Laryngeal adenoid cystic carcinoma: Radical or conservative surgery?

PURPOSE: The present paper describes our experience in surgical treatment of laryngeal ACC, and discuss the effectiveness of conservative surgery. METHODS: We retrospectively reviewed the clinical charts of 17 patients with laryngeal ACC treated surgically at the Otolaryngology Unit of Vittorio Veneto Hospital (Italy) from November 1989 to April 2020. RESULTS: Fourteen patients underwent partial laryngectomy, and three had a total laryngectomy. Five patients (29%) experienced a laryngeal ACC relapse after a disease-free survival of 66.6 ± 50.1 months. The distant metastasis rate was 17%. At latest follow-up, two patients had died of distant metastatic disease after 156 and 243 months. CONCLUSIONS: Radical surgery for laryngeal ACC does not warrant free margins and even cases with positive deep margins rarely experience any relapsing disease. We recommend that surgical treatment for laryngeal ACC be as conservative as possible.

Colorectal polypoid lesions and expression of vascular endothelial growth factor in a consecutive series of endoscopic and surgical patients.

Colorectal cancer incidence in patients undergoing screening protocols is decreasing because of the higher rate of discovered preneoplastic colonic lesions; however, adenomatous polyps may not always be removable endoscopically and surgery may still be necessary. The aim of this study was to assess the vascular endothelial growth factor expression in the different steps of colorectal carcinogenesis to explore its potential role as a marker of malignancy in polypoid lesions. A total of 92 subjects with colonic adenoma or cancer who underwent screening colonoscopy or surgery were prospectively enrolled. Real-time reverse transcription polymerase chain reaction for VEGF-A messenger RNA expression and immunohistochemistry for VEGF-A were performed. Immunoassays for VEGF-A, VEGF-C, VEGFR-1, VEGFR-2, and VEGFR-3 were also performed. Non-parametric statistics, receiver operating characteristic curve analysis, and logistic multiple regression analysis were used. VEGF-A messenger RNA expression was higher in patients with high-grade dysplasia or colorectal cancer than in those with low-grade dysplasia adenomas (p = 0.01). At immunohistochemistry, VEGF-A expression was significantly higher in colorectal cancer patients compared to dysplastic adenomas (p < 0.001), and the accuracy of VEGF-A expression for prediction of malignancy was 91.7 (95% confidence interval = 78.7-97.9). VEGF-C protein expression was lower in colorectal cancer patients than in simple adenomas (p = 0.02). VEGF-A levels were directly correlated to polyp size (rho = 0.73, p = 0.0062). Multivariate analysis demonstrated that malignancy and polyp size were independent predictors of VEGF-A mucosal levels. This study demonstrated that the VEGF-A expression changes along the colorectal carcinogenesis pathway showing a neat step up at the passage from high-grade dysplasia to invasive cancer. This feature might potentially be useful to stratify colorectal polyps in different risks of progression classes. Moreover, the high level of VEGF-A expression predicted the presence of lymphovascular invasion with good accuracy.

Sensory neuropathy hampers nociception-mediated bone marrow stem cell release in mice and patients with diabetes.

AIMS/HYPOTHESIS: Upon tissue injury, peripheral sensory neurons release nociceptive factors (e.g. substance P [SP]), which exert local and systemic actions including the recruitment of bone marrow (BM)-derived haematopoietic stem and progenitor cells (HSPCs) endowed with paracrine pro-angiogenic properties. We herein explore whether diabetic neuropathy interferes with these phenomena. METHODS: We first investigated the presence of sensory neuropathy in the BM of patients with type 2 diabetes by immunohistochemistry and morphometry analyses of nerve size and density and assessment of SP release by ELISA. We next analysed the association of sensory neuropathy with altered HSPC release under ischaemia or following direct stimulation with granulocyte colony-stimulating factor (G-CSF). BM and circulating HSPCs expressing the neurokinin 1 receptor (NK1R), which is the main SP receptor, were measured by flow cytometry. We finally assessed whether an altered modulation of SP secretion interferes with the mobilisation and homing of NK1R-HSPCs in a mouse model of type 2 diabetes after limb ischaemia (LI). RESULTS: Nociceptive fibres were reduced in the BM of patients and mice with type 2 diabetes. Patients with neuropathy showed a remarkable reduction in NK1R-HSPC mobilisation under ischaemia or upon G-CSF stimulation. Following LI, diabetic mice manifested an altered SP gradient between BM, peripheral blood and limb muscles, accompanied by a depressed recruitment of NK1R-HSPCs to the ischaemic site. CONCLUSIONS/INTERPRETATION: Sensory neuropathy translates into defective liberation and homing of reparative HSPCs. Nociceptors may represent a new target for treatment of diabetic complications.

Assessment of Contrast-Enhanced Ultrasound (CEUS) and Computed Tomography (CT) diagnostic accuracy in the evaluation of challenging cystic renal masses.

PURPOSE: To assess the diagnostic accuracy of contrast-enhanced ultrasound (CEUS) and computed tomography (CT) within Bosniak IIF/III categories. METHODS: After cystic renal mass diagnosis by contrast-enhanced CT, all patients with Bosniak score ≥ II also underwent CEUS between March 2017 and March 2019. Their exams were retrospectively analyzed. One experienced uro-radiologist performed every CEUS and reviewed the exams according to the EFSUMB 2020 Position Statement, while blinded to clinical data. CT Bosniak scores were retrospectively given blindly by two uro-radiologists (CT 1 and CT 2). We compared CEUS, CT 1 and CT 2 scores to clinical findings and histological tests. Clinical performance characteristics and area under the receiver operating characteristic (ROC) curves (AUCs) were determined separately for CEUS and CT, and then compared. RESULTS: 101 cystic masses were analyzed. In Bosniak categories IIF and III, the AUCs were 0.854 for CT 1, 0.779 for CT 2, and 0.746 for CEUS. CONCLUSION: Despite some statistical limitations, this study confirms that among cystic renal masses, those classified as Bosniak IIF and III are the most difficult to assess. The diagnostic performances of CEUS and CT are similar within this group. However, in experienced hands, CEUS could be valuable in further evaluation of ambiguous cystic masses, and in more ductile, safer, and cost-effective surveillance of those classified as Bosniak IIF and III. When challenging cystic renal masses occur, CEUS is a useful tool for clinical management and for the follow-up of non-surgical lesions.

MLH1 Deficiency Down-Regulates TLR4 Expression in Sporadic Colorectal Cancer.

Patients with mismatch repair (MMR)-deficient colorectal cancer (CRC) have a more favorable prognosis than patients with tumors with intact MMR. In order to obtain further insights on the reasons for this different outcome, we investigated the interplay between MMR genes and TLR4/MyD88 signaling. The cancer genome atlas (TCGA) databases were selected to predict the differential expression of TLR4 in colon cancer and its correlation with MMR genes. Moreover, the expression of MMR genes and TLR4 was evaluated by immunohistochemistry in 113 CRC samples and a cohort of 63 patients was used to assess TLR4 mRNA expression and MLH1 epigenetic silencing status. In vitro, the effect of MLH1 knockdown on TLR4 expression was quantified by Real Time PCR. TLR4 expression resulted dependent on MMR status and directly correlated to MLH1 expression. In vitro, MLH1 silencing decreased TLR4 expression. These observations may reflect the better prognosis and the chemoresistance of patients with CRC and MMR defects.

Pituitary metastasis of Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a malignant neuroendocrine tumor of the skin that demonstrates a remarkable tendency to metastasize. However, only a few cases of MCC brain metastases have been reported in the literature. We here present a unique case of a pituitary metastasis of MCC in a 65-year-old patient with a history of pituitary adenoma. This case is particularly novel due to the fact that the primary site of the MCC is unknown.

Sclerosis of the arytenoid cartilage and glottic carcinoma: A clinical-pathological study.

BACKGROUND: Given the relevance of any tumor invasion of the arytenoid cartilage or crico-arytenoid unit to the planning open partial horizontal laryngectomy (OPHL) for laryngeal squamous cell carcinoma (LSCC), it is important to have a reliable radiological test to assess impairments of these structures. METHODS: We retrospectively compared the endoscopic, radiological, and pathological findings in patients with glottic LSCC who underwent OPHL. RESULTS: The endoscopic finding of a reduced (impaired or absent) vocal cord motility proved more sensitive, with better positive and negative predictive values, but less specific than the radiological finding of complete arytenoid sclerosis in detecting histologically assessable infiltration of the arytenoid cartilage. CONCLUSIONS: Endoscopy retains a key role in the preoperative workup for glottic LSCC. CT evidence of complete sclerosis of the arytenoid cartilage is related to a dangerous contiguity of the tumor to the cartilage.

Could the infiltration of the thyroarytenoid muscle define the pT2 glottic carcinoma?

BACKGROUND: The involvement of the thyroarytenoid (TA) muscle by glottic cancer may be related to an impaired vocal cord mobility, which is classified as cT2 disease. The primary endpoint was to evaluate the prognostic significance of TA muscle involvement in early glottic cancer treated with transoral laser microsurgery (TLM). METHODS: A review was conducted on a cohort of 209 patients consecutively treated with TLM for early glottic carcinoma. Univariate analysis was used to examine the prognostic meaning of clinical and pathological parameters. RESULTS: The statistical analysis showed that TA muscle infiltration correlated significantly with a worse prognosis in terms of recurrence rate and disease-free survival, and this was confirmed even in the subcohort with pT1a glottic cancer. CONCLUSIONS: Our preliminary findings suggest that it could be considered as a criterion for upstaging a glottic cancer from pT1 to pT2.

The impact of P53 and P21(waf1) expression on the survival of patients with the germinal center phenotype of diffuse large B-cell lymphoma.

Immunohistochemically detected over-expression of P53-related protein (P53+++) and absence of P21(waf1) expression (P21-) correspond to loss of function of the P53-gene in diffuse large B-cell lymphoma (DLBCL) patients. Using immunohistochemistry we examined 80 patients with DLBCL and found that 23% had the P53+++/P21- phenotype while 51% had a germinal center (GC) pattern. Both the P53+++/P21- phenotype and the non-GC pattern were associated with inferior outcome. Notably, the prognostic power of the P53+++/P21- phenotype was restricted to patients with a GC pattern, without effect on outcome of patients with a non-GC phenotype. Our results show that immunohistochemistry can parallel gene expression profiling in addressing clinical variability of DLBCL patients.

Concomitant chronic lymphocytic leukemia and acute myeloid leukemia: evidence of simultaneous expansion of two independent clones.

The simultaneous appearance of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) has been rarely reported, with AML occurring more frequently as a secondary event in patients receiving cytotoxic drugs for a primary lymphoproliferative disorder. We describe a case of simultaneous CLL and AML documented by morphological and cytometric analysis in a previously untreated patient. In particular, on the basis of morphological and immunological features, the patient was diagnosed as being affected by CD34 + /CD13 + /CD33 + /HLA-DR + /CD7 + FAB-M2 AML, along with a B-CLL characterized by neoplastic cells expressing a VH3-53/D3-22/JH4 Ig, bearing, on average, 3.9% IgVH mutations without evidence of antigen-driven selection. To establish whether the two neoplastic cell populations shared some common molecular signature, we performed IgH gene rearrangement studies on CD34 + /CD19- and CD34-/CD19 + immunomagnetically sorted cell populations: only genomic DNA from the CD19 + /CD34- cell fraction revealed the presence of the IgH gene rearrangement. These results provide evidence that the rare concomitant association of CLL and AML likely arises from simultaneous expansion of two independent clones.

[Environmental pollution from dioxins and soft tissue sarcomas in the population of Venice and Mestre: an example of the use of current electronic information sources]. / Indagine su inquinamento ambientale da diossine e sarcomi dei tessuti molli nella popolazione di Venezia e Mestre: un esempio di utilizzo di fonti informative elettroniche correnti.

OBJECTIVE: Estimating the potential carcinogenic risk associated with exposure to dioxins generated by industrial emissions and urban incinerators. DESIGN: We conducted a geographical investigation on the relationship between Soft Tissue Sarcomas (STS) and other tumours, and estimated levels of exposures to dioxins. Estimates ofthe population's exposure were derived from a historical analysis of emissions of dioxins and other pollutants, conducted by the Province of Venice in all the Venetian area in 1980-1990. Cancer cases were selected from two electronic pathology databases of Venice and Mestre, computerized since 1987. All STS diagnoses were revised in order to improve the quality of the cases in the study and cases of Kaposi sarcoma were excluded from the analysis. The 198 remaining STS--Hodgkin's lymphoma, non-Hodgkin' lymphoma and subjects with at least one cancer--were linked to the registry of residents and mapped according to the pollutant level estimates using GIS techniques. The same procedure was applied to cases of non-Hodgkin's lymphoma (n=822), Hodgkin's lymphoma (n=142) and to 25.568 cases of all cancer at other sites, with microscopic confirmation for comparison. SETTING: Venetian AULSS 12. RESULTS: Risks for STS (measured as Standardized Incidence Ratios SIR) did not show any trend related to categories of dioxin pollution. Among women, a statistically significant increased SIR of 1.69 was estimated for the highest category of exposure. The corresponding SIR for Hodgkins lymphoma was 1.94 (I.C. 1.08-1.19). No major excesses were estimated for other cancer sites. CONCLUSION: Overall, no consistent association between cancer risk and estimated exposure to dioxins was detected in the population under study However, a statistically significant excess of STS among women in the highest exposure category allows for the possibility of a role of environmental exposure.

Rabbit monoclonal antibodies: a comparative study between a novel category of immunoreagents and the corresponding mouse monoclonal antibodies.

Rabbit monoclonal antibodies (RabMAbs) represent a novel category of immunoreagents that may combine the best properties of both mouse monoclonal antibodies (MMAs) and of rabbit antisera. In the attempt to verify the performance of this new class of antibodies on paraffin-embedded tissue, RabMAbs against estrogen receptor, progesterone receptor, Ki-67, cyclin D1, CD3, CD5, CD23, and synaptophysin were tested on several tumor types as well as normal tissues. The results were compared with those obtained with classic MMAs against the same antigens. RabMAbs appear to offer increased sensitivity with no apparent loss of specificity. On routine use they permit higher working dilutions (5 to 10 times on average), allowing significant improvement in terms of laboratory efficiency. The robustness of RabMAbs is further proved by the fact that in some instances optimal staining can be obtained even without antigen retrieval. In consideration of the high performance observed, routine use of RabMAbs may contribute significantly to standardize diagnostic immunohistochemical procedures.

Mismatch repair gene defects in sporadic colorectal cancer enhance immune surveillance.

BACKGROUND: There is evidence that colorectal cancers (CRC) with DNA mismatch repair deficiency (MMR-D) are associated with a better prognosis than the generality of large bowel malignancies. Since an active immune surveillance process has been demonstrated to influence CRC outcome, we investigated whether MMR-D can enhance the immune response in CRC. PATIENTS AND METHODS: A group of 113 consecutive patients operated for CRC (42 stage I or II and 71 with stage III or IV) was retrospectively analyzed. The expression of MMR genes (MSH2, MLH1, MSH6 and PSM2) and co-stimulatory molecule CD80 was assessed by tissue microarray immunohistochemistry. In addition, tumor infiltrating mononuclear cells (TIMC) and T cell subpopulations (CD4, CD8, T-bet and FoxP-3) were quantified. The effect of specific siRNA (siMSH2, siMLH1, siMSH6 and siPSM2) transfection in HT29 on CD80 expression was quantified by flow cytometry. Non parametric statistics and survival analysis were used. RESULTS: Patients with MMR-D showed a higher T-bet/CD4 ratio (p = 0.02), a higher rate of CD80 expression and CD8 lymphocyte infiltration compared to those with no MMR-D. Moreover, in the MMR-D group, the Treg marker FoxP-3 was not expressed (p = 0.05). MMR-D patients with stage I or II and T-bet expression had a significant better survival (p = 0.009). Silencing of MSH2, MLH1 and MSH6, but not PSM2, significantly increased the rate of CD80+ HT29 cells (p = 0.007, p = 0.023 and p = 0.015, respectively). CONCLUSIONS: CRC with MMR-D showed a higher CD80 expression, and CD8+ and Th1 T-cell infiltration. In vitro silencing of MSH2, MLH1 and MSH6 significantly increased CD80+ cell rate. These results suggest an enhanced immune surveillance mechanism in presence of MMR-D.

Primary Synovial Sarcoma (SS) of the digestive system: a molecular and clinicopathological study of fifteen cases.

BACKGROUND: Recently a few cases of synovial sarcoma (SS) of the abdominal viscera have been reported, raising awareness about the potential for confusion between this entity and KIT-negative gastrointestinal stromal tumors (GIST). We report the clinicopathological, immunophenotypical and molecular features of fifteen more SS occurring in the stomach (8 cases), epigastric region (one case), small intestine (one case), large intestine (three cases), involving both the terminal ileum and the caecum (one case) and liver (one case). METHODS: Immunostains for SMA, DESMIN, CD34, CD117, S100, EMA, CK AE1/3, TLE1, CD56, CD99, BCL2, DOG1 were performed. Rearrangement of SS18 gene region was screened in all cases: by conventional karyotype in one case, the remaining cases were screened either by interphase FISH or Q-PCR or both. RESULTS: Ten patients were male and five female, with an age range of 17-61 years (median 44). Tumor size ranged from 2 to 15 cm (median 8). Mitoses per 10 HPF ranged from 4 to 27 (median 9.5). Eleven tumors were monophasic fibrous SS, one biphasic SS and three poorly differentiated SS. SMA, Desmin, CD34, CD117 and S100 were negative in all cases, whereas EMA and/or CK AE1/AE3 were positive in all cases. TLE1, BCL2 and CD56 were positive in all tested cases. DOG1 was positive in one case. SS18 gene region rearrangement was demonstrated in all cases. A fusion transcript was amplified in eight cases: either SS18-SSX2 or SS18-SSX1 respectively in four cases each. CONCLUSIONS: SS is increasingly recognized at visceral sites. Molecular analyses play a key role when dealing with usual histotypes in unusual sites. Correct diagnosis is crucial for appropriate therapy.

Prognostic significance of circulating and endothelial progenitor cell markers in type 2 diabetic foot.

Objective. We studied circulating precursor cells (CPC) in type 2 diabetes mellitus (T2DM) with neuropathic foot lesions with or without critical limb ischemia and relationships between endothelial precursor cells (EPC) and peripheral neuropathy. Methods and Subjects. We measured peripheral blood CD34, CD133, and CD45 markers for CPC and KDR, CD31 markers for EPC by citofluorimetry and systemic neural nociceptor CGRP (calcitonin gene related protein) by ELISA in 8 healthy controls (C) and 62 T2DM patients: 14 with neuropathy (N), 20 with neuropathic foot lesions (N1), and 28 with neuroischemic recent revascularized (N2) foot lesions. Timing of lesions was: acute (until 6 weeks), healed, and not healed. Results. CD34+ and CD133+ were reduced in N, N1, and N2 versus C, and CD34+ were lower in N2 versus N1 (P = 0.03). In N2 CD34+KDR+ remain elevated in healed versus chronic lesions and, in N1 CD133+31+ were elevated in acute lesions. CGRP was reduced in N2 and N1 versus C (P < 0.04 versus C 26 ± 2 pg/mL). CD34+KDR+ correlated in N2 with oximetry and negatively in N1 with CGRP. Conclusions. CD34+ CPC are reduced in diabetes with advanced complications and diabetic foot. CD34+KDR+ and CD31+133+ EPC differentiation could have a prognostic and therapeutic significance in the healing process of neuropathic and neuroischemic lesions.

Obesity is a risk factor for multifocal disease and recurrence after colorectal cancer surgery: a case-control study.

BACKGROUND: Several studies have demonstrated that obesity is a risk factor for colorectal cancer (CRC), but few data are available regarding its role in multifocal disease and postoperative recurrence. The present study aimed to assess the role of obesity as a risk factor for multifocal disease and postoperative recurrence in patients with CRC. PATIENTS AND METHODS: The records of 940 consecutive patients with CRC admitted to three surgical centres between January 2006 and January 2011 were retrospectively analysed. The 595 individuals whose preoperative body mass index (BMI) values were available were included in the study. Following WHO guidelines, the patients were stratified into four groups depending on their BMI values. Age at disease onset, clinical presentation, tumor invasiveness, the presence of multiple foci, and the colon cancer recurrence rate in the four groups were assessed and compared. RESULTS: At multivariate analysis, diagnosis of familial adenomatous polyposis (FAP) and a BMI>30 were found to be independent predictors of synchronous polyps (Odd Ratio [OR]=10.7, 95% Confidence interval (CI)=2-75, p=0.005; and OR=2.2, 95% CI=1.3-3.9, p=0.003, respectively). The cancer recurrence rate in the patients with stage 2 CRC was significantly higher in the obese with respect to the non-obese (p=0.05). At multivariate analysis, BMI>30, FAP, and positivity by the Bethesda criteria were found to be independent predictors of recurrence after CRC surgery. CONCLUSION: Obese patients diagnosed with CRC require thorough colonic exploration prior to surgery and necessitate more frequent postoperative endoscopic examinations with respect to patients without any risk factors.

An unusual mediastinal outline.

Thymoma is the most common primary neoplasm of the anterior mediastinum. We describe the case of a 40-year-old man with asymptomatic thymoma involving the right atrium, and the diagnostic pathway.

Cytogenetic evidence of metastatic myxoid liposarcoma and therapy-related myelodysplastic syndrome in a bone marrow biopsy.

Myxoid liposarcoma exhibits a peculiar clinical behavior, with a tendency to spread to serosal membranes, distant soft tissues, and bones, even in the absence of lung metastases. Therapy-related hematological neoplasms are well-known side effects of cytotoxic chemotherapy. We describe an exceptional case of metastatic myxoid liposarcoma of the spine associated with therapy-related refractory anemia with excess of blasts in a 37-year-old woman who underwent multi-agent chemotherapy for a myxoid liposarcoma of the left thigh. Microscopic examination of the bone marrow biopsy revealed dysplastic features, with abnormal localization of immature precursors and micromegakaryocytes, and islands of undifferentiated oval small/medium-size cells, suggestive of acute myeloid leukemia arising in the setting of a myelodysplastic syndrome. Immunohistochemistry was not discriminant. Cytogenetic analyses of bone marrow aspirate disclosed the presence of 2 different rearrangements, subsequently confirmed by fluorescent in situ hybridization and was crucial in making the correct diagnosis.