CXCR4-CXCL12 axis and distant metastatic outgrowth in head and neck malignancy

Abstract Background: To analyze whether distant metastatic outgrowth in different head and neck malignancies (HNM) underlies the CXCR4-CXCL12 axis as overriding molecular mechanism. Methods: Clinic-pathological data of 1,250 HNM was included. HNM were collected due to different capability to exhibit distant metastasis comprising basal cell, squamous cell, and adenoid-cystic carcinoma as well as melanoma. MMP2/9, TIMP1/2, CXCR4, and CXCL12 immunohistochemistry was done in 190 randomly selected specimens.Results: Immunohistochemistry visualized a significant increase in MMP2/9, TIMP1/2, CXCR4, and CXCL12 protein expression following the clinical occurrence of distant metastasis. CXCR4, CXCL12, and TIMP2-expression significantly increases with number of affected organs by distant metastasis. Cox regression demonstrated CXCR4-overexpression and advanced T-status being independent risk factors of distant metastasis associated death.Conclusion: The CXCR4-CXCL12 axis is associated with the occurrence of distant metastases in different HNM. The increased risk of distant metastasis associated death was identified at primary tumour site and, therefore, potentially influences further treatment protocols.

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Factors Predictive of Distant Metastases in Patients With Breast Cancer Who Have a Pathologic Complete Response After Neoadjuvant Chemotherapy

Journal of Clinical Oncology ◽

10.1200/jco.2005.11.124 ◽

2005 ◽

Vol 23 (28) ◽

pp. 7098-7104 ◽

Cited By ~ 78

Author(s):

Ana M. Gonzalez-Angulo ◽

Sean E. McGuire ◽

Thomas A. Buchholz ◽

Susan L. Tucker ◽

Henry M. Kuerer ◽

...

Keyword(s):

Breast Cancer ◽

Regression Analysis ◽

Neoadjuvant Chemotherapy ◽

Distant Metastasis ◽

Cox Regression ◽

Clinical Stage ◽

Pathologic Complete Response ◽

Distant Metastases ◽

Complete Response ◽

Cox Regression Analysis

Purpose To identify clinicopathological factors predictive of distant metastasis in patients who had a pathologic complete response (pCR) after neoadjuvant chemotherapy (NC). Methods Retrospective review of 226 patients at our institution identified as having a pCR was performed. Clinical stage at diagnosis was I (2%), II (36%), IIIA (27%), IIIB (23%), and IIIC (12%). Eleven percent of all patients were inflammatory breast cancers (IBC). Ninety-five percent received anthracycline-based chemotherapy; 42% also received taxane-based therapy. The relationship of distant metastasis with clinicopathologic factors was evaluated, and Cox regression analysis was performed to identify independent predictors of development of distant metastasis. Results Median follow-up was 63 months. There were 31 distant metastases. Ten-year distant metastasis-free rate was 82%. Multivariate Cox regression analysis using combined stage revealed that clinical stages IIIB, IIIC, and IBC (hazard ratio [HR], 4.24; 95% CI, 1.96 to 9.18; P < .0001), identification of ≤ 10 lymph nodes (HR, 2.94; 95% CI, 1.40 to 6.15; P = .004), and premenopausal status (HR, 3.08; 95% CI, 1.25 to 7.59; P = .015) predicted for distant metastasis. Freedom from distant metastasis at 10 years was 97% for no factors, 88% for one factor, 77% for two factors, and 31% for three factors (P < .0001). Conclusion A small percentage of breast cancer patients with pCR experience recurrence. We identified factors that independently predicted for distant metastasis development. Our data suggest that premenopausal patients with advanced local disease and suboptimal axillary node evaluation may be candidates for clinical trials to determine whether more aggressive or investigational adjuvant therapy will be of benefit.

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Clinical, pathophysiologic, and genomic analysis of the outcomes of primary head and neck malignancy after pulmonary metastasectomy

Scientific Reports ◽

10.1038/s41598-019-49212-y ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Hsueh-Ju Lu ◽

Chih-Cheng Hsieh ◽

Chi-Chun Yeh ◽

Yi-Chen Yeh ◽

Chun-Chi Wu ◽

...

Keyword(s):

Head And Neck ◽

Signaling Pathways ◽

Clinical Outcomes ◽

Distant Metastasis ◽

Cancer Metastasis ◽

Pulmonary Metastasectomy ◽

Head And Neck Malignancy ◽

Head And Neck Malignancies ◽

Histological Types ◽

Neck Malignancy

Abstract The median overall survival (OS) of some head and neck malignancies, such as head and neck squamous cell carcinoma (HNSCC), with metastatic lesions was only 12 months. Whether aggressive pulmonary metastasectomy (PM) improves survival is controversial. Patients with primary head and neck malignancy undergoing PM were enrolled. Clinical outcomes were compared among different histological types. Whole-exome sequencing was used for matched pulmonary metastatic samples. The genes where genetic variants have been identified were sent for analysis by DAVID, IPA, and STRING. Forty-nine patients with primary head and neck malignancies were enrolled. Two-year postmetastasectomy survival (PMS) rates of adenoid cystic carcinoma, thyroid carcinoma, nasopharyngeal carcinoma, and HNSCC were 100%, 88.2%, 71.4%, and 59.2%, respectively (P = 0.024). In HNSCC, the time to distant metastasis was an independent predictive factor of the efficacy of PM. Several pathways, such as branched-chain amino acid (BCAA) consumption, were significantly associated with the progression of HNSCC [P < 0.001, fold enrichment (FE) = 5.45]. Moreover, metabolism-associated signaling pathways also seemed to be involved in cancer metastasis. Histological types and time to distant metastasis were important factors influencing the clinical outcomes of PM. For HNSCC, metabolic-associated signaling pathways were significantly associated with tumor progression and distant metastasis. Future validations are warranted.

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Home and Inpatient Hospice Care of Terminal Head and Neck Cancer Patients

Journal of Palliative Care ◽

10.1177/082585979701300103 ◽

1997 ◽

Vol 13 (1) ◽

pp. 9-14 ◽

Cited By ~ 13

Author(s):

Yoav P. Talmi ◽

Michaela Bercovici ◽

Alexander Waller ◽

Zeev Horowitz ◽

Abraham Adunski

Keyword(s):

Head And Neck Cancer ◽

Head And Neck ◽

Neck Cancer ◽

Hospice Care ◽

Oral Candidiasis ◽

Distant Metastases ◽

Treatment Protocols ◽

Clinical Series ◽

Lower Pain ◽

Oral Cavity Tumor

The objective is to evaluate and compare data on a cohort of terminal head and neck cancer (HNC) patients from both home and hospital-based hospice programs and to define the particular problems and needs of those patients. The setting was a tertiary academic referral centre in Tel Hashomer, Israel. We carried out a retrospective survey of patient charts based on hospice databases and death certificates of the hospital tumor registry. Charts of 102 HNC patients admitted to the hospice between 1988 and 1994 and 24 charts of HNC patients cared for by the home hospice program between 1990 and 1994 were studied. Pain, airway problems, and dysphagia were the common problems reported. A comparison of the two programs showed home hospice patients to be younger and with lower pain levels, less weight loss, and less oral candidiasis. There were fewer oral cavity tumor patients in the home hospice group. The incidence of distant metastases was in the 50% range in both groups. Judging by chart entries relating to pain, airway care, and food intake, treatment protocols were effective in both programs in the alleviation of pain and other symptoms. Both programs appeared to provide adequate care for terminal HNC patients. The main differences in care between the two groups stemmed from the decisions of referring physicians and not from a predetermined level of care. The incidence of distant metastases was higher than that reported in earlier clinical series.

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Survival outcome differences based on treatments used and knowledge of the primary tumour site for patients with cancer of unknown and known primary in Ontario

Current Oncology ◽

10.3747/co.25.4003 ◽

2018 ◽

Vol 25 (5) ◽

Cited By ~ 1

Author(s):

C. S. Kim ◽

M. B. Hannouf ◽

S. Sarma ◽

G. B. Rodrigues ◽

P. K. Rogan ◽

...

Keyword(s):

Median Survival ◽

Cox Regression ◽

Metastatic Cancer ◽

Primary Tumour ◽

Primary Site ◽

Unknown Primary ◽

Survival Outcomes ◽

Tumour Site ◽

Ontario Health Insurance Plan ◽

Primary Tumour Site

IntroductionPatients with cancer of unknown primary (cup) have pathologically confirmed metastatic tumours with unidentifiable primary tumours. Currently, very little is known about the relationship between the treatment of patients with cup and their survival outcomes. Thus, we compared oncologic treatment and survival outcomes for patients in Ontario with cup against those for a cohort of patients with metastatic cancer of known primary site.Methods Using the Ontario Cancer Registry and the Same-Day Surgery and Discharge Abstract databases maintained by the Canadian Institute for Health Information, we identified all Ontario patients diagnosed with metastatic cancer between 1 January 2000 and 31 December 2005. Ontario Health Insurance Plan treatment records were linked to identify codes for surgery, chemotherapy, or therapeutic radiation related to oncology. Multivariable Cox regression models were constructed, adjusting for histology, age, sex, and comorbidities.Results In 45,347 patients (96.3%), the primary tumour site was identifiable, and in 1743 patients (3.7%), cup was diagnosed. Among the main tumour sites, cup ranked as the 6th largest. The mean Charlson score was significantly higher (p < 0.0001) in patients with cup (1.88) than in those with a known primary (1.42). Overall median survival was 1.9 months for patients with cup compared with 11.9 months for all patients with a known-primary cancer. Receipt of treatment was more likely for patients with a known primary site (n = 35,012, 77.2%) than for those with cup (n = 891, 51.1%). Among patients with a known primary site, median survival was significantly higher for treated than for untreated patients (19.0 months vs. 2.2 months, p < 0.0001). Among patients with cup, median survival was also higher for treated than for untreated patients (3.6 months vs. 1.1 months, p < 0.0001).Conclusions In Ontario, patients with cup experience significantly lower survival than do patients with metastatic cancer of a known primary site. Treatment is associated with significantly increased survival both for patients with cup and for those with metastatic cancer of a known primary site.

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High CXCR4 expression in adenoid cystic carcinoma of the head and neck is associated with increased risk of locoregional recurrence

Journal of Clinical Pathology ◽

10.1136/jclinpath-2019-206273 ◽

2020 ◽

Vol 73 (8) ◽

pp. 476-482 ◽

Cited By ~ 1

Author(s):

Thomas J W Klein Nulent ◽

Robert J J van Es ◽

Matthijs H Valstar ◽

Ludwig E Smeele ◽

Laura A Smit ◽

...

Keyword(s):

Adenoid Cystic Carcinoma ◽

Head And Neck ◽

Primary Tumour ◽

Treatment Options ◽

Cxcr4 Expression ◽

Proportional Hazard ◽

Free Survival ◽

Cox Proportional Hazard ◽

Adenoid Cystic ◽

Increased Risk

AimTreatment options for head and neck adenoid cystic carcinoma (AdCC) are limited in advanced disease. Chemokine receptor type 4 (CXCR4) is present in various tumour types, including AdCC. Upregulation is associated with tumour recurrence and metastasis. New CXCR4-specific diagnostic and therapeutic target agents have recently been available. This study aimed to analyse CXCR4 expression in a cohort of primary head and neck AdCC.MethodsAfter histopathological revision, tumour tissues of 73 consecutive patients with AdCC over 1990–2016 were sampled on a tissue microarray. Slides were immunohistochemically stained for CXCR4 and semiquantitatively scored. Associations between protein expression and cliniopathological parameters were tested. HRs were calculated using a Cox proportional hazard model.ResultsSixty-six tumours could be analysed. CXCR4 expression was present in 81% of the tumours with a median of 29% (IQR 1–70) positive cells. Expression was univariately correlated to perineural growth (Spearman ρ .26, p=0.04) and bone invasion (Spearman ρ .32, p=0.01), but not with tumour grade.CXCR4 expression in the primary tumour was significantly higher in tumours that recurred as compared with those that did not recur (median 60%, IQR 33–72 vs 12%, IQR 1–70, Kruskal-Wallis p=0.01). After dichotomisation, >25% of CXCR4 expressions proved an independent prognosticator for a reduced recurrence-free survival (RFS) (HR 7.2, 95% CI 1.5 to 72.4, p=0.04).ConclusionCXCR4 is expressed in the majority of primary AdCCs and independently correlated to worse RFS, suggesting CXCR4 as a target for imaging and therapy purposes in patients with advanced AdCC.

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Patterns of failure and survival in patients with nasopharyngeal carcinoma treated with intensity modulated radiation therapy in Saudi Arabia.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.3_suppl.e295 ◽

2016 ◽

Vol 34 (3_suppl) ◽

pp. e295-e295

Author(s):

Ahmed M Maklad ◽

Yasser Bayoumi ◽

Mohamed Abdalaziz Senosy ◽

AbuSaleh A. Elawadi ◽

Hussain AlHussain ◽

...

Keyword(s):

Radiation Therapy ◽

Nasopharyngeal Carcinoma ◽

Distant Metastasis ◽

Cox Regression ◽

Intensity Modulated Radiation Therapy ◽

Disease Free Survival ◽

Distant Metastases ◽

Concurrent Chemotherapy ◽

Patterns Of Failure ◽

Intensity Modulated

e295 Background: We aimed to investigate the patterns of failure (locoregional and distant metastasis), associated factors, treatment outcomes in nasopharyngeal carcinoma (NPC) patients treated with intensity modulated radiation therapy (IMRT) combined with chemotherapy, results of reirradiation in recurrent cases and its toxicity. Methods: From April 2006 to December 2011, 68 NPC patients were treated with IMRT and chemotherapy at our hospital. Median radiation doses delivered to gross tumor volume (GTV) and positive neck nodes were 66–70 Gy/33-35fractions. For recurrent cases reirradiation was given by SRS 25 -30 Gy/5 fractions or IMRT 50-60 Gy/25-30 fractions according to volume of recurrence and surrounding critical structures. The clinical toxicities, patterns of failures, locoregional control (LRC), distant metastasis control (DMC), disease free survival (DFS) and overall survival (OS) were observed. Results: The median follow up time was 52.2 months (range: 11-87). EBV infection positive was 63.2%.There were 7 locoregional recurrences, 3 regional recurrences with distant metastases and 11 distant metastases. The median interval from the date of diagnosis to failure was 26.5 months (range, 16-50 months). 6/10 (60%) locoregional recurrences were treated with re-irradiation +/- concurrent chemotherapy. Acute grade 3 and 4 mucositis were observed in 2 patients (28.6%); however no significant late toxicities were seen after reirradiation. Nodal recurrences were salvaged by neck dissection. The 5-year LRC, DMC, DFS and OS rates of whole cohort were 81.1%, 74.3%, 60.1% and 73.4% respectively. Cox regression analyses revealed that neoadjuvant chemotherapy, age and Epstein-Barr virus (EBV) were independent predictors for DFS. Conclusions: Distant metastasis is the most common pattern of failure after IMRT with SIB technique with or without neoadjuvant and concurrent chemotherapy in Saudi patients with NPC. Early detection of local and locoregional recurrences is important as reirradiation with IMRT or SRT with or without chemotherapy is still feasible option with acceptable toxicity. However, efforts should be made for proper patient selection.

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HER3-EGFR score to predict clinical outcomes in triple-negative breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.11612 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 11612-11612

Author(s):

Angela Ogden ◽

Shristi Bhattarai ◽

Andrew R. Green ◽

Mohammed A. Aleskandarany ◽

Emad A. Rakha ◽

...

Keyword(s):

Breast Cancer ◽

Distant Metastasis ◽

Prognostic Value ◽

Proportional Hazards ◽

Distant Metastases ◽

Cox Proportional Hazards ◽

Erbb Family ◽

Increased Risk ◽

Canonical Pathways ◽

The Individual

11612 Background: Limited preclinical evidence suggests that the ErbB family member HER3 may have prognostic value in TNBC. However, HER3 is a pseudokinase that cannot homodimerize, so in order to signal it must bind to other ErbB family members such as HER2 or EGFR. EGFR is frequently overexpressed in TNBC; consequently, it may be necessary to consider HER3 levels in the context of EGFR levels in TNBC to derive clinically meaningful insights. Methods: Towards this end, we tested the prognostic value of a combined immunohistochemical HER3-EGFR score (the sum of the individual H-scores, with the median used as a cutpoint) in a multi-institutional study of n = 510 TNBC patients using Cox proportional hazards regression. We also compared the HER3-EGFR-high and low groups in terms of 105 immunohistochemical biomarkers using Mann-Whitney U tests as well as Ingenuity canonical pathways using gene expression data from RNA-seq. Results: Among chemotherapy-treated TNBC patients, high HER3-EGFR score conferred a 2.30-fold increased risk of dying from breast cancer and a 1.78-fold increased risk of distant metastasis (p = 0.006 and p = 0.041, respectively) after adjusting for age and stage. Individual HER3 and EGFR H-scores were not associated with outcomes in simple or multivariable models. We also found that tumors from chemotherapy-treated TNBC patients with high HER3-EGFR scores exhibited higher immunohistochemical expression of luminal cytokeratins, DNA damage response proteins, and P-cadherin compared with tumors from chemotherapy-treated TNBC patients with low scores (q < 0.25). The top canonical pathway whose components were overexpressed in HER3-EGFR-high TNBCs was Hepatic Fibrosis (p = 0.008), which is linked to distant metastasis, and the top upstream regulator was HNF4A (p = 0.012), a transcription factor for ERBB3 with isoforms that promote liver and gut tumorigenesis. Conclusions: Collectively, our study reveals that HER3-EGFR score may identify chemotherapy-treated TNBC patients at increased risk for distant metastases and death whose tumors may be characterized by fibrotic processes. Our immunohistochemical test thus identifies high-risk TNBCs who may benefit from agents that inhibit HER3-EGFR signaling.

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Survival Predictors of Head and Neck Burkitt’s Lymphoma: An Analysis of the SEER Database

Otolaryngology ◽

10.1177/01945998211041533 ◽

2021 ◽

pp. 019459982110415

Author(s):

Salma Ahsanuddin ◽

Joshua B. Cadwell ◽

Neel R. Sangal ◽

Jordon G. Grube ◽

Christina H. Fang ◽

...

Keyword(s):

Head And Neck ◽

Cox Regression ◽

Medical Center ◽

Academic Medical Center ◽

Population Level ◽

Burkitt’S Lymphoma ◽

Burkitt's Lymphoma ◽

Seer Database ◽

Increased Risk ◽

Ann Arbor

Objective To analyze population-level data for Burkitt’s lymphoma of the head and neck. Study Design Retrospective study of a national cancer database. Setting Academic medical center. Methods The SEER database (Surveillance, Epidemiology, and End Results) identified all patients with primary Burkitt’s lymphoma of the head and neck from 1975 to 2015. Demographic, clinicopathologic, and treatment characteristics were analyzed. Multivariable Cox regressions analyzed factors associated with survival while controlling for baseline differences. Results A total of 920 patients with a mean (SD) age of 37.6 years (25.0) were identified. A majority of patients were White (82.8%) and male (72.3%). The most primary common sites included the lymph nodes (61.3%), pharynx (17.7%), and nasal cavity/paranasal sinuses (5.2%). The majority of patients received chemotherapy (90.5%), while fewer underwent surgery (42.1%) or radiotherapy (12.8%). Choice of treatment differed significantly among patients of different ages, year of diagnosis, primary site, nodal status, and Ann Arbor stage. Overall 10-year survival was 67.8%. On multivariable Cox regression, patients with older age (hazard ratio [HR], 1.05 per year; P < .001) and higher stage at presentation had increased risk of mortality ( P < .001). Furthermore, cases diagnosed between 2006 and 2015 (HR, 0.35; P < .001) and 1996 and 2005 (HR, 0.53; P = .001) had lower mortality when compared with those diagnosed between 1975 and 1995. Treatment including surgery and chemotherapy tended to have the best survival ( P < .001). Conclusion Burkitt’s lymphoma of the head and neck diagnosed in more recent years has had improved survival. Factors significantly associated with survival include age, Ann Arbor stage, and treatment regimen. Treatment including surgery and chemotherapy was associated with the highest survival.

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Distant metastases in terminal head and neck cancer patients

The Journal of Laryngology & Otology ◽

10.1017/s0022215100137624 ◽

1997 ◽

Vol 111 (5) ◽

pp. 454-458 ◽

Cited By ~ 12

Author(s):

Yoav P. Talmi ◽

Daniel Cotlear ◽

Alexander Waller ◽

Zeev Horowitz ◽

Abraham Adunski ◽

...

Keyword(s):

Head And Neck Cancer ◽

Head And Neck ◽

Cancer Patients ◽

Neck Cancer ◽

Squamous Cell ◽

Squamous Cell Cancer ◽

Primary Tumour ◽

Cell Cancer ◽

Distant Metastases ◽

Clinical Series

AbstractWith improved control of cancer above the clavicles, distant metastases (DM) are frequently more seen and are becoming a more common cause of morbidity and mortality. The present study defined the incidence of distant metastases in a cohort of terminal head and neck cancer patients (HNCP) and compared it to current reported data. The incidence of distant metastases in relation to the primary tumour was evaluated and their impact on survival was assessed. A retrospective survey of patient charts was made, based on the hospice database and original referring hospital charts. Data of 59 patients admitted to the hospice were evaluated. The incidence and location of locoregional and distant disease were studied and effects on survival analyzed.The overall survival from diagnosis to demise was 42.7 months. Thyroid cancer was seen in 20.3 per cent of cases and squamous cell cancer was seen in 59.3 per cent. Distant metastases were found in 83 per cent and 48.6 per cent of patients respectively. Laryngeal cancer patients had a 54.5 per cent incidence of distant metastases. Locoregional disease was seen in 47 per cent of cases and 35.7 per cent of them had distant metastases while a 64.3 per cent incidence of distant metastases was found in cases without locoregional disease. Mean survival was 47.3 months with distant metastases vs 36.5 months without metastases. The difference was not statistically significant.The incidence of distant metastases in squamous cell cancer in terminalHNCP was 48.6 per cent. This is the highest reported incidence of metastases in a clinical series. Patients without locoregional disease had almost a two-fold incidence of metastases. Survival was not affected by metastases in this series.

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The RET polymorphic allele S836S is associated with early metastatic disease in patients with hereditary or sporadic medullary thyroid carcinoma

Endocrine Related Cancer ◽

10.1677/erc-09-0312 ◽

2010 ◽

Vol 17 (4) ◽

pp. 953-963 ◽

Cited By ~ 25

Author(s):

Débora R Siqueira ◽

Mírian Romitti ◽

Andreia P da Rocha ◽

Lucieli Ceolin ◽

Camila Meotti ◽

...

Keyword(s):

Lymph Node ◽

Thyroid Carcinoma ◽

Medullary Thyroid Carcinoma ◽

Metastatic Disease ◽

Cox Regression ◽

Distant Metastases ◽

Medullary Thyroid ◽

Kaplan Meier ◽

Increased Risk

The possible role of RET variants in modifying the natural course of medullary thyroid carcinoma (MTC) is still a matter of debate. Here, we investigate whether the RET variants L769L, S836S, and G691S/S904S influence disease presentation in hereditary or sporadic MTC patients. One hundred and two patients with hereditary MTC and 81 patients with sporadic MTC attending our institution were evaluated. The frequencies of RET polymorphisms in hereditary MTC were as follows: L769L, 17.3%; S836S, 7.95%; and S904S/G691S, 18.2%. No associations were observed between these polymorphisms and pheochromocytoma, hyperparathyroidism, lymph node, or distant metastasis. However, patients harboring the S836S variant were younger than those without this allele (17±8.2 vs 28.6±14.4 years, P=0.01), suggesting that these patients had metastases at a young age. Accordingly, the cumulative frequency of local and/or distant metastases as estimated by Kaplan–Meier curves showed that lymph node and distant metastases occurred earlier in patients harboring the S836S variant (P=0.003 and P=0.026 respectively). The S836S allele frequency was higher in sporadic MTC patients than in controls (10.5 vs 3.1%, P=0.01). Individuals harboring the S836S variant were younger (38.6±13.3 vs 48.5±16.7 years, P=0.02) and showed a higher percentage of lymph node and distant metastases (P=0.02 and P=0.04 respectively). Kaplan–Meier estimates of lymph node and distant metastases yielded distinct curves for patients with or without the S836S allele (P=0.002 and P=0.001 respectively). Additional analyses using a COX regression model showed that the S836S variant was independently associated with metastatic disease (hazard ratio 2.82 (95% confidence interval 1.51–5.26), P=0.001). In conclusion, the RET S836S variant is associated with early onset and increased risk for metastatic disease in patients with hereditary or sporadic MTC.

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