype and status of their internal genital tract. This study uses prospective data from 12 institutions across the United States that specialize in DSD care. We focused on patients raised female. Eligible patients had moderate to severe genital atypia (defined as Prader score >2), were ≤2 years of age at entry, and had no prior genitoplasty. The aim of this study is to describe early post operative complications for young patients undergoing modern approaches to feminizing genitoplasty. Of the 91 participants in the cohort, 57 (62%) were reared female. The majority had congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (n=52), 1 had ovo-testicular syndrome, 2 had mixed gonadal dysgenesis and 2 had partial androgen insensitivity syndrome (PAIS). Of the 50 participants who received early genitoplasty, 43 (86%) had follow-up at 6-12 months post-surgery. Thirty-two participants (64%) received a clitoroplasty, 31 (62%) partial urogenital mobilization and 4 (8%) total urogenital sinus mobilization. Eighteen percent (9/50) experienced post-surgical complications with 7 (14%) being rated as Clavien-Dindo grade III. Both parents and surgeons reported improved satisfaction with genital appearance of participants following surgery compared to baseline. This information on post-operative complications associated with contemporary approaches to feminizing genitoplasty performed in young children will help guide families when making decisions about whether or not to proceed with surgery for female patients with moderate to severe genital atypia.

A retrospective cohort study of the diagnostic value of different subtypes of atypical pigment network on dermoscopy

Atypical network encompasses several patterns. Few studies assess the sensitivity, specificity, and positive and negative predictive values of network subtypes. We assessed the diagnostic value of atypical network subtypes and their histopathologic correlates in cutaneous melanocytic lesions. A retrospective search (2014-2018) from a high-risk melanoma clinic for cases scored for atypical network with accompanying dermoscopic photographs yielded 120 lesions (15 melanoma; 30 severely, 38 moderately, and 32 mildly atypical nevi; 4 compound nevi; and 1 junctional nevus). A dermatopathologist blinded to diagnosis assessed dermoscopic and histologic features. Network abnormality correlates with histopathology and clinical diagnoses were assessed with sensitivity, specificity, positive and negative predictive values, and odds ratios. A multivariable model with shiny white streaks (odds ratio 3.02) and inverse network (OR 4.46) was most predictive of melanoma or severe atypia. Positive predictive value for melanoma or severe atypia in decreasing order was inverse network (73.9%), shiny white streaks (71.4%), loss of network (46%), branched streaks (29.4%), and thick brown lines (28.4%). Cases were retrospectively found from a pigmented lesion clinic and evaluated by a single dermatopathologist. Shiny white streaks and inverse network are most predictive of melanoma or severe atypia and warrant biopsy if found on dermoscopy.

The role of reflectance confocal microscopy in differentiating melanoma in situ from dysplastic nevi with severe atypia: A cross-sectional study

Melanoma in situ and dysplastic nevi with severe atypia present overlapping histopathologic features. Reflectance confocal microscopy findings can be integrated with the dermatopathology report to improve differentiation between melanoma and dysplastic nevi with severe atypia. To compare prevalence of reflectance confocal microscopy findings between melanoma in situ and dysplastic nevi with severe atypia. This retrospective observational study compared reflectance confocal microscopy findings in dermatopathologically diagnosed dysplastic nevi with severe atypia and melanoma in situ, collected between 2007 and 2017 at a private pigmented-lesion clinic. Concordant pathologic diagnosis was defined as unanimous agreement between 3 dermatopathologists who independently reviewed all cases; all other cases were classified as discordant. The study included 112 lesions, 62 concordant melanomas in situ, 28 concordant dysplastic nevi with severe atypia, and 22 discordant lesions. In comparing reflectance confocal microscopy findings in concordant cases, melanoma in situ showed more frequently than dysplastic nevi with severe atypia the presence of epidermal atypical melanocytes as round cells (19/62 vs 0/28; P<.001) and dendritic cells (50/62 vs 6/28; P<.001), as well as a diffuse distribution of epidermal atypical melanocytes (50/54 vs 3/6; P=.002). In contrast, dysplastic nevi with severe atypia showed the presence of dense melanocytic nests more frequently than melanoma in situ did (15/28 vs 14/62; P=.003). The study was based on a limited number of lesions originating from a single clinic. Reflectance confocal microscopy findings may help differentiate a subset of dysplastic nevi with severe atypia from melanoma in situ.

Mitotically active fibrothecoma in association with sclerous peritonitis

Mitotically active fibrothecoma associated with sclerosing peritonitis is an enigmatic and rare condition, described by Clement et al. in 1994, with fewer than 50 pathologically characterized cases. Association of these two lesions is extremely rare and the etiology currently remains unclear; therefore, association with anti-epileptic drugs was suggested.

Fine-needle aspiration cytology for the diagnosis of solid basaloid adenoid cystic carcinoma of the breast: Its role, limitation, and perspective.

Solid basaloid adenoid cystic carcinoma (SB-AdCC) is a subtype of breast AdCC which shows more aggressive clinical behavior than other subtypes. Fine-needle aspiration (FNA) cytology is a useful diagnostic tool for breast malignancies. However, most of the diagnostic cytological characteristics of AdCC are not present in SB-AdCC and cytomorphological studies of this subtype are limited. Here, we evaluated the utility of FNA in the diagnosis of SB-AdCC of the breast. A search of the pathology archives of our institutions for FNA specimens of histologically confirmed SB-AdCC between 2012 and 2019 identified four patients with SB-AdCC of the breast. All patients were female and the average age was 60 years. Cytologically, one case was classified as malignant, two as indeterminate, and one as unsatisfactory. Smears had low to moderate cellularity. All smears showed ribbon-like material surrounding the clusters and a vertical nuclear arrangement toward the peripheral rim. Hyaline globules appeared only in one case. Cells in all cases showed an oval, angular, and spindle shape hyperchromatic nuclei with mild to severe atypia, and also dispersed naked nuclei similar to the cells of the clusters were detected in one case. In histological sections, these cytological findings were compatible with the histological findings and divergent histological differentiation was detected. Diagnosing of few cellular smears of SB-AdCC is difficult whereas the features of peripheral rim of the clusters, naked nuclei, and the divergent differentiation may be important for diagnosing SB-AdCC of the breast.

Risk Stratification of Severely Dysplastic Nevi by Non-Invasively Obtained Gene Expression and Mutation Analyses

Background: Strategies to non-invasively detect cutaneous melanoma generally focus on differentiating melanoma from non-melanoma lesions. However, given the variabilities in practice and lack of guidelines, it is important for clinicians to understand how such strategies and technologies perform on borderline lesions of uncertain clinical behavior. Objective: To evaluate LINC and PRAME gene expression and the presence of somatic mutations in BRAF, NRAS, and/or TERT in severely dysplastic nevi (SDN) and to assess, how combining gene expression and mutation analyses may impact test performance.Materials and Methods: One hundred three eligible skin lesions clinically suspicious for melanoma were non-invasively sampled via adhesive patches to enable genomic analyses. Afterward, these same lesions were immediately surgically biopsied to enable comparisons of genomic analyses with histopathologic diagnoses rendered by a panel of three dermatopathologists. Twenty-three of these lesions analyzed were deemed borderline lesions of SDN histology by at least one dermatopathologist. RNA-based gene expression positivity by Pigmented Lesion Assay (PLA) analysis was defined by detectable levels of LINC and/or PRAME. DNA-based mutation positivity was defined as detection of somatic mutations in BRAF (non-V600E), NRAS, and/or the TERT promoter. Results: Adding TERT mutation analyses to PLA gene expression increases the test’s sensitivity to rule out melanoma from 93% to 97% in this study. In addition, 61% of PLA positive lesions that were not diagnosed as melanoma were found to have severe histologic atypia. PLA-positive lesions histopathologically diagnosed as melanomas harbored TERT mutations in 70% of cases while both SDN and non-melanoma lesions including nevi without severe histologic atypia harbored TERT mutations in 4% of cases. BRAF non-V600E and NRAS mutations were only found in the melanoma group and adding these mutations did not further enhance the test’s sensitivity. Conclusions and Relevance: PLA positivity increases with histologic atypia of pigmented skin lesions. Combining TERT mutation analyses with melanoma-associated gene expression provides additional genetic information to further non-invasively risk-stratify pigmented lesions. These findings furthermore support that pigmented lesions exist on a spectrum of genomic atypia that may prove useful in identifying borderline lesions beyond their morphological appearance.

"Napoleon Hat" Sign: A Distinctive Cytologic Clue to Reactive Pneumocytes.

Various types of acute and subacute lung injury can cause severe reactive pneumocyte atypia, which may mimic malignant proliferations and present a major diagnostic pitfall. This particularly applies to cytologic preparations and frozen sections, where background inflammatory injury may be subtle or not apparent. Although several distinguishing morphologic features of reactive pneumocytes have been suggested, there is significant overlap with neoplastic proliferations. In this article, a highly distinctive but underrecognized feature of reactive pneumocytes is highlighted that can serve as a useful diagnostic clue. The feature refers to the distinctive pinched shape of reactive pneumocytes, for which the author has coined the term "Napoleon hat" sign to draw the analogy with the iconic headwear. The analogy vividly captures the distinctive shape of reactive pneumocytes, and can serve as a useful diagnostic and teaching tool in the interpretation of pulmonary specimens.

What do we know about the cytological features of pure intraductal carcinomas of the salivary glands?

Intraductal carcinomas (IDCs) are rare, poorly characterised salivary gland tumours. The cytological features of IDCs are even less known. In this paper, a systematic literature review of pure IDCs (without stromal invasion, not associated with other histotypes) of low-grade (LG-IDCs) and high-grade (HG-IDCs) was performed. The bibliographic research included multiple databases (PubMed, Scopus, Web of Science). Mild-moderate nuclear atypia favoured LG-IDCs, severe atypia favoured HG-IDCs. Preoperative fine-needle aspiration cytology (FNAC) was performed in 13/94 published cases (14%): 10 parotid; two oral; one submandibular. All the cases were histologically LG-IDCs, except two parotid IDCs. FNAC results included: negative for malignancy (three of 13 cases, 23%); tumour of uncertain malignant potential (seven of 13, 54%); malignancy (three of 13, 23%). The ductal component was identified in two cases; mucoepidermoid carcinoma was suggested in two additional cases. The grade was underestimated on FNAC evaluation in one HG-IDC as focal high-grade features were present on subsequent histological examination. The cases diagnosed as malignant tumours or describing intermediate atypia resulted in LG-IDCs on subsequent histology. Occasional mitoses were described only in one HG-IDC; this feature may have not been considered in the remaining published cases. FNAC and clinico-pathological correlation are important aids for clinicians and pathologists. FNAC could assist surgery even if an accurate diagnosis is sometimes impossible. Discrepancy in grading the nuclear atypia between the FNAC material and the resected specimen can occur, sometimes being unavoidable. Further studies are needed to better characterise this rare tumour.

Solid variant of papillary thyroid carcinoma: an under-recognized entity.

Solid variant of papillary thyroid carcinoma (SVPTC) is a rare morphological variant of papillary thyroid carcinoma (PTC). SVPTC is histologically characterized by predominant solid, trabecular and insular nests of tumor cells while cytological features of PTC such as nuclear grooves and nuclear inclusions are preserved. In fine needle aspiration cytology smears, tumor cells of SVPTC may be presented in cohesive, syncytial or trabecular clusters accompanied by some discohesiveness in the absence of necrosis. Although SVPTC and poorly differentiated thyroid carcinoma (PDTC) share similar histological findings of solid nests, SVPTC can be differentiated from PDTC in the lack of tumor necrosis, severe nuclear atypia, and a higher mitotic index. Immunohistochemical expression of CK19 and HBME-1, common markers of PTC, is decreased in solid nests of SVPTC. In pediatric patients exposed to radiation after the Chernobyl nuclear accident, there was a higher prevalence of SVPTC with RET/PTC3 type rearrangement. BRAF mutations are also reported in a small number of adult patients with SVPTC without any prior radiation exposure. Patients with SVPTC may have a slightly higher incidence of metastasis and recurrence of the tumor compared to conventional PTC, although overall survival rate is comparable. In this article, the current knowledge of SVPTC will be reviewed and discussed with an emphasis on the histopathological feature.

Analysis of salivary detection of P16INK4A and RASSF1A promoter gene methylation and its association with oral squamous cell carcinoma in a Colombian population.

BackgroundEpigenetic factors play a fundamental role in the etiopathogenesis of oral squamous cell carcinoma (OSCC). This study evaluated if salivary detection of P16INK4A/RASSF1A gene promoter methylation might be linked to the clinical/histological features of OSCC in a Colombian population. Material and MethodsMethylation-specific polymerase chain reaction (MSP-PCR) was used to detect the methylation frequency of P16INK4A/RASSF1A genes in DNA obtained from whole saliva collected of 40 healthy controls (HC) and 43 OSCC patients. Determination of the clinical performance of MSP-PCR assay was based on standard algorithms derived from two-way contingency table analysis. The association of methylation status of targeted genes with OSCC was analyzed in a multivariate binary logistic regression model. ResultsThere were significantly higher proportions of promoter methylation of these target genes in OSCC patients when compared with HC. The analysis of single methylated genes showed high specificity, good positive and negative predictive values, but was accompanied by a low sensitivity. OSCC cases with clinical stage III/IV, poorly differentiated, and severe cellular atypia showed a significantly greater proportion of methylated than that of unmethylated targeted genes in saliva samples. Logistic regression analysis indicated an independent association of P16INK4A and RASSF1A promoter methylation with OSCC diagnosis. A significant interaction effect between ageing and P16INK4A promoter methylation was also detected. ConclusionsSalivary detection of P16INK4A and RASSF1A promoter methylation appears to be independently associated with OSCC and may be linked to the tumor activity in the present population. Consequently, the targeting of these genes in saliva samples might constitute an important tool for diagnosis and prognosis purposes. Key words:Gene methylation, oral squamous cell carcinoma, P16INK4A, RASSF1A, saliva.

Primary Leiomyosarcoma of the Penis: A Review and Update of the Literature

Less than 50 cases of Primary Leiomyosarcomas of the Penis (PLOP) have been reported despite this PLOPs are the second most common sarcomas of the penis. The usual site for the development of PLOP is the shaft or base of the penis but the malignancy can affect any site of the penis. PLOPs are likely to be superficially located above the tunica albuginea in comparison with deep seated PLOPs. Superficial PLOPs may be asymptomatic or they may present as lumps, ulcers or nodules on the penis. Deep PLOPs may manifest with dysuria and difficulty with micturition when they compress the urethra. Diagnosis of PLOP is based upon the pathology examination features of specimens of the penile lesion that show interlacing fascicles of spindled-cells that have abundant eosinophilic cytoplasm, focal juxta-nuclear vacuoles and blunt ended nuclei and moderate to severe nuclear atypia, rarely atypical multi-nucleated giant cells and focal necrosis tend to be seen. There may be evidence of many mitoses. Immunohistochemistry studies of PLOP tend to show tumor cells that exhibit positive staining for desmin, muscle specific-actin, and alpha smooth muscle actin. Most often superficial PLOPs tend to be treated by wide complete excision of the tumor with tumor free and clear surgical resection margins. Deep seated PLOPs have also been treated by complete excision in various forms depending upon the site and size of the tumor and some of these have included Wide excision, partial penectomy and total penectomy alone and sometimes with adjuvant chemotherapy/radiotherapy. Some cases of deep PLOPs tend to be associated with the development of recurrences and metastases as well as death of the patient and hence deep PLOPs are aggressive tumors. Some people are of the opinion that chemotherapy and radiotherapy are not effective for the adjuvant treatment of PLOP. For this reason it would appear that there is need for the development of new chemotherapy medicaments that would effectively destroy PLOP tumor cells. There is need to undertake a global multi-center treatment trial of immunotherapy, chemotherapy and radiotherapy in order to streamline the treatment of PLOPs especially deep PLOPs.

Anxiety and depression in COPD patients and correlation with sputum and BAL cytology

&#x0D; &#x0D; &#x0D; Background and aims: Anxiety and depression are common in patients with chronic obstructive pulmonary disease (COPD). The degree of lung function may not explain anxiety and depression. The aim of our study was to assess the psycholog- ical aspects of COPD, to test the BODE index (a composite score of body mass, obstruction, dyspnea and exercise capac- ity), and to evaluate the association between atypical cyto- logic findings of sputum, bronchoalveolar lavage (BAL) and the pyschological components of the disease.&#x0D; Methods: COPD was classsified according to the GOLD stages based on forced expiratory volume in 1 second (FEV1) in 60 stable patients. The BODE index was calculated for grading COPD. The Hospital anxiety and depression (HAD) scale was used to appraise the anxiety and depression symptoms. Cytologic examination of sputum and BAL samples were per- formed in each patient. The cytologic findings were classified as normal, mild, moderate or severe atypia.&#x0D; Results: The overall prevalance of anxiety and depression symptoms was 41.7% and 46.7% respectively. The prevalance of these symptoms increased with increasing BODE stages and correlated well with the severity of atypical BAL cytology results (p &lt; 0.001). Dyspnea and reduced exercise capacity were the predominant mechanisms leading to anxiety and depression symptoms associated with COPD.&#x0D; Conclusions: We conclude that the BODE index is superior to GOLD stratification for explaining anxiety and depression symptoms in COPD. BAL cytologic findings, which reflect the distal parenchymal lung structure, correlated significantly with the presence of the anxiety and depression symptoms.&#x0D; &#x0D; &#x0D;

Predictors of Psychosocial Distress in Parents of Young Children with Disorders of Sex Development.

We evaluated demographic, financial and support predictors of distress for parents of young children with disorders of sex development including atypical genital development, and characterized early parental experiences. This work extends our previous findings to identify those parents at risk for distress. Participants included mothers (76) and fathers (63) of a child (78) diagnosed with disorders of sex development characterized by moderate to severe genital atypia. Parents completed a demographic questionnaire, measures of anxious and depressive symptoms, quality of life, illness uncertainty and posttraumatic stress symptoms, and rated their satisfaction with the appearance of their child's genitalia. Depressive and posttraumatic stress symptoms of caregivers were comparable to standardized norms while levels of anxious symptoms were below norms. A subset of parents reported clinically elevated symptoms. Overall 26% of parents reported anxious symptoms, 24% reported depressive symptoms and 17% reported posttraumatic stress symptoms. Levels of illness uncertainty were lower than those of parents of children with other chronic illnesses. Differences by parent sex emerged, with mothers reporting greater distress. Lower income, increased medical care and travel expenses, and having no other children were related to increased psychosocial distress. Early psychosocial screening is recommended for parents of children with disorders of sex development. Clinicians should be aware that financial burden and lack of previous parenting experience are risk factors for distress.