Epidemiological distribution of high-risk human papillomavirus genotypes and associated factors among patients with esophageal carcinoma at Bugando medical center in Mwanza, Tanzania.

BACKGROUND: Esophageal carcinoma is a growing concern in regions that have a high incidence of human papillomavirus (HPV) infection such as East Africa. HPV, particularly the high-risk genotypes, is increasingly recognized as a risk factor for esophageal carcinoma. We set out to investigate the prevalence and associated factors of high-risk HPV in formalin-fixed paraffin-embedded (FFPE) tissue blocks with esophageal carcinoma at Bugando Medical Center, a tertiary referral hospital in Mwanza, Tanzania, East Africa. METHODS: A total of 118 esophageal carcinoma FFPE tissue blocks, collected from January 2021 to December 2022, were analyzed. Genomic DNA was extracted from these tissues, and multiplex polymerase chain reaction (PCR) was performed to detect HPV using degenerate primers for the L1 region and type-specific primers for detecting HPV16, HPV18, and other high-risk HPV genotypes. Data were collected using questionnaires and factors associated with high-risk HPV genotypes were analyzed using STATA version 15 software. RESULTS: Of the 118 patients' samples investigated, the mean age was 58.3 ± 13.4 years with a range of 29-88 years. The majority of the tissue blocks were from male patients 81/118 (68.7%), and most of them were from patients residing in Mwanza region 44/118 (37.3%). Esophageal Squamous Cell Carcinoma (ESCC) was the predominant histological type 107/118 (91.0%). Almost half of the tissue blocks 63/118 (53.3%) tested positive for high-risk HPV. Among these, HPV genotype 16 (HPV16) was the most common 41/63 (65.1%), followed by HPV genotype 18 (HPV18) 15/63 (23.8%), and the rest were other high-risk HPV genotypes detected by the degenerate primers 7/63 (11.1%). The factors associated with high-risk HPV genotypes were cigarette smoking (p-value < 0.001) and alcohol consumption (p-value < 0.001). CONCLUSION: A substantial number of esophageal carcinomas from Bugando Medical Center in Tanzania tested positive for HPV, with HPV genotype 16 being the most prevalent. This study also revealed a significant association between HPV status and cigarette smoking and alcohol consumption. These findings provide important insights into the role of high-risk HPV in esophageal carcinoma in this region.

Evaluation of Breast Health Promotion Intervention Among Catholic Nuns in Lake Zone 'Tanzania.

Objective: Despite facing unique barriers, Catholic nuns in Tanzania require accessible breast health promotion. This study explores interventions to empower nuns through knowledge, improved attitudes, and positive practices, ultimately promoting well-being and early detection for better breast cancer outcomes. Materials and Methods: A quasi-experimental design study guided by the Health Belief Model was conducted to monitor the implementation of a breast health intervention program aimed at increasing breast cancer screening knowledge among 385 Catholic nuns aged 20 to over 60 years old within Lake Zone, Tanzania. Data were collected at two-time points: pre-intervention (baseline) and implementation phase intervention (after three months). The intervention consisted of a 2-hour educational session. Participants had opportunities to ask questions and provide feedback. Results: The breast health promotion intervention was well-received by Catholic nuns, with 339 (88%) expressing strong motivation to learn and promote awareness. The training effectively increased knowledge and positive attitudes towards breast cancer screening. Researcher assistants successfully delivered the program, and 354 (92%) of participants expressed interest in continued education and support. The intervention addressed cultural barriers and empowered nuns to take charge of their health, though some challenges remain meanwhile 158 (41%) had limited prior knowledge, 81 (21%) hesitated to discuss breast health due to religious beliefs, and some faced difficulty applying the learnings. Conclusion: Overall, the breast health promotion intervention had a positive outcome on the Catholic nuns' awareness and knowledge of breast health. However, addressing the identified barriers and challenges is crucial to further enhance the intervention's effectiveness and sustainability.

BCMA CAR-T cells in multiple myeloma-ready for take-off?

Although the approval of new drugs has improved the clinical outcome of multiple myeloma (MM), it was widely regarded as incurable over the past decades. However, recent advancements in groundbreaking immunotherapies, such as chimeric antigen receptor T cells (CAR-T), have yielded remarkable results in heavily pretreated relapse/refractory patients, instilling hope for a potential cure. CAR-T are genetically modified cells armed with a novel receptor to specifically recognize and kill tumor cells. Among the potential targets for MM, the B-cell maturation antigen (BCMA) stands out since it is highly and almost exclusively expressed on plasma cells. Here, we review the currently approved BCMA-directed CAR-T products and ongoing clinical trials in MM. Furthermore, we explore innovative approaches to enhance BCMA-directed CAR-T and overcome potential reasons for treatment failure. Additionally, we explore the side effects associated with these novel therapies and shed light on accessibility of CAR-T therapy around the world.

p53 and ovarian carcinoma survival: an Ovarian Tumor Tissue Analysis consortium study.

Our objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high-grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi-institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of TP53 mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93.4% (4,630/4,957) in HGSC compared to 11.9% (116/973) in EC and 11.5% (86/748) in CCC. In HGSC, there were no differences in overall survival across the abnormal p53 expression patterns. However, in EC and CCC, abnormal p53 expression was associated with an increased risk of death for women diagnosed with EC in multivariate analysis compared to normal p53 as the reference (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.36-3.47, p = 0.0011) and with CCC (HR = 1.57, 95% CI 1.11-2.22, p = 0.012). Abnormal p53 was also associated with shorter overall survival in The International Federation of Gynecology and Obstetrics stage I/II EC and CCC. Our study provides further evidence that functional groups of TP53 mutations assessed by abnormal surrogate p53 IHC patterns are not associated with survival in HGSC. In contrast, we validate that abnormal p53 IHC is a strong independent prognostic marker for EC and demonstrate for the first time an independent prognostic association of abnormal p53 IHC with overall survival in patients with CCC.

The trend of schistosomiasis related bladder cancer in the lake zone, Tanzania: a retrospective review over 10 years period.

INTRODUCTION: Bladder cancer is a possible outcome of chronic urinary schistosomiasis in many endemic countries. In Tanzania, the Lake Victoria area is one of the areas with the highest prevalence of urinary schistosomiasis and higher incidences of squamous cell carcinoma (SCC) of the urinary bladder. A previous study in the area over one decade (2001-2010) showed SCC to be common in patients aged below 50 years. With various prevention and intervention programs there are likely to be notable changes in schistosomiasis-related urinary bladder cancer, which is currently unknown. Updated information on the status of SCC in this area will be useful for giving an insights into efficacy of control interventions implemented and help guide the initiation of new ones. Therefore, this study was done to determine the current trend of schistosomiasis-related bladder cancer in lake zone, Tanzania. METHODS: This was a descriptive retrospective study of histologically confirmed urinary bladder cancer cases diagnosed at the Pathology Department of Bugando Medical Centre over 10 years period. The patient files and histopathology reports were retrieved and information was extracted. Data were analyzed using Chi-square and student t-test. RESULTS: A total of 481 patients were diagnosed with urinary bladder cancer during the study period whereby, 52.6% were males and 47.4% were females. The mean age regardless of histological type of cancer was 55 ± 14.2 years. The SCC was the commonest histological type accounting for 57.0%, followed by transitional cell carcinoma 37.6%, and 5.4% were adenocarcinomas. The Schistosoma haematobium eggs were observed in 25.2% and were commonly associated with SCC (p = 0.001). Poorly differentiated cancers were observed mostly in females (58.6%) compared to males (41.4%) (p = 0.003). Muscular invasion of the urinary bladder by cancer was observed in 11.4% of the patients, and this was significantly higher in non-squamous than in squamous cancers (p = 0.034). CONCLUSION: Schistosomiasis-related cancers of the urinary bladder in the Lake zone of Tanzania is still a problem. Schistosoma haematobium eggs were associated with SCC type indicating the persistence of infection in the area. This calls for more efforts on preventive and intervention programs to reduce the burden of urinary bladder cancer in the lake zone.

High prevalence of sexually transmitted infections among asymptomatic women opting for the intrauterine contraceptive device use in Mwanza, Tanzania: An urgent call for control interventions.

Objective: Placement of intrauterine contraceptive device (IUCD) in asymptomatic woman infected with sexually transmitted infection (STIs) can lead to pelvic inflammatory diseases (PID) and infertility if not well treated. The current study investigated the magnitude of sexually transmitted infections among women opting for IUCD use in the city of Mwanza, Tanzania. Methods: A cross-sectional study involving 150 asymptomatic women was conducted from August to December 2017. Detection of Chlamydia trachomatis antigen from endocervical swabs was done using immunochromatographic rapid tests while sera were used for detection of Treponema pallidum, human immunodeficiency virus (HIV) and herpes simplex virus Type 2 (HSV-2) antibodies. Results: The overall prevalence of STIs was 45/150 (30%, 95% CI: 22-37) while that of individual STIs were 27.3%, 5.3%, and 2.6% for C trachomatis, T pallidum, and HSV-2, respectively. History of dysuria (aOR 6.6; 95% CI 2.3-18.8; p < 0.001) and history of STIs (aOR 4.6; 95%CI 1.0-20.8; p = 0.049) independently predicted presence of STIs. Conclusions: Prevalence of STIs among women opted for IUCD use in the city of Mwanza, Tanzania is alarmingly high and is predicted by past history of dysuria and history of partner's STIs, calling for the need of screening of the STIs among high-risk women in low- and middle-income countries (LMICs) opting for IUCD use.

Bacteria Patterns on Tonsillar Surface and Tonsillar Core Tissue among Patients Scheduled for Tonsillectomy at Bugando Medical Centre, Mwanza, Tanzania.

BACKGROUND: Tonsillitis is an inflammation of the tonsils due to either viruses or bacteria. Here, we report the bacteria patterns on the tonsillar surface and tonsillar core tissue among patients scheduled for tonsillectomy at Bugando Medical Centre (BMC), Mwanza Tanzania. METHODS: The study included 120 patients planned for tonsillectomy between April and July 2019. Swab samples from tonsillar surface pre-tonsillectomy and core post-tonsillectomy were collected. Culture was performed following the microbiology laboratory standard operating procedures. Data analysis was completed using STATA version 13, as per the study objectives. RESULTS: The slight majority of participants were males (73; 60.83%) with median age of 6 years (interquartile range 4-11). The proportion of positive culture growth was higher on the surface than in core swab samples: 65 (54.2%) vs. 42 (35.0%), p = 0.003. The commonest bacterial pathogen detected from the surface and core were S. aureus in 29 (40.3%) and 22 (51.2%) participants, followed by S. pyogenes in 17 (23.6%) and 11 (25.6%), respectively. Methicillin-resistant Staphylococcus aureus (MRSA) was observed in 20/51 (39%) of isolates. Streptococcus pyogenes resistance to macrolides ranged from 8.3% for core isolates to 35.3% for surface isolates. Features suggestive of tonsillitis on histology were reported in 83 (73.5%) samples. CONCLUSION: More than two-thirds of patients undergoing tonsillectomy had a positive culture for possible bacterial pathogens. Staphylococcus aureus and Streptococcus pyogenes were the predominant bacteria detected with more than one third of Staphylococcus aureus being MRSA. More studies to investigate the treatment outcome of these patients are highly recommended.

Utility of ultrasound guided versus conventional fine needle aspiration cytology in diagnosing breast malignancies among patients with palpable breast lumps at Bugando Medical Centre, Mwanza Tanzania.

INTRODUCTION: breast lump is the commonest presentation for both benign and maligant breast conditions. Both ultrasound guided and conventional fine needle aspiration cytology (FNAC) have been used for diagnosing of breast malignancy among patients with palpable breast lumps. This study compared diagnostic utility of ultrasound guided versus conventional FNAC in diagnosing breast malignancies among patients with palpable breast lumps at Bugando Medical Centre. METHODS: this was a hospital based cross sectional study with a follow up component that combined both retrospective data (from January 2017 to June 2018) and prospective data (from July 2018 to June 2019). RESULTS: during the study, total of 354 patients (male; female = 1: 32) were enrolled in the study. A total of 134 (37.9%) patients had malignant lesions while 220 (62.1%) of patients had benign lesions confirmed on histology. The diagnostic utility (sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy) for conventional FNAC was 86.7%, 95.7%, 93.5%, 91.1% and 92.0% with an 8% error margin versus ultrasound guided FNAC all were 100% with a 0% error margin respectively. CONCLUSION: both ultrasound guided and conventional FNAC show almost perfect agreement with histology. However, ultrasound guided FNAC has a higher diagnostic utility relative to conventional FNAC in diagnosing breast malignancies.

Ovarian cancer: diagnostic accuracy and tumor types distribution in East Africa compared to North America.

BACKGROUND: Ovarian cancer is a spectrum of several histologically distinct tumor types that differ in etiology, response to therapy, and prognosis. In resource-limited settings, the diagnosis of ovarian cancer can be challenging. This study describes the distribution of ovarian cancer tumor types in East Africa as well as assessing the diagnostic accuracy by using contemporary methods. METHODS: Data from 210 women identified from the records with a diagnosis of ovarian cancer in a period of 15 years were included. Two tissue microarrays were constructed and stained with 20 antibodies relevant to ovarian cancer subtyping. An integrated diagnosis was reached by the review of full Haematoxylin and Eosin stained sections, with consideration of immunohistochemical results. The integrated diagnoses were compared with the original diagnoses, and the degree of agreement was evaluated by percentage and Kappa statistics. RESULTS: Though limited by selection bias, the results suggest lower rates of ovarian cancer in East Africa compared to a North American population from Alberta, Canada. There was a higher proportion of sex cord stromal tumors and germ cell tumors in the East African population. Diagnostic accuracy for main ovarian tumor type categories was substantial (Kappa 0.70), but only fair for specific ovarian carcinoma histotypes (Kappa 0.34). Poor Haematoxylin and Eosin stain was the main factor hindering the correct diagnosis, which was not related to tissue processing. CONCLUSIONS: In a resource-limited setting, where immunohistochemistry is not routinely carried out, diagnostic accuracy for the main categories of ovarian carcinoma is substantial and could be further improved by standardization of the basic Haematoxylin and Eosin stain.

Combined CCNE1 high-level amplification and overexpression is associated with unfavourable outcome in tubo-ovarian high-grade serous carcinoma.

CCNE1 amplification is a recurrent alteration associated with unfavourable outcome in tubo-ovarian high-grade serous carcinoma (HGSC). We aimed to investigate whether immunohistochemistry (IHC) can be used to identify CCNE1 amplification status and to validate whether CCNE1 high-level amplification and overexpression are prognostic in HGSC. A testing set of 528 HGSC samples stained with two optimised IHC assays (clones EP126 and HE12) was subjected to digital image analysis and visual scoring. DNA and RNA chromogenic in situ hybridisation for CCNE1 were performed. IHC cut-off was determined by receiver operating characteristics (ROC). Survival analyses (endpoint ovarian cancer specific survival) were performed and validated in an independent validation set of 764 HGSC. Finally, combined amplification/expression status was evaluated in cases with complete data (n = 1114). CCNE1 high-level amplification was present in 11.2% of patients in the testing set and 10.2% in the combined cohort. The optimal cut-off for IHC to predict CCNE1 high-level amplification was 60% positive tumour cells with at least 5% strong staining cells (sensitivity 81.6%, specificity 77.4%). CCNE1 high-level amplification and overexpression were associated with survival in the testing and validation set. Combined CCNE1 high-level amplification and overexpression was present in 8.3% of patients, mutually exclusive to germline BRCA1/2 mutation and significantly associated with a higher risk of death in multivariate analysis adjusted for age, stage and cohort (hazard ratio = 1.78, 95 CI% 1.38-2.26, p < 0.0001). CCNE1 high-level amplification combined with overexpression identifies patients with a sufficiently poor prognosis that treatment alternatives are urgently needed. Given that this combination is mutually exclusive to BRCA1/2 germline mutations, a predictive marker for PARP inhibition, CCNE1 high-level amplification combined with overexpression may serve as a negative predictive test for sensitivity to PARP inhibitors.

Histological and molecular diversity and heterogeneity of precancerous lesions associated with inflammatory bowel diseases.

AIMS: Inflammatory bowel disease (IBD)-associated precancerous lesions may be adenomatous or non-adenomatous with various histomorphologies. We aim to validate the newly proposed classification, to explore the neoplastic nature of the non-adenomatous lesions and to elucidate the molecular mechanisms underlying the different histomorphologies. METHODS: 44 background precursor lesions identified in 53 cases of surgically resected IBD-associated colorectal and ileal carcinomas were reviewed for the histomorphological features (classified into adenomatous, mucinous, sessile serrated adenoma (SSA)-like, traditional serrated adenoma-like, differentiated, eosinophilic and serrated not otherwise specified (NOS)) and analysed for a key panel of colonic cancer-related molecular markers. RESULTS: Approximately 60% of the lesions were adenomatous, of which some had mixed serrated, mucinous or eosinophilic changes. The remaining non-adenomatous lesions, including all other types except SSA-like type, mostly showed mixed features and focal adenomatous dysplasia. KRAS mutation and p53 mutant-type expression were found in about half cases across all types, while PIK3CA mutation only in some of adenomatous and eosinophilic lesions and MLH1/PMS2 loss in a subset of adenomatous, mucinous and eosinophilic but not in differentiated and serrated lesions. SAT-B2 or PTEN loss and IMP3 overexpression were seen in a small subset of lesions. No BRAF, NRAS or EGFR gene mutation was detected in any type. Certain molecular-morphological correlations were demonstrated; however, no single or combined molecular alteration(s) was specific to any particular morphological type. CONCLUSIONS: IBD-associated precancerous lesions are heterogeneous both histologically and molecularly. True colitis-associated adenomatous lesions are unlikely conventional adenomas. Non-adenomatous lesions without frank cytologic dysplasia should also be regarded as neoplastic.

A combination of the immunohistochemical markers CK7 and SATB2 is highly sensitive and specific for distinguishing primary ovarian mucinous tumors from colorectal and appendiceal metastases.

Primary ovarian mucinous tumors can be difficult to distinguish from metastatic gastrointestinal neoplasms by histology alone. The expected immunoprofile of a suspected metastatic lower gastrointestinal tumor is CK7-/CK20+/CDX2+/PAX8-. This study assesses the addition of a novel marker SATB2, to improve the diagnostic algorithm. A test cohort included 155 ovarian mucinous tumors (105 carcinomas and 50 borderline tumors) and 230 primary lower gastrointestinal neoplasms (123 colorectal adenocarcinomas and 107 appendiceal neoplasms). All cases were assessed for SATB2, PAX8 CK7, CK20, and CDX2 expression on tissue microarrays. Expression was scored in a 3-tier system as absent, focal (1-50% of tumor cells) and diffuse ( >50% of tumor cells) and then categorized into either absent/present or nondiffuse/diffuse. SATB2 and PAX8 expression was further evaluated in ovarian tumors from an international cohort of 2876 patients (expansion cohort, including 159 mucinous carcinomas and 46 borderline mucinous tumors). The highest accuracy of an individual marker in distinguishing lower gastrointestinal from ovarian mucinous tumors was CK7 (91.7%, nondiffuse/diffuse cut-off) followed by SATB2 (88.8%, present/absent cut-off). The most effective combination was CK7 and SATB2 with accuracy of 95.3% using the 3-tier interpretation, absent/focal/diffuse. This combination outperformed the standard clinical set of CK7, CK20 and CDX2 (87.5%). Re-evaluation of outlier cases confirmed ovarian origin for all but one case. The accuracy of SATB2 was confirmed in the expansion cohort (91.5%). SATB2 expression was also detected in 15% of ovarian endometrioid carcinoma but less than 5% of other ovarian histotypes. A simple two marker combination of CK7 and SATB2 can distinguish lower gastrointestinal from ovarian primary mucinous tumors with greater than 95% accuracy. PAX8 and CDX2 have value as second-line markers. The utility of CK20 in this setting is low and this warrants replacement of this marker with SATB2 in clinical practice.

Proteomics-Derived Biomarker Panel Improves Diagnostic Precision to Classify Endometrioid and High-grade Serous Ovarian Carcinoma.

PURPOSE: Ovarian carcinomas are a group of distinct diseases classified by histotypes. As histotype-specific treatment evolves, accurate classification will become critical for optimal precision medicine approaches. EXPERIMENTAL DESIGN: To uncover differences between the two most common histotypes, high-grade serous (HGSC) and endometrioid carcinoma, we performed label-free quantitative proteomics on freshly frozen tumor tissues (HGSC, n = 10; endometrioid carcinoma, n = 10). Eight candidate protein biomarkers specific to endometrioid carcinoma were validated by IHC using tissue microarrays representing 361 cases of either endometrioid carcinoma or HGSC. RESULTS: More than 500 proteins were differentially expressed (P < 0.05) between endometrioid carcinoma and HGSC tumor proteomes. A ranked set of 106 proteins was sufficient to correctly discriminate 90% of samples. IHC validated KIAA1324 as the most discriminatory novel biomarker for endometrioid carcinoma. An 8-marker panel was found to exhibit superior performance for discriminating endometrioid carcinoma from HGSC compared with the current standard of WT1 plus TP53 alone, improving the classification rate for HGSC from 90.7% to 99.2%. Endometrioid carcinoma-specific diagnostic markers such as PLCB1, KIAA1324, and SCGB2A1 were also significantly associated with favorable prognosis within endometrioid carcinoma suggesting biological heterogeneity within this histotype. Pathway analysis of proteomic data revealed differences between endometrioid carcinoma and HGSC pertaining to estrogen and interferon signalling. CONCLUSIONS: In summary, these findings support the use of multi-marker panels for the differential diagnosis of difficult cases resembling endometrioid carcinoma and HGSC.

Nuclear ß-catenin and CDX2 expression in ovarian endometrioid carcinoma identify patients with favourable outcome.

AIMS: Ovarian endometrioid carcinoma (EC) generally has a good prognosis. Adjuvant chemotherapy can be spared in low-stage disease, but prognostic biomarkers are needed to refine the treatment threshold. Wnt/ß-catenin signalling is commonly altered in EC. We examined immunohistochemical expression of nuclear ß-catenin and CDX2 as prognostic biomarkers for EC; both are mediators of the Wnt pathway. METHODS AND RESULTS: We evaluated two ovarian EC cohorts, discovery set (n = 183) and validation set (n = 174), with ovarian cancer-specific survival (OCSS) as the primary end-point. In univariable analysis, nuclear ß-catenin expression was significantly associated with longer OCSS in the discovery set [hazard ratio (HR) = 0.36, 95% confidence interval (CI) = 0.16-0.74, P = 0.004] and the validation set (HR = 0.35, 95% CI = 0.11-0.89, P = 0.006). Similar significant associations were observed with CDX2 expression in the discovery set (HR = 0.25, 95% CI = 0.11-0.50, P < 0.001) and validation set (HR = 0.27, 95% CI = 0.07-0.75, P = 0.020). In multivariable analysis, combined positivity of both markers was significantly associated with longer OCSS in the discovery set (HR = 0.20, 95% CI = 0.06-0.49, P < 0.001) and in the validation set (HR = 0.33 95% CI = 0.07-0.1.06, P = 0.047). In a stratified analysis for stage IC/II EC, combined positivity identified a subset of patients with a significantly longer OCSS in the discovery cohort but only a non-significant trend in the validation cohort. CONCLUSIONS: Nuclear ß-catenin and CDX2 expression individually or in combination are validated prognostic markers for ovarian EC. However, their full potential to stratify low risk patients at adjuvant threshold awaits further multimarker study.

Disseminated cryptococcosis in a HIV-negative patient: Case report of a newly diagnosed hypertensive adult presenting with hemiparesis.

We report a case of disseminated cryptococcosis in a 42-year old immunocompetent female. Prior to admission at Bugando Medical Center, the patient was attended at three hospitals for hypertension and clinically diagnosed malaria. Following diagnosis of disseminated Cryptococcus at our center, she was successfully treated with fluconazole but remained with visual loss. Blood cultures should be considered in the management of any adult presenting with fever to enable early detection of the least expected differentials like in this case.

Association of p16 expression with prognosis varies across ovarian carcinoma histotypes: an Ovarian Tumor Tissue Analysis consortium study.

We aimed to validate the prognostic association of p16 expression in ovarian high-grade serous carcinomas (HGSC) and to explore it in other ovarian carcinoma histotypes. p16 protein expression was assessed by clinical-grade immunohistochemistry in 6525 ovarian carcinomas including 4334 HGSC using tissue microarrays from 24 studies participating in the Ovarian Tumor Tissue Analysis consortium. p16 expression patterns were interpreted as abnormal (either overexpression referred to as block expression or absence) or normal (heterogeneous). CDKN2A (which encodes p16) mRNA expression was also analyzed in a subset (n = 2280) mostly representing HGSC (n = 2010). Association of p16 expression with overall survival (OS) was determined within histotypes as was CDKN2A expression for HGSC only. p16 block expression was most frequent in HGSC (56%) but neither protein nor mRNA expression was associated with OS. However, relative to heterogeneous expression, block expression was associated with shorter OS in endometriosis-associated carcinomas, clear cell [hazard ratio (HR): 2.02, 95% confidence (CI) 1.47-2.77, p < 0.001] and endometrioid (HR: 1.88, 95% CI 1.30-2.75, p = 0.004), while absence was associated with shorter OS in low-grade serous carcinomas (HR: 2.95, 95% CI 1.61-5.38, p = 0.001). Absence was most frequent in mucinous carcinoma (50%), and was not associated with OS in this histotype. The prognostic value of p16 expression is histotype-specific and pattern dependent. We provide definitive evidence against an association of p16 expression with survival in ovarian HGSC as previously suggested. Block expression of p16 in clear cell and endometrioid carcinoma should be further validated as a prognostic marker, and absence in low-grade serous carcinoma justifies CDK4 inhibition.

MyD88 and TLR4 Expression in Epithelial Ovarian Cancer.

OBJECTIVE: To evaluate myeloid differentiation primary response gene 88 (MyD88) and Toll-like receptor 4 (TLR4) expression in relation to clinical features of epithelial ovarian cancer, histologic subtypes, and overall survival. PATIENTS AND METHODS: We conducted centralized immunohistochemical staining, semi-quantitative scoring, and survival analysis in 5263 patients participating in the Ovarian Tumor Tissue Analysis consortium. Patients were diagnosed between January 1, 1978, and December 31, 2014, including 2865 high-grade serous ovarian carcinomas (HGSOCs), with more than 12,000 person-years of follow-up time. Tissue microarrays were stained for MyD88 and TLR4, and staining intensity was classified using a 2-tiered system for each marker (weak vs strong). RESULTS: Expression of MyD88 and TLR4 was similar in all histotypes except clear cell ovarian cancer, which showed reduced expression compared with other histotypes (P<.001 for both). In HGSOC, strong MyD88 expression was modestly associated with shortened overall survival (hazard ratio [HR], 1.13; 95% CI, 1.01-1.26; P=.04) but was also associated with advanced stage (P<.001). The expression of TLR4 was not associated with survival. In low-grade serous ovarian cancer (LGSOC), strong expression of both MyD88 and TLR4 was associated with favorable survival (HR [95% CI], 0.49 [0.29-0.84] and 0.44 [0.21-0.89], respectively; P=.009 and P=.02, respectively). CONCLUSION: Results are consistent with an association between strong MyD88 staining and advanced stage and poorer survival in HGSOC and demonstrate correlation between strong MyD88 and TLR4 staining and improved survival in LGSOC, highlighting the biological differences between the 2 serous histotypes.

High-grade Endometrioid Carcinoma of the Ovary: A Clinicopathologic Study of 30 Cases.

Although infrequently encountered, the diagnosis of ovarian high-grade endometrioid carcinoma remains a diagnostic challenge with potential consequences for targeted therapies and genetic counselling. We studied the clinical, morphologic, and immunohistochemical features of ovarian high-grade endometrioid carcinomas and their diagnostic reproducibility compared with tuboovarian high-grade serous carcinomas. Thirty cases confirmed as International Federation of Gynecology and Obstetrics grade 3 endometrioid carcinomas were identified from 182 ovarian endometrioid carcinomas diagnosed in Alberta, Canada, between 1978 and 2010, from the population-based Alberta Ovarian Tumor Types cohort. Cases of lower grade endometrioid and high-grade serous carcinoma served for comparison. Ten immunohistochemical markers were assessed on tissue microarrays. Clinical data were abstracted and survival analyses performed using Cox regression. Interobserver reproducibility for histologic type was assessed using 1 representative hematoxylin and eosin-stained slide from 25 randomly selected grade 3 endometrioid carcinomas and 25 high-grade serous carcinomas. Histotype was independently assigned by 5 pathologists initially blinded to immunohistochemical WT1/p53 status, with subsequent reassessment unblinded to WT1/p53 status. Patients diagnosed with grade 3 endometrioid carcinoma had a significantly longer survival compared with high-grade serous carcinoma in univariate analysis (hazard ratio [HR]=0.34, 95% confidence interval [CI]=0.16-0.67, P=0.0012) but not after adjusting for age, stage, treatment center, and residual tumor (HR=1.01, 95% CI=0.43-2.16, P=0.98). Grade 3 endometrioid carcinoma cases (N=30) were identical to grade 2 endometrioid carcinoma cases (N=23) with respect to survival in univariate analysis (HR=1.07, 95% CI=0.39-3.21, P=0.89) and immunohistochemical profile. Using histomorphology alone, interobserver agreement for the diagnosis of grade 3 endometrioid or high-grade serous carcinoma was 69%, which significantly increased (P<0.0001) to 96% agreement with the knowledge of WT1/p53 status. Our data support the diagnostic value of WT1/p53 status in differentiating between grade 3 endometrioid carcinoma and high-grade serous carcinoma. However, grade 3 and grade 2 endometrioid carcinomas showed no differences in immunophenotype or clinical parameters, suggesting that they could be combined into a single group.

Homologous Recombination DNA Repair Pathway Disruption and Retinoblastoma Protein Loss Are Associated with Exceptional Survival in High-Grade Serous Ovarian Cancer.

Purpose: Women with epithelial ovarian cancer generally have a poor prognosis; however, a subset of patients has an unexpected dramatic and durable response to treatment. We sought to identify clinical, pathological, and molecular determinants of exceptional survival in women with high-grade serous cancer (HGSC), a disease associated with the majority of ovarian cancer deaths.Experimental Design: We evaluated the histories of 2,283 ovarian cancer patients and, after applying stringent clinical and pathological selection criteria, identified 96 with HGSC that represented significant outliers in terms of treatment response and overall survival. Patient samples were characterized immunohistochemically and by genome sequencing.Results: Different patterns of clinical response were seen: long progression-free survival (Long-PFS), multiple objective responses to chemotherapy (Multiple Responder), and/or greater than 10-year overall survival (Long-Term Survivors). Pathogenic germline and somatic mutations in genes involved in homologous recombination (HR) repair were enriched in all three groups relative to a population-based series. However, 29% of 10-year survivors lacked an identifiable HR pathway alteration, and tumors from these patients had increased Ki-67 staining. CD8+ tumor-infiltrating lymphocytes were more commonly present in Long-Term Survivors. RB1 loss was associated with long progression-free and overall survival. HR deficiency and RB1 loss were correlated, and co-occurrence was significantly associated with prolonged survival.Conclusions: There was diversity in the clinical trajectory of exceptional survivors associated with multiple molecular determinants of exceptional outcome in HGSC patients. Concurrent HR deficiency and RB1 loss were associated with favorable outcomes, suggesting that co-occurrence of specific mutations might mediate durable responses in such patients. Clin Cancer Res; 24(3); 569-80. ©2017 AACRSee related commentary by Peng and Mills, p. 508.

Association of Hormone Receptor Expression with Survival in Ovarian Endometrioid Carcinoma: Biological Validation and Clinical Implications.

This paper aims to validate whether hormone receptor expression is associated with longer survival among women diagnosed with ovarian endometrioid carcinoma (EC), and whether it identifies patients with stage IC/II tumors with excellent outcome that could be spared from toxic chemotherapy. Expression of estrogen receptor (ER) and progesterone receptor (PR) was assessed on 182 EC samples represented on tissue microarrays using the Alberta Ovarian Tumor Type (AOVT) cohort. Statistical analyses were performed to test for associations with ovarian cancer specific survival. ER or PR expression was present in 87.3% and 86.7% of cases, respectively, with co-expression present in 83.0%. Expression of each of the hormonal receptors was significantly higher in low-grade tumors and tumors with squamous differentiation. Expression of ER (Hazard Ratio (HR) = 0.18, 95% confidence interval 0.08-0.42, p = 0.0002) and of PR (HR = 0.22, 95% confidence interval 0.10-0.53, p = 0.0011) were significantly associated with longer ovarian cancer specific survival adjusted for age, grade, treatment center, stage, and residual disease. However, the five-year ovarian cancer specific survival among women with ER positive stage IC/II EC was 89.0% (standard error 3.3%) and for PR positive tumors 89.9% (standard error 3.2%), robustly below the 95% threshold where adjuvant therapy could be avoided. We validated the association of hormone receptor expression with ovarian cancer specific survival independent of standard predictors in an independent sample set of EC. The high ER/PR co-expression frequency and the survival difference support further testing of the efficacy of hormonal therapy in hormone receptor-positive ovarian EC. The clinical utility to identify a group of women diagnosed with EC at stage IC/II that could be spared from adjuvant therapy is limited.