MON-764 Concomitant Primary Hyperparathyroidism and Metastatic Papillary Thyroid Carcinoma in a Patient

Solitary bone and brain metastasis in a patient with papillary thyroid carcinoma mimicking cavernous angioma

RAS mutations are common in thyroid tumors and confer a high risk of cancer when detected in fine-needle aspiration (FNA) specimens. Specific characteristics of RAS-positive thyroid cancers are not well described. From April 2007 to April 2009, 921 consecutive patients undergoing FNA were evaluated prospectively with a panel of molecular markers. Ultrasonographic, cytological, histological, and surgical outcomes were retrospectively assessed. Sixty-eight aspirates from 66 patients were positive for RAS mutations including 63 cytologically indeterminate (93%), 3 malignant (4%), and 2 benign (3%) specimens. Cancer was histologically confirmed in 52 of 63 aspirates (83%) including the following: 46 papillary thyroid cancers, 4 follicular thyroid cancers, 1 medullary cancer, and 1 anaplastic cancer. All 46 RAS-positive papillary thyroid cancers, including 1 metastatic cancer, had follicular variant histology papillary thyroid cancer; only 11 tumors demonstrated vascular/capsular invasion and 4 had infiltrative growth. Of 48 patients with differentiated thyroid cancer, lymph node metastasis was uncommon and bilateral cancer was present in 48%. Only 33% of malignant nodules were suspicious by preoperative ultrasonography. At a mean follow-up of 22 months, 31 of 35 differentiated thyroid cancer patients (89%) have no evidence of recurrence, 4 patients (9%) have detectable thyroglobulin, 1 patient has bone metastases, and both patients with medullary and anaplastic cancer have died. Most RAS-positive thyroid cancers have indeterminate cytology, lack suspicious ultrasound features, and are histologically low-grade follicular variant histology papillary thyroid cancer. Lymph node and distant metastases are uncommon but bilateral disease is frequent. Total thyroidectomy should be considered for initial surgical management of most patients with RAS-positive FNA results. The role of prophylactic lymphadenectomy remains unclear.

Outcomes and Trends of Treatments in High-Risk Differentiated Thyroid Cancer.

Background: Prevalence of tumor thrombus associated with thyroid cancer has been reported to be 0.2-3.8% . Tumor thrombus has been seen in follicular, Ḧurthle, papillary, insular and anaplastic thyroid cancers. Follicular and Ḧurthle cell carcinomas are the most common forms of thyroid cancer associated with tumor thrombus, as they pose angioinvasive features and can spread by direct extension. Determining the presence of tumor thrombi in all patients with thyroid masses has an important clinical significance as it helps in the planning of operative procedure and prevents misdiagnosis of venous thrombus. Total thyroidectomy with thrombectomy or segmental resection of the internal jugular vein is recommended for management. Case report: A 72 year old lady underwent removal of her left thyroid lobe in the 1990s with benign pathology. In 2005 she had biopsy of a right thyroid nodule which was negative for malignancy. She presented to our clinic in October of 2006 for follow up of the thyroid nodule. Thyroid ultrasound showed a 2.8 cm nodule in the midpole and 2 cm nodule in the lower pole of the right thyroid lobe and a lobulated, extremely hypervascular mass that arose from the upper pole and extended laterally and into the right internal jugular vein. Fine needle aspirate of the larger thyroid nodule and extra thyroidal mass were consistent with benign thyroid nodules. TSH was 2.16 mIU/L (n 0.3- 4.2 mIU/L) and thyroglobulin was 4306 ng/mL (athyrotic < 0.1, intact thyroid ≤ 33 ng/ml). The patient was lost to follow up until 2014. She underwent fine needle aspiration of two right thyroid nodules; one of the results was suspicious. In June of 2014, she underwent thyroidectomy elsewhere. Pathology showed a well-differentiated follicular carcinoma. After the surgery, she was treated with radioactive iodine after Thyrogen stimulation, and a whole body scan showed intense localization in the thyroid bed, but nowhere else. TSH = 0.24 mIU/L, thyroglobulin antibody was negative and thyroglobulin tumor marker was 589 ng/mL. An ultrasound of the neck showed a non-occlusive tumor thrombus measuring 6.2 x 1.0 x 1.3 cm within the right internal jugular vein. She underwent removal ofright internal jugular vein and tumor in March of 2015. Pathology showed right internal jugular vein with tumor consistent with metastatic thyroid follicular carcinoma. Post operatively, TSH = 0.2 mIU/L, thyroglobulin antibody was negative and thyroglobulin decreased from 589 ng/mL to 3.9 ng/mL. Conclusion: We present this 72 year old lady with follicular thyroid cancer and chronic well localized tumor thrombus in the right internal jugular vein that was present for at least 9 years. Thyroid tumor thrombus was accounting for substantial elevation of thyroglobulin that was persistent after she underwent total thyroidectomy. She underwent removal of right internal jugular vein and thyroid tumor with significant reduction in thyroglobulin level.

The aim of the present study was to evaluate total and membranous Na+/I- symporter (NIS) expressions in papillary thyroid carcinoma (PTC) tissue, correlation of NIS expression between primary and metastatic lymph node (LN) PTC tissues, and relationship of NIS expression with I131 whole body scan (WBS) uptake between primary and metastatic LN PTC tissues by analyzing 17 pairs of primary and metastatic LN PTC tissues. Staining positivity was calculated, and staining intensity was graded as negative (0), weak (1+), moderate (2+) and strong (3+). In primary PTC tissues, positivities and intensities of normal cells were higher than those of carcinoma cells but had no correlation with those in matched metastatic LN PTC tissues. In classic type, positivities, intensities and membranous intensities (mIS) were correlated between primary and matched metastatic LN PTC tissues. In patients aged younger than 45 yr, positivities and intensities in primary PTC tissues had correlation with those in matched metastatic LN PTC tissues. Positivities, intensities, mIS and pathological subtype of carcinoma cells in primary PTC tissues were not correlated with age, tumor size, TNM stage, MACIS score and thyroglobulin (Tg) levels at the time of I131 WBS. Sensitivity, specificity, as well as positive and negative predicted values of mIS in patients with I131 WBS uptake were 69.2, 75, 90 and 42.9% in primary PTC tissues, and 92.3, 100, 100 and 80% in metastatic LN PTC tissues. The results of mIS taken either as positive or negative were correlated with those of I131 WBS after controlling for age. Our results demonstrate that PTC tissues have altered total and membranous NIS expressions, suggesting that NIS expression in primary PTC tissues may predict NIS expression and I131 WBS uptake in matched metastatic LN PTC tissues.

Background: Schwannomas originate from peripheral nerve sheath Schwann cells and develop in various locations, commonly seen in the head and neck in up to 45% of cases. On ultrasound, they appear hypoechoic, lack a hilum, and can resemble a metastatic lymph node in patients with thyroid cancer. We describe a case of a schwannoma masquerading as metastatic papillary thyroid carcinoma. Clinical Case: A 59-year-old woman presented to our clinic with a history of Graves’ disease and papillary thyroid cancer (PTC) for which she underwent surgery over fifteen years ago at an outside institution. Pathology revealed two microfoci of PTC (0.5 and 0.4 cm) and 0 of 3 positive lymph nodes, with no other concerning features. She underwent radioactive iodine therapy (RAI) with 100 mCi postoperatively. There was no evidence of metastasis on her post-treatment scan. She had surveillance including neck ultrasounds with no evidence of recurrence. Five years later, neck ultrasound revealed a 5 mm nodule in the right neck posterior to the jugular vein. This nodule remained stable a year later and was not mentioned on subsequent ultrasounds. Two years ago upon presentation to our institution, she was found to have a suspicious hypoechoic solid mass on neck ultrasound. It was located in the lateral neck deep to the internal jugular vein and immediately adjacent and lateral to the common carotid and measured 8 x 7 x 7 mm enlarging to 13 x 9 x 10 mm in the next year. On one of the ultrasounds, the mass was noted to be inseparable from the surrounding nerve fibers and the possibility of nerve sheath tumor was suggested although a metastatic lymph node could not be excluded. This nodule enlarged to 13 x 9 x 10 mm in the next year. Due to the location, biopsy was deemed difficult and she underwent surgical resection of the mass. Intraoperatively, the lesion was noted to be very firm and intimately involved with the vagus nerve, which had to be sacrificed as it could not be dissected off. Pathology revealed a schwannoma, which was confirmed by immunohistochemical staining. Conclusion: This case highlights the importance of recognizing subtle but important ultrasonographic features of a schwannoma in the neck as it can resemble a metastatic lymph node, especially in a patient with history of thyroid cancer. Clinicians should consider this in the differential diagnosis when there are appropriate imaging findings that may be consistent with a schwannoma, including homogeneous hypoechogeneity and nerve continuity.

The pathologic nodal staging of prostatic adenocarcinoma is binary for regional lymph nodes. Stages pN0 and pN1 indicate the absence or presence of regional nodal metastasis, respectively, whereas patients with metastasis to nonregional lymph nodes are staged as pM1a. To determine the risk of recurrence of pN1 prostatic adenocarcinoma patients based on the extent of nodal tumor burden. We retrospectively reviewed pN1 patients with prostatic adenocarcinoma managed with radical prostatectomy seen between 2011 and 2019. Kaplan-Meier and Cox regression analyses were performed to compare disease-free survival. Ninety-six patients were included (median [interquartile range] age, 62 years [57-67 years]; 70 of 96 [73%] White). On univariate analysis, age >65 years (P = .008), ≥2 positive regional lymph nodes (P < .001), and a maximum size of the tumor deposit ≥2 mm (P = .004) were significantly associated with an unfavorable outcome. Controlling for age, stage, metastatic deposit size, margin status, and the presence of extranodal extension, patients with ≥2 positive regional lymph nodes were 3.03 times more likely (95% confidence interval, 1.39-6.60; P = .005) to have an unfavorable outcome. Patients with pN1M1a stage showed a disease-free survival similar to that of pN1M0 patients, after controlling for the number of positive regional lymph nodes (P = .36). Overall, pN1 patients with ≥2 positive regional lymph nodes are 3 times more likely to have an unfavorable outcome. The results suggest a benefit in further stratifying patients with metastatic prostatic adenocarcinoma to the lymph nodes into prognostically significant risk categories that could help the treating clinicians tailor subsequent patient follow-up and therapy.

Biomarkers in Thyroid Tumor Research: New Diagnostic Tools and Potential Targets of Molecular-Based Therapy

Thyroid cancer is the most common endocrine malignancy, and incidences are rising. MAP kinase (MAPK) signaling has been implicated in playing a critical role in the initiation and maintenance of thyroid cancer, as evidenced by the high incidence of non-overlapping mutations of the genes encoding RET and TRK, as well as of NRAS, HRAS, KRAS and BRAF. Follicular thyroid cancer (FTC) is commonly associated with mutations of the RAS family of oncoproteins, while papillary thyroid cancer (PTC) is often associated with mutations in BRAF. To determine whether mode of MAPK activation played a role in thyroid cancer development in mice, we generated HrasG12V and BrafV600E knock-in models. We report that a thyroid specific knock-in of HrasG12V and Pten inactivation leads to the development of FTCs and poorly differentiated thyroid cancer (PDTCs) by 47-52 weeks of age in HrasG12V/Ptenhom/TPO-cre mice. In stark contrast, mice with a thyroid specific knock-in of BrafV600E and loss of Pten (BrafV600E/Ptenhom/TPO-cre) rapidly develop PDTCs and anaplastic thyroid cancer with complete lethality by weaning, suggesting that Braf and Hras, in cooperation with PI3K signaling, likely play distinct roles in the development and progression of disease. We next sought to dissect the role of Hras versus Braf activation in FTC versus PTC development. We derived stable cell lines from HrasG12V/Ptenhom/TPO-cre and BrafV600E/Ptenhom/TPO-cre tumors in order to identify cellular and molecular consequences of Hras versus Braf activation and their potential impact on tumor phenotype. We have found significant differences in phosphorylation of kinases in response to Hras versus Braf activation. Hras activation leads to increased phosphorylation of mTOR effectors, while Braf activation increases CREB activation. Studies are ongoing to identify the molecular mechanism of these observed differences. We have also shown a significant decrease in the growth of HrasG12V/Ptenhom (p=0.0009) and BrafV600E/Ptenhom (p=0.0001) cells treated with the MEK1/2 inhibitor PD0325901, suggesting that activated Hras or Braf-even in the context of Pten loss-partially relies on MAPK signaling to reach its full oncogenic potential. We have recently employed a PCR array approach to identify differences in the expression of genes related to the MAPK pathway in HrasG12V/Ptenhom and BrafV600E/Ptenhom cell lines. We noted an up-regulation of Myc, Cdkn1a, and Sfn in BrafV600E/Ptenhom cells in comparison to HrasG12V/Ptenhom cells, which may contribute to the different pathophysiology of HrasG12V/Ptenhom and BrafV600E/Ptenhom tumor sub-types. Because FTCs and PTCs have different responses to therapy, we seek to identify the cellular and physiological consequences of Ras versus Raf activation which will hopefully aid in the discovery of novel therapeutic and prevention strategies for thyroid cancer. Citation Format: Lee Ann King, Jeffrey Knauf, Ronald Ghossein, James Fagin, Aime T. Franco. Hras versus Braf activation determines follicular versus papillary thyroid cancer development. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4291. doi:10.1158/1538-7445.AM2013-4291

The aim of this study was to determine the significance of HBME-1 immunostaining in the differentiation between intranodal benign thyroid tissue and metastatic papillary thyroid carcinoma in the lymph node. Immunohistochemically we examined normal-appearing intranodal thyroid tissue in four patients who did not show evidence of papillary carcinoma histologically or clinically. We also examined follicular-pattern-predominant papillary carcinoma with metastatic foci in the lymph nodes. Normal-appearing intranodal thyroid tissue and normal thyroid showed no immunopositivity for HBME-1. In contrast, all papillary carcinomas in both the lymph nodes and thyroid demonstrated strong positivity for HBME-1. HBME-1 was predominantly positive for the luminal surface of the tumor cells. The immunopositivity of the cuboidal and low columnar carcinoma cells was more intensive than that of the flat-shaped cells in the lymph nodes and thyroid. The results probably indicate that HBME-1 immunostaining is helpful in distinguishing between intranodal benign thyroid tissue and metastatic papillary carcinoma in lymph nodes. We emphasize that the HBME-1 reactivity should be evaluated in connection with the histological findings, and that positive and negative controls stained in parallel are necessary.

The TNM classification (tumor-node-metastasis) was adopted by the American Joint Committee on Cancer and the International Union against Cancer a decade ago to avoid heterogeneity of prognostic classification schemes used for differentiated thyroid cancers. To date, however, clinical data based on this classification are lacking. We retrospectively evaluate the prognosis of 700 patients (208 men and 492 women) with papillary (89%) and follicular (11%) thyroid cancers according to the pathological TNM (pTNM) staging system, treated over a 25-yr period (1970-1995). Patients who received primary treatment at our center constituted 87.4% of the cases; the majority underwent total thyroidectomy, followed by 131I ablative therapy in high risk groups, as standard treatment. Clinical and follow-up data were obtained from the medical records and our cancer registry. Disease-free and cancer-specific survival data were analyzed by Kaplan-Meier product limit estimates and Cox proportional hazard models. Patient distribution by the pTNM system were: stage I, 516 patients; stage II, 57 patients; stage III, 104 patients; and stage IV, 23 patients. Over a mean +/- SE follow-up of 11.3 +/- 0.3 yr, the overall cancer recurrence and mortality rates were 20.5% and 8.4%, respectively. However, the respective cancer recurrence and mortality rates were distinctly different in the various pTNM stages: 15.4% and 1.7% in stage I, 22% and 15.8% in stage II, 46.4% and 30% in stage III, and 66.7% and 60.9% in stage IV tumors. Using actuarial survival plots, a clear separation in both disease-free survival and cancer-specific survival was noted among all the stages (P < 0.0001). Risk factors analyses showed a significant association between all the prognostic variables used in TNM staging (age, tumor size, extent of primary tumor, and presence of nodal or distant metastases) and the observed end points of recurrence or death from thyroid cancer. After correcting for TNM stages, the risk of cancer recurrence was halved in female compared to male patients, whereas this was 1.7-fold higher in multifocal than unifocal tumors. Conversely, cancer mortality was 3.4-fold higher in follicular than papillary thyroid cancer. In the analysis of effect of primary treatment among 492 patients with tumor more advanced than the T1N0M0 category, patients who underwent less extensive surgery (lobectomy or subtotal thyroidectomy) had a 2.5-fold risk of cancer recurrence (P < 0.0001) and a 2.2-fold risk of death (P < 0.01) compared to those who underwent total or near-total thyroidectomy. Patients not treated with 131I ablation had a 2.1-fold greater risk of cancer recurrence (P < 0.0001) than those given 131I ablation, although no difference was noted in deaths from thyroid cancer. Based on our data, the pTNM classification is useful in distinguishing patients with different prognostic outcomes. However, the small patient numbers in pTNM stages other than stages I precludes us from evaluating its usefulness as a guide for therapy. Until prospective data could be accrued from controlled treatment trials, we support the standard practice of total thyroidectomy followed by 131I ablative therapy (if focal iodide uptake was noted) in patients with papillary thyroid cancer more advanced than the T1N0M0 category or of multicentric nature and in the majority of patients with follicular thyroid cancer.

This study of 542 patients with follicular thyroid cancer, 366 patients with the follicular variant and 1452 patients with the classical variant of papillary thyroid cancer, and 819 patients with sporadic medullary thyroid cancer operated at a tertiary referral center aimed to determine risk patterns of distant metastasis for each tumor entity, which are ill-defined. On multivariable logistic regression analyses, lymph node metastasis consistently emerged as an independent risk factor of distant metastasis, yielding odds ratios (ORs) of 2.4 and 2.8 for follicular thyroid cancer and the follicular variant of papillary thyroid cancer, and ORs of 5.9 and 6.4 for the classical variant of papillary thyroid cancer and sporadic medullary thyroid cancer. Another independent risk factor consistently associated with distant metastasis, most strongly in follicular thyroid cancer and the follicular variant of papillary thyroid cancer (OR 3.5 and 4.0), was patient age >60 years. Altogether, 2 distinct risk patterns of distant metastasis were identified, which were modulated by other cancer type-dependent risk factors: one with lymph node metastasis as leading component (classical variant of papillary thyroid cancer and sporadic medullary thyroid cancer), and another one with age as leading component (follicular thyroid cancer and the follicular variant of papillary thyroid cancer). Distant metastasis was exceptional in node-negative patients with sporadic medullary thyroid cancer (1.7%) and the classical variant of papillary thyroid cancer (1.4%), and infrequent in node-negative patients with the follicular variant of papillary thyroid cancer (4.4%). These findings delineate windows of opportunity for early surgical intervention before distant metastasis has occurred.

Papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC) contribute to more than 95% of thyroid malignancies. However, synchronous PTC and FTC are less common; it is most commonly discovered incidentally as synchronous malignancies during operation, which adds difficulties to intraoperative decision-making and postoperative treatment. Therefore, we analyzed the clinicopathological characteristics and prognosis of patients with PTC and FTC in our center. We conducted a search of single PTC, single FTC, and synchronous PTC/FTC patients who received initial surgery treatment at Fudan University Shanghai Cancer Center from 2006 to 2018 and collected paraffin-embedded samples of synchronous patients. Clinicopathological characteristics were collected from the electronic medical record system. Follow-up was performed through telephone contact or medical records. Exome sequencing was performed by ThyroLead panel. Total of 42 synchronous PTC/FTC patients, 244 single FTC patients, and 2,959 single PTC patients were included. It showed a similarity between the clinicopathological features of synchronous thyroid cancer patients and single PTC patients, with a greater proportion of females, higher probabilities of lymph node metastasis, and higher rate of concurrence of Hashimoto's disease. The disease-free survival (DFS) curve indicated a worse prognosis of the synchronous group and single PTC group compared to the single FTC group, who had a propensity for neck lymph node recurrence; however, logistic multivariate regression analysis did not find any factor related to recurrence in the synchronous group. After re-checking pathology, DNA extraction, and quality control, genetic alteration information of 62 samples including primary tumors and metastatic lymph nodes from 35 synchronous cancer patients was displayed. In total, 81 mutations and 1 fusion gene were identified, including mutations related to outcomes and targeted therapy. Besides, some rare mutations in thyroid cancer were found in these patients. To conclude, synchronous PTC/FTC tend to be incidentally discovered during or after operation, behaving more like single PTC. The prognosis of synchronous patients is worse than that of single FTC patients and supplemental cervical lymph node dissection, total thyroidectomy, and postoperative radioiodine therapy should be taken into consideration after diagnosis. The next-generation sequencing (NGS) showed a unique molecular feature of synchronous patients with some rare mutations.

Anaplastic thyroid carcinoma (ATC) is a rare and lethal form of thyroid cancer. Overall prognosis is unclear when it arises focally in a background of papillary thyroid cancer (PTC). Clinicopathologic features and outcomes of tumors with coexisting PTC and ATC histologies (co-PTC/ATC) were categorized. The National Cancer Database was queried for histologic codes denoting PTC, ATC, and co-PTC/ATC, defined as Grade 4 PTC, diagnosed from 2004 to 2017. Clinicopathologic features, OS, and treatment outcomes were analyzed by histologic type. A total of 386,862 PTC, 763 co-PTC/ATC, and 3,880 ATC patients were identified. Patients with co-PTC/ATC had clinicopathologic features in-between those of PTC and ATC, including rates of tumor size >4 cm, extrathyroidal extension, and distant metastases. On multivariable Cox proportional hazards modeling, age >55 years, Charlson-Deyo score ≥2, positive lymph nodes, lymphovascular invasion, distant metastases, and positive surgical margins were associated with worse OS, whereas radioactive iodine (RAI) and external beam radiation therapy (EBRT) were associated with improved OS, irrespective of margin status. OS was worse for co-PTC/ATC than for PTC but better than for ATC and differed based on the presence or absence of "aggressive" tumor features, including lymph node positivity, lymphovascular invasion, distant metastases, and positive surgical margins. Survival of patients with co-PTC/ATC is dependent on the presence of aggressive clinicopathologic features and lies within a spectrum between that of PTC and ATC. Adjuvant RAI and EBRT treatment may be beneficial, even after R0 resection.

To study the roles of matrix metalloproteinases-9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1), vascular endothelial growth factor (VEGF) and transforming growth factor β-1 (TGFβ-1) in differentiation, invasiveness and metastatic potential of papillary carcinoma and follicular carcinoma of thyroid. Eighty-five cases of papillary thyroid carcinoma and 59 cases of follicular thyroid carcinoma were enrolled into the study. Immunohistochemistry using EnVision method was carried out for assessment of the expression of MMP-9, TIMP-1, VEGF and TGFβ-1 in the tumor tissue. MMP-9, TIMP-1, VEGF and TGFβ-1 were expressed in the cytoplasm of tumor cells. The positivity rates of MMP-9, TIMP-1, VEGF and TGFβ-1 in papillary thyroid carcinoma (83.5%, 81.2%, 90.6% and 75.3%, respectively) were similar to or lower than those in follicular thyroid carcinoma (93.2%, 86.4%, 89.9% and 78.0%, respectively). The expression rates in papillary thyroid carcinoma with lymph node metastasis were also higher than those in tumors without lymph node metastasis. The expression rates of MMP-9, VEGF and TGFβ-1 in poorly-differentiated follicular thyroid carcinoma were higher than those in well-differentiated follicular thyroid carcinoma. The expression of TIMP-1 however showed a negative correlation with the tumor cell differentiation. In general, the expression of VEGF and MMP-9 was higher than that of TIMP-1 and TGFβ-1 in papillary thyroid carcinoma and follicular thyroid carcinoma. Immunohistochemical detection of MMP-9, TIMP-1, VEGF and TGFβ-1 expression may carry clinical significance in evaluating the degree of differentiation, invasiveness, metastatic potential and prognosis of papillary thyroid carcinoma and follicular thyroid carcinoma.