Duodenal Follicular Lymphoma: Track or Treat?

Duodenal follicular lymphoma (DFL) is a rare variety of non-Hodgkin's lymphoma of the gastrointestinal tract that usually carries a favorable course, recognized as a new entity in 2016. It is usually diagnosed at an early stage located predominantly in the second portion of the duodenum. We report the case of a 74-year-old male patient with epigastric pain in whom gastroscopy revealed white mucosal nodules that were pathologically diagnosed as grade 1-2 DFL. Staging investigations revealed secondary lesions in the spleen and at the base of the tongue together with latero-cervical adenopathy. The tumor was stage IV according to the Lugano staging system. We reviewed the recent (last five years) literature defining the importance of combination therapy in the advanced stage. The patient achieved complete remission of the disease through chemoimmunotherapy following the Rituximab-Bendamustine scheme.

Clinical, dermoscopic and reflectance confocal microscopy features of sebaceous neoplasms in Muir-Torre syndrome.

BACKGROUND: Muir-Torre syndrome (MTS) is an autosomal-dominant disorder characterized by the association of sebaceous tumors or keratoacanthomas with an early onset visceral cancer in the spectrum of Lynch syndrome. OBSERVATIONS: A total of 20 sebaceous tumors including 18 sebaceous adenoma and two sebaceomas of six patients with MTS were analysed. Two main clinico-dermoscopic features were observed: (1) clinically pink to white papules/nodules with a central crater, dermoscopically characterized by radially arranged, elongated crown vessels surrounding opaque structureless yellow areas at times covered by blood crusts (n = 13) and (2), clinically pink to yellow papules/nodules without a central crater, dermoscopically exhibiting a few, loosely arranged yellow comedo-like globules and branching arborizing vessels (n = 7). Confocal microscopy was available in three sebaceous adenomas and revealed a good histopathologic correlation; sebaceous lobules were composed by clusters of ovoid cells with dark nuclei and bright, highly refractile glistening cytoplasm. They were delimited by a rim of epithelial cells, corresponding to basaloid cells. CONCLUSIONS: A better characterization of clinical, dermoscopic and confocal microscopy features of sebaceous tumors may improve their recognition and consequently, aid to rise the suspect for MTS.

Gene variants associated to malignant thyroid disease in familial adenomatous polyposis: a novel APC germline mutation.

BACKGROUND AND AIM: Familial adenomatous polyposis (FAP) is an autosomal inherited syndrome characterized by hundreds to thousands colorectal adenomatous polyps with oncological transformation lifetime risk of 100%. FAP is mainly associated with mutations in APC (autosomal dominant inheritance) or MUTYH (autosomal recessive inheritance) genes. Affected individuals are at increased risk of developing extra-intestinal tumors. Lifetime risk of developing thyroid carcinoma has been described in previous reports of about 2-12%, mainly in females, and the mean age is below 30 yr. About 95% of cancers are papillary thyroid carcinomas (PTC), mostly multifocal. The aim of this study was to evaluate the frequency of PTC among our series of FAP patients and to assess the type of gene mutation associated with the disease. METHODS: Fifty-four subjects from 36 FAP families were selected (29 females/25 males) and the mean age (±SD) at diagnosis was 28.8±10.8 yr. All patients underwent blood examination for thyroid hormones and antibodies, germline mutational analysis of APC and/or MUTYH genes, thyroid ultrasound, and endocrinological evaluation. RESULTS: In 13/54 (24.1%) subjects, an eumetabolic thyroid disease was found: plurinodular disease in 7/54 (13.0%); single nodule in 4/54 (7.4%); in 2/54 patients (3.7%), we found a malignant nodule characterized after total thyroidectomy as a classical PTC. Both patients were female and showed a classic FAP phenotype. Mutational analysis revealed in the first patient the APC germline mutation 3183_87del ACAAA and in the second patient the del9-10 (del9080dup11) novel APC variant; the first mutation has been already reported in association with PTC; to our knowledge the second mutation has never been previously reported in association with FAP. CONCLUSIONS: In the population examined, the estimated prevalence of thyroid malignant diseases was 3.7%. In both patients, the identified APC gene pathogenetic variants mapped within the 5' region of the gene, previously reported as a PTC-associated mutational hot spot. Both patients had classic FAP phenotype and genetic analysis revealed two pathogenetic APC mutations: c.3183_87delACAAA, a recurrent pathogenetic variant and del9-10 (del9080dup11), a novel, not previously described genomic rearrangement. In agreement with previous studies, the morpho-functional surveillance of thyroid in FAP series should be recommended. A better insight into the overall genotype-phenotype correlation of APC gene mutations would be helpful for the identification of at-risk individuals.

Unbalanced germ-line expression of hMLH1 and hMSH2 alleles in hereditary nonpolyposis colorectal cancer.

We analyzed the hMLH1 and hMSH2 genes in 30 unrelated hereditary nonpolyposis colorectal cancer (HNPCC) patients using mutational and immunohistochemical analyses combined whenever possible with primer extension assays, designed to estimate hMLH1 and hMSH2 transcript expression in peripheral blood lymphocytes. Single-strand conformational polymorphism screening and PCR-direct sequencing revealed seven hMLH1 and five hMSH2 sequence variants in 14 unrelated HNPCC patients, including three definite pathogenic mutations, four amino acid substitutions of uncertain pathogenic significance, and five polymorphisms. Immunohistochemistry indicated the lack of either hMLH1 or hMSH2 protein expression in tumors from 13 patients, and the absence of both hMLH1 and hMSH2 immunostaining was observed in the tumor from one additional case. The lack of hMLH1 or hMSH2 immunostaining was associated with the presence of microsatellite instability in the corresponding tumor and was also observed in tumors from patients negative for pathogenic mutations by mutational screening. There was a marked unbalance in the allelic expression of either hMLH1 or hMSH2 transcripts in three of eight unrelated HNPCC patients that could be analyzed, although a less marked unbalance was detected in two additional patients. Tumors from patients with germ-line unbalance in hMLH1 or hMSH2 transcript expression did not express the corresponding mismatch repair protein and displayed microsatellite instability. Our results indicate that constitutional alterations in hMLH1 and hMSH2 transcript expression may represent genetic markers for HNPCC carrier status also in cases in which mutational analysis did not detect a definite pathogenic variant. This suggests that transcript deregulation may represent a relevant mode of germ-line inactivation for mismatch repair genes.

Novel allele of the hMLH1 gene bearing a TTC deletion in the 3' untranslated region.

SSCP analysis of the hMLH1 gene in two kindreds affected by hereditary nonpolyposis colorectal cancer (HNPCC) revealed the presence of unique conformers in all patients affected by colorectal cancer. Sequence analysis of the corresponding region of the gene revealed a 3 base pairs deletion within a TTC tandem repeat (G TTC TCC T-->G TTC T) beginning 29 base pairs downstream of the termination codon of the gene in the 3' untranslated region. This deletion causes the loss of an MboII restriction site. Analysis extended to 113 healthy unrelated individuals and 27 unrelated HNPCC patients demonstrated the occurrence of this novel variant of the hMLH1 gene at similar frequencies in unrelated HNPCC patients (3.7%) and in control individuals (2.2%). The allele bearing the TTC deletion appears to be expressed at levels comparable to those of the wild-type allele.

Activation of c-MYC and c-MYB proto-oncogenes is associated with decreased apoptosis in tumor colon progression.

BACKGROUND: An increasing amount of evidence suggests that progression from normal mucosa to colorectal cancer is accompanied by morphological and genetic alterations. Genetic abnormalities affect malignant transformation via a gradual imbalance of normal tissue homeostasis involving programmed cell death (PCD) or apoptosis. Therefore, it has been hypothesized that alterations in apoptosis may contribute to carcinogenesis. The aim of the present work was to investigate the relationship between frequency of spontaneous apoptosis during transition adenoma-to-carcinoma of the colorectal tract and the incidence of activation of c-myc and c-myb proto-oncogenes, involved both in colon tumorigenesis and apoptosis. MATERIALS AND METHODS: Ninety-five tissue specimens (60 polyps and 35 adenocarcinomas) were removed with autologous normal adjacent mucosa from colon cancer patients. Genomic DNA was extracted and analyzed for both apoptosis frequency (DNA fragmentation assay) and proto-oncogene activation (Southern blot analysis). On the same samples, Bcl-2 protein expression was evaluated by immunohistochemistry. RESULTS: Our results showed that: i) a significant relationship exists between apoptosis and genesis of colorectal cancer since, compared to adenomatous polyps and adjacent normal mucosa, cell death is markedly inhibited in tumors (p = 0.01); ii) during colon tumor progression, apoptosis and amplifications of c-myc/c-myb genes are inversely related; iii) Bcl-2 expression is retained in colon tumors even though at a significantly lower level with respect to adenomatous polyps. CONCLUSION: These results indicate that failure of the normal apoptotic process together with de-regulation of c-myc and c-myb proto-oncogenes might promote the development of colorectal tumors.

Comparative analysis of CA 242 and CA 19-9 serum tumor markers in colorectal cancer patients. A longitudinal evaluation.

OBJECTIVE: Following the encouraging results obtained on CA 242 as an adjunctive marker for colorectal cancer this study was designed to compare the clinical behavior of CA 242 to that of its related marker CA 19-9. PATIENTS AND METHODS: Sera from 630 patients with benign (n = 201) or malignant (n = 429) colorectal diseases were evaluated. Moreover, 50 patients with colorectal cancer were longitudinally monitored during. post-surgical follow-up for either a minimum of 5 years or until time of recurrence. Serum CEA, CA 19-9 and CA 242 levels were determined before treatment and at each scheduled follow-up. RESULTS: The distribution of CA 242 levels in colorectal cancer patients demonstrated a similar positivity rate (32.9%) compared to that of CA 19-9 (29.8%), although both sensitivities were lower than that of CEA (43.8%). Moreover, elevated CA 242 serum levels were found in metastatic disease (58.2%). A longitudinal evaluation demonstrated that serum CEA, CA 19-9 and CA 242 levels were elevated in 63.9%, 63.9% and 66.7% of recurrences. Combined evaluation of CEA, CA 19-9 and CA 242 serum levels in the overall population demonstrated a complementarity of CEA with the latter two markers. Conversely, a highly significant correlation was observed, suggesting that the two assays might recognize the same macromolecular complex. CONCLUSION: CA 242 determination does not seem to offer a particular advantage over CA 19-9, while CEA remains the marker of choice in monitoring colorectal cancer patients.

Colorectal cancer complicating ulcerative colitis: an institutional series.

Ulcerative colitis predisposes to colorectal cancer: the risk increases along with disease duration and extension. Also some subsets of patients are at increased risk, namely patients with early onset of colitis, and patients with primary sclerosing cholangitis. Cancer complicating ulcerative colitis affects evenly all the colon, and is not located more frequently in the rectum and in the sigmoid colon, as well as the sporadic counterpart. Multiple cancers and cancers associated with high grade dysplasia are not infrequent in ulcerative colitis; for this reason, and for controlling the colitis, the treatment of choice is total colectomy, with or without colostomy. The prognosis of cancer complicating ulcerative colitis is similar to the sporadic counterpart. The Authors present a colon cancers series as a complication of colitis occurred at Regina Elena Cancer Institute of Rome, Italy, over the period 1975-1998.

Endoscopic follow-up in resected colorectal cancer patients.

Patients resected for colorectal cancer are at risk for anastomotic recurrence, for adenomatous polyps and for metachronous cancer. The present retrospective study was conducted to evaluate the incidence of neoplasms of the colon, both metachronous or recurrent, in 322 patients. They were observed and resected for colorectal cancer between 1970 and 1988, with complete staging, and all agreed to be included in a follow-up program (median followup: 105 months). All the patients were submitted to colonoscopy once yearly for the first 5 years and then every 2 years. Anastomotic recurrence was observed in 22 of the 253 patients who underwent resection for rectal or sigmoid adenocarcinoma (8.7%). Sixteen of these patients were submitted to a second curative resection with a median survival of 35 months; the median survival was 6 months in the 6 patients who could not undergo this operation (p=0.0018). Metachronous adenomas of the residual colon were found in 24 patients and metachronous cancers in 5 at Stage A, according to Dukes' classification. In conclusion, a regular colonoscopic surveillance in patients resected for colorectal cancer is justified for early detection and potential resection of anastomotic recurrences, new primary cancer and adenomatous polyps. In patients resected for rectal or sigmoid carcinoma, a sigmoidoscopy should be performed every 6 months for the first 2 years for the early detection of anastomotic recurrences. In all cases, a colonoscopy should be performed every 5 years after surgery to detect metachronous lesions. Before surgery, a "clean colon" should always be established to detect possible synchronous lesions.

Palliative treatment of esophageal tumors.

In malignant dysphagia expandable metal stents are commonly used as palliative treatment, but early and late complications and the improvement of dysphagia have not been well described. This report summarizes our experience with expandable metal stents for malignant dysphagia. From 1995 to 2000, we placed 38 metal stents in 36 patients with malignant dysphagia from unresectable esophageal cancer (94.4%). Dysphagia scores, complications and modality of reintervention were evaluated. Dysphagia scores decreased from 3.2 before the stent placement to 2. Immediate complications occured in one patient because of severe pain, it was not possible to perform endoscopic treatments. Other complications included tracheoesophageal fistula (2 patients), tumor overgrowth (5 patients), new stent placements (2 patients), dislocation (2 patients). In conclusions expandable metal stents are safe and effective in the treatment of malignant dysphagia.

Turcot syndrome: case report and nosological aspects.

The Turcot syndrome has been defined as the simultaneous presence of multiple polyposis of the colon and a malignant brain tumor. This association is supposed to be genetically transmitted, even though we still do not exactly know whether this occurs in a dominant or recessive way. The case of a 47-year-old man submitted to a right hemicolectomy for cancer and polyposis, following a series of endoscopic polypectomies and, finally, removal of left temporal glioma is here presented.

Endoscopic follow-up in oncological diseases of the gastrointestinal tract: the experience of the Regina Elena Cancer Institute.

In oncology, follow-up refers to the medical procedures aimed to control, over time, both patients at risk of developing cancer, or those already submitted to surgical treatments for neoplastic lesions. The usefulness of an endoscopic follow-up in oncological diseases of the gastrointestinal tract is still being debated and, in some cases, a variety of different protocols are often employed for the same disease. At Regina Elena Cancer Institute, after a critical review of our data and literature, we established and followed guidelines of endoscopic follow-up for patients both at risk and submitted to curative surgery for cancer.

Medium-large polyps of the colon: a contribution for their clinical profile and a proper surveillance.

A retrospective analysis of polypoid lesions of the colon larger than 1 cm was performed with the aim to study their characteristics and a proper surveillance schedule. We reviewed all colon polypoid lesions larger than 1 cm found and treated during the period January 1984- December 1993 that were not considered cancer macroscopically. The records of 361 patients with 391 polyps are the object of this report. The polyps were divided into subgroups according to size: A) less than 20 mm, B) between 21 and 30 mm, and C) larger than 30 mm. Out of 391 polypoid lesions 373 were adenomas: 60% were found in males. The age group distribution showed no differences among the subgroups. The pedunculated type showed a decrease from 69.1% to 43.3% with the increasing of size: inverse figures were observed for sessile polyps. The lesions were mainly located in left colon. Synchronous adenomas were found in 25.4% patients, and metachronous and previous adenomas respectively in 24.8% and 5.2%: no significant difference was present in the subgroups. Synchronous malignancy in the colon was found in 2% of the patients. Histological characteristics demonstrated a decrease of tubular adenoma from 46.5% to 22.6% from subgroup A to C, while villous adenomas increased inversely from 6.6% to 15.1%. The presence of severe dysplasia ranged from 20.9% to 56.1% in subgroups A and C, respectively, and adenomas with invasive cancer showed a significant increase from the subgroup A to C, respectively from 4.3% to 10.5%. During an average 36-month follow-up we observed 2 metachronous colon cancers, surgically treated in Dukes stage B, 84 metachronous adenomas, all less than 10 mm and without malignant alterations. Our data confirm other literature reports regarding the profile of colon adenomas with an increasing risk of malignancy with the increase of size and the presence of villous structure. In our opinion the assessment of a "clean colon" status is important when an adenoma is found in the colon. The proper follow-up for adenomas must be tailored for any individual patient when risk factors such as size, villous structure, personal and family history of neoplastic lesions of the colon are present. The follow-up schedule, presently recommended for colon adenomas, must be flexible according to these parameters.

C-MYB, serum P-53M, genetic instability, labeling index and endoscopic findings in patients with adenoma or colorectal cancer.

Structural alterations of c-myb proto-oncogenes and serum p53 mutant level, Mitomycin C-induced chromosomal aberrations and sister chromatid exchanges and proliferative activity of mucosa (H3-thymidine -labeling index LI) are often determined to obtain more information about the diagnosis and prognosis of neoplastic and preneoplastic lesions of the colon. The aim of this study was to evaluate the endoscopic findings of a 5 year follow-up in three groups of subjects (normal, adenoma or cancer patients) and to correlate these findings with the biological alterations in the same subjects between 1990 and 1993. We analyzed 200 subjects (118 Male and 82 Female), 78 normal subjects (group A), 60 patients with adenoma (group B) and 62 with carcinoma (group C). Data regarding endoscopic lesions was collected from June 1998 to December 2000 after a 5 year follow-up and correlated with the biological alterations in the same subjects between 1990--1993. We obtained endoscopic findings from 23/137 subjects (16.8%), 6/137 (4.4%) died from other causes and 108/137 (78.8 %) were negative for lesions. The percentage of disease after 5 years is not statistically different among the three groups (groups A, B and C). There was no statistically significant association between values of the labeling index, structural alterations of c-myb, p-53-M serum levels and chromosomal aberrations and endoscopic findings in the 5 year follow-up. We conclude that the biological markers considered are not able to stratify patients in terms of risk of progression to malignant disease.

Current trends in screening and secondary prevention of colorectal cancer.

Colorectal cancer is one of the most frequent neoplasms in Western countries with an estimated 400,000 deaths per year worldwide. Several randomized studies have demonstrated that screening programs with FOBT (Fecal Occult Blood Test) reduce mortality from 18 to 33%, whereas case-control and cohort studies with endoscopy have shown a mortality reduction ranging from 60 to 76%. The target population for secondary prevention is men and women aged more than 50 years and younger subjects in case first-degree relatives are affected or the family pedigree raises the suspicion of a genetic syndrome. This report summarizes the results of different screening strategies for average risk patients (FOBT, anamnestic risk questionnaire, sigmoidoscopy, colonoscopy and virtual colonoscopy) and the surveillance protocols applicable to high-risk patients, particularly for hereditary syndromes such as HNPCC and FAP.

[Colonic varices secondary to recurrent acute pancreatitis]. / Varici del colon secondarie a pancreatite acuta ricorrente.

Colonic varices are a rare finding, with variable clinical features. The authors describe the first case of colonic varices secondary to acute recurrent pancreatitis, and associated with colon cancer. There are about 70 reports of colonic varices; none of them is related to acute recurrent pancreatitis, whereas 52 are related to portal hypertension, and 9 are on a familial basis. Association with colon cancer is reported in one case, and seems to be occasional.

[The Lynch syndrome]. / La sindrome di Lynch.

Lynch syndrome is a peculiar disease, accounting for 5% of the total burden of colon cancer. Characteristics of this disease are autosomal dominant transmission, early onset, and frequent right colon localization. Diagnostic criteria, aimed to collaborative studies, are based on these features (so called Amsterdam criteria). Lynch syndrome has specific biomolecular features (microsatellite instability); mismatch repair genes have been identified as responsible of this syndrome. Lynch syndrome causes high risk for extracolonic malignancies, particularly for endometrial cancer, supposed to be related to mutation of hMSH2 gene. Another feature of Lynch syndrome tumours is better survival with respect to sporadic counterpart. Genetic test allows identifying the state of mutation carriers and selects the patients to submit to screening. Endoscopic screening has been demonstrated to reduce incidence of colorectal malignancies in this syndrome.

[Utility of endoscopic follow-up after resection of colorectal cancer]. / Utilità di un follow-up endoscopico nei pazienti resecati per cancro del colon retto.

PURPOSE: Patients resected for colorectal cancer are at increased risk for an anastomotic recurrence, for adenomatous polyps and for a metachronous cancer. A regular colonoscopic surveillance in these patients is justified for early detection and potential resection of anastomotic recurrences, new primary cancer and adenomatous polyps. PATIENTS AND METHODS: 322 patients were observed and resected for colorectal cancer between 1970 and 1988, with complete staging agreed to be included in a follow-up program (median follow-up: 105 months). To December 1993 all the patients were submitted to colonoscopy once yearly for the first 5 years and then every 2 years. RESULTS: Anastomotic recurrence was observed in 22 of the 253 patients who underwent resection for rectal or sigmoid adenocarcinoma (8.7%). Sixteen of these patients were submitted to a second curative resection with a median survival of 35 months; the median survival was 6 months in the 6 patients who could not undergo this operation (p = 0.0018). Metachronous adenomas of the residual colon were found in 24 patients (7.4%) and metachronous cancers in 5 (1.5%) at Stage A, according to Dukes' classification. CONCLUSIONS: In patients resected for rectal or sigmoid carcinoma, a sigmoidoscopy should be performed every 6 months for the first 2 years for the early detection of anastomotic recurrences. In all cases, a colonoscopy should be performed every 5 years after surgery to detect metachronous lesions at early stage. Before surgery, a "clean colon" should always be established to detect possible synchronous lesions.

Co-localization of IgA and TG3 on healthy skin of coeliac patients.

BACKGROUND: Dermatitis herpetiformis (DH), the skin's expression of coeliac disease (CD), is induced by the presence of IgA antibodies and epidermal transglutaminase (TG3) as the main autoantigen, stored in the papillary dermis and on the vessel walls. AIMS: To evaluate the presence of IgA and TG3 deposits, considered to be the first step in inducing DH, in healthy skin of coeliac patients without cutaneous manifestations. METHODS: Punch biopsies were taken from 11 consecutive coeliac patients, two with DH and nine without cutaneous manifestations, three of whom were adhering to a gluten-free diet (GFD), and evaluated for the presence of deposits in the upper dermis and vessel walls by immunofluorescence and confocal microscopy. RESULTS: In coeliac patients affected by DH we found the presence of IgA and TG3 deposits mainly on the upper dermis, but also in vessel walls. In all coeliac patients without DH and also in those patients who were following a strict GFD, we found widely variable deposits of IgA and TG3 in both the papillary dermis and the vessel walls, although a lower intensity of the fluorescence signal was detected than with coeliac patients affected by DH. Double immunostaining with anti-IgA and anti-TG3 antibodies showed a strong co-localization in the upper dermis in patients with DH and a weaker co-localization in those without DH. CONCLUSIONS: We have demonstrated the presence of IgA and TG3 deposits in the healthy skin of coeliac patients, which are considered to play a central role in the pathogenesis of DH.

Endoscopy and associated sampling techniques in the diagnosis and surveillance of gastric ulcer.

In the present report we have analyzed data reported in literature on the diagnostic accuracy of endoscopy and associated sampling techniques compared to standard and double contrast radiological examinations, as well as the rate of malignant transformation of benign gastric ulcer. Data on 117 patients with benign gastric ulcer examined in our Center between 1974 and 1984 are reported. From our experience, we may state that only one case underwent to malignant transformation, i.e. a rate of 1.2%, in agreement with recent literature. Three cases of malignant-ulcer had gone undiagnosed at first endoscopy, but were correctly diagnosed at a short-term re-examination. The present study, other than reconfirming the importance of the endoscopic examination with associated techniques, stresses the importance of aimed cytology and of short-term endoscopic re-examination as a mean for lowering the rate of false negative diagnoses.