Clinical utility of pathology data: endometrial and tubo-ovarian carcinomas.

Cancer resection specimens are usually reported using standardised proformas that consist of a list of elements, which include core (required) and non-core (recommended) items. Although all elements are generally included in the reports, the clinical importance of a particular parameter often depends on a variety of factors, including the clinical setting, local management guidelines and other pathological parameters. In this review, we briefly outline how histopathology data are used to guide management of patients with endometrial and tubo-ovarian cancers, the most common gynaecological malignancies, and provide advice as to which data elements are important in particular scenarios.

Dedifferentiation in Breast Metastasis of Endometrial Carcinoma: A Diagnostic Dilemma.

Most breast tumors are primary to this site; breast metastasis of endometrial origin is extremely rare. Low-grade endometrioid endometrial carcinomas can undergo dedifferentiation to undifferentiated carcinoma but such transformation at a metastatic site has been reported previously in only 2 cases. We report a case of dedifferentiation occurring in an isolated solitary breast metastasis of a low-grade endometrioid endometrial carcinoma. A 64-yr-old woman presented with a breast mass 2 yr after initial diagnosis of a grade 1 FIGO stage IIIA endometrioid endometrial carcinoma. Ultrasound guided biopsy of the breast mass showed a grade 1 endometrioid carcinoma which was diffusely estrogen receptor and PAX8-positive, consistent with metastasis from the previous endometrial carcinoma. The tumor initially responded to Letrozole therapy but then abruptly increased in size. Mastectomy revealed a poorly differentiated malignant tumor with morphology and immunophenotype (including loss of ARID1A and ARID1B immunoreactivity) consistent with undifferentiated endometrial carcinoma with no residual low-grade component. Awareness of the phenomenon of dedifferentiation of endometrial carcinoma in a metastatic site is important to avoid misdiagnosis as a primary breast cancer or metastasis from another primary site.

Unusual Manifestations of Vulval Paget Disease.

Vulval extramammary Paget disease (vEMPD) is an uncommon epithelial malignancy that may arise within the vulva (primary vEMPD) or represent vulval skin involvement by a noncutaneous carcinoma (secondary vEMPD). Primary vEMPD is most often an in situ carcinoma arising within the epidermis but may be associated with dermal invasion (invasive vEMPD) or represent intraepidermal spread of an adenocarcinoma originating in vulval skin adnexa or anogenital mammary-like glands. The latter, termed mammary gland-like adenocarcinoma (MGLA), exhibits morphologic, immunohistochemical, and molecular features of various breast carcinomas but, as far as we are aware, the metaplastic variant of MGLA has not been reported on the vulva. We report 2 cases of metaplastic MGLA of the vulva with associated Paget disease and postulate that some cases of vulval MGLA may arise from Paget disease rather than originating in mammary-like glands. We also report a unique case of secondary vEMPD resulting from spread of urothelial carcinoma in situ that subsequently progressed to invasive urothelial carcinoma within the vulva.

Pathologists can get it right the first time.

It is established good practice for histopathologists to obtain a second opinion in difficult cases. However, it is becoming more common for histology material to be reviewed either at the time of reporting (double-reporting) or as part of the preparation for multidisciplinary team meetings. Routine histological review does not provide 'value for money' and could even increase the risk of diagnostic error. The focus should be on error prevention as opposed to error detection. If pathologists get it right the first time, then there would be less need for 'double checking'. Increased subspecialisation could increase diagnostic confidence and reduce error rates. Double-reporting and retrospective review should be limited to selected cases. We describe a protocol for clearly recording the process and outcome of such reviews.

Molecular Characterization of Neuroendocrine Carcinomas of the Endometrium: Representation in All 4 TCGA Groups.

High-grade neuroendocrine carcinomas (NEC) of the endometrium are rare and account for <1% of all endometrial carcinomas. Both small cell neuroendocrine carcinoma (SCNEC) and large cell neuroendocrine carcinoma (LCNEC) morphologies have been reported. Little is known regarding the molecular features of endometrial NEC including how they compare to pulmonary NEC (the most common site for these neoplasms) and the more common endometrial carcinoma histotypes. In this study, we investigated the molecular alterations in a series of endometrial NEC using a targeted next generation sequencing panel (Oncopanel). Fourteen NEC were sequenced; pure NEC (n=4) and mixed (n=10) with endometrioid adenocarcinoma (n=9) or carcinosarcoma (n=1). The NEC components of mixed tumors comprised LCNEC (n=6) and SCNEC (n=4). The 4 pure NEC comprised LCNEC (n=2) and SCNEC (n=2). Molecular analysis classified tumors into the 4 The Cancer Genome Atlas groups: (1) POLE-mutated/ultramutated (1/14; 7%), (2) microsatellite instability/hypermutated (6/14; 43%), (3) TP53 mutated/copy number high (2/14; 14%), or (4) no specific molecular profile (5/14; 36%). Overall, 50% of cases were ultramutated or hypermutated. In 8 cases of mixed carcinomas, the different histologic components were macrodissected and separately sequenced; molecular alterations were nearly identical among the 2 components, with the non-NEC component harboring slightly increased tumor mutational burden. Only 2 carcinomas (both with pure SCNEC morphology) had a molecular profile that would be expected in typical pulmonary SCNEC (RB1 deletion and TP53 mutations). Our findings, similar to data from NECs of other anatomic sites, suggest that the molecular context may be important when selecting therapies for women with endometrial NEC. Immune checkpoint inhibition may be a reasonable approach to treatment of microsatellite instability-NEC and we thus recommend that all endometrial NEC be tested for mismatch repair abnormalities, either molecularly or by mismatch repair protein immunohistochemistry.

MammaPrint guides treatment decisions in breast Cancer: results of the IMPACt trial.

BACKGROUND: Increased usage of genomic risk assessment assays suggests increased reliance on data provided by these assays to guide therapy decisions. The current study aimed to assess the change in treatment decision and physician confidence based on the 70-gene risk of recurrence signature (70-GS, MammaPrint) and the 80-gene molecular subtype signature (80-GS, BluePrint) in early stage breast cancer patients. METHODS: IMPACt, a prospective, case-only study, enrolled 452 patients between November 2015 and August 2017. The primary objective population included 358 patients with stage I-II, hormone receptor-positive, HER2-negative breast cancer. The recommended treatment plan and physician confidence were captured before and after receiving results for 70-GS and 80-GS. Treatment was started after obtaining results. The distribution of 70-GS High Risk (HR) and Low Risk (LR) patients was evaluated, in addition to the distribution of 80-GS compared to IHC status. RESULTS: The 70-GS classified 62.5% (n = 224/358) of patients as LR and 37.5% (n = 134/358) as HR. Treatment decisions were changed for 24.0% (n = 86/358) of patients after receiving 70-GS and 80-GS results. Of the LR patients initially prescribed CT, 71.0% (44/62) had CT removed from their treatment recommendation. Of the HR patients not initially prescribed CT, 65.1% (41/63) had CT added. After receiving 70-GS results, CT was included in 83.6% (n = 112/134) of 70-GS HR patient treatment plans, and 91.5% (n = 205/224) of 70-GS LR patient treatment plans did not include CT. For patients who disagreed with the treatment recommended by their physicians, most (94.1%, n = 16/17) elected not to receive CT when it was recommended. For patients whose physician-recommended treatment plan was discordant with 70-GS results, discordance was significantly associated with age and lymph node status. CONCLUSIONS: The IMPACt trial showed that treatment plans were 88.5% (n = 317/358) in agreement with 70-GS results, indicating that physicians make treatment decisions in clinical practice based on the 70-GS result. In clinically high risk, 70-GS Low Risk patients, there was a 60.0% reduction in treatment recommendations that include CT. Additionally, physicians reported having greater confidence in treatment decisions for their patients in 72% (n = 258/358) of cases after receiving 70-GS results. TRIAL REGISTRATION: "Measuring the Impact of MammaPrint on Adjuvant and Neoadjuvant Treatment in Breast Cancer Patients: A Prospective Registry" (NCT02670577) retrospectively registered on Jan 27, 2016.

Primary Angiosarcoma of the Cervix: Case Report of a Rare Lesion.

Angiosarcomas of the female genital tract are rare and primary angiosarcoma of the cervix is extremely rare with only one prior case report. We report a case of a primary cervical angiosarcoma in a 43-yr-old woman who presented with heavy vaginal bleeding. Cervical biopsy and subsequent radical hysterectomy showed a malignant vascular tumor which was composed of spindled and epithelioid cells and formed abortive vascular channels. Immunohistochemically, the tumor cells were diffusely positive for CD31, CD34, ERG, and cyclin D1 and focally positive for D2-40. A reverse transcription polymerase chain reaction test for YWHAE-NUTM2 genetic fusion was negative excluding a YWHAE-translocated high-grade endometrial stromal sarcoma. The tumor formed a 5 cm mass within the cervix with microscopic involvement of the endometrium, superficial myometrium, and vagina. Metastatic microscopic tumor deposits were present in both ovaries, left fallopian tube, one paracervical lymph node, and one pelvic lymph node. In reporting this unusual case we discuss the differential diagnosis.

Singapore Neonatal Resuscitation Guidelines 2016.

We present the revised Neonatal Resuscitation Guidelines for Singapore. The 2015 International Liaison Committee on Resuscitation Neonatal Task Force's consensus on science and treatment recommendations (2015), and guidelines from the American Heart Association and European Resuscitation Council were debated and discussed. The final recommendations of the National Resuscitation Council, Singapore, were derived after the task force had carefully reviewed the current available evidence in the literature and addressed their relevance to local clinical practice.

Molecular subtyping of mammary-like adenocarcinoma of the vulva shows molecular similarity to breast carcinomas.

AIMS: Mammary-like adenocarcinoma (MLA) of the vulva is thought to be derived from vulvar mammary-like glands. The aim of this study was to characterize a series of MLAs by using an immunohistochemical algorithm that identifies the major molecular subtypes of breast cancer. METHODS AND RESULTS: Seven cases of vulval MLA were stained for oestrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), Ki67, epidermal growth factor receptor (EGFR), cytokeratin (CK) 5, nestin, and inositol polyphosphate-4-phosphatase (INPP4b). Seventeen cases of vulval extramammary Paget disease (EMPD), seven with invasion, were studied for comparison. The median age of patients with MLA was 72 years. All tumours except one were early-stage tumours. On the basis of an immunohistochemical panel, three of seven tumours were classified as luminal B, two of seven as HER2-enriched, one of seven as luminal A, and one of seven as basal-like. ER was expressed in four of seven tumours, PR in three of seven, HER2 in three of seven, EGFR in two of seven, and CK5 in one of seven, and the Ki67 index was >15% in six of seven cases. Nestin and INPP4b were, respectively, negative and positive in all cases. Of the seven cases of invasive EMPD, two showed a luminal A profile, three a luminal B profile (two of three with HER2 amplification), one a HER2-enriched profile, and one a basal-like profile. Three of seven were HER2-amplified. Among the 10 cases of EMPD without invasion, seven showed a luminal A profile and three showed a luminal B profile (all HER2-amplified); no HER2-enriched or basal-like subtypes were identified. CONCLUSIONS: Breast cancer subtyping can be applied to vulvar MLAs. All four intrinsic molecular subtypes are seen, with frequencies similar to those in breast carcinoma. Our results support the potential use of breast cancer molecular profiling algorithms to guide treatment for these cancers.

Reducing radiation hazard opportunities in neonatal unit: quality improvement in radiation safety practices.

AIM: Guided by the ALARA - "As Low As Reasonably Achievable" principle in radiation safety, a quality improvement project to optimise the bedside diagnostic imaging process to the best standards of care was conducted over a six month period. The goal was too reduce the radiation hazard opportunities in the neonatal intensive care unit by at least 75% from the existing level at Q2/2015, within 6 months. METHODS: The existing bedside imaging process was critically analysed and the following quality improvement initiatives were implemented namely, mandatory lead protective gear to healthcare staff, gonadal shield for neonates, guidelines for optimal collimation of X-ray beam and optimal positioning of neonates. Radiation dosimetry results, regular staff awareness sessions and strong collaboration between neonatologists, radiologists, radiographers and neonatal nurses helped to ensure compliance to the revised imaging process. Radiation hazard opportunities were measured by analysing all radiographs done during the period under baby exposure and healthcare staff exposure categories. SUMMARY OF RESULTS: Radiation hazard opportunities were reduced by 100% to healthcare staff and 75% to neonates, and the overall reduction was 83%. The rate of discordance between radiograph request forms and images taken was measured as a surrogate marker for compliance to the project initiatives and it declined by 77%. Mandatory orientation of staff to the revised policy on the standardised diagnostic imaging process, regular radiation awareness talks and staff feedback sessions are among several measures taken to sustain the project.

What is the Most Suitable Time Period to Assess the Time Trends in Cancer Incidence Rates to Make Valid Predictions--an Empirical Approach.

Projections of cancer cases are particularly useful in developing countries to plan and prioritize both diagnostic and treatment facilities. In the prediction of cancer cases for the future period say after 5 years or after 10 years, it is imperative to use the knowledge of past time trends in incidence rates as well as in population at risk. In most of the recently published studies the duration for which the time trend was assessed was more than 10 years while in few studies the duration was between 5-7 years. This raises the question as to what is the optimum time period which should be used for assessment of time trends and projections. Thus, the present paper explores the suitability of different time periods to predict the future rates so that the valid projections of cancer burden can be done for India. The cancer incidence data of selected cancer sites of Bangalore, Bhopal, Chennai, Delhi and Mumbai PBCR for the period of 1991-2009 was utilized. The three time periods were selected namely 1991-2005; 1996-2005, 1999-2005 to assess the time trends and projections. For the five selected sites, each for males and females and for each registry, the time trend was assessed and the linear regression equation was obtained to give prediction for the years 2006, 2007, 2008 and 2009. These predictions were compared with actual incidence data. The time period giving the least error in prediction was adjudged as the best. The result of the current analysis suggested that for projections of cancer cases, the 10 years duration data are most appropriate as compared to 7 year or 15 year incidence data.

Endometrial involvement in pseudomyxoma peritonei secondary to low-grade appendiceal mucinous neoplasm: report of 2 cases.

Pseudomyxoma peritonei is a clinical condition characterized by the presence of mucinous ascites, usually with variable amounts of neoplastic enteric-type mucinous epithelium, and most commonly secondary to spread from a low-grade appendiceal mucinous neoplasm. We report 2 cases of pseudomyxoma peritonei associated with low-grade appendiceal mucinous neoplasms where there was colonization of the endometrium (both cases) and cervical mucosa (1 case) by low-grade atypical enteric-type mucinous epithelium (CK20 positive and CK7 negative). The patients had symptoms of mucoid vaginal discharge and endometrial biopsies in both (1 patient had multiple endometrial biopsies over a period of 11 mo) and were initially interpreted as representing mucinous metaplasia. Pseudomyxoma peritonei may rarely result in endometrial and cervical mucosal involvement, presumably secondary to transtubal spread.

A model approach to calculate cancer prevalence from 5 years survival data for selected cancer sites in India--part II.

OBJECTIVE: Prevalence is a statistic of primary interest in public health. In the absence of good follow-up facilities, it is often difficult to assess the complete prevalence of cancer for a given registry area. An attempt is made to arrive at the complete prevalence including limited duration prevalence with respect of selected sites of cancer for India by fitting appropriate models to 1, 3 and 5 year cancer survival data available for selected registries of India. METHODOLOGY: Cancer survival data, available for the registries of Bhopal, Chennai, Karunagappally, and Mumbai was pooled to generate survival for the selected cancer sites. With the available data on survival for 1, 3 and 5 years, a model was fitted and the survival curve was extended beyond 5 years (up to 30 years) for each of the selected sites. This helped in generation of survival proportions by single year and thereby survival of cancer cases. With the help of estimated survived cases available year wise and the incidence, the prevalence figures were arrived for selected cancer sites and for selected periods. In our previous paper, we have dealt with the cancer sites of breast, cervix, ovary, lung, stomach and mouth (Takiar and Jayant, 2013). RESULTS: The prevalence to incidence ratio (PI ratio) was calculated for 30 years duration for all the selected cancer sites using the model approach showing that from the knowledge of incidence and P/I ratio, the prevalence can be calculated. The validity of the approach was shown in our previous paper (Takiar and Jayant, 2013). The P/I ratios for the cancer sites of lip, tongue, oral cavity, hypopharynx, oesophagus, larynx, nhl, colon, prostate, lymphoid leukemia, myeloid leukemia were observed to be 10.26, 4.15, 5.89, 2.81, 1.87, 5.43, 5.48, 5.24, 4.61, 3.42 and 2.65, respectively. CONCLUSION: Cancer prevalence can be readily estimated with use of survival and incidence data.