Ileal collision tumor associated with gastrointestinal bleeding: A case report and review of literature.

BACKGROUND: Collision tumors involving the small intestine, specifically the combination of a hamartomatous tumor and a lipoma, are extremely rare. To our knowledge, no previous case report has described a collision tumor composed of two benign tumors of different origins in the small intestine. CASE SUMMARY: Here, we present the case of an 82-year-old woman who presented with hemorrhagic shock and was found to have a mass measuring approximately 50 mm × 32 mm × 30 mm in the terminal ileum. Based on computed tomography scan findings, the mass was initially suspected to be a lipoma. A subsequent colonoscopy revealed a pedunculated submucosal elevation consisting of two distinct parts with a visible demarcation line. A biopsy of the upper portion suggested a juvenile polyp (JP). Owing to the patient's advanced age, multiple comorbidities, and poor surgical tolerance, a modified endoscopic submucosal dissection was performed. Histopathological examination of the excised mucosal mass revealed a lipoma at the base and a JP at the top, demonstrating evidence of rupture and associated bleeding. The patient's overall health remained satisfactory, with no recurrence of hematochezia during the six-month follow-up period. CONCLUSION: This case report provides new evidence for the understanding of gastrointestinal collision tumors, emphasizing their diverse clinical presentations and histopathological characteristics. It also offers diagnostic and therapeutic insights as well as an approach for managing benign collision tumors.

Resection of an anal fistula with endoscopic submucosal dissection.

A 34-year-old man presented with paroxysmal hypogastralgia during defecation for 2 weeks. Physical and laboratory examination findings were unremarkable, other than a depression located 1 cm above the dentate line, accompanied by mild tenderness and a clubbed induration extending to the rectum. Colonoscopy showed a 2.0×0.8 cm longitudinal, protruding mass in the posterior wall of the lower rectum. Endosonography revealed a mixed echogenic mass originating from the rectal submucosa, with no sign of muscular wall disruption. There was no evidence of Crohn's or other diseases. Following anorectal consultation, we suspected a submucosal or internal blind fistula since the patient was symptomatic with a superficial mass which communicated to the rectum. The location and depth of the mass indicated that endoscopic resection might allow for removal of the lesion without impairment of the anorectal anatomy and function. After obtaining the patient's consent, endoscopic submucosal dissection (ESD) was performed. En bloc resection was achieved using a disposable, high-frequency knife (Micro-Tech, China). No adverse events occurred. Histopathological examination revealed a benign fistula composed of local submucous granulomatous tissue proliferation and a focal mucous epithelial defect. The patient's symptoms were relieved postoperatively, and no recurrence was evident after 6 months.

Clinical and histopathological features of chronic hepatitis B virus infected patients with high HBV-DNA viral load and normal alanine aminotransferase level: A multicentre-based study in China.

BACKGROUND: The aim of this study is to reveal the clinical and histopathological features of HBsAg-positive and HBeAg-positive chronic hepatitis B infected patients with high level of HBV DNA, from 17 hospitals and medical centres in China, with alanine aminotransferase levels within the lower region of normal range versus those with levels within the upper region of normal range and to investigate the clinical risk factors for the requirement of treatment through the examination of liver biopsy. METHODS: Liver biopsy was performed on high level of HBV DNA of 455 patients with HBsAg-positive and HBeAg-positive chronic hepatitis B infection and persistently normal alanine aminotransferase level. Liver necroinflammation and fibrosis were graded per the Knodell histological activity index and Ishak's fibrosis score, respectively. Univariate analysis of the clinical parameters versus necroinflammation and fibrosis was carried out. RESULTS: Of the subjects in this multicentre-based study, 5.49% and 10.11% had significant necroinflammation with Knodell histological activity index ≥ 9 and hepatic fibrosis stages with Ishak scores ≥ 3, respectively. The subjects were stratified into three age groups (30-39, 40-49 and ≥ 50 years), and our data clearly suggested that age, particularly in the age group over 50, was an independent predictor of liver necroinflammation and fibrosis. Lower HBV-DNA viral levels were found in patients with Knodell histological activity index ≥ 9 or advanced fibrosis (Ishak scores ≥ 3). CONCLUSION: Our results showed that histological changes in liver tissues were observed in a significant proportion of patients with persistently normal alanine aminotransferase level. According to the data evaluation results, liver biopsy is advisable for HBeAg-positive chronic hepatitis B infected patients aged older than 40 and high HBV-DNA viral load in China.

GATA-3 is superior to GCDFP-15 and mammaglobin to identify primary and metastatic breast cancer.

PURPOSE: Despite numerous studies on the utility of GATA-3 as breast cancer marker, its comparison with other breast markers, its concordance between primary and metastatic tumors and its expression in primary cancers from sites with frequent breast metastases remains unclear. METHODS: To address these questions, totally 993 invasive breast cancers (IBC), 254 paired nodal metastases, 23 distant metastases, and 208 lung carcinomas were included. GATA-3 expression was analyzed by immunohistochemistry and compared to other breast markers [gross cystic disease fluid protein 15 (GCDFP-15) and mammaglobin (MGB)]. RESULTS: GATA-3 was expressed in 82.5% of IBC, predominantly in luminal (93.9%), and lower in non-luminal cancers [59.6% of HER2 overexpressing (HER2-OE) and 38.1% of triple negative breast cancer (TNBC) subtypes]. GATA-3 identified more IBC than GCDFP-15 (23.9%) and MGB (46.6%). However, MGB showed a comparable sensitivity for non-luminal cancers to GATA-3. Combining MGB and GATA-3 improved sensitivity for both HER2-OE (80.8%) and TNBC cases (55.4%). GATA-3 showed a high sensitivity for nodal metastases and distant metastases, with good concordance with primary tumors. GATA-3 was expressed in 1.0% of lung carcinomas, with sensitivity and specificity of 82.5 and 99.0% in differentiating IBC and lung carcinoma. CONCLUSIONS: GATA-3 expression was the highest in luminal breast carcinomas, and showed higher sensitivity than GCDFP-15 and MGB. However, in the poorly differentiated IBC, its utility was still limited. One should be aware of the possible GATA-3 expression in lung carcinomas.

Immunohistochemistry in the diagnosis of papillary lesions of the breast.

AIMS: Many immunohistochemical markers have been studied for differentiating papillary lesions. However, their differentiating power has not been evaluated comprehensively. Additionally, assessment of some markers will require the difficult task of identifying different cell types. In the current study, we aimed to devise a simple papillary panel which can aid in diagnosis irrespective of architectural pattern and cell type differentiation. METHODS AND RESULTS: Immunohistochemical analysis of papillary lesions using myoepithelial markers [p63 and smooth muscle actin (SMA)], high molecular weight cytokeratins (HMWCKs: CK5, CK5/6, CK14 and 34ßE12), hormone receptors (ER and PR) and neuroendocrine markers (chromogranin and synaptophysin) was performed. Among them, neuroendocrine markers showed high specificity but low sensitivity. HMWCK specificity was better than that for myoepithelial markers. Homogeneous staining pattern for hormonal receptors rather than their percentage positivity was more effective in identifying malignant lesions. Negative staining for two or more of HMWCKs, namely CK5/6, CK14 and 34ßE12, achieved the best overall specificity and sensitivity of 87.8% and 94.1%, respectively, irrespective of the architecture. Their discriminatory power was validated with an independent cohort of core needle biopsies. CONCLUSIONS: A marker panel with HMWCKs could be used in differentiating papillary lesions irrespective of architectural pattern or cell type differentiation.

Androgen receptor expression shows distinctive significance in ER positive and negative breast cancers.

BACKGROUND: Androgen receptor (AR), a nuclear steroid hormone receptor, is differentially expressed in breast cancer subgroups with distinct clinical implications. METHODS: To investigate the clinical significance of AR in breast cancers more precisely, the expression of AR in a large cohort of breast cancer was correlated with clinicopathological features, biomarker expression, and patients' survival according to different molecular groupings in this study. RESULTS: Higher AR expression was found in ER+ (57.8 %) than in ER- (24.7 %) cancers. In the ER+ cancers, AR expression was associated with favorable clinicopathological features, including lower grade (p < .001), lower pT stage (p < .001), and positivity for PR (p < .001). It was an independent prognostic factor for longer disease-free survival, mainly in the HER2+ luminal B cancers (hazard ratio [HR] = 0.251, 95 % CI 0.065-0.972, p = .045). In ER- cancers, AR expression was associated with features distinct from basal-like breast cancer, and such features were found in molecular apocrine (MA) cancers. AR correlated with presence of extensive in situ component (p = .006) and apocrine phenotype (p < .001), HER2 (p = .026), and EGFR (p = .048), but negatively with c-kit (p = .041), CK5/6 (p < .001), CK14 (p = .002), and αB-crystallin (p = .038). However, AR expression was found only in 37.8 % of immunohistochemically defined MA. Of note, AR-MA appeared to have a trend of worse overall survival than AR+MA. CONCLUSIONS: AR expression was different in ER+ and ER- cancers and had different clinical implications. AR alone may not be a good marker for MA subtype. Its expression in MA may have substantial prognostic implication and as such warrants further validation.

TTF-1 expression in breast carcinoma: an unusual but real phenomenon.

AIMS: To evaluate thyroid transcription factor-1 (TTF-1) expression in a large cohort of invasive breast carcinomas (IBCs) using two commercially available monoclonal antibody clones (8G7G3/1 and SPT24). METHODS AND RESULTS: Nuclear and cytoplasmic TTF-1 expression was evaluated in 1132 primary IBCs and 208 primary pulmonary carcinomas using tissue microarray (TMA) sections. TTF-1 nuclear expression was detected in one of 1132 (0.09%) IBCs by 8G7G3/1. In pulmonary carcinoma, TTF-1 expression was detected in 149 (71.6%) and 147 (70.6%) cases by 8G7G3/1 and SPT24, respectively, with no significant difference being seen between the two clones (P = 0.839), and there was good consistency between these two antibodies in differentiating breast and pulmonary carcinomas (kappa value 0.905; P < 0.001). Both clones showed high specificity but relatively low sensitivity. Cytoplasmic TTF-1 expression was detected in 44 IBCs by 8G7G3/1, and this particular expression pattern was an independent adverse prognostic factor. CONCLUSIONS: Both TTF-1 antibodies (clones 8G7G3/1 and SPT24) were useful in differentiating breast from pulmonary carcinomas. Nuclear expression of TTF-1 was detected in IBCs by 8G7G3/1, but not by SPT24. Cytoplasmic expression of 8G7G3/1 was seen in IBC for the first time, and was an independent unfavourable prognostic factor.

Columnar cell-like changes in the male breast.

AIMS: Columnar cell lesions are known as a link between normal breast and low grade neoplastic lesions in female, but have not been established in the male breast. This study evaluated the presence of ducts showing columnar cell-like features in the male breast. METHODS: Seventy-one consecutive surgical resections from men (6 invasive breast carcinoma of grade 3, 1 atypical ductal hyperplasia and 64 other lesions) were reviewed to identify foci of dilated ducts with columnar epithelial cells, and their morphological features including apical snouts, intraluminal secretions and calcifications were assessed. The expression of CK5/6 and estrogen receptor (ER) was evaluated immunohistochemically. Clinicopathological features including patients' age, histological diagnosis and gynaecomastoid hyperplasia were documented. RESULTS: Ducts showing columnar cell-like features were identified in 39 cases, morphologically as distended ducts with round or undulating outline. There was an outer layer of myoepithelial cells and an inner layer of columnar luminal cells showing apical snouts, but without intraluminal secretions or calcifications. Immunohistochemically, these columnar epithelial cells were negative for CK5/6 in 38/39 cases and all were ER heterogeneously positive. These changes were associated with older age, but their incidence did not differ whether they were associated with invasive breast carcinoma, atypical ductal hyperplasia and other lesions. CONCLUSIONS: In the male breast, there is an entity sharing morphological features and immunohistochemical profile of columnar cell lesions.

Expression and clinical significance of carcinoembryonic antigen-related cell adhesion molecule 6 in breast cancers.

Carcino-embryonic antigen-related cell adhesion molecule 6 (CEACAM6), one of the members of human carcino-embryonic antigens, is a multifunctional regulatory protein involved in various cellular processes in cancers. Its role in malignant transformation and the clinical significance has been extensively studied in colonic and pancreatic cancers. However, relatively few studies have been done on breast cancers. In the current study, CEACAM6 expression in two independent cohorts of invasive breast cancers were evaluated immunohistochemically and correlated with clinico-pathological features, biomarker profiles and patient survival. In the primary cohort, CEACAM6 expression was detected in 37.1 % (312/840) of primary invasive cancers. It was positively correlated with HER2 (p < 0.001). Concordantly, HER2-OE subtype showed the highest CEACAM6 expression (62.7 %) among all molecular subtypes; whereas, other subtypes also showed substantial CEACAM6 expression (21.8-37.5 %). Interestingly, a significantly worse overall survival was found in high pN stage HER2 positive cancers with CEACAM6 positivity (log-rank = 4.452, p = 0.035) and this could be validated in an independent cohort. Additionally, HER2 signaling was found to induce SMAD3 phosphorylation and CEACAM6 expression in a cell line model. Likewise, in the primary tumors, a positive association was found between HER2 and SMAD3 phosphorylation in CEACAM6 positive cancers (p = 0.012). Overall, CEACAM6 was widely expressed in different molecular subtypes, but highest and significantly in HER2-OE breast cancer. Within this group, CEACAM6 was associated with adverse high nodal stage patient outcome. Given the wide expression of CEACAM6 in all breast cancers, its roles as prognostic marker and therapeutic target warrant further evaluation.

P-cadherin and vimentin are useful basal markers in breast cancers.

Basal-like breast cancer (BLBC) is the breast cancer subtype defined by gene profiling and generates keen clinical interest. Immunohistochemical panels using basal cytokeratins and epidermal growth factor receptor are widely adopted for its identification. Nonetheless, there are concerns about the risk for missing some true BLBCs. Both P-cadherin and vimentin have been proposed as BLBC markers, but their usefulness for BLBC classification has not been well documented. In this study, we evaluated by immunohistochemistry their expression in a large cohort of breast carcinoma. Cancers expressing vimentin or P-cadherin showed BLBC-related morphological features (high grade, presence of necrosis, and lymphocytic infiltration; P < .001 for all except P = .006 for vimentin with lymphocytic infiltration) and immunohistochemical profile (P < .001 for all markers tested except P = .007 for vimentin with human epidermal growth factor receptor 2). Concordantly, they were significantly associated with BLBC (P < .001 for both). Nonetheless, they did not appear to be good stand-alone BLBC markers. Compared with the commonly used reference panel, the specificity (95.9%) and sensitivity (43.1%) of coexpression of vimentin and P-cadherin were better than most single markers or their combinations tested. Moreover, their coexpression was significantly associated with basal features in non-BLBCs and worse disease-free survival in triple-negative breast cancers (hazard ratio, 2.232; P = .027). This raised the possibility that the vimentin and P-cadherin combination can be used to identify BLBC especially those that were missed by the commonly used basal cytokeratins and epidermal growth factor receptor panel. Together, P-cadherin and vimentin could be adjunctive to the commonly used immunohistochemical surrogates for BLBC identification.

CX3CL1 expression is associated with poor outcome in breast cancer patients.

The significance of chemokines in cancer biology has been widely recognized in recent years. CX3CL1 is a unique subclass of chemokine with complex functions, including recruitment of anti-tumor leukocytes and promoting cancer survival, thus affecting cancer progression in both the directions. It is not clear how these different functions interact in breast cancers. This is further complicated by the heterogeneity of breast cancer, and differential association of CX3CL1 with different subgroups could be present. There is only limited knowledge of CX3CL1 expression profile, its relationship with different biological features, subtypes, and outcomes in breast cancers. In this study, CX3CL1 expression was examined in a large cohort of breast cancers by immunohistochemistry and its association with clinicopathological factors, biomarker expression, and impact on patients' survival was assessed. High CX3CL1 expression was detected in 33.3 % (252/757) of primary invasive cancers. In line with its chemo-attractant function, CX3CL1 expression correlated positively with increased tumor infiltrating lymphocytes (TIL) (p = 0.005). In addition, CX3CL1 also correlated positively with adverse features in breast cancers, including lymph node involvement (p = 0.007), high Ki67 (p = 0.002), α-B crystallin expression (p = 0.008), and luminal B (worse prognosis luminal cancers) subtype (p = 0.024). Consistently, breast cancers with high expression of CX3CL1 were found to have a poorer overall survival (χ(2) = 4.797, p = 0.029). Interestingly, the adverse effect of CX3CL1 on outcome appeared to be more prominent in cancers with low TIL. These findings indicated that CX3CL1 could also have a pro-tumor role in breast cancer, despite its previously suggested role in enhancing anti-tumor immunity. The results highlighted the complicated functions of CX3CL1 in breast carcinogenesis. Further studies are needed to clarify the relative contribution of these anti- and pro-tumor functions in order to understand the true prognostic and potential therapeutic values of CX3CL1.

Expression of mammaglobin and gross cystic disease fluid protein-15 in breast carcinomas.

Immunohistochemical analysis of gross cystic disease fluid protein-15 (GCDFP-15) and mammaglobin (MGB) is frequently used in routine practice for assessment of metastases or regional recurrences of breast origin. Breast cancer is highly heterogeneous. Expression of these 2 markers in various breast cancer subtypes has not been well studied. In addition, the usefulness of these two markers in combination in detecting breast origin has not been explored. In this study, a large cohort of breast cancers was evaluated for GCDFP-15 and MGB expression, both individually and combined. Their expression was correlated with cancer subtypes, other biomarkers and clinicopathologic parameters. A higher sensitivity for MGB (42.3%) than GCDFP-15 (31.6%) in detecting cancers of breast origin was observed. Combining both increased the sensitivity further, both for primary tumor (53.0%) and for nodal metastases (69.0%). GCDFP-15 was associated significantly with a breast cancer profile of good prognosis tumors, including lower grade (P < .001), pN (P = .029) and Ki-67 (P < .001) as well as negative basal markers expression (P = .043, .009, and .049 for c-Kit, CK5/6 and epidermal growth factor receptor, respectively) and, thus, may not be sensitive for detection of poor prognosis tumors. MGB has the highest expression in HER2-overexpressing cancers (56.6%), and may be a potentially useful marker for this subtype. Nonetheless, both markers showed low expression in the basal like (BLBC) subtype (11.9% and 21.4% for GCDFP-15 and MGB respectively), therefore, the detection of BLBC remains problematic. Negative results need to be interpreted with caution, and correlation with other clinical findings may be required to exclude the possibility of metastatic BLBC.

Keratin expression in breast cancers.

Cytokeratin (CK) immunohistochemistry can play an important role in breast carcinoma evaluation. We evaluated the expression of a panel of commonly used CKs in a large cohort of breast cancers and assessed its correlation with other biomarkers and breast cancer subtypes. Expression of CK7, CK8, CK18 and CK19 was observed in more than 90 % of all breast carcinomas in this study, confirming their efficacy in immunohistochemical identification of breast cancer. A combination of CK8 and CK7 gave the highest sensitivity for detection of a minute number of breast cancer cells. Expression of other CKs, including CK5/6, CK14 and CK20, correlated positively with high tumour grade. The expression of CK5/6 and CK14 in a significant number of high-grade tumours raised concern regarding the use of absence of their expression to identify breast carcinoma. For identification of the basal subtype, CK5/6 gave a higher detection rate than CK14. CK20 expression was found more frequently than reported in previous studies, might constitute an indicator of poor prognosis and may be associated with the molecular apocrine subtype. This study highlights the diagnostic and prognostic relevance of the unique CK expression patterns in breast cancer.

Epidermal growth factor receptor gene amplification and protein overexpression in basal-like carcinoma of the breast.

AIMS: Epidermal growth factor receptor (EGFR) is frequently expressed in basal-like breast cancer (BLBC). The aim of this study was to evaluate their correlation as detected by immunohistochemistry (IHC) or fluorescence in-situ hybridization (FISH). METHODS AND RESULTS: IHC for oestrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor (HER) 2, cytokeratin (CK) 5/6 and EGFR, and FISH for EGFR amplification, were performed in 59 cases of BLBC. EGFR IHC results were scored semiquantitatively, and compared with its gene amplification status. ER, PR and HER2 were negative in all cases, whereas 35 and 55 cases were positive for CK5/6 and EGFR. For EGFR IHC, 20, 11, 11 and 17 cases showed a negative, a low, an intermediate or a high staining level, respectively, and seven cases showed gene amplification by FISH, with two, 19, 11 and 20 cases showing balanced monosony, disomy, trisomy, and polysomy respectively. Immunohistochemical expression in gene-amplified tumours was significantly higher than in those without amplification, including balanced polysomy tumours. EGFR immunohistochemical expression also correlated with the EGFR/chromosome 7 ratio. High sensitivity (86%) and negative predictive value (98%) were achieved with high-level immunohistochemical expression as a cut-off to predict gene amplification. CONCLUSIONS: High-level EGFR immunohistochemical expression correlated with and predicted EGFR amplification, and may be used as a screening method to exclude gene amplification.

Increased alpha-B-crystallin expression in mammary metaplastic carcinomas.

AIMS: Mammary metaplastic carcinoma is a rare breast carcinoma, and may present diagnostic difficulty. Alpha-B-crystallin has been recently reported to be expressed in basal-like and metaplastic carcinomas. METHODS AND RESULTS: Thirty-three metaplastic carcinomas, 44 conventional high-grade carcinomas and 28 mesenchymal spindle cell neoplasms as controls were assessed for their expression of αB-crystallin and conventional basal-like phenotypic markers CK5/6, CK14, p63, c-kit and epidermal growth factor receptor (EGFR) by immunohistochemistry. Alpha-B-crystallin staining was positive in 68% of the metaplastic carcinomas with cytoplasmic staining in all tumour cell components. CK5/6, CK14, p63, c-kit and EGFR stained 43%, 68%, 45%, 21% and 25% of the metaplastic carcinomas, respectively. Combining these markers, 84% of the metaplastic carcinomas expressed either αB-crystallin or CK14. In comparison, only 14% (six cases) of conventional high-grade carcinoma and 7% (two cases) of mesenchymal spindle cell neoplasm expressed αB-crystallin; all but one of these carcinomas were ER/PR/HER2 triple-negative. CONCLUSIONS: Using αB-crystallin for diagnosis of metaplastic carcinoma gives a 68% sensitivity, 88% specificity, 74% positive predictive value, 85% negative predictive value and 78% accuracy. The sensitivity is enhanced to 84% with combinations of αB-crystallin/CK14. Alpha-B-crystallin may be used as an adjunct marker in the diagnosis of metaplastic carcinoma.

A subset of breast cancer predisposes to brain metastasis.

This study evaluated the expression of biological markers of breast cancers with brain metastases. Eighteen paired tumors were assessed, with 42 non-brain-metastasizing breast cancers that were stained with ER, PR, HER2, CK5/6, p63, and Ki67, and were also classified into intrinsic subtypes. The expression patterns between the breast tumors with brain metastases were compared to the brain metastases and the controls. Breast cancers with brain metastases were of higher grade and showed higher incidence of lymph node metastases at initial diagnosis and higher EGFR, p63, and Ki67 expression. In the group of breast cancers with brain metastases, the brain metastases showed higher HER2, CK5/6, and Ki67 expression compared to the breast primaries. There was also a higher incidence of basal subtype and a lower incidence of luminal subtype. When tumors metastasized, changes in hormonal receptor (22%) and HER2 (6%) status were observed. We concluded that breast cancers with higher grade, lymph node involvement at diagnosis, high EGFR, p63, and Ki67 expression, and of basal subtype were at higher risk for brain metastases, and that both hormonal receptors and HER2 status may change in brain metastases.