Secondary tumors of the GI tract: origin, histology, and endoscopic findings.

BACKGROUND AND AIMS: The GI tract is rarely affected by secondary tumors. Patients often present at an advanced stage of the disease, and prognosis is dismal. This study aimed to analyze the clinical, endoscopic, and pathologic features of secondary tumors that had been diagnosed endoscopically. METHODS: We conducted a retrospective database analysis of 217 patients with secondary tumors of the GI tract. Endoscopic findings and histologic diagnoses were systematically re-evaluated. RESULTS: Malignant melanoma (n = 33, 15%), breast cancer (n = 32, 15%), and pancreatic cancer (n = 27, 12%) were the most common corresponding primaries. About one-third of secondary tumors were detected in the stomach (n = 76, 35%), followed by small intestine (n = 54, 25%) and rectum (n = 53, 24%). The median time between the diagnoses of primary and secondary tumors was 19 months (mean, 31; range, 0-251), and this time was particularly long for renal cell carcinoma and breast cancer (median, 38 and 45 months, respectively). Direct invasion from extra-GI malignancies was more common (56%) than vascular cancer spread (44%) and depended on both sites of tumor involvement and corresponding primary. The lesions presented with various endoscopic patterns. In patients for whom a definitive diagnosis of cancer was known before the examination (n = 168), a secondary tumor was included in the differential diagnosis in only 48% of lesions. It is of note that the remaining cases were diagnosed endoscopically as primary tumors and rarely also as nonneoplastic change. CONCLUSIONS: Secondary tumors may affect all parts of the GI tract. Malignant melanoma and breast and pancreatic cancer represent the most common primaries. Diagnosis based on examination of biopsy specimens is crucial to avoid misclassification.

Interleukin-38 is released from apoptotic cells to limit inflammatory macrophage responses.

Different modes of cell death regulate immunity. Whereas necrotic (necroptotic, pyroptotic) cell death triggers inflammation, apoptosis contributes to its resolution. Interleukin-1 (IL-1) family cytokines are key players in this interaction. A number of IL-1 family cytokines are produced by necrotic cells to induce sterile inflammation. However, release of IL-1 family proteins from apoptotic cells to regulate inflammation was not described. Here we show that IL-38, a poorly characterized IL-1 family cytokine, is produced selectively by human apoptotic cells to limit inflammation. Depletion of IL-38 in apoptotic cells provoked enhanced IL-6 and IL-8 levels and AP1 activation in co-cultured human primary macrophages, subsequently inducing Th17 cell expansion at the expense of IL-10-producing T cells. IL-38 was N-terminally processed in apoptotic cells to generate a mature cytokine with distinct properties. Both full-length and truncated IL-38 bound to X-linked interleukin-1 receptor accessory protein-like 1 (IL1RAPL1). However, whereas the IL-38 precursor induced an increase in IL-6 production by human macrophages, truncated IL-38 reduced IL-6 production by attenuating the JNK/AP1 pathway downstream of IL1RAPL1. In conclusion, we identified a mechanism of apoptotic cell-dependent immune regulation requiring IL-38 processing and secretion, which might be relevant in resolution of inflammation, autoimmunity, and cancer.

Tumor budding is an independent predictor of outcome in AJCC/UICC stage II colorectal cancer.

BACKGROUND: In colorectal cancer, the morphology of the invasive tumor margin may reflect aggressiveness of tumor growth, thus providing important prognostic information. The tumor growth pattern according to Jass and the extent of tumor budding were analyzed in patients with American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) stage II disease. METHODS: Tumors of 120 randomly selected patients with AJCC/UICC stage II disease were retrospectively reviewed for tumor growth pattern (expanding vs. infiltrating) and the extent of tumor budding, with high-grade budding reflecting presence of 10 or more budding foci scattered at the invasive tumor margin. Progression-free and cancer-specific survivals were determined by the Kaplan-Meier method. For multivariable analysis, Cox's proportional hazards regression models were performed. RESULTS: The infiltrating growth pattern was significantly associated with histological subtype and lymphovascular invasion, while high-grade budding was significantly associated with tumor grade and lymphovascular invasion. High-grade budding, but not the infiltrating growth pattern, was significantly associated with outcome in univariable analysis. Cox's proportional hazards regression models proved tumor budding to be an independent predictor of disease progression (hazard ratio 3.91, 95 % confidence interval 1.3-11.77; P = 0.02) and cancer-related death (hazard ratio 5.90, 95 % confidence interval 1.62-21.51; P = 0.007). The combination of infiltrating growth pattern and high-grade budding did not have a stronger prognostic significance than tumor budding alone. CONCLUSIONS: Tumor budding independently predicted patient outcome in patients with AJCC/UICC stage II colorectal cancer and may therefore be used for accurate prognostication, patient counseling, and design of clinical trials by using integrated multimodal therapy.

Is there a rationale to record lymphatic invasion in node-positive colorectal cancer?

This study aimed to evaluate the prognostic significance of lymphatic invasion in colorectal cancers that have already spread to regional lymph nodes. 168 patients with node-positive tumours (colon, n=98; rectum, n=70) were retrospectively evaluated. Lymphatic invasion was assessed on H&E stained slides and univariable and multivariable analyses were applied. Lymphatic invasion was detected in 95 (57%) cases and was significantly associated with tumour and node classification and tumour differentiation. Patients with tumours showing lymphatic invasion had decreased progression-free survival (p=0.025) and cancer-specific survival (p=0.082). Stratified by location, lymphatic invasion was significantly associated with decreased progression-free (p=0.010) and cancer-specific (p=0.023) survival in colon cancers, yet not in rectal cancers. Multivariable analysis proved T4 (HR 2.18, 95% CI 1.40 to 3.39; p<0.001) and N2 (HR 1.68, 95% CI 1.07 to 2.66; p=0.03) as independent predictors of progression-free survival and T4 (HR 1.90, 95% CI 1.17 to 3.07; p=0.009), N2 (HR 2.27, 95% CI 1.38 to 3.73; p=0.001) and poor tumour differentiation (HR 2.18, 95% CI 1.39 to 3.43; p<0.001) as independent predictors of cancer-specific survival, while for lymphatic invasion no influence on outcome was noted. In conclusion, only tumour and node classification, and tumour differentiation proved to be independent prognostic variables in node-positive colorectal cancer and merit special attention in clinical decision-making.

Mucinous differentiation in colorectal cancer--indicator of poor prognosis?

AIMS: To analyse the prognostic impact of mucinous differentiation in colorectal mucinous adenocarcinomas and adenocarcinomas with a mucinous component. METHODS AND RESULTS: A total of 381 tumours were reviewed for mucinous differentiation by two independent pathologists. Mismatch repair status was assessed by immunohistochemistry. Prognostic significance was assessed by univariate and multivariate analyses. Eighty-one (21%) tumours were Union Internationale Contre le Cancer (UICC) Stage I, 120 (31%) Stage II, 126 (33%) Stage III and 54 (14%) Stage IV. Mucinous adenocarcinomas accounted for 12% and adenocarcinomas with a mucinous component for 19% of tumours. Mucinous differentiation was associated significantly with mismatch repair protein deficiency. The presence of extracellular mucin, regardless of extent, did not affect patients' outcome, while tumour grade, vascular and perineural invasion, tumour border configuration and budding were associated significantly with outcome. Cox analysis proved venous invasion to be an independent predictor of outcome in mucinous adenocarcinomas and both venous invasion and tumour budding as independent predictors of outcome in adenocarcinomas with any amount of mucin. CONCLUSIONS: Mucinous adenocarcinomas and/or adenocarcinomas with mucinous component do not differ from conventional adenocarcinomas with respect to prognosis and histological predictors of outcome. Hence, recording of mucinous differentiation may be used as an indicator of mismatch repair deficiency, but not for prognostic stratification.

Keratin 20 - a diagnostic and prognostic marker in colorectal cancer?

Colorectal cancer cells characteristically show strong expression of keratin 20 (K20) and lack expression of keratin 7 (K7). The biological significance of reduced K20 expression, however, is unclear. 381 colorectal cancers with 148 corresponding metastases were evaluated for K20 and K7 expression by immunohistochemistry using a tissue microarray technique. K20 immunoreactivity was assessed semiquantitatively as either negative, low (<50% of cancer cells) or high (≥50% of cancer cells). Progression-free and cancer-specific survivals were determined using the Kaplan-Meier method. Expression of K20 was observed in 348 out of 372 (94%) evaluable primary tumors, with 135 (36%) cases showing low K20 and 213 (57%) cases high K20 expression, while 24 (6%) tumors completely lacked K20 immunoreactivity. Reduced K20 expression (lack of staining or low expression) was significantly associated with poor differentiation, large tumor size and mismatch repair deficiency, but did not significantly affect patients' outcome. Immunoreactivity of K20 and K7 in metastatic tissues matched well with that of corresponding primary tumors, with high concordance for lymph node (p<0.001) and distant metastases (p<0.001), respectively. In conclusion, our data illustrate the value of keratin subtyping in carcinoma of unknown primary (CUP) syndrome: K20 expression is common in colorectal cancer and the K20 high / K7 negative immunoprofile represents the predominant phenotype. Reduced K20 expression may, however, lead to false-negative assessment of metastatic deposits if only small amounts of tissue are obtained (e.g. in needle biopsies), particularly in poorly differentiated cancers. Reduced expression of K20 may be used to select tumors for microsatellite instability testing.

Intramural and extramural vascular invasion in colorectal cancer: prognostic significance and quality of pathology reporting.

BACKGROUND: Blood vessel invasion has been associated with poor outcome in colorectal cancer (CRC), whereas the prognostic impact of lymphatic invasion is less clear. The authors of this report evaluated venous and lymphatic invasion as potential prognostic indicators in patients with CRC focusing on lymph node-negative patients and compared routine and review pathology diagnoses. METHODS: In total, 381 tumors from randomly selected patients were retrospectively reviewed. The presence of vascular invasion was related to disease-free and cancer-specific survival using the Kaplan-Meier method. For multivariable analysis, Cox proportional hazards regression models were performed. RESULTS: Lymphatic invasion and venous invasion were observed in 126 patients (33%) and 87 patients (23%), respectively, and were associated significantly with tumor classification, lymph node status, American Joint Committee on Cancer/International Union Against Cancer (AJCC/UICC) disease stage, tumor differentiation, pattern of invasion, and extent of tumor budding. The detection of vascular invasion was related to the number of examined tissue blocks. Venous and lymphatic invasion proved to be significant prognostic variables in univariable and multivariable analyses. Extramural vascular involvement was of particular significance. When the analysis was restricted to patients with (AJCC/UICC) stage II disease, venous invasion, but not lymphatic invasion, was identified as an independent prognostic variable. Review pathology diagnoses differed significantly from routine diagnoses with respect to prognostic impact. CONCLUSIONS: Venous and lymphatic invasion proved to be significant prognostic variables in patients with CRC. The detection of vascular invasion and, consequently, risk stratification of affected patients were related to the quality of pathology workup, ie, the number of examined tissue blocks. Observed differences between review and routine pathology diagnoses illustrated the need for high-quality pathology reporting and also for standardized quality control.

Keratin 7 expression in colorectal cancer--freak of nature or significant finding?

AIMS: To assess the prevalence of keratin 7 (K7) expression in colorectal cancer and to correlate findings with clinicopathological parameters and patients' outcome. METHOD AND RESULTS: A total of 370 patients were evaluated for K7 expression by immunohistochemistry using a tissue microarray technique. K7 expression was scored semiquantitatively as either focal (<10%), moderate (10-50%) or extensive (>50%). In all, 32 (9%) tumours were immunoreactive for K7, with five cases showing extensive, four moderate and 23 focal expression, respectively. K7 expression was associated with poor tumour differentiation (P = 0.005) and the extent of tumour budding (P = 0.02). In whole sections, K7 immunoreactivity prevailed in single cells and small clusters of cells at the invasion front. Analysis of serial sections showed that K7-positive cells colocalized with keratin 20, whereas they lacked immunoreactivity for E-cadherin, MUC2 and MIB-1. Disease progression occurred in 52% of patients with K7-positive tumours and 41% with K7-negative tumours (P = 0.19); 48% of patients with K7-positive tumours but only 33% with K7-negative tumours died of disease (P = 0.06). CONCLUSIONS: Aberrant expression of K7 in budding cancer cells represents a modification of the epithelial phenotype ('epithelial-epithelial transition': EET) which may be linked to gains in motility and invasive potential.

Gastric cancer and concomitant renal cancer: a systematic immunohistochemical and molecular analysis.

The frequency of gastric cancer in patients with renal cell carcinoma (RCC) is exceptionally high in our region suggesting a common molecular basis. Our study aimed to characterize tumors and to analyze possible underlying molecular features in 12 patients with gastric cancer and concomitant RCC. We performed an immunohistochemical analysis including p53 protein expression, proliferative activity (MIB-1), mismatch repair status (hMLH1, hMSH2, hMSH6, PMS2) and E-cadherin expression in gastric cancers, which were additionally analyzed for Epstein-Barr-Encoded-RNA (EBER) by in situ hybridization. Microsatellite instability was analyzed with a PCR multiplex system and capillary electrophoresis. KRAS mutations in codons 12 and 13 were tested by pyrosequencing. All patients had clear cell RCCs, 10 of which were well differentiated and diagnosed in an early stage, while the gastric cancers of these patients were generally poorly or undifferentiated and diagnosed in an advanced stage. Gastric cancers showed reduced E­cadherin staining in 10 out of 12 cases. Two gastric cancers demonstrated loss of hMLH1 and PMS2, which was confirmed by molecular analysis showing a high degree of microsatellite instability. All RCCs were microsatellite stable. KRAS mutation was detected in one of the two instable gastric cancers, while none of the RCCs had KRAS mutations. Another gastric cancer was positive for EBV. In conclusion, a coherent cause for gastric cancer and concomitant RCC, such as Lynch syndrome, a prominent role of KRAS mutation or EBV infection, was not found in our series. Other factors leading to a higher susceptibility for cancer must be explored to explain why individuals with RCC have a higher risk of developing gastric cancer in our region.

Value of tumor size as a prognostic variable in colorectal cancer: a critical reappraisal.

OBJECTIVES: Vertical tumor growth, reflected by T classification, represents the most important prognostic variable in colorectal cancer. Our study aimed to investigate the impact of tumor size, particularly the maximum tumor diameter, on outcome of affected patients. METHODS: A total of 381 colorectal cancer specimens were re-evaluated. Tumor size and location were extracted from the medical history and were known for 359 patients (94%). Receiver-operator characteristic analysis was applied to identify the optimal (maximum of sum of sensitivity and specificity) cut-off values with respect to prognostic impact. RESULTS: Median tumor size was 4.5 cm (range, 0.6-15). Tumor size exceeding 4.5 cm was observed in 159 patients (44%) and was associated with high T and N classification, UICC stage, and tumor grade. At median follow-up of 45 months (range, 0-180), 141 patients (40%) showed tumor progression. Although 4.5 cm was identified as the optimal cut-off value within the whole group of patients, receiver-operator characteristic analysis restricted to different parts of the large bowel determined 5 cm, 5.3 cm, 3.9 cm, and 3.4 cm as cut-off values with the strongest discriminatory capacity in colon, right-sided colon, left-sided colon, and rectum cancers, respectively. Applying these cut-off values, tumor size was significantly associated with progression-free and cancer-specific survival in univariate and multivariate analyses in colon, yet not in rectum cancers. CONCLUSIONS: Tumor size proved to be an independent prognostic parameter for patients with colorectal cancer. Optimal cut-off values vary among different parts of the large bowel. Whereas prognostic significance is strong within the colon, it appears to be of minor value within the rectum.

Tumor necrosis is a new promising prognostic factor in colorectal cancer.

The prognostic significance of tumor necrosis in colorectal cancer is unclear. Our study aimed to analyze the prognostic value of tumor necrosis with respect to progression-free and cancer-specific survival and to relate findings to expression of proteins involved in the control of cancer cell death, such as p53 and bcl-2. A total of 381 colorectal cancer specimens were retrospectively reevaluated. The extent of tumor necrosis was semiquantitatively assessed and recorded as either absent, focal (≤10% of the tumor area), moderate (10%-30%), or extensive (≥30%). Expression of p53 and bcl-2 was assessed immunohistochemically and recorded as either positive (using a cutoff value of 10%) or negative. In addition, mismatch repair protein status was assessed by immunohistochemistry using antibodies directed against hMLH1, hMSH2, and hMSH6. Tumor necrosis was observed in 365 (96%) cases, with 180 (47%) tumors showing focal necrosis, 119 (31%) moderate necrosis, and 66 (17%) extensive necrosis, respectively. Extent of necrosis was significantly associated with high T classification (P < .001), high N classification (P = .005), high International Union Against Cancer stage (P < .001), poor tumor differentiation (P < .001), large tumor size (P < .001), and blood vessel invasion (P = .01). No association of tumor necrosis with expression of p53, bcl-2, and mismatch repair protein status was observed. Tumor necrosis proved to be an independent prognostic variable with respect to progression-free and cancer-specific survival. In conclusion, tumor necrosis showed significant impact on prognosis of colorectal cancer patients. Its presence is readily assessable in hematoxylin and eosin-stained sections and should therefore routinely be commented upon in the pathology report.

Clinicopathological significance of prolactin receptor expression in colorectal carcinoma and corresponding metastases.

The role of human prolactin and its receptor, the prolactin receptor, in colorectal cancer is largely unknown. Our study aimed to assess the prevalence of prolactin receptor expression, its association with clinicopathological variables, as well as its prognostic value, comparing results of primary tissues with those of corresponding metastases. In all, 373 primary colorectal cancer and 171 corresponding metastases were evaluated for prolactin receptor expression by immunohistochemistry using a tissue microarray technique. Immunoreactivity was semiquantitatively scored as either focal (<10% of tumor cells positive), moderate (10-50%), or extensive (>50%). Prolactin receptor expression was related to clinicopathological parameters as well as patient outcome. To substantiate our findings, prolactin receptor expression was additionally assessed in HT-29 and SW-480 colorectal cancer cell lines using western blot. Prolactin receptor expression was observed in 360 out of 373 (97%) primary tumors, with 21 (6%) cases showing focal, 55 (15%) moderate, and 284 (76%) extensive expression, respectively. Extensive prolactin receptor expression was significantly associated with tumor size (P=0.002) and grade (P<0.001) as well as histological subtype (P<0.001). Somer's D coefficients for concordance of primary tumors with corresponding lymph node and distant metastases were D=0.719 (P<0.001) and D=0.535 (P=0.001), respectively. Extensive prolactin receptor expression was significantly associated with disease progression (P=0.03) and cancer-specific survival (P=0.04) in patients with high-grade cancers. In conclusion, prolactin receptor expression is common in colorectal cancer, with high concordance between primary tumors and corresponding metastases. In view of evolving targeted therapy concepts in colorectal cancer, widespread prolactin receptor expression may offer a therapeutic perspective in affected patients.

Clinical significance of pT sub-classification in surgical pathology of colorectal cancer.

PURPOSE: Tumour stage is the strongest prognostic parameter in colorectal cancer. The study aimed to evaluate the prognostic impact of pT2, pT3, and pT4 sub-classification. METHODS: Three hundred eighty-one surgical colorectal cancer specimens were retrospectively re-evaluated. pT2 tumours were sub-classified according to infiltration of the inner circumferential (pT2a) or outer longitudinal (pT2b) layer of the muscularis propria. pT3 tumours were sub-classified by measuring the maximal tumour invasion beyond the outer border of the muscularis propria (pT3a 1-5 mm, pT3c > 5-15 mm, and pT3d > 15 mm). pT4 tumours were sub-classified according to invasion of other organs or structures (pT4a) or perforation of the visceral peritoneum (pT4b). Data were correlated with other pathological parameters and patient outcome. RESULTS: Seventy pT2 tumours were re-classified as 37 pT2a and 33 pT2b tumours. There was no significant association with tumour grade, angioinvasion, or lymph node involvement and no significant impact on prognosis. Two hundred eighteen pT3 tumours were re-classified as 49 pT3a, 83 pT3b, 53 pT3c, and 33 pT3d tumours. pT3 sub-classification was significantly associated with tumour grade, angioinvasion, and lymph node involvement and proved to be an independent prognostic variable with respect to progression-free and cancer-specific survival. A cut-off level of 5 mm is recommended. Sixty-five pT4 tumours were re-classified as 15 pT4a and 50 pT4b tumours. There was no significant association with tumour grade, angioinvasion, or lymph node involvement and no significant impact on prognosis. CONCLUSIONS: pT3 sub-classification was significantly associated with patient outcome. In contrast, pT2 and pT4 sub-classification did not show clinical significance.

Renal cell carcinoma metastatic to the stomach: single-centre experience and literature review.

OBJECTIVES: To investigate the incidence, clinical presentation and therapy of gastric metastases, an uncommon finding, in a large group of patients with renal cell carcinoma (RCC). PATIENTS AND METHODS: We systematically searched the computerized RCC database of our institute, covering 2082 patients (1180 men and 902 women) who had surgery between January 1984 and September 2005, to identify those with a synchronous and/or metachronous diagnosis of cancer in gastric biopsies or resection specimens. The histopathological slides of both renal and gastric cancer probes, and the clinical presentation, treatment and outcome of affected patients, were reassessed. RESULTS: Twelve patients with primary gastric cancer, one with local RCC recurrence affecting the antrum and five with clear cell RCC (three men and two women; mean age 73 years, range 65-83) with haematogenous cancer spread to the stomach were detected. The mean (range) time to gastric metastasis was 6.9 (1.7-13.1) years. There were metastases to other organs, most often the lung, in all patients. Three patients presented with symptoms of gastrointestinal bleeding, which was successfully controlled by local endoscopic therapy. Four patients died from disease at 3-19 months after diagnosis. One patient is still alive with disease after approximately 2 years. CONCLUSIONS: Gastric metastasis in patients with RCC appears to be a late event in the course of the disease. Most patients show concomitant tumour spread to other organs, and the outcome is generally poor. The use of targeted drugs might offer a new perspective for affected patients.