Search

Objective The phenotype mediated by HNF4A/HNF1A mutations is variable and includes diazoxide-responsive hyperinsulinaemic hypoglycaemia (HH) and maturity-onset diabetes of the young (MODY). Design We characterised an international multicentre paediatric cohort of patients with HNF4Aor HNF1Amutations presenting with HH over a 25-year period (1995–2020). Methods Clinical and genetic analysis data from five centres were obtained. Diazoxide responsiveness was defined as the ability to maintain normoglycaemia without intravenous glucose. Macrosomia was defined as a birth weight ≥90th centile. SPSS v.27.1 was used for data analysis. Results A total of 34 patients (70.6% female, n = 24) with a mean age of 7.1 years (s.d. 6.4) were included. A total of 21 different heterozygous HNF4Amutations were identified in 29 patients (four novels). Four different previously described heterozygous HNF1A mutations were detected in five patients. Most (97.1%, n = 33) developed hypoglycaemia by day 2 of life. The mean birth weight was 3.8 kg (s.d. 0.8), with most infants macrosomic (n = 21, 61.8%). Diazoxide was commenced in 28 patients (82.3%); all responded. HH resolved in 20 patients (58.8%) following a median of 0.9 years (interquartile range (IQR): 0.2–6.8). Nine patients (n = 9, 26.5%) had developmental delay. Two patients developed Fanconi syndrome (p.Arg63Trp, HNF4A) and four had other renal or hepatic findings. Five (14.7%) developed MODY at a median of 11.0 years (IQR: 9.0–13.9). Of patients with inherited mutations (n = 25, 73.5%), a family history of diabetes was present in 22 (88.0%). Conclusions We build on the knowledge of the natural history and pancreatic and extra-pancreatic phenotypes of HNF4A/HNF1Amutations and illustrate the heterogeneity of this condition.

Although diagnosis of high-grade uterine mesenchymal tumors (high-grade UMTs) exhibiting classic morphologic features is straightforward, diagnosis is more challenging in tumors in which prototypical features are poorly developed, focal and/or co-exist with features seen in other neoplasms. Here, we sought to define the repertoire of somatic genetic alterations in diagnostically challenging UMTs with myomelanocytic differentiation, including some reported as perivascular epithelioid cell tumors (PEComas). In 17 samples from 15 women, the tumors were histologically heterogeneous. Immunohistochemical expression of at least one melanocytic marker (HMB45, Melan-A or MiTF) was identified in all tumors, and of myogenic markers (desmin or SMA) in most tumors. Targeted massively parallel sequencing revealed several genetic alterations, most commonly in TP53 (41% mutation, 12% deletion), TSC2 (29% mutation, 6% deletion), RB1 (18% deletion), ATRX (24% mutation), MED12 (12% mutation), BRCA2 (12% deletion), CDKN2A (6% deletion) as well as FGFR3, NTRK1 and ERBB3 amplification (each 6%). Gene rearrangements (JAZF1-SUZ12; DNAJB6-PLAG1 and SFPQ-TFE3) were identified in three tumors. Integrating histopathologic, immunohistochemical and genetic findings, tumors from 4 patients were consistent with malignant PEComa (one TFE3-rearranged); 6 were classified as leiomyosarcomas; 3 showed overlapping features of PEComa and other sarcoma types (leiomyosarcoma or low-grade endometrial stromal sarcoma); and 2 were classified as sarcoma, not otherwise specified. Our findings suggest that diagnostically challenging UMTs with myomelanocytic differentiation represent a heterogeneous group of neoplasms which harbor a diverse repertoire of somatic genetic alterations; these genetic alterations can aid classification.

Background Non-islet cell tumour hypoglycemia (NICTH) is rarely encountered in clinical practice. Insulin-like growth factor 2 (IGF2) is the most common cause of NICTH observed in the setting of mesenchymal and epithelial neoplasia. This is a paraneoplastic syndrome caused by IGF2 activation of the insulin receptor. Case presentation An 80 year old female presented with a short history of recurrent episodes of confusion with laboratory confirmed hypoglycemia with a plasma glucose of 2.7 mmol/L on fasting which fulfilled Whipple’s triad. Diagnostic clues to the aetiology at presentation include the fasting pattern of hypoglycemia, hypokalaemia and the absence of weight gain. A 72 hour fast with results showed early hypoglycemia and suppression of serum insulin, c-peptide, and proinsulin. Serum insulin antibody was not detected. Subsequent measurement of the serum IGF2:IGF1 ratio was elevated at 22.3 and consistent with IGF-2 mediated hypoglycemia and imaging studies demonstrated a pelvic mass. Dietary intervention and oral prednisolone abated hypoglycemia prior to surgery. Ultimately, hypoglycemia resolved following operative intervention and steroid therapy was successfully withdrawn. Histopathology was remarkable for dual neoplastic processes with uterine solitary fibrous tumour (SFT) confirmed as the source of IGF2 hypersecretion on IGF-2 immunohistochemistry and a coincidental invasive high grade serous carcinoma involving the fimbria of the right fallopian tube. Conclusion The paradox in this case is that the benign solitary fibrous tumour accounted for patient morbidity through secretion of IGF2 and without treatment, posed a mortality risk. This is despite the synchronous presence of a highly malignant fallopian tube neoplasm. This case reinforces the need for thorough clinical evaluation of hypoglycemia to allow prompt and definitive management.

Endometrial carcinoma (EC), as described by Bokhman, has historically been classified as Type I (low-grade, hormone-dependant, young patients, good prognosis) or Type II (high-grade, hormone-independent, older patients, poor prognosis). This classification is no longer pragmatic, however, as EC is a much more heterogeneous disease. Four molecular subtypes of EC were identified by The Cancer Genome Atlas (TCGA), and subsequent studies have demonstrated its utility in predicting prognosis. While endometrial serous carcinoma (ESC), the prototypical Type II EC, largely occurs in older women, younger women with ESC were not accounted for in the Bokhman model and were underrepresented in the TCGA study. We hypothesized that a subset of ESCs in young patients do not represent bona fide serous carcinomas but rather high-grade endometrioid carcinomas mimicking a serous phenotype. We identified ESCs and mixed endometrioid/serous carcinomas in women

Acinic cell carcinoma of breast is a rare subtype of triple-negative breast carcinoma and demonstrates extensive morphologic overlap with acinic cell carcinoma of the salivary gland. In this study, we perform a detailed morphologic and immunohistochemical description of 2 cases of this rare entity and undertake a comprehensive review of all reported cases of breast acinic cell carcinoma in the English language literature to date. One-third of reported cases of breast acinic cell carcinoma have been associated with the presence of a ductal carcinoma not otherwise specified component, which is frequently poorly differentiated. Breast acinic cell carcinoma can demonstrate focal morphologic features similar to microglandular adenosis; these areas are frequently negative for collagen IV and laminin on immunohistochemistry. The true relationship between these 2 entities remains unclear, but we advocate that microglandular adenosis–like areas at the periphery of a breast acinic cell carcinoma should be considered part of the carcinomatous process and re-excised if this process extends to the initial surgical margins.

Perineural and intraneural infiltration is most often considered a diagnostic feature of malignancy but has been demonstrated in benign entities in a variety of organs. This brief report describes benign glands apparently infiltrating nerves around bile ducts in a resected extra-hepatic biliary tree performed on a background of recurrent cholangitis and prior cholecystectomy. To our knowledge, benign glands infiltrating nerves within bile ducts has not been reported outside of the setting of end stage primary sclerosing cholangitis where one example has been described. We identify several features which support the benign nature of this process including bland cytomorphology, identical appearance to adjacent glands and an exuberant neural rather than glandular proliferation supporting the probability of a reactive neural proliferation akin to traumatic neuroma. We propose a pathogenesis that is somewhat analogous to traumatic neuroma of the biliary tree which, despite its rarity, is a documented complication of cholecystectomy, comprising a reactive proliferation of nerve tissue in response to injury. This article is protected by copyright. All rights reserved.

To the Editor We read the provocative narrative by Lonnqvist et al [1][1] entitled ‘Should the ESP block be renamed the RIP II block?’ with great interest. The authors identified numerous parallels between the erector spinae plane block (ESPB) and the almost-forgotten interpleural block

Breast carcinoma in young women aged less than 40 years attracts a high level of mainstream media coverage, and there is a gap between societal perceptions of the disease as a growing problem and epidemiological trends. Several population studies have reported that the overall incidence of breast carcinoma in young women is stable, while one recent article suggested that the relative proportion of breast carcinoma in young women that is metastatic at diagnosis is growing. We sought to establish whether these trends were apparent at our institution. In this study, the clinical database at a breast carcinoma tertiary center was reviewed in terms of clinicopathologic data on patient age, diagnosis, clinical and pathologic stage, hormone receptor status, and HER-2 overexpression status for the period 2000-2011. Over the study period, young patients represented a decreasing proportion of all breast carcinoma cases (10.8% [2000-2003] to 8.7% [2008-2011]; p < 0.0001) treated at our institution. Young patients were more likely than patients aged 40 years or older to present with metastatic (M1) disease (5.4% versus 4.4%; p = 0.009), to be triple negative (21.6% versus 13%; p < 0.001), or to be HER-2 positive (24.3% versus 14.8%; p < 0.01). Young patients with HER-2-positive cancers were significantly more likely to present with metastatic disease (8.3% versus 4.8%; p = 0.004). This study showed no demonstrable increase in the relative proportion of breast cancer occurring in patients aged

Sertoli-Leydig cell tumors are characterized by the presence of somatic DICER1 hotspot mutations. In this study, we sought to define the association between DICER1 hotspot mutations and different morphologic subtypes of ovarian Sertoli-Leydig cell tumors. Furthermore, we aimed to assess whether DICER1 hotspot mutations occur in other ovarian sex cord-stromal tumors, testicular sex cord-stromal tumors, or other female genital tract tumors with rhabdomyosarcomatous differentiation. We subjected a series of ovarian Sertoli-Leydig cell tumors (n=32), Sertoli cell tumors (n=5) and gynandroblastomas (n=5), testicular sex cord-stromal tumors (n=15) and a diverse group of female genital tract tumors with rhabdomyosarcomatous morphology (n=10) to DICER1 hotspot mutation analysis using Sanger sequencing. We also tested two gynandroblastomas for the presence of FOXL2 hotspot mutations (p.C134W; c.402C>G). Twenty of 32 (63%) Sertoli-Leydig cell tumors harbored a DICER1 hotspot mutation, of which 80% had the p.E1705K mutation. No association was found between DICER1 mutation status and the presence of heterologous or retiform differentiation in Sertoli-Leydig cell tumors. DICER1 mutations were found at similar frequencies in gynandroblastoma (2/5; 40%) and ovarian Sertoli cell tumors (5/8; 63%; P>0.1), and all mutated tumors harbored a p.E1705K mutation. DICER1 hotspot mutations were also identified in a single cervical rhabdomyosarcoma and in the rhabdomyosarcomatous component of a uterine carcinosarcoma. No DICER1 mutations were detected in testicular sex cord-stromal tumors. Two DICER1 wild-type gynandroblastomas harbored a p.C134W FOXL2 hotspot mutation in both tumor components. In this study we confirmed that DICER1 hotspot mutations occur in over half of ovarian Sertoli-Leydig cell tumors, and are unrelated to tumor differentiation. We also widened the spectrum of ovarian sex cord-stromal tumors with sertoliform differentiation, in which DICER1 mutations are known to occur, to include Sertoli cell tumors and gynandroblastomas. Our results suggest that DICER1 mutations may not have a role in testicular sex cord-stromal tumorigenesis.

Small cell carcinoma of the ovary, hypercalcemic type is an aggressive tumor generally affecting young women with limited treatment options. Mutations in SMARCA4, a catalytic subunit of the SWI/SNF chromatin remodeling complex, have recently been identified in nearly all small cell carcinoma of the ovary, hypercalcemic type cases and represent a signature molecular feature for this disease. Additional biological dependencies associated with small cell carcinoma of the ovary, hypercalcemic type have not been identified. SMARCA2, another catalytic subunit of the SWI/SNF complex mutually exclusive with SMARCA4, is thought to be post-translationally silenced in various cancer types. We analyzed 10 archival small cell carcinoma of the ovary, hypercalcemic type cases for SMARCA2 protein expression by immunohistochemistry and found that SMARCA2 expression was lost in all but one case. None of the 50 other tumors that primarily or secondarily involved the ovary demonstrated concomitant loss of SMARCA2 and SMARCA4. Deep sequencing revealed that this loss of SMARCA2 expression is not the result of mutational inactivation. In addition, we established a small cell carcinoma of the ovary, hypercalcemic type patient-derived xenograft and confirmed the loss of SMARCA2 in this in vitro model. This patient-derived xenograft model, established from a recurrent tumor, also had unexpected mutational features for this disease, including functional mutations in TP53 and POLE. Taken together, our data suggest that concomitant loss of SMARCA2 and SMARCA4 is another hallmark of small cell carcinoma of the ovary, hypercalcemic type—a finding that offers new opportunities for therapeutic interventions.

Optimal management of a lesion yielding radial scar (RS) without epithelial atypia on breast biopsy is controversial. In this single-institution study spanning 17 years, 53 patients with this biopsy diagnosis were evaluated in terms of clinical, radiologic, and pathologic features and outcomes. RSs were categorized as either "incidental" or as the "targeted" lesion according to defined criteria. Of 48 patients who underwent surgical excision after a diagnosis of RS on biopsy, only 1 had an "upgrade" diagnosis of malignancy (2%). No "incidental" RS was associated with the presence of malignancy on surgical excision. Meta-analysis of 20 RS excision studies demonstrated an overall upgrade rate of 10.4%, with a higher rate in patients with a diagnosis of RS with atypia (26%). The upgrade rate for RS without atypia was 7.5% overall. The lower rate of upgrade to malignancy in this study (2%) is likely related to the thorough radiologic-pathologic review undertaken. In the setting of multidisciplinary agreement and careful radiologic-pathologic correlation, it may be appropriate for patients with a biopsy diagnosis of RS without atypia to forego surgical excision in favor of imaging follow-up.

Perivascular epithelioid tumours (PEComas) of the gynaecological tract are rare tumours which were first recognised and diagnosed within the last 20 years. They represent a unique diagnostic challenge with regard to their accurate and reproducible distinction from more common entities such as smooth muscle tumours of the uterine corpus. In this review article, we trace the development of the concept of the PEComa tumour family, highlight what is known about extra-gynaecological tract PEComa at an immunohistochemical, molecular and therapeutic level and then present a summary of all reported cases of gynaecological tract PEComa to date. In the summary, we highlight rare subtypes of gynaecological tract PEComa and compare the performances of extant prognostic classification systems for malignancy in these tumours.

Endometrial stromal sarcomas (ESS) are often underpinned by recurrent chromosomal translocations resulting in the fusion of genes involved in epigenetic regulation. To date, only YWHAE-NUTM2 rearrangements are associated with distinctive high-grade morphology and aggressive clinical behavior. We identified 3 ESS morphologically mimicking myxoid leiomyosarcoma of the uterus and sought to describe their unique histopathologic features and identify genetic alterations using next-generation sequencing. All cases displayed predominantly spindled cells associated with abundant myxoid stroma and brisk mitotic activity. Tumors involved the endometrium and demonstrated tongue-like myometrial infiltration. All 3 were associated with an aggressive clinical course, including multisite bony metastases in 1 patient, progressive peritoneal disease after chemotherapy in another, and metastases to the lung and skin in the last patient. All 3 ESS were found to harbor ZC3H7B-BCOR gene fusions by targeted sequencing and fluorescence in situ hybridization. On the basis of the review of these cases, we find that ESS with ZC3H7B-BCOR fusion constitutes a novel type of high-grade ESS and shares significant morphologic overlap with myxoid leiomyosarcoma.

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare ovarian neoplasm that occurs in young women and has a poor prognosis. The histologic diagnosis of SCCOHT can be challenging due to its rarity and relatively nonspecific histologic features, which range from the classic, first-described small cell morphology to a pattern in which there are large cells with abundant eosinophilic cytoplasm. Many entities can be in the differential diagnosis and to date, immunohistochemical stains have shown no distinctive profile and have been of limited aid. SMARCA4 (also known as BRG1) mutations have recently been reported at high frequency in these tumors. SMARCA4 is an important component of the SWI/SNF complex that regulates gene expression through alteration of nucleosome conformation. Studies to date have suggested that immunohistochemical loss of expression of SMARCA4 is associated with the presence of a SMARCA4 mutation in most cases. In this study, the sensitivity and specificity of the immunohistochemical loss of SMARCA4 expression for the diagnosis of SCCOHT is examined in the context of the differential diagnosis with other primary or metastatic ovarian tumors. All but one of the SCCOHT showed loss of SMARCA4 expression (16/17; 94%), while of 279 other tumors tested, only two tumors (one clear cell carcinoma and one ovarian melanoma) showed loss of SMARCA4 expression. We conclude that SMARCA4 immunohistochemistry is highly sensitive and specific for a diagnosis of SCCOHT and is of clinical utility in the differential diagnosis of poorly differentiated ovarian tumors.

Oncotype Dx Breast Cancer Assay is a 21-gene assay used in estrogen receptor (ER)-positive breast cancer to predict benefit from chemotherapy (CT). Tumors are placed into one of three risk categories based on their recurrence score (RS). This paper explores the impact of tumor histopathologic features and Oncotype Dx RS on the treatment plan for invasive lobular carcinoma (ILC). Invasive lobular carcinoma cases submitted for Oncotype Dx testing were identified from a clinical data base. The histopathologic and immunohistochemical features and RS subcategory of each tumor, and treatment regimen and medical oncologic assessments of each patient were reviewed. A total of 135 cases of ILC had RS testing, which represented 15% of all ILC diagnosed at the institution over the time period. 80% of ILC was of the classical subtype and all tumors were ER positive and human epidermal growth factor receptor 2 (HER-2) negative by immunohistochemistry. Sixty three percent of cases were low risk (LR), 35.5% were intermediate risk (IR) and 1.5% were high risk (HR). Both HR cases were pleomorphic ILC. Sixty eight percent of classical ILC had a LR score, while 70% of pleomorphic ILC had an IR score. Patients in the IR category were significantly more likely to undergo CT than patients in the LR category (54% versus 18%; p < 0.0001). In the LR category, those undergoing CT were significantly younger and more likely to have positive lymph nodes (p < 0.05). Qualitative analysis of medical oncologic assessments showed that RS played a role in decision-making on CT in 74% of cases overall. At our institution, Oncotype Dx RS currently plays a role in the management of a proportion of ILC and impacts on treatment decisions.

Context: Familial tumoral calcinosis (TC) results from disruptions in phosphate metabolism and is characterized by high serum phosphate with normal or elevated 1,25 dihydroxyvitamin vitamin D concentrations and ectopic and vascular calcifications. Recessive loss-of-function mutations in UDP-N-acetyl-α-d-galactosamine-polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3) and fibroblast growth factor-23 (FGF23) result in TC. Objective: The objective of the study was to determine the relationship between GALNT3 and FGF23 in familial TC. Design, Setting, and Patients: We assessed the major biochemical defects and potential genes involved in patients with TC. Intervention: Combination therapy consisted of the phosphate binder Sevelamer and the carbonic anhydrase inhibitor acetazolamide. Results: We report a patient homozygous for a GALNT3 exon 1 deletion, which is predicted to truncate the encoded protein. This patient had high serum FGF23 concentrations when assessed with a C-terminal FGF23 ELISA but low-normal FGF23 levels when tested with an ELISA for intact FGF23 concentrations. Matrix extracellular phosphoglycoprotein has been identified as a possible regulator of phosphate homeostasis. Serum matrix extracellular phosphoglycoprotein levels, however, were normal in the family with GALNT3-TC and a kindred with TC carrying the FGF23 S71G mutation. The tumoral masses of the patient with GALNT3-TC completely resolved after combination therapy. Conclusions: Our findings demonstrate that GALNT3 inactivation in patients with TC leads to inadequate production of biologically active FGF23 as the most likely cause of the hyperphosphatemic phenotype. Furthermore, combination therapy may be effective for reducing the tumoral burden associated with familial TC.

Duodenal gastric heterotopia (DGH) is a common incidental finding at endoscopy, generally assumed to be congenital in origin. A recent study has suggested a possible association with gastric fundal gland polyps (FGPs). In this review of 37 patients with histologically confirmed DGH, the background to our present understanding of the DGH lesion is reviewed, the clinical and pathological associations of the condition in our cohort are identified, and the histological and immunohistochemical features of the DGH lesion are described. An association with the presence of FGPs is again demonstrated, whereas an inverse relationship with Helicobacter pylori is also shown. Immunohistochemical staining demonstrates that the fundic-type glands of DGH express the proton pump antigen (H(+)K(+)ATPase), whereas the overlying surface mucosa expresses the mucin profile of normal gastric-type mucosa (mucin-5AC positive, mucin-2 negative). DGH may represent a further component of the iatrogenic hypergastrinemia-related hypothesis for FGP development, although further study is required to confirm this.

BACKGROUND: Automated scanning devices and image analysis software provide a means to overcome the limitations of manual semiquantitative scoring of immunohistochemistry. Common drawbacks to automated imaging systems include an inability to classify tissue type and an inability to segregate cytoplasmic and nuclear staining. METHODS: Immunohistochemistry for the membranous marker α-catenin, the cytoplasmic marker stathmin and the nuclear marker Ki-67 was performed on tissue microarrays (TMA) of archival formalin-fixed paraffin-embedded tissue comprising 471 (α-catenin and stathmin) and 511 (Ki-67) cases of prostate adenocarcinoma. These TMA were quantitatively analysed using two commercially available automated image analysers, the Ariol SL-50 system and the Nuance system from CRi. Both systems use brightfield microscopy for automated, unbiased and standardised quantification of immunohistochemistry, while the Nuance system has spectral deconvolution capabilities. RESULTS: Overall concordance between scores from both systems was excellent (r=0.90; 0.83-0.95). The software associated with the multispectral imager allowed accurate automated classification of tissue type into epithelial glandular structures and stroma, and a single-step segmentation of staining into cytoplasmic or nuclear compartments allowing independent evaluation of these areas. The Nuance system, however, was not able to distinguish reliably between tumour and non-tumour tissue. In addition, variance in the labour and time required for analysis between the two systems was also noted. CONCLUSION: Despite limitations, this study suggests some beneficial role for the use of a multispectral imaging system in automated analysis of immunohistochemistry.

Thrombosis is common in ovarian cancer. However, the interaction of platelets with ovarian cancer cells has not been critically examined. To address this, we investigated platelet interactions in a range of ovarian cancer cell lines with different metastatic potentials [HIO-80, 59M, SK-OV-3, A2780, A2780cis]. Platelets adhered to ovarian cancer cells with the most significant adhesion to the 59M cell line. Ovarian cancer cells induced platelet activation [P-selectin expression] in a dose dependent manner, with the most significant activation seen in response to the 59M cell line. The platelet antagonists [cangrelor, MRS2179, and apyrase] inhibited 59M cell induced activation suggesting a P2Y12 and P2Y1 receptor mediated mechanism of platelet activation dependent on the release of ADP by 59M cells. A2780 and 59M cells potentiated PAR-1, PAR-4, and TxA2 receptor mediated platelet activation, but had no effect on ADP, epinephrine, or collagen induced activation. Analysis of gene expression changes in ovarian cancer cells following treatment with washed platelets or platelet releasate showed a subtle but valid upregulation of anti-apoptotic, anti-autophagy pro-angiogenic, pro-cell cycle and metabolic genes. Thus, ovarian cancer cells with different metastatic potential adhere and activate platelets differentially while both platelets and platelet releasate mediate pro-survival and pro-angiogenic signals in ovarian cancer cells.

It is often assumed that critical care outcomes in the elderly are uniformly poorer than those in younger populations. We examined the pattern of admissions to our intensive care unit in Dublin, Ireland, between 2002 and 2005 to determine the admission characteristics and mortality in those aged 80 years and older.Data were collected retrospectively from a local audit database and patient charts.The very elderly represented 5.1% of ICU admissions over the period with an ICU mortality of 15.4%. Age-adjusted APACHE II scores were similar to those in the younger group (median, 7 for both groups). The average length of ICU stay (+/-SD) was similar in the very elderly and younger groups (4.03+/-0.51 v 4.86+/-0.31 days; P=0.52), as were readmission rates (5.7% v 5.2%). Age was not predictive of ICU mortality. The most important determinants of ICU mortality were emergency (versus elective) admission, non-operative (versus postoperative) source of admission and higher age-adjusted APACHE II score.The nature of the admission and severity of illness, but not age, are determinants of ICU survival. Evidence-based criteria are needed to assess the appropriateness of ICU admission in the very elderly. Clear criteria would help to prevent initiation of futile therapies and also to ensure that the very elderly are not denied potentially beneficial ICU care. We need to study triage patterns and outcome data further to ensure that the very elderly have the same opportunities to access appropriate intensive care treatment as the rest of the population.

Objective: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and aggressive subtype of ovarian cancer with limited treatment options. Inactivating SMARCA4 germline and somatic mutations are present in nearly all SCCOHT cases, representing a signature molecular feature of this disease. Concomitant loss of SMARCA2, a mutually exclusive catalytic subunit of the SWI/SNF chromatic remodeling complex, has been attributed to worse overall survival in non-small cell lung carcinoma (NSCLC) when compared to cases with loss of SMARCA4 only. The objective of this study was to evaluate the mutational status and expression of SMARCA2 in SCCOHT. Methods: We evaluated 10 archival cases of SCCOHT and 1 newly established case from a PDX model of recurrent disease. Specialty gynecologic pathologists reviewed all cases to confirm the diagnosis. DNA was extracted from formalin-fixed, paraffin-embedded (FFPE) tumors with at least 50% tumor cell nuclei. Using the MSK-IMPACT assay, samples were deep-sequenced for a panel of 341 known oncogenes and tumor suppressor genes frequently altered in cancer. Identified SMARCA4 mutations were validated using Sanger sequencing. Sequencing of the SMARCA2 coding regions and splice sites was done using AmpliSeq. We performed immunoblotting for SMARCA4 and SMARCA2 on available frozen tumor samples using standard protocol. To confirm loss of protein expression, immunohistochemistry (IHC) for the SMARCA4 and SMARCA2 was performed on FFPE slides of all cases; the absence of tumor cell nuclear staining in the presence of internal positive controls scored as loss-of-expression. For cell-line over-expression studies, SCCOHT BIN67 and NSCLC H1299 cells were transiently transfected with an expression plasmid containing cDNA for SMARCA4 using FuGene reagent (Invitrogen) according to manufacturer's instructions. Immunoblotting for SMARCA2 and SMARCA4 was performed on protein lysates extracted from cell pellets. Results: IHC demonstrated loss of SMARCA2 expression in 9 (90%) of 10 archival SCCOHT cases and the PDX model. Sequencing of the SMARCA2 coding region and splice sites revealed no mutations, suggesting a non-mutational etiology of SMARCA2 protein loss. Previous work revealed biallelic SMARCA4 mutations in the 9 archival cases with SMARCA2 loss. SMARCA4 mutations were confirmed in both the PDX model and the one additional archival case, resulting in universal SMARCA4 mutations. The only case with normal SMARCA2 expression was also the only case with retained SMARCA4 expression. To explore the relationship between SMARCA2 and SMARCA4, we re-introduced SMARCA4 into BIN67 SCCOHT and H1299 NSCLC cell lines that lack expression. Wild-type BIN67 cells have very low levels of SMARCA2 expression, while wild-type H1299 cells express SMARCA2 normally. After transfection with plasmid cDNA and confirmation of SMARCA4 expression by immunoblotting, there was no increase in SMARCA2 expression in either BIN67 or H1299 cells. Conclusions: Concomitant loss of SMARCA2 and SMARCA4 expression was seen in nearly all SCCOHT cases and our PDX model. While loss of SMARCA4 expression is due to biallelic mutations, the absence of SMARCA2 expression is non-mutational and potentially the result of epigenetic or post-translational silencing. Our data suggest that concomitant loss of SMARCA2 and SMARCA4 is another hallmark of SCCOHT. The reversal of SMARCA2 loss may serve as a potential novel therapeutic approach for SCCOHT. Citation Format: Jill H. Tseng, Petar Jelinic, Brooke A. Schlappe, Niamh Conlon, Narciso Olvera, Fanny Dao, Jennifer J. Mueller, Yaser Hussein, Robert A. Soslow, Douglas A. Levine. Concomitant loss of SMARCA2 and SMARCA4 expression in small cell carcinoma of the ovary, hypercalcemic type. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr B15.

Percutaneous needle core biopsy is the standard of care in the assessment of suspicious breast lesions. The diagnostic term “Atypia” is used in breast biopsy reporting when histologic appearances are suspicious but not diagnostic of malignancy. Multiple histopathological appearances are encompassed by the umbrella term “atypia”, including atypical ductal hyperplasia (ADH), columnar cell change with atypia (CCCWA), which is also known as flat epithelial atypia (FEA), and a miscellaneous group of diagnoses, known as atypia NOS. A pathologic diagnosis of “atypia” in breast core biopsies usually leads to a recommendation to surgically excise the lesion. Many studies have correlated the diagnosis of “atypia” in core biopsies with the subsequent finding of carcinoma in the surgical excisions, and the percentage of carcinoma found represents the positive predictive value (PPV) of the diagnosis. To date, there is no agreed target PPV for the diagnosis of breast atypia on biopsy, but the most studies have demonstrated a PPV of 20- 40%. Individual “atypia” diagnoses such as CCCWA have an even lower PPV of 10-15%. One method of performance review is an audit of the average breast-atypia PPV within individual pathology departments, which then can be monitored and studied over time, to detect trends and “diagnostic drift” at an early stage. In addition, assessment of the individual PPV of each breast pathologist allows for analysis of the consistency of the diagnostic practice of each individual with their colleagues. Surprisingly, there have been no major studies assessing the intradepartmental range of PPVs for breast atypia diagnoses to date. In contrast, the American College of Radiology has designed the BIRADS classification system in order to audit and monitor the PPV of breast imaging in diagnosing malignancy. We undertook to measure the departmental PPV for malignancy following a biopsy diagnosis of breast atypia, and performed an anonymized subanalysis in order to establish the range of PPVs of atypia diagnoses between the sub-specialized breast pathologists within the department. This study established that the baseline PPV in our department is comparable to previously reported studies at 24%, while the range of PPV for an atypia diagnosis between pathologists is between 22.8 and 25% for 5 of 6 pathologists, with one pathologist demonstrating a higher PPV of 36.8%. ADH was the most common diagnosis of the atypia subtypes, and the PPV for ADH alone was 29.9%. 15% of ADH diagnoses were described as “ADH bordering on low grade DCIS”; within this subgroup the PPV was 48.5%. The PPV for a diagnosis of CCCWA alone was 10%. This study demonstrates that the PPV for breast atypia in a major tertiary cancer center is approximately 24%. We have demonstrated very reproducible use of this diagnostic term within the department. We plan to use the findings of this study to identify subgroups of patients with a sufficiently low PPV to justify a decision not to proceed to surgical intervention. We aim to develop an algorithm for use in the clinical setting in order to direct further patient management. The ultimate aim of this research is to reduce the number of patients undergoing unnecessary surgical interventions. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-02-09.

The authors describe the case of a 16-month-old girl who presented with bilateral hydronephrosis and renal failure secondary to bilateral renal pelvic botryoid Wilms' tumour (nephroblastoma). The term 'botryoid' describes an intrapelvic polypoid renal Wilms tumour, either extending from the renal parenchyma or primarily pelvis-based tumour. Both tumours filled the renal pelvis and extended down the proximal ureter, with no intraparenchymal tumour seen. Bilateral intralobar nephrogenic rests were present. Histological examination demonstrated triphasic nephroblastoma, with focal rhabdomyomatous differentiation of the stromal element bilaterally. Postchemotherapy, the patient underwent bilateral nephrectomy. Post complete resection of her bilateral disease, this patient has had an excellent outcome. This is only the third reported case of bilateral botryoid Wilms' tumour. While the condition is extremely rare, it should be included in the differential diagnosis of a young child with bilateral renal pelvic masses.