Supplementary Data from Relapsed Classic E-Cadherin (CDH1)–Mutated Invasive Lobular Breast Cancer Shows a High Frequency of HER2 (ERBB2) Gene Mutations

Mutant Allele Frequencies of the Mutated Genes in 22 cases of ILC

Lymphocytic colitis (LC) is characterized by chronic watery diarrhea and unremarkable endoscopic findings. Only one case of LC presenting as multiple colonic polyps has been reported. We report a case series of histologic LC pattern of injury (LCPI), presenting as endoscopic polyps, and compare them with typical LC cases. Eighteen archived (2009-2019) polypoid LCPI cases without an associated cause of polyp, such as adenoma, hyperplastic change, or lymphoid aggregate, were retrieved from 17 (12 female and 5 male) patients. The clinical history and endoscopic findings were noted. A total of 40 conventional LC cases were used as controls. Fisher's exact test was performed to evaluate associations between two variables. The mean age of the patients was 61.1 years. The indication for colonoscopy was chronic watery diarrhea (56%), screening/surveillance (33%), and rectal bleeding (11%). The mean number and size of the polyps was 1.6 and 2.9 mm, respectively. Seventy-six percent were located in the left colon, and 48% were sessile. When biopsied (14/18; 78%), the background colonic mucosa showed LCPI. There was no significant difference in age, gender, and the average number of lymphocytes in the two groups. Hypertension and history of malignancy was more common in the polypoid LCPI group than in the control LC group (P < 0.05). LCPI may present as endoscopic polyps, frequently in patients with hypertension and history of malignancy. Polypoid LCPI may be a harbinger of LCPI in the background nonpolypoid colonic mucosa. A subset of polypoid LCPI (56%) cases represents true LC. (C) 2020 Elsevier Inc. All rights reserved.

Summary Lymphocytic colitis (LC) is characterized by chronic watery diarrhea and unremarkable endoscopic findings. Only one case of LC presenting as multiple colonic polyps has been reported. We report a case series of histologic LC pattern of injury (LCPI), presenting as endoscopic polyps, and compare them with typical LC cases. Eighteen archived (2009–2019) polypoid LCPI cases without an associated cause of polyp, such as adenoma, hyperplastic change, or lymphoid aggregate, were retrieved from 17 (12 female and 5 male) patients. The clinical history and endoscopic findings were noted. A total of 40 conventional LC cases were used as controls. Fisher\u0027s exact test was performed to evaluate associations between two variables. The mean age of the patients was 61.1 years. The indication for colonoscopy was chronic watery diarrhea (56%), screening/surveillance (33%), and rectal bleeding (11%). The mean number and size of the polyps was 1.6 and 2.9 mm, respectively. Seventy-six percent were located in the left colon, and 48% were sessile. When biopsied (14/18; 78%), the background colonic mucosa showed LCPI. There was no significant difference in age, gender, and the average number of lymphocytes in the two groups. Hypertension and history of malignancy was more common in the polypoid LCPI group than in the control LC group (P

The aganglionic segment of bowel in Hirschsprung's disease (HD) varies in length. It is not clear whether total colonic aganglionosis (TCA) merely represents a long form of HD or a different phenotype of the disease. Animal model studies suggest that TCA may have a longer transition zone (TZ) than conventional colorectal HD. We compared mucosal innervation of TZ in 2 TCA cases and 10 conventional colorectal HD cases by quantifying calretinin-positive mucosal nerve fibers using image processing and analysis. One TCA was associated with esophageal atresia-tracheoesophageal fistula, the other with trisomy 21. The gradients of calretinin-stained pixel count increase per distance from the beginning of TZ (slope) for TCA were not significantly different from those for the conventional HD group. Given this observation, it is speculated that the length of TZ in TCA may fall within the range of and may not be much longer than conventional colorectal HD.

Introduction Excessive fat accumulation in the gastrointestinal tract is pathologic. Gastric mucosal polyposis due to excessive submucosal fat infiltration in a bariatric partial gastrectomy specimen was encountered, which has not been described in the literature. This observation prompted us to assess the extent of fat in gastric submucosa and study the incidence of mucosal polyposis due to submucosal fat accumulation in morbidly obese patients. Materials and Methods Archived pathology slides of 128 bariatric partial gastrectomy specimens including the index case and 89 control cases obtained from Whipple's procedure were examined. The amount of submucosal fat was categorized as 0 (no fat), 1 (up to 70% fat), and 2 (> 70% fat). The maximum submucosal fat thickness was measured with the interval cutoff of 5 mm and 10 mm. Results Of the 128 cases, 90 (70.3%) were category 1 and 31 (24.2%) were category 2. Maximum submucosal fat thickness was > 10 mm in 3 (2.3%) cases including the index case. The extent of submucosal fat accumulation correlated with the body mass index. The frequencies of category 2 and > 10 mm of fat thickness were higher in the bariatric patient group compared with the control group. Conclusion We propose a submucosal fat thickness of > 10 mm and diffuse (> 70%) fat accumulation as diagnostic criteria for gastric lipohyperplasia. Using these criteria, the prevalence of gastric lipohyperplasia in the morbidly obese population is 2.3%. A subset of these may present as gastric mucosal polyps.

Background: Implant brachytherapy (IBT) is a well-recognized treatment modality for early stage prostate cancer. Rectal ulcer and rectourethral fistula complicating IBT may cause an alteration of the normal anatomic landmarks. In this context, pseudomalignant radiation-induced changes within prostatic epithelium may be misinterpreted as a primary rectal malignancy. Such challenging and misleading findings have not been described, and may not be recognized as such. Materials and methods: We present the clinical and pathologic aspects of two patients who underwent IBT for low stage prostate cancer that was complicated by deep rectal ulcer. Both patients underwent extensive palliative surgical resection for disease control. Results: The histologic changes in both cases were noteworthy for extensive necrosis and inflammation of the prostate, associated with loss of recto-prostatic anatomical landmarks. Prostate glands showed striking radiation-induced atypia and pseudomalignant epithelial changes extending to the rectal ulcer bed, with no residual viable tumor. The first patient had undergone a biopsy of the rectal ulcer bed that was misinterpreted as a rectal adenocarcinoma prior to surgery. The similarity between atypical glands of the biopsy and the benign prostatic tissue with radiation-induced atypia in resection specimen confirmed their benign nature. Conclusions: Deep rectal ulcer complicating IBT may lead to distortion of the normal recto-prostatic anatomical landmarks, resulting in detection of pseudo-malignant prostatic glands at the ulcer base. Such findings may be mistaken for a primary rectal malignancy in limited biopsy material if not familiar to the pathologist.

Gastric lipomatosis (GL) is an extremely rare entity where gastric submucosa is diffusely expanded by accumulation of fat, but without well-defined histological criteria. GL presenting as multiple polyps is not reported in the literature. We encountered such a case in a bariatric partial gastrectomy specimen, which prompted the current study to assess extent of fat in gastric submucosa in morbidly obese patients. H&E slides of 128 bariatric partial gastrectomy specimens including the index case were examined. The amount of submucosal fat was categorized as 0 (no fat), 1 (up to 70% fat), and 2 (> 70% fat). The maximum submucosal thickness was measured with the interval cutoff of 5 mm (radiologic upper normal thickness) and 10 mm. The index case was of a 46-year-old morbidly obese man, who underwent preoperative endoscopy followed by bariatric partial gastrectomy. Multiple gastric polyps were noted endoscopically as well as grossly upon pathologic examination. Histological evaluation revealed GL with polypoid thickening of the submucosa up to 12 mm by fat. Of the 128 cases, seven (5.4%) fell in category 0, 90 (70.3%) in category 1, and 31 (24.2%) in category 3. Maximum submucosal thickness was <5 mm in 104 (81.3%) and ≥5 mm in 24 (18.8%) cases, in which three (2.3%) cases, including the index case, showed ≥10 mm of submucosal fat. We report a first case of GL presenting as gastric polyposis. Gastric submucosa is significantly thickened by fat and/or shows diffuse fat accumulation in 18.8% and 24.2% of morbidly obese patients, respectively. Based on our findings, we propose a submucosal thickness of a minimum of 10 mm and diffuse (>70%) fat accumulation as diagnostic criteria for GL. Using these criteria, the prevalence of GL in the morbidly obese population is 2.3%. A subset of these may present as polyps and gastric polyps secondary to GL may be under-recognized.

Whether total colonic aganglionosis (TCA), defined as aganglionosis involving the entire colorectum and up to 50 cm of the distal ileum, is within the spectrum of Hirschsprung disease (HD) or not is controversial. There are only three case reports of concurrent colonic HD and esophageal atresia with tracheoesophageal fistula (EA-TEF) in the literature. TCA associated with EA-TEF has not been documented. A female infant, born at term to a 26-year-old woman, was diagnosed with EA-TEF (gross type C) and was noted to have abdominal distention. The patient continued to have abdominal distention and vomiting following a repair of EA-TEF. A contrast follow-through showed partial obstruction in the distal small bowel. She underwent an exploratory laparotomy with intraoperative rectal biopsies, small bowel resection, and diverting end ileostomy. Calretinin immunohistochemistry was performed on the small bowel resection specimen. The intraoperative rectal biopsies showed an absence of ganglion cells. The exploratory laparotomy revealed a dilated small bowel with a possible transition zone in the ileum, 17 cm from the ileocecal valve. The possible transition zone was resected and the presence of ganglion cells in the proximal margin was confirmed by frozen section. A diverting end ileostomy was created at the resection site. The resected segment of small bowel showed an absence of ganglion cells in the distal portion and a gradual increase of ganglion cells in the proximal portion. Calretinin immunohistochemistry confirmed the presence of calretinin-positive mucosal nerve fibers in the proximal portion. The patient has been eating and gaining weight, without evidence of Down syndrome. We report a first case of concurrent TCA and EA-TEF. Although concurrent HD and EA-TEF is exceedingly rare as well, our case supports a speculation that TCA and HD may share a common pathogenesis, especially when associated with concurrent EA-TEF.

Aims Routine application of PD-L1 immunohistochemistry (IHC) in colorectal cancer (CRC) is limited due to lack of standardized scoring criteria, antibody clones, and intratumoral staining heterogeneity. We assessed PD-L1 protein expression on full face CRC tissue sections and applied two algorithms based on the published clinical trials that support the recent FDA approval for immune checkpoint inhibitors (ICPI) therapy in non-small cell lung cancer (NSCLC). Methods PD-L1/CD274 IHC (Roche/Ventana, clone SP142) was performed on representative tumour blocks from 52 mismatch repair-deficient (MMR-D) and 52 MMR-proficient (MMR-P) CRCs. Membranous PD-L1 expression was scored for the tumour cell (TC) and tumour-infiltrating immune cell (IC) components. PD-L1 positivity status was determined based on the published NSCLC clinical trials that utilized the Ventana SP142 assay. Hybrid capture-based comprehensive genomic profiling (CGP) was performed on a separate set of 2268 clinically advanced CRCs and the frequency of PD-L1/PD-L2 amplification was determined. Results PD-L1 expression in the TC and IC correlated with MMR-D (p=0.013, p<0.0001), T stage (p=0.036, p=0.0036) and clinical stage (p=0.022, p=0.0037). PD-L1 positivity status correlated with MMR-D by two algorithms. Five of 2268 (<1%) advansced CRCs demonstrated amplification of either the PD-L1 or PD-L2 genes by CGP. Conclusions PD-L1 expression in TC and IC is associated with advanced stage and MMR-D. PD-L1 positivity status by the published algorithm is associated with MMR-D. PD-L1 amplification is extremely uncommon in CRC. Evaluation of whole tissue section and incorporation of IC staining enhance the sensitivity to screen patients who may benefit from ICPI therapy.

Pure mucinous breast carcinoma (pmucBC) is a distinctive variant of breast cancer (BC) featuring an excellent overall prognosis. However, on rare occasions, pmucBC pursues an aggressive clinical course. We queried whether comprehensive genomic profiling (CGP) would uncover clinically relevant genomic alterations (CRGA) that could lead to targeted therapy treatment for patients with an advanced and metastatic form of pmucBC.

CONTEXT:Metastatic metaplastic breast carcinoma (MPBC) is an uncommon, but aggressive, tumor resistant to conventional chemotherapy.OBJECTIVE:To learn whether next-generation sequencing could identify potential targets of therapy for patients with relapsed and metastatic MPBC.DESIGN:Hybridization capture of 3769 exons from 236 cancer-related genes and 47 introns of 19 genes commonly rearranged in cancer was applied to a minimum of 50 ng of DNA extracted from 20 MPBC formalin-fixed, paraffin-embedded specimens and sequenced to high uniform coverage.RESULTS:The 20 patients with MPBC had a median age of 62 years (range, 42-86 years). There were 9 squamous (45%), 9 chondroid (45%), and 2 spindle cell (10%) MPBCs, all of which were high grade. Ninety-three genomic alterations were identified, (range, 1-11) with 19 of the 20 cases (95%) harboring an alteration that could potentially lead to a targeted treatment option. The most-common alterations were in TP53 (n = 69; 75%), PIK3CA (n = 37; 40%), MYC (n = 28; 30%), MLL2 (n = 28; 30%), PTEN (n = 23; 25%), CDKN2A/B (n = 19; 20%), CCND3 (n = 14; 15%), CCNE1 (n = 9; 10%), EGFR (n = 9; 10%), and KDM6A (n = 9; 10%); AKT3, CCND1, CCND2, CDK4, FBXW7, FGFR1, HRAS, NF1, PIK3R1, and SRC were each altered in a single case. All 16 MPBCs (100%) that were negative for ERBB2 (HER2) overexpression by immunohistochemistry and/or ERBB2 (HER2) amplification by fluorescence in situ hybridization were also uniformly (100%) negative for ERBB2 amplification by next-generation sequencing-based copy-number assessment.CONCLUSIONS:Our results indicate that genomic profiling using next-generation sequencing can identify clinically meaningful alterations that have the potential to guide targeted treatment decisions in most patients with metastatic MPBC.

Abstract Background: RUNX2, a member of the RUNX family of transcription factors, regulates normal bone, cartilage and skeletal muscle morphogenesis. Aberrant RUNX2 expression has correlated with malignant cell migration, invasion and bone metastases. In the following study, we evaluated the prognostic significance of RUNX2 protein expression in a large cohort of tumors from each of three sites of origin - prostate, colon and breast. Design: Formalin-fixed paraffin-embedded tissue sections from 121 PAC, 104 CRC and 82 invasive BC [64 ductal (IDC); 18 lobular (ILC)] were immunostained by a manual method (DAKO LSAB+ System-HRP) using mouse monoclonal RUNX2 (Santa Cruz). Nuclear and/or cytoplasmic immunoreactivity was scored based on intensity and percentage of positive cells in both the tumor (T) and adjacent benign (B) epithelium in each case. Cases were assessed as tumor>benign (T>B), tumor = benign (T = B), tumor Results: RUNX2 immunoreactivity was predominately nuclear in PAC, CRC and BC and noted as follows: in PACs: T>B 58%, T = B 31%, T = Gleason grade 7] vs low [< = Gleason grade 6] tumor grade (p = 0.001), advanced [stage III, IV] vs early [stage I, II] tumor stage (p = 0.039) and biochemical disease recurrence (p = 0.008). In CRCs, immunoreactivity was noted as: T>B 61%, T = B 22%, TB 65% and T = B 35%; and correlated overall with early [stage I, II] vs advanced [stage III, IV] tumor stage (p = 0.05); ER positive status (p = 0.028); and on Cox univariate analysis, correlated with both lengthened recurrence free (p = 0.033) and overall (p = 0.042) survival; and showed a trend toward association with PR positive status (p = 0.075). Within the ER negative BC subgroup, RUNX2 immunoreactivity correlated with early tumor stage (p = 0.008) and PR positive status (p = 0.033). Conclusion: While RUNX2 protein expression correlates with adverse prognostic variables in prostate and colon cancers, RUNX2 immunoreactivity portends favorable prognosis in breast cancer. Further study of RUNX2 expression and its potential role as a therapeutic target particularly in PAC and CRC appear warranted. Citation Format: Bhaskar V.S. Kallakury, Albert Huho, Ann B. Boguniewicz, David M. Jones, Tipu Nazeer, Hwa Jeong Lee, Christine E. Sheehan, Jeffrey S. Ross. Prognostic significance of RUNX2 protein expression in carcinomas of the prostate (PAC), colon (CRC), and breast (BC). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4355. doi:10.1158/1538-7445.AM2015-4355