Defining the surgical margins of adenoid cystic carcinoma and their impact on outcome: An international collaborative study.

BACKGROUND: The mainstay of treatment in adenoid cystic carcinoma (ACC) of the head and neck is surgical resection with negative margins. The purpose of this study was to define the margin status that associates with survival outcomes of ACC of the head and neck. METHODS: We conducted univariate and multivariate analyses of international data. RESULTS: Data of 507 patients with ACC of the head and neck were analyzed; negative margins defined as ≥5 mm were detected in 253 patients (50%). On multivariate analysis, the hazard ratios (HRs) of positive margin status were 2.68 (95% confidence interval [CI], 1.2-6.2; p = .04) and 2.63 (95% CI, 1.1-6.3; p = .03) for overall survival (OS) and disease-specific survival (DSS), respectively. Close margins had no significant impact on outcome, with HRs of 1.1 (95% CI, 0.4-3.0; p = .12) and 1.07 (95% CI, 0.3-3.4; p = .23) for OS and DSS, respectively, relative with negative margins. CONCLUSION: In head and neck ACC, positive margins are associated with the worst outcome. Negative or close margins are associated with improved outcome, regardless of the distance from the tumor. © 2017 Wiley Periodicals, Inc. Head Neck 39: 1008-1014, 2017.

International collaborative validation of intraneural invasion as a prognostic marker in adenoid cystic carcinoma of the head and neck.

BACKGROUND: The purpose of this study was to characterize the incidence, pattern of spread, and prognostic correlation of nerve invasion in patients with adenoid cystic carcinoma (ACC). METHODS: Using 3 different pathological categories of perineural invasion, intraneural invasion, and perineural inflammation, we investigated the prognostic value of nerve invasion in a total of 495 ACCs from 9 international patient cohorts with median follow-up 90 months (range, 12-288 months). RESULTS: Of 239 patients (48%) with nerve invasion, 174 (73%) had perineural invasion, 65 (27%) intraneural invasion, and 37 (15%) perineural inflammation. Multivariate Cox regression analysis identified tumor site (p = .008; hazard ratio [HR] = 1.8; 95% confidence interval [CI] = 0.07-3.7) and intraneural invasion (p < .001; HR = 5.9; 95% CI = 0.8-12.3) as independent prognostic markers for both overall survival (OS) and disease-specific survival (DSS), but not of distant metastases. CONCLUSION: Although perineural invasion has no impact on survival, intraneural invasion is an independent predictor of poor prognosis. Recognition of intraneural invasion may help optimize treatment of patients with head and neck ACC.

Defining the outcome of patients with delayed diagnosis of differentiated thyroid cancer.

OBJECTIVES/HYPOTHESIS: In the present study we sought to define the outcome of patients with delay in diagnosis and treatment (>1 year) of well-differentiated thyroid carcinoma (WDTC) due to initial benign cytology (IBC). STUDY DESIGN: Retrospective medical record review and analysis of survival outcomes. METHODS: The records of 47 patients with delayed diagnosis of thyroid cancer were reviewed. In 38, surgery was performed for growing nodules and in nine due to malignant cytology during follow-up. Median time to delayed surgery was 52 months (range, 13-205 months). Multivariate analysis was performed to assess variables associated with outcome. RESULTS: Most patients (32/47) underwent total thyroidectomy, whereas 15/47 had hemithyroidectomy. With a median follow-up of 96 months (range, 12-184 months), the 5-year disease-free survival of these patients was 96%. Multivariate analysis showed that the outcome of these patients was not statistically different than that of patients (n = 162) who underwent immediate surgery for similar disease. CONCLUSIONS: We show that patients with delayed diagnosis and treatment for WDTC due to IBC have excellent outcome. LEVEL OF EVIDENCE: 4.

Endoneurial macrophages induce perineural invasion of pancreatic cancer cells by secretion of GDNF and activation of RET tyrosine kinase receptor.

Perineural invasion of cancer cells (CPNI) is found in most patients with pancreatic adenocarcinomas (PDA), prostate, or head and neck cancers. These patients undergo palliative rather than curative treatment due to dissemination of cancer along nerves, well beyond the extent of any local invasion. Although CPNI is a common source of distant tumor spread and a cause of significant morbidity, its exact mechanism is undefined. Immunohistochemical analysis of specimens excised from patients with PDAs showed a significant increase in the number of endoneurial macrophages (EMΦ) that lie around nerves invaded by cancer compared with normal nerves. Video microscopy and time-lapse analysis revealed that EMΦs are recruited by the tumor cells in response to colony-stimulated factor-1 secreted by invading cancer cells. Conditioned medium (CM) of tumor-activated EMΦs (tEMΦ) induced a 5-fold increase in migration of PDA cells compared with controls. Compared with resting EMΦs, tEMΦs secreted higher levels of glial-derived neurotrophic factor (GDNF), inducing phosphorylation of RET and downstream activation of extracellular signal-regulated kinases (ERK) in PDA cells. Genetic and pharmacologic inhibition of the GDNF receptors GFRA1 and RET abrogated the migratory effect of EMΦ-CM and reduced ERK phosphorylation. In an in vivo CPNI model, CCR2-deficient mice that have reduced macrophage recruitment and activation showed minimal nerve invasion, whereas wild-type mice developed complete sciatic nerve paralysis due to massive CPNI. Taken together, our results identify a paracrine response between EMΦs and PDA cells that orchestrates the formation of cancer nerve invasion.

Cytogenetic analysis of 101 skull base tumors.

BACKGROUND: Skull base tumors are rare neoplasms and the cytogenetic data on these tumors are limited. The authors cytogenetically analyzed a large series of tumors and compared the findings with patients' pathologic data. METHODS: The karyotypes of pathologically confirmed samples of 101 patients, who were operated for oncological extirpation of tumors, were analyzed using G-banding and spectral-karyotyping techniques. RESULTS: Of the 67 malignant tumors, 32 (48%) had chromosomal aberrations, some with complex numerical and structural chromosomal anomalies. Recurrent chromosomal breakpoints were identified in squamous cell carcinomas, adenoid cystic carcinomas (ACCs), sinonasal undifferentiated carcinomas, chordomas, and sarcomas. Specific breakpoints established the diagnosis of various soft tissue sarcomas. Novel chromosomal aberrations were found in various other malignant and benign tumors. CONCLUSION: This study highlights the value of cytogenetic analysis for diagnosis of skull base tumors. The data add further information on the biological behavior of these rare neoplasms.

Cytogenetic analysis of sinonasal carcinomas.

BACKGROUND: Sinonasal carcinomas, including nonkeratinizing (NK) squamous cell carcinoma (SCC) and sinonasal undifferentiated carcinoma (SNUC), are uncommon malignant neoplasms arising from the Schneiderian respiratory epithelium of the nasal cavity and paranasal sinuses. Due to their low frequency, the cytogenetic data on these tumors is limited. METHODS: Seventeen patients who were operated on in our institution for extirpation of paranasal carcinomas were enrolled in this study. Fourteen pathologically confirmed samples of sinonasal carcinomas were cytogenetically analyzed using G-banding techniques after short-term culture. Three samples did not grow on culture. RESULTS: Five of the 14 sinonasal carcinomas had an abnormal karyotype (36%). Of the 9 NK SCCs, 3 had abnormal karyotypes with numerical and structural chromosomal anomalies. Of the 5 patients with SNUC, 2 had an abnormal karyotype. One case of SNUC had a diploid complex karyotype. Another case of SNUC had a near triploid composite karyotype with 60-69 chromosomes. The chromosome arms that involved frequent breakpoint and rearrangements were: 1p, 6p, 7p, and 12q. We found that 3 of the 3 patients who died of disease displayed an abnormal karyotype, whereas 2 of the 11 patients who are alive displayed an abnormal karyotype (P = 0.027). CONCLUSIONS: The study revealed that more than a third of the paranasal carcinomas carry an abnormal karyotype. No specific common aberrations were found in these tumors. To our knowledge this is the first attempt to investigate sinonasal squamous and undifferentiated carcinomas on a genetic level using G-banding technique. Additional studies are required in order to determine whether cytogenetic data may serve as an adjunct to conventional pathology for the diagnosis and prognosis assessment of these rare and highly aggressive tumors.

Two novel translocations, t(2;4)(q35;q31) and t(X;12)(q22;q24), as the only karyotypic abnormalities in a malignant peripheral nerve sheath tumor of the skull base.

Malignant peripheral nerve sheath tumor (MPNST) is a rare neoplasm that originates from Schwann cells and comprises 5%-10% of soft tissue sarcomas. Cytogenetic analysis of this tumor has shown a highly complex karyotype, and no single chromosomal aberration has been reported to date. We combined spectral karyotyping analysis and G-banding for cytogenetic characterization of this unique tumor, which originated in the anterior skull base. We report the simultaneous occurrence of a t(2;4)(q35;q31) and a t(X;12)(q22;q24) as the only chromosomal abnormalities in this tumor. To the best of our knowledge, apparently balanced translocations have not been identified previously in MPNST.