Lymphoglandular Complex-Like Colorectal Carcinoma-A Series of 20 Colorectal Cases, Including Newly Reported Features of Malignant Behavior.

Distinguishing colon carcinoma that is surrounded by well-circumscribed lymphoid tissue from adenomas involving lymphoglandular complexes can be difficult. We assessed a multi-institutional international cohort of 20 colorectal carcinomas with associated prominent lymphoid infiltrates, which we referred to as lymphoglandular complex-like carcinoma (LGCC). We collected clinical and endoscopic features, including lesion size, endoscopic appearance, location, procedure, follow-up, AJCC stage, and mismatch repair status. We recorded the presence of the following histologic features: haphazard gland distribution, gland angulation, gland fusion, solid nest formation, single-cell formation, stromal desmoplasia, presence of lymphovascular invasion and perineural invasion, presence of lamina propria, cytologic atypia as low- or high-grade, presence of goblet cells in the invasive component, and the presence of a surface lesion. Most cases (9 of 13) were described endoscopically as sessile polyps with an average size of 1.56 cm. Most cases (90%) were associated with a surface lesion, of which the majority were tubular adenomas, though a subset was associated with sessile serrated lesions with dysplasia (3 of 18). All cases of LGCC demonstrated haphazard gland distribution and either gland angulation, fusion, or solid nest formation. A portion of cases demonstrated single-cell infiltration (35%) and desmoplasia (50%), and rarely lymphovascular invasion was present (5%). A subset (10%) of cases invaded beyond the submucosa. Deficient mismatch repair was present in 22% (2 of 9) of cases for which it was performed. In cases of colectomy or completion colectomy, nodal metastasis was present in 38% (3 of 8). No cases demonstrated disease recurrence or disease-specific mortality. Overall, LGCC represents an enigmatic subset of carcinomas that is important to distinguish from adenomas involving lymphoglandular complexes due to its varying prognostic outcomes.

Colorectal Carcinoma With Sarcomatoid Components: Report of 15 Cases and Literature Review of an Exceedingly Rare Carcinoma Subtype.

Colorectal carcinoma with sarcomatoid components (which includes so-called carcinosarcomas and sarcomatoid carcinomas) is a rare subtype with 50 reported cases in the literature and overlapping criteria with undifferentiated carcinoma. We collected and described 15 cases from 10 men and 5 women, with a mean age of 66 years. Symptoms included abdominal pain and gastrointestinal bleeding. Most tumors presented in the rectosigmoid region, with a mean size of 8.2 cm. The sarcomatoid component, on average, represented 58% of the tumors and took many forms, including spindled (10 cases), anaplastic (9 cases), and rhabdoid (3 cases); one case showed osteoid matrix. Tumor budding was usually high, and tumor-infiltrating lymphocytes were usually low. The sarcomatoid component was keratin-positive in 10 cases. One case showed loss of mismatch repair protein expression, and 2 cases showed SMARCA4 loss (1 also with SMARCA2 loss). Molecular testing identified mutations in KRAS (n=1), NRAS (n=2), BRAF (n=2), APC (n=1), and TP53 (n=1) in a few cases. Tumors often presented at advanced stage, with 11 cases pT4, 9 cases with nodal metastases, and 7 cases with distant metastases. Follow-up was available for 10 cases (median: 2 months), with 2 alive without disease, 3 alive with disease, and 5 dead. Our findings roughly corresponded with those in previously reported cases. Colorectal carcinoma with sarcomatoid components is rare and aggressive, with a poor prognosis for many patients. We suggest that spindled cells, anaplasia, heterologous elements, and/or a component with definable sarcomatous lineage be used to distinguish colorectal carcinoma with sarcomatoid components from undifferentiated carcinoma.

Human Neutrophil α-Defensins 1-3 Are Upregulated in the Microenvironment of Fibrotic Liver.

Background and Objectives: Neutrophil infiltration is an established signature of Non-Alcoholic Fatty Liver Disease (NAFLD) and Steatohepatitis (NASH). The most abundant neutrophilic peptide, alpha-defensin, is considered a new evolving risk factor in the inflammatory milieu, intimately involved in lipid mobilization. Our objective is to assess for potential association between alpha-defensin immunostains and NAFLD severity. Materials and Methods: We retrospectively investigated the liver biopsies of NAFLD/NASH patients, obtained at Hillel Yaffe Medical center between the years 2012 and 2016. Patients' characteristics were recorded, including relevant blood tests at the time of biopsy. Each biopsy was semi-quantitatively scored using NAFLD Activity Score (NAS) and NASH fibrosis stage. The biopsies were immunostained for alpha-defensin. The precipitation of alpha-defensin was correlated to NAS and fibrosis. Results: A total of 80 biopsies were evaluated: male ratio 53.2%, mean age 44.9 ± 13.2 years, 54 had fibrosis grades 0-2, and 26 were grade 3-4. Conventional metabolic risk factors were more frequent in the high-grade fibrosis group. Immunostaining for alpha-defensin disclosed higher intensity (a.u.) in grade 3-4 fibrosis relative to grades 0-2, 25% vs. 6.5%, p < 0.05, respectively. Moreover, alpha-defensin staining was nicely co-localized with fibrosis. Conclusions: In our group of NASH/NAFLD patients, higher metabolic risk profile was associated with higher fibrosis grade. Immunostaining for alpha-defensin showed patchy intense staining concordant with high fibrosis, nicely co-localized with histological fibrosis. Whether alpha-defensin is a profibrotic risk factor or merely risk marker for fibrosis must be clarified in future studies.

Rapid intraoperative diagnosis of gynecological cancer by ATR-FTIR spectroscopy of fresh tissue biopsy.

A rapid and reliable intraoperative diagnostic technique to support clinical decisions was developed using Fourier-transform infrared (FTIR) spectroscopy. Twenty-six fresh tissue samples were collected intraoperatively from patients undergoing gynecological surgeries. Frozen section (FS) histopathology aimed to discriminate between malignant and benign tumors was performed, and attenuated total reflection (ATR) FTIR spectra were collected from these samples. Digital dehydration and principal component analysis and linear discriminant analysis (PCA-LDA) models were developed to classify samples into malignant and benign groups. Two validation schemes were employed: k-fold and "leave one out." FTIR absorption spectrum of a fresh tissue sample was obtained in less than 5 minutes. The fingerprint spectral region of malignant tumors was consistently different from that of benign tumors. The PCA-LDA discrimination model correctly classified the samples into malignant and benign groups with accuracies of 96% and 93% for the k-fold and "leave one out" validation schemes, respectively. We showed that a simple tissue preparation followed by ATR-FTIR spectroscopy provides accurate means for very rapid tumor classification into malignant and benign gynecological tumors. With further development, the proposed method has high potential to be used as an adjunct to the intraoperative FS histopathology technique.

IGF1R Axis Inhibition Restores Dendritic Cell Antitumor Response in Ovarian Cancer.

Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy. The insulin-like growth factor (IGF) system plays a key role in regulating growth and invasiveness in several malignancies, including ovarian cancer. IGF1R targeting showed antiproliferative activity of EOC cells. However, clinical studies failed to show significant benefit. EOC cells suppress antitumor immune responses by inducing dendritic cell (DC) dysfunction. The IGF1 axis can regulate DC maturation. The current study evaluated involvement of the IGF1 axis in DC differentiation in EOC. Studies were conducted on EOC and on a human monocyte cell line. Tissue microarray analysis (TMA) was performed on 36 paraffin blocks from EOC patients. Expression of IGF1R, p53, Ki67, BRCA1, and DC markers was evaluated using immunohistochemistry. Co-culture of EOC cells with DC pretreated with IGF1R inhibitor blocked cancer cell migration. TMA demonstrated higher rate of IGF1R protein expression in patients with advanced (76.9%) as compared to early (40%) EOC. A negative correlation between IGF1R protein expression and the CD1c marker was found. These findings provide evidence that IGF1R axis inhibition could be a therapeutic strategy for ovarian cancer by restoring DC-mediated antitumor immunity.

SATB2 and Hep Par 1 Immunohistochemistry Is Helpful in Distinguishing Between Inflamed and Architecturally Altered Ileal Pouch and Rectal Cuff Mucosa.

The management of patients with ulcerative colitis after proctocolectomy with ileal pouch-anal anastomosis includes independent histological assessments of inflammation in the ileal pouch and the rectal cuff. However, the distinction between pouchitis and cuffitis can be impeded both endoscopically and histologically by the combined effects of inflammation and regeneration. We investigated the use of 2 markers, hepatocyte paraffin 1 (Hep) and SATB2 (special AT-rich sequence-binding protein 2), which are expressed immunohistochemically in the small and large bowel epithelium, respectively, as ancillary methods to deal with this problem. Immunohistochemical staining was performed retrospectively on 20 consecutive pairs of post-ileal pouch-anal anastomosis biopsies with varying degrees of histological inflammation and architectural distortion, which had each been designated as "ileal pouch" or "rectal cuff" by the referring endoscopists. Expression was graded as focal (10% to 74% stained cells) or diffuse (75% to 100%). Among the ileal pouch biopsies, 20 (100%) expressed Hep either diffusely (75%) or focally (25%), whereas SATB2 staining was either negative in 15 (75%) or focal in 5 (25%), the latter group all expressing Hep diffusely. Among the rectal cuff biopsies, 14 expressed SATB2 diffusely. Of these, Hep was either negative in 11 (79%) or focally positive in 3 (21%), the latter group all expressing SATB2 diffusely. Six ostensibly rectal cuff biopsies (30%) expressed Hep diffusely and were negative for SATB2, suggesting endoscopic misidentification. None of the 40 biopsies expressed both markers diffusely. We conclude that in doubtful cases, diffuse expression of either Hep or SATB2 can be helpful in discriminating between ileal pouch and rectal cuff mucosa, respectively.

Serrated epithelial colorectal polyps (hyperplastic polyps, sessile serrated adenomas) with perineurial stroma: Clinicopathological and molecular analysis of a new series.

Serrated colorectal fibroblastic polyps (FPs) are rare benign mucosal lesions composed of serrated epithelial crypts separated and distorted by intimately associated bland spindle cell proliferations with perineurial-like phenotype. We herein describe 21 new FPs affecting 10 females and 9 males aged 45 to 80 yrs. (mean, 62 yrs). Lesions originated in the sigmoid colon/rectosigmoid junction (n = 16), rectum (n = 2), and other parts of the colon (n = 3). Most patients had additional synchronous or metachronous polyps: classical adenomas (12 patients), sessile serrated adenoma/SSA (1 patient), hyperplastic polyps/HPs (7 patients), both HPs and adenomas (6 patients) and colorectal cancer (2 patients). Size of the lesions varied from 1 to 6 mm (mean: 3 mm). Histologically, all lesions were composed of serrated epithelial crypts that were separated and distorted by spindle cell stromal proliferations (consistently EMA+, claudin-1+ and GLUT-1+). The epithelial component displayed features of HPs (n = 17) and SSA (n = 4). Laser-microdissection-guided molecular testing was successful for 13 epithelial and 9 stromal components (9 paired samples). The BRAF V600E mutation was detected in 54% of the epithelial but in none of the stromal components. In conclusion, colorectal FPs represent genuine serrated epithelial polyps corresponding either to HP or (less frequently) SSA and should be better classified as such with a note on the presence of the stromal component. A more concise terminology reflecting their epithelial nature is needed to fulfill the requirements for colorectal cancer risk assessment and hence adopt appropriate follow-up strategies.

Lobular Carcinoma of the Breast Metastatic to the Spleen and Accessory Spleen: Report of a Case.

Despite the fact that accessory spleen (also known as supernumerary spleen, splenunculus, or splenule) can be found in 10-30% of patients undergoing autopsies, metastatic disease occurring in this organ has been barely reported. A case of lobular breast carcinoma metastatic to the spleen and accessory spleen found incidentally at therapeutic splenectomy for severe anemia and thrombocytopenia is described. On microscopic examination both organs revealed severe fibrocongestive changes and extramedullary hematopoiesis with no obvious carcinomatous involvement. Cytokeratin 7, estrogen receptors, and GATA3 immunohistochemistry disclosed the presence of numerous metastatic breast carcinoma cells infiltrating the splenic parenchyma. This case demonstrates that metastatic carcinoma can be encountered, although rarely, in accessory spleens and that cytokeratin stain should be performed in sections of spleens and/or accessory spleens excised from cancer patients in which the presence of malignant epithelial cells is not recognized on routine sections.

Neonatal Chest Wall Rhabdomyosarcoma.

An infant was born at term with a huge chest mass diagnosed as rhabdomyosarcoma. Treatment consisted of surgical resection and chemotherapy. We describe this very rare congenital mass and the problematic therapeutic management of such a tumor in a newborn.

Metastatic carcinoma occurring in a gastric hyperplastic polyp mimicking primary gastric cancer: the first reported case.

Hyperplastic polyps of the stomach are regarded as benign. However, in rare cases they may contain incipient primary carcinomas. To our knowledge, breast carcinoma metastatic to a gastric hyperplastic polyp has not yet been reported. We describe the case of a 69-year-old woman to whom a gastric polyp was endoscopically excised. The patient had previously undergone a right mastectomy for mixed, invasive ductal and lobular carcinoma 5 years earlier. Histological sections from the gastric lesion showed typical features of hyperplastic polyp with foci of poorly differentiated adenocarcinoma including signet ring cells infiltrating the lamina propria. The histologic findings were consistent with a primary gastric cancer. However, the carcinoma cells were immunopositive for estrogen and progesterone receptors and GATA3 and negative for CDX2, Hep Par 1, and MUC5AC. E-cadherin showed membranous reactivity in some of the carcinoma cells while in others it was negative. Accordingly, metastatic mixed, lobular and ductal breast carcinoma was diagnosed. We conclude that metastatic adenocarcinoma mimicking primary gastric cancer can be rarely encountered in hyperplastic gastric polyps.

Small intestinal amyloidosis: a rare cause of diverticular disease.

Systemic amyloidosis frequently involves the small intestine. However, its association with diverticular disease has been seldom reported to date. To draw attention to this rare but potentially harmful association, we herein present an additional case of small bowel diverticular disease associated with amyloidosis.

Angiolipofibroma of the cecum: a rare type of submucosal polyp.

Mesenchymal type tumors originated in the submucosa represent a small percentage of colorectal polyps. This is particularly true for polyps composed of more than one mesenchymal tissue type. We herein present the pathological features of an unusual polypoid proliferation of mature fatty, fibrous, and vascular tissues including vessels of diverse nature and size. The histological findings support a hamartomatous rather than a true neoplastic origin for this rare lesion.

Colonic perineuriomas with and without crypt serration: a comparative study.

Colorectal perineuriomas are characterized by a mucosal proliferation of benign stromal cells expressing perineurial markers leading to separation and/or disorganization of the crypts that frequently display a serrated/hyperplastic architecture. Previous studies demonstrated a high prevalence of a BRAF p.V600E mutation in perineuriomas with serrated crypts and suggested that perineuriomas without crypt serration may represent an unrelated, different type of polyp. Yet, these molecular analyses included only 2 cases of perineuriomas without crypt serration. In fact, no previous studies can be found in the literature that have separately analyzed serrated and nonserrated perineuriomas and made a comparison between them. We retrospectively evaluated the clinical, histologic, immunohistochemical, and molecular features of 15 perineuriomas without and 45 with crypt serration (NSPs and SPs, respectively). No significant differences were found between the groups with regard to sex, age, location, and size. Histologically, the perineurial proliferation in SPs and NSPs demonstrated similar features with fascicles or bundles of bland, plump spindle cells surrounding and separating the crypts. All lesions showed expression with at least 2 of 4 perineurial cell markers (epithelial membrane antigen, claudin-1, GLUT-1, and collagen type IV). Molecular analysis performed in 20 cases (8 SPs and 12 NSPs) identified BRAF mutation of codon 600 in 5 (62%) SPs including 3 with p.V600E (c.1799T>A) and 2 with p.V600R (c.GT1798_99GT>AG). In contrast, no case of NSPs harbored BRAF mutations (p value 0.004). Our findings confirm that BRAF mutations originate in the serrated epithelium of SPs and demonstrate that SPs and NSPs have similar clinical and endoscopic characteristics and similar stroma, suggesting that they might represent 2 variants of a single lesion.

Hepatocyte antigen (Hep Par 1) is helpful in distinguishing between inflamed and architecturally altered ileal and colonic mucosa.

In chronic inflammatory states, the ileal mucosa may flatten, whereas the colonic mucosa may develop a villiform surface. Accordingly, pathologic biopsies labeled by the endoscopist as "ileocolic" or "ileocecal" may generate confusion or uncertainty as to their specific origin. To facilitate distinguishing between architecturally altered ileal and colonic mucosae, we assessed the hepatocyte paraffin 1 (Hep Par 1) antibody, reported to react with normal and metaplastic small bowel epithelium but not with normal colonic epithelium, in 25 ileal biopsies (10 normal and 15 pathologic), 25 colonic biopsies (10 normal and 15 pathologic), and 20 samples labeled as "ileocecal" or "ileocolic" in which the organ of origin could not be definitely established because of mucosal inflammation and distortion. The latter group included 8 cases diagnosed as being of "probable ileal origin," 7 cases diagnosed as being of "probable colonic origin," and 5 cases diagnosed as "uncertain." Diffuse granular cytoplasmic Hep Par 1 expression was detected in all normal and pathologic ileal mucosal biopsies, whereas all colonic biopsies were negative or focally reactive. Cases of "probable ileal origin" were diffusely positive (granular cytoplasmic pattern), whereas those of "probable colonic origin" were negative or focally reactive. Two of the "uncertain" cases expressed Hep Par 1, whereas 3 were negative, thus supporting their ileal and colonic derivation, respectively. In conclusion, Hep Par 1 is diffusely expressed by pathologic ileal mucosa, being negative or only focally positive in pathologic colonic mucosa. Accordingly, it represents a valuable tool for recognizing the tissue source in problematic ileocolonoscopic biopsies.

Small intestine perforation due to metastatic uterine cervix interdigitating dendritic cell sarcoma: a rare manifestation of a rare disease.

Interdigitating Dendritic Cell Sarcoma (IDCS) is an infrequent dendritic cell tumor which mainly affects the lymphatic system. Intestinal metastasis from uterine IDCS is extremely rare. Here we report a case of a 76-year-old female presenting with vaginal bleeding and acute abdomen. The final diagnosis revealed a small bowel perforation due to metastatic involvement from uterine cervix IDCS. In this paper, we report the clinical manifestation, computed tomography and histopathological findings helpful for the accurate diagnosis of this rare tumor.

Early colonic perineurioma: a report of 11 cases.

Colonic perineurioma has been depicted as characterized by a mucosal proliferation of monomorphic spindle perineurial cells leading to an evident separation, distortion, and entrapment of colonic crypts. The authors, however, believe that a sizable subset of the cases differ in that they display only a limited perineurial proliferation leading to only mild crypt separation without crypt entrapment. This morphological variant (early perineurioma) has not yet been documented. The authors herein present the clinicopathological and immunohistochemical features of 11 cases. Polyp size ranged from 2 to 4 mm, and 8 (73%) were located in the sigmoid. Histologically, they revealed small, frequently noncontiguous nests or bundles of uniform round to oval cells, causing slight separation of parallel or mildly distorted crypts, which displayed a serrated/hyperplastic architecture in 8 (73%) cases. Immunostaining for perineurial markers showed strong expression for claudin-1, GLUT-1, and collagen type IV and weak reactivity for epithelial membrane antigen. In conclusion, early perineurioma is a morphological variant of colonic perineurioma in which the perineurial proliferation is limited and consequently more difficult to recognize. Using perineurial markers is helpful in reaching an accurate diagnosis.

Heparanase expression by Barrett's epithelium and during esophageal carcinoma progression.

Enzymatic activity responsible for the cleavage of heparan sulfate, commonly known as heparanase, is abundant in tumor-derived cells. Heparanase cleaves heparan sulfate side chains, presumably at sites of low sulfation, thus facilitating structural alterations of the extracellular matrix and basement membrane underlying epithelial and endothelial cells. Traditionally, heparanase activity was correlated with the metastatic potential of tumor-derived cells, attributed to enhanced cell dissemination as a consequence of heparan sulfate cleavage and remodeling of the extracellular matrix barrier. More recently, heparanase upregulation was documented in an increasing number of human carcinomas and hematological malignancies, correlating with increased tumor metastasis, vascular density, and shorter post-operative survival of cancer patients. Although heparanase upregulation and its pro-malignant features are well documented, the instance of its induction in the course of tumor development was less investigated. Here, we used immunohistochemical analysis to investigate heparanase expression in normal esophagus, Barrett's esophagus without dysplasia, Barrett's esophagus with low-grade dysplasia, Barrett's esophagus with high-grade dysplasia, and adenocarcinoma of the esophagus. We report that heparanase expression is already induced in Barrett's epithelium without dysplasia, and is further increased during progression through distinct pathological stages, namely, low-grade dysplasia, high-grade dysplasia, and adenocarcinoma. Notably, heparanase induction correlated with increased cell proliferation index revealed by Ki-67 staining. These findings suggest that heparanase function is not limited to the process of tumor metastasis, but rather is engaged at the early stages of esophagus carcinoma initiation and progression.

Fibroblastic polyp of the colon and colonic perineurioma: 2 names for a single entity?

Fibroblastic polyps of the colon and intestinal perineuriomas are unusual mucosal lesions with identical clinical and histologic features, and apparent different immunohistochemical and ultrastructural characteristics. However, immunohistochemical distinction was solely based on the results obtained with epithelial membrane antigen (EMA), an antibody whose reactivity on perineuriomas is difficult to demonstrate. Likewise, accurate ultrastructural diagnosis may be flawed by sampling error, preservation artifacts, or paucity of specific diagnostic features. In a recent short communication, it was suggested that both lesions may represent the same entity. To further evaluate this hypothesis, 28 colorectal polyps with clinical and histologic features of colonic fibroblastic polyps/perineuriomas (including 10 cases previously reported as fibroblastic polyps) were stained immunohistochemically for 4 markers of perineurial differentiation, that is, claudin-1, GLUT-1, collagen type IV, and EMA (the latter performed using an extended protocol for antigen retrieval and a kit for signal amplification). In addition, electron microscopy was performed in 4 cases. EMA and claudin-1 stained 26 of 28 (93%) polyps whereas GLUT-1 and collagen type IV were expressed in all of them. EMA reactivity was mostly focal and weak whereas the other markers displayed a diffuse and strong signal. Ultrastructural examination revealed elongated cells with features of perineurial differentiation including long, slender cytoplasmic processes with pinocytotic vesicles and an external lamina. Our findings support the hypothesis that fibroblastic polyps and perineuriomas of the colon represent the same entity. We suggest reclassifying fibroblastic polyps reactive to perineurial markers as perineuriomas. To reach an accurate diagnosis, we recommend employing at least 2 markers of perineurial differentiation, and performing EMA immunostaining with high antibody concentration, prolonged incubation time, and/or extended protocol for antigen retrieval.

Utility of MIB-1 (Ki-67) in evaluating diminutive colorectal polyps with cautery artifact.

CONTEXT: Accurate interpretation of colorectal polyp histology is essential in the decision-making process during treatment and surveillance following polypectomies. However, interpretation of diminutive colorectal polyps removed by thermal electrocoagulation (hot biopsy technique) is often problematic as a result of cautery artifact. OBJECTIVE: To evaluated the usefulness of the proliferation marker MIB-1 (Ki-67) as an aid in the differential diagnosis of diminutive colorectal polyps with cautery artifact, as adenomatous and nonadenomatous polyps display different patterns of epithelial proliferation. DESIGN: Seventy-five diminutive colorectal polyps with extensive cautery artifact displaying at least the upper portions of 3 adjacent crypts with the corresponding surface epithelium were evaluated and immunolabeled with MIB-1. They included 25 cases in which a definitive or presumptive diagnosis could not be reached (indeterminate polyps), 25 cases diagnosed as compatible with adenomatous polyp, and 25 cases diagnosed as compatible with nonadenomatous polyp. RESULTS: MIB-1 immunoreactivity was well preserved in the cauterized areas. Among indeterminate polyps, MIB-1 stained upper crypts and surface epithelium in 14 cases (adenomatous polyp staining pattern) and revealed minimal or absent staining in these areas in 11 cases (nonadenomatous polyp staining pattern). All cases diagnosed as compatible with adenomatous polyp displayed the adenomatous polyp staining pattern. In contrast, all cases diagnosed as compatible with nonadenomatous polyp revealed the nonadenomatous polyp staining pattern. CONCLUSIONS: Immunoreactivity for MIB-1 may be used as a beneficial adjunctive test to help diagnose diminutive colorectal polyps with extensive cautery artifact.