Non-conventional dysplasias of the tubular gut: a review and illustration of their histomorphological spectrum.

The increasing use of gastrointestinal endoscopic procedures has led to the recognition by histopathologists of non-conventional (or special-type) dysplasias of the gastrointestinal tract. These lesions can be recognised in association with prevalent underlying gastrointestinal conditions, such as Barrett oesophagus, chronic atrophic gastritis, and inflammatory bowel disease. The diagnosis of these special types can be challenging, and their biological behaviours are not fully characterised. The aim of this review is to provide a global view of non-conventional dysplastic lesions observed in the various segments of the tubular gastrointestinal tract and describe their salient features. Furthermore, as the clinical implications of these various subtypes have not been broadly tested in practice and are not represented in most management guidelines, we offer guidance on the best management practices for these lesions.

Smooth muscle tumors of the gastrointestinal tract: an analysis of prognostic features in 407 cases.

Smooth muscle tumors represent the second most common mural mesenchymal neoplasm in the gastrointestinal tract, but established criteria for prognostic assessment of these tumors are lacking. A large cohort of surgically resected intramural gastrointestinal smooth muscle tumors from 31 institutions was analyzed to identify potential prognostic features. Pathologic features were assessed by expert gastrointestinal and/or soft tissue pathologists at each center. Immunohistochemical confirmation was required. A total of 407 cases from the esophagus (n = 97, 24%), stomach (n = 180, 44%), small bowel (n = 74, 18%), and colorectum (n = 56, 14%) were identified. Patients ranged in age from 19 to 92 years (mean 55 years), with a slight female predominance (57%). Mean tumor size was 5.4 cm, with the largest tumor measuring 29 cm. Disease progression following surgery, defined as local recurrence, metastasis, or disease-related death, occurred in 56 patients (14%). Colorectal tumors were most likely to progress, followed by small bowel and gastric tumors. None of the esophageal tumors in this series progressed. Receiver operator characteristic analysis identified optimal cutoffs of 9.8 cm and 3 mitoses/5 mm2 for discriminating between progressive and non-progressive tumors. Histologic features strongly associated with progression by univariate analysis included moderate-to-severe atypia, high cellularity, abnormal differentiation (defined as differentiation not closely resembling that of normal smooth muscle), tumor necrosis, mucosal ulceration, lamina propria involvement, and serosal involvement (P < 0.0001 for all features). Age, sex, and margin status were not significantly associated with progression (P = 0.23, 0.82, and 0.07, respectively). A risk assessment table was created based on tumor site, size, and mitotic count, and Kaplan-Meier plots of progression-free survival for each subgroup revealed progression-based tiers. Based on our findings, it appears that nonesophageal gastrointestinal smooth muscle tumors measuring >10 cm and/or showing ≥3 mitoses/5 mm2 may behave aggressively, and therefore close clinical follow-up is recommended in these cases.

Relapse-free survival in patients with nonmetastatic, surgically resected pancreatic neuroendocrine tumors: an analysis of the AJCC and ENETS staging classifications.

BACKGROUND: The risk of metastatic spread among patients with early-stage pancreatic neuroendocrine tumors has not been well established. The authors sought to evaluate whether the new TNM staging systems proposed by the American Joint Committee on Cancer (AJCC) and European Neuroendocrine Tumor Society (ENETS) are prognostic for relapse-free survival (RFS) after surgical resection. METHODS: Patients with surgically resected localized or locally advanced pancreatic NETs treated at the H. Lee Moffitt Cancer Center between 1999 and 2010 were assigned a stage (I-III) based on the AJCC and ENETS classifications. RFS and overall survival were measured using Kaplan-Meier methodology, with log-rank testing for evaluation of the 2 tumor staging systems. Multivariate analysis was performed controlling for tumor grade, location, surgery type, functional hormonal status, and incidental diagnosis. RESULTS: The authors identified 123 patients with nonmetastatic, surgically resected pancreatic NETs. When using the AJCC classification, 5-year RFS rates for stages I through III were 78%, 53%, and 33%, respectively (P < 0.01). Using the ENETS classification, 5-year RFS rates for stages I to III were 100%, 70%, and 53% (P < 0.18). When excluding patients who were referred after their metastatic recurrence, the 5-year RFS rates for stages I to III were 90%, 73%, and 66% according to the AJCC classification, and 100%, 84%, and 75% according to the ENETS classification. Recurrence rates peaked at approximately 2 years after surgery. CONCLUSIONS: The AJCC and ENETS TNM classifications for pancreatic NETs are prognostic for recurrence-free survival and can be adopted in clinical practice.

A phase I/Ib study of regorafenib and nivolumab in mismatch repair proficient advanced refractory colorectal cancer.

AIM: In contrast to mismatch repair deficient (dMMR) colorectal cancer (CRC), mismatch repair proficient (pMMR) CRC is usually unresponsive to anti-PD-1 immunotherapy. Recent preclinical data suggest that regorafenib may enhance the antitumor activity of anti-PD-1 immunotherapy. However, the safety and efficacy of regorafenib plus nivolumab have not been established in patients with refractory metastatic pMMR CRC. This study aimed to evaluate the safety and efficacy of regorafenib plus nivolumab in metastatic pMMR metastatic CRC. METHOD: This was a phase I/Ib study with standard 3 + 3 design plus dose expansion of the maximum tolerated dose (MTD) in patients with refractory metastatic pMMR CRC. Patients were treated with regorafenib combined with nivolumab. The primary end-points were dose-limiting toxicity (DLT) and MTD. The secondary end-points were objective response rate, safety and overall survival (OS). RESULTS: A total of 52 patients were enrolled, and 51 patients received at least one dose of treatment. Three patients experienced DLT (all grade 3 rash). MTD was regorafenib 80 mg and nivolumab 240 mg every 2 weeks. Most common grade 3/4 treatment-related adverse events were hypertension (16%), rash (10%) and anaemia (6%). Among 40 evaluable patients, four (10%) achieved partial response, including one unconfirmed response, 21 (53%) achieved stable disease, and disease control rate was 63%. The median progression-free survival and OS were 4.3 and 11.1 months, respectively. CONCLUSIONS: Regorafenib plus nivolumab appears to be well tolerated with limited anticancer activity in metastatic pMMR CRC. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03712943.

Post-transplant relapse of therapy-related MDS as gastric myeloid sarcoma: Case report and review of literature.

INTRODUCTION: Myelodysplastic syndrome (MDS) are hematologic neoplasms characterized by morphologic dysplasia and ineffective hematopoiesis in the bone marrow. The only potentially curative therapy is stem cell transplant. However, relapse remains a major challenge and is seen in about 25-40% of cases. Myeloid sarcoma presenting as relapse post allogeneic transplant for myeloid neoplasms is rare. We report the sentinel case of a patient with MDS who relapsed as gastric myeloid sarcoma 1 ½ years after allogeneic stem cell transplant. CASE PRESENTATION: Sixty-nine-year-old male who was diagnosed with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) in 2006 and transitional cell bladder carcinoma in 2008. In 2011, he developed therapy-related myeloid neoplasm t(7;22) and no excess blasts. He was treated with Vidaza followed by a MUD hematopoietic stem cell transplant on 8/24/2012. In 2013 the patient developed anorexia and gastric biopsies showed severe gastritis. Repeat gastric biopsy on 02/05/2014 showed an extensive mononuclear infiltrate which could easily be confused with lymphocytes but staining showed myeloid sarcoma. Marrow was negative. The patient remained refractory to therapy and expired 08/10/2016. CONCLUSION: In summary, we report the first case of GI relapse of MDS as a myeloid sarcoma post-transplant. We seek to alert our audience of this potentially serious diagnostic pitfall, particularly one that can be relatively easily resolved on the basis of immunohistochemical profiling.

Management of Severe Hidradenitis Suppurativa.

Hidradenitis suppurativa (HS) is a devastating and disfiguring disease of the skin involving the terminal follicular epithelium within the apocrine-gland-bearing skin. We present an interesting case of a 58-year-old female who presented with a 10-year history of refractory HS of the gluteal, perineal, perianal, and groin region. She had been chronically treated with multiple antibiotics in the past with no improvement. The patient subsequently underwent surgical local excision with complex closure. Medical management alone may not be optimal, especially in refractory disease. Early and aggressive surgical intervention and interdisciplinary approach are needed for patients with chronic and advanced stage of HS.

The significance of histological activity measurements in immune checkpoint inhibitor colitis.

BACKGROUND: Colitis is a significant complication of immune checkpoint inhibitors (ICI). Currently, clinical and endoscopic severity are used to guide therapy. AIMS: To investigate associations between clinical, endoscopic, and histological features with outcomes METHODS: We identified 149 patients from seven institutions with biopsy-proven ICI colitis. Biopsies were evaluated for histological features including the Geboes score, and the Robarts histopathological index (RHI) was calculated. Clinical, endoscopic, and histological data were tested for associations with biological use and adverse colitis outcomes (biological-refractory colitis, colectomy or death from colitis). RESULTS: Three mutually exclusive histological patterns were identified: acute colitis, chronic active colitis and microscopic colitis. Microscopic colitis was associated with older age (68.5 vs 61 years for acute colitis pattern, P = 0.02) and longer time to colitis (5.5 vs 3 months for the other patterns, P = 0.05). Biological use was associated with earlier time to colitis (2 vs 3 months, P = 0.04) and higher RHI (18 vs 12, P = 0.007). On multivariate analysis, RHI ≥14 was associated with biological use with an odds ratio of 4.5 (95% CI 1.4-13.8; P = 0.01). Adverse colitis outcomes were associated with shorter time to colitis (2 vs 3 months, P = 0.008) and higher RHI (24 vs 14, P = 0.001). On multivariate analysis, RHI ≥24 was associated with adverse colitis outcomes with an odds ratio 9.5 (95% CI 2.1-42.3 P = 0.003). CONCLUSION: Histological activity as measured by RHI is the only factor independently associated with biological use and adverse colitis outcomes. Prospective studies are needed to validate these findings to determine if histological activity should be incorporated into therapeutic algorithms.

A Mathematical Model to Estimate Chemotherapy Concentration at the Tumor-Site and Predict Therapy Response in Colorectal Cancer Patients with Liver Metastases.

Chemotherapy remains a primary treatment for metastatic cancer, with tumor response being the benchmark outcome marker. However, therapeutic response in cancer is unpredictable due to heterogeneity in drug delivery from systemic circulation to solid tumors. In this proof-of-concept study, we evaluated chemotherapy concentration at the tumor-site and its association with therapy response by applying a mathematical model. By using pre-treatment imaging, clinical and biologic variables, and chemotherapy regimen to inform the model, we estimated tumor-site chemotherapy concentration in patients with colorectal cancer liver metastases, who received treatment prior to surgical hepatic resection with curative-intent. The differential response to therapy in resected specimens, measured with the gold-standard Tumor Regression Grade (TRG; from 1, complete response to 5, no response) was examined, relative to the model predicted systemic and tumor-site chemotherapy concentrations. We found that the average calculated plasma concentration of the cytotoxic drug was essentially equivalent across patients exhibiting different TRGs, while the estimated tumor-site chemotherapeutic concentration (eTSCC) showed a quadratic decline from TRG = 1 to TRG = 5 (p < 0.001). The eTSCC was significantly lower than the observed plasma concentration and dropped by a factor of ~5 between patients with complete response (TRG = 1) and those with no response (TRG = 5), while the plasma concentration remained stable across TRG groups. TRG variations were driven and predicted by differences in tumor perfusion and eTSCC. If confirmed in carefully planned prospective studies, these findings will form the basis of a paradigm shift in the care of patients with potentially curable colorectal cancer and liver metastases.

Rare Abdominal Wall Metastasis following Curative Resection of Gastric Cancer: What Can Be Learned from the Use of Percutaneous Catheters?

In cancer care, tissue seeding after curative resections is a known potential complication, despite precautions taken during surgical treatment. We present an uncommon case of an abdominal wall metastasis along the tract of a surgical drain following gastrectomy for gastric adenocarcinoma. To our knowledge, this is the first case of such an occurrence in the setting of a negative staging peritoneal lavage. Aside from the rarity of such a recurrence, this instance highlights an opportunity to reevaluate best practices with regard to the extent of coverage of postoperative salvage radiotherapy. The oncologic patient provides many challenges and may require multiple catheters for drainage and at times infusion of nutrition or therapeutic agents. These foreign bodies should be scrutinized both clinically and radiographically, as they may create vulnerabilities in keeping malignant diseases contained and controlled. We provide a review of the literature with reasonable treatment options for the benefit of future patients.

Gangliocytic paraganglioma of the appendix with features suggestive of malignancy, a rare case report and review of the literature.

We report a case of appendicial paraganglioma in a 40 year old female who presented with acute appendicitis and underwent laparoscopic appendectomy. To the best of our knowledge this is the first reported case of appendicial gangliocytic paraganglioma with features suggestive of malignancy in the modern literature. Van Eeden S. et al. reported the first case of appendicial paraganglioma in a 47 year old man who also presented with acute appendicitis. The appendectomy specimen showed a distended appendix with thickened wall, and a 1.3 cm mucosal based yellow lesion. Microscopically this lesion was centered in the submucosa and consisted of three different cell types: (a) epithelioid cells with pale eosinophilic finely granular cytoplasm containing bland oval nucleus with stippled chromatin, that form solid nests lying in a trabecular pattern and in formations reminiscent of 'Zellballen' as seen in paragangliomas (b) second type cells have large vesicular nuclei with prominent nucleoli and abundant cytoplasm that are scattered singly, (c) third type cells with bland elongated nuclei form broad fascicle and envelop the epithelioid and ganglion cells. Immunohistochemical analysis showed the epithelioid cell nests immunoreactive for synaptophysin and the ganglion-like cells and spindle Schwann cells to be immunoreactive for S100 protein, whereas all three cells populations were negative for CAM5.2 and Pancytokeratin. We do believe that an accurate diagnosis of Gangliocytic paraganglioma (GP) of the appendix was rendered, detailed microscopic examination of doubled hematoxylin and eosinophil stained sections as well as the immunohistochemical phenotype of the three components have been undertaken to confirm the diagnosis of GP.

Thirty-five-year-old woman with signet ring cell gastric carcinoma secondary to the chernobyl nuclear accident: a case report.

The 1986 Chernobyl nuclear accident resulted in radiation exposures throughout much of Europe, with the highest exposures within the city of Pripyat, Ukraine, where the accident occurred. We report a woman who was exposed to the Chernobyl accident at age 13. Beginning in her early thirties, she experienced several years of upper abdominal pain that became progressively more severe. At age 35, she underwent upper endoscopy and gastric biopsy. Histological examination revealed a signet ring cell (SRC) gastric carcinoma. The tumor was discovered at an advanced stage and proved unresectable. She died 3 months following her diagnosis. The mean age for SRC gastric carcinoma diagnosis is about 62 years; the median survival following diagnosis is 13 months. The early appearance and aggressive clinical course of this malignancy in relation to the Chernobyl nuclear accident is discussed.

Primary uterine cervix schwannoma: a case report and review of the literature.

Schwannoma (neurilemmoma) is a benign peripheral nerve sheath tumor that occurs in a wide variety of locations; however, its finding in the uterine cervix is extremely rare. We report a case of an incidental primary benign cervical schwannoma in a 48-year-old woman. In the English literature, a few cases of primary schwannoma of the cervix have been reported, which include seven cases of primary malignant cervical schwannoma and only two that are benign. These cases are reviewed in the following discussion.

Activation of the serine/theronine protein kinase Akt in enteropancreatic neuroendocrine tumors.

BACKGROUND: Akt is a regulator of cell proliferation, tumorigenesis and apoptosis. This study evaluated the incidence of Akt activation in a subset of neuroendocrine tumors (NETs) and its correlation to clinical pathological parameters. MATERIALS AND METHODS: A subset of 46 samples from patients with enteropancreatic NETs (26 male and 20 female) were selected for evaluation. The tissue slides were stained with a mouse monoclonal antiphospho-Akt antibody using the avidin-biotin-complex method. RESULTS: The tumors were from the small (n = 18) and large bowel (n = 9) and from the pancreas (n = 16). Activation of Akt was detected in 61% (28/46) of cases. No statistical correlation was found between the p-Akt score and tumor grade (p = 0.72), tumor size (p = 0.72) and the presence of metastases (p = 0.52). CONCLUSION: This study shows activation of Akt in a subset of enteropancreatic NET for the first time. This finding suggests a role of p-Akt in NET carcinogenesis.

Correlation between Mcl-1 and pAKT protein expression in colorectal cancer.

Mcl-1 inhibits apoptosis in well-differentiated cells by sequestering BAD, BID, and BAX and other apoptotic molecules. pAKT blocks apoptotsis by facilitating the interaction of BAD with BCL-XL. Expression of pAKT and Mcl-1 have been described in colon cancer, however, the relationship between pAKT and Mcl-1 has not. Mcl-1 and pAKT immunohistochemistry was performed using colorectal cancer tissue microarray (TMA). The Holm step-down method was used to adjust for multiple testing. Mcl-1 and pAKT scores, stage, and grade were compared using Spearman's correlation coefficient. Metastasis and no metastasis groups were compared using the Wilcoxon rank sum test. Mcl-1 and pAKT scores were compared for normal colorectal mucosa (NR), adenoma (AD), and colorectal cancer (CRC) cohorts. The mean (SD) pAKT expression in NR (14) was 2.0 (1.4), in AD (8) was 3.0 (1.7), and in CRC (101) was 5.6 (2.4). These differences were statistically significant. For Mcl-1 the mean (SD) expression was 4.1 (1.7) in NR, 3.2 (1.2) in AD, and 3.3 (2.6) in CRC. Mcl-1 and pAKT scores were directly correlated during various stages of colon car-cinogenesis (p = 0.04). Mcl-1 showed direct correlation with tumor grade (p = 0.001) and tumor stage (p = 0.02) and with presence of metastasis (p = 0.008). We report the correlation of Mcl-1 protein expression with higher grade and stage in colorectal cancer. Mcl-1 correlated also with pAKT expression. We also report the up regulation of pAKT during the transition from NR to CRC.