Predictive Factors of Lymph Node Metastasis in Follicular Variant of Papillary Thyroid Carcinoma.

BACKGROUND: Compared with conventional papillary thyroid carcinoma (PTC), follicular variant of PTC (FV-PTC) shows less aggressive behavior and better prognosis. Nonetheless, regional lymph node (LN) metastasis was found in 22.8% of FV-PTC patients. Because LN metastasis is a proven predictor of recurrence in PTC, it is important to assess LN metastasis in FV-PTC patients. METHODS: We retrospectively reviewed 134 FV-PTC patients who underwent thyroidectomy with neck dissection. RESULTS: Central LN metastasis (CLNM) and lateral LN metastasis (LLNM) were found in 50 (37.3%) and 16 (11.9%) patients, respectively. In the multivariate analysis for CLNM, male sex (adjusted OR 4.735, p = 0.001), nonencapsulated form (adjusted OR 2.863, p = 0.022), and tumor size >1.0 cm (adjusted OR 3.157, p = 0.008) were independent predictors of high prevalence of CLNM in FV-PTC patients. In the multivariate analysis for LLNM, microscopic extrathyroidal extension (ETE) (adjusted OR 3.939, p = 0.041) and CLNM (adjusted OR 13.340, p = 0.001) were independent predictors of high prevalence of LLNM in FV-PTC patients. CONCLUSIONS: Meticulous perioperative evaluation and prophylactic central neck dissection may be beneficial for FV-PTC patients with male sex, nonencapsulated form, and tumor size >1.0 cm. Moreover, cautious perioperative evaluation of lateral neck LN may be mandatory for FV-PTC patients with microscopic ETE and CLNM.

Multifocal choroidal metastases from thyroid carcinoma: a case report.

We present the case of a 62-year-old female patient, with follicular variant of papillary thyroid carcinoma, which presented to our department for a severe decrease in vision at right eye level. Despite a complex therapy, that included a near-total thyroidectomy, thyroid I-131 ablation, suppressive therapy with LT4, and external beam radiotherapy with cobalt- 60, the patient developed multiple lung, mediastinal, liver, and bone metastases, followed after 1 year, by multifocal choroidal metastases. The complex ocular investigations performed for the diagnosis and follow-up of the choroidal metastases are presented. A review of the literature was also performed. The rarity of choroidal metastases in patients with thyroid carcinoma imposes, for their detection, periodic ocular examinations.

Peroperative detection with a gamma probe of pelvic metastasis after differentiated thyroid carcinoma in female patients: about two cases and management reflections.

BACKGROUND: Distant metastases of differentiated thyroid cancers are exceptionally localized in the soft tissues and the pelvic cavity. This last event complicates diagnosis, especially in female patients because of false positive nuclear imaging and unrelated iodine uptakes. False positive due to body secretions, urinary and fecal iodine retention and iodine uptake by non-thyroid tissues or ectopic thyroid tissue and bone metastasis of differentiated thyroid carcinoma. METHODS: We present two cases of metastasectomy, guided by a peroperative gamma probe and intraoperative frozen sections of the specimens. In females patients because of potentially false positive nuclear imaging and iodine uptakes unrelated to pathology, it is very difficult to identify a pelvic metastasis. Our experience of two cases underlines these pitfalls and the possibilities to avoid them: the use of 131 Iodine SPECT/CT whole body scan, peroperative gamma probe and intraoperative frozen sections of specimen. CONCLUSION: Preoperative localization needs a precise 3D imaging and the surgical treatment must be guided by a peroperative gamma probe and frozen sections.

Radioiodine therapy of metastatic lesions of differentiated thyroid cancer.

Seventy years after the first successful radioiodine treatment of metastatic differentiated thyroid cancer (DTC), radioiodine (131I) therapy for this type of tumor is still without alternative. During the last decade, some key issues such as individual dosimetry, and preparation of 131I therapy by recombinant human TSH have been addressed, but this has not yet lead to conclusive results; furthermore a number of questions related to indication, preparation, and treatment protocol of 131I therapy still remain unanswered. In this review, we will address the literature pertaining to the latest developments in the field of 131I therapy of advanced DTC and we will give an overview of the state of the art regarding patient preparation, dosimetry, and therapy.

Breast metastasis of papillary thyroid carcinoma.

Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer, and regional neck metastasis is more common than distant metastasis. If present, metastasis most frequently occurs in lungs and bones. Follicular variant of papillary thyroid carcinoma (FVPTC) is a mixture of the classic and follicular thyroid carcinoma and metastasizes in the same fashion as the PTC with cervical lymph nodes as the most common site. A case of atypical presentation of FVPTC with rib metastasis is reported. We present a case of an old man with a left-sided palpable breast mass for 2 months in duration without breast pain. Initially, the breast mass was categorised as Breast Imaging Reporting and Data System (BI-RADS) 4a via ultrasonography. Subsequent immunohistochemistry demonstrated that the mass was metastatic thyroid cancer. Consequently, a CT scan revealed a tumour originating from the rib. The patient was finally diagnosed with metastatic FVPTC.

Metastatic insular thyroid carcinoma in the pediatric patient.

OBJECTIVES: The clinical history of a pediatric patient with metastatic insular thyroid carcinoma will be reviewed. Previously reported cases will be examined to allow for comparison of prognosis. METHODS: A 4-year-old female with the complaint of chronic cough, progressive shortness of breath, and weight loss for 2 months underwent cervical lymph node biopsy. The biopsy revealed metastatic thyroid carcinoma. Preoperative imaging was suspicious for miliary metastatic spread to the lungs. RESULTS: Surgical intervention included total thyroidectomy with bilateral paratracheal and modified radical neck dissections. The right internal jugular vein and recurrent laryngeal nerve were removed at the time of surgery because of gross tumor invasion. Final pathologic finding revealed papillary thyroid carcinoma with insular variant features and bilateral regional metastasis. Postoperatively, the patient underwent radioactive iodine I 131 treatment. CONCLUSION: Pediatric metastatic insular thyroid carcinoma is an uncommon form of thyroid malignancy requiring aggressive surgical treatment and adjuvant radioactive iodine.

Medical therapy for differentiated thyroid carcinoma.

While some of the studies with new therapeutic modalities are encouraging, all are in their early experimental phases. It is likely that better understanding of the molecular basis for differentiated thyroid carcinoma will lead to new therapy in the next decade.

Symptomatic hyponatremia in association with a low-iodine diet and levothyroxine withdrawal prior to I131 in patients with metastatic thyroid carcinoma.

BACKGROUND: Strategies to improve I131 uptake in thyroid carcinoma include levothyroxine (LT4) withdrawal or thyrotropin (TSH) administration along with a low-iodine diet. We report five patients with papillary or follicular thyroid carcinoma who developed symptomatic hyponatremia during LT4 withdrawal and low-iodine diet. RESULTS: Four patients had pulmonary and/or brain metastases. All had restricted iodine intakes during LT4 withdrawal. Presenting complaints included weakness, dizziness, fainting spells, lethargy, and/or nausea. Baseline serum sodium levels while on LT4 suppression were normal. During presentation all were hypothyroid and serum sodium ranged from 110 to 121 mmol/L (normal 135-148). Despite hyponatremia, the plasma renin activity and serum aldosterone levels were suppressed, indicating volume expansion. The hyponatremia responded to fluid restriction and normalized after LT4 replacement. Low sodium intake, inappropriate antidiuretic hormone secretion syndrome (SIADH)-like disorder secondary to hypothyroidism and/or lung or cerebral metastases may have contributed to hyponatremia. CONCLUSIONS: The development of hyponatremia during LT4 withdrawal and low-iodine diet in otherwise healthy patients with thyroid carcinoma is extremely rare. However, elderly patients with metastatic thyroid carcinoma need observation during LT4 withdrawal combined with a low-iodine diet and should receive instruction to take iodine-free sodium chloride. Free water restriction may be necessary in some patients.

Regional metastases in well-differentiated thyroid carcinoma: pattern of spread.

OBJECTIVES/HYPOTHESIS: To determine the pattern of spread of WDTC to regional lymph nodes, in patients who presented with clinically positive nodes. STUDY DESIGN: Retrospective chart review. MATERIALS AND METHODS: Between October 2001 and December 2006, a total of 27 consecutive patients (12 males, 15 females) with clinical evidence of cervical metastasis of well-differentiated thyroid carcinoma (WDTC) underwent 28 neck dissections (ND) with a mean follow-up 33.7 months. Papillary carcinoma was found in 24 patients and follicular carcinoma in 3. All neck dissection specimens were separated during surgery into levels, and analysis was done with respect to the levels of the neck. Clinical and demographic parameters were correlated to the pathologic parameters, including number of pathologic nodes, size of tumor, and the patient's age, with univariate and multivariate analysis. RESULTS: The mean number of pathologic nodes in ND specimen was 6.7. The predominant site of metastasis was level VI (95%), followed by level III (68%), level IV (57%), and level II (54%). Metastases above the XI nerve were found in 7% of the patients. Level V showed 20% of nodal metastasis. A correlation was found between size of primary tumor and number of positive pathologic lymph nodes (P = .02) and an inverse correlation between the age of the patient and the number of pathologic nodes (P = .043). CONCLUSIONS: The high incidence of metastatic disease in levels II through VI supports the recommendation for posterolateral and anterior ND in patients with WDTC and clinically positive nodes. The correlation between tumor size, the age of the patient, and the number of positive nodes is an interesting finding that warrants further study.

Total thyroidectomy and adjuvant radioiodine treatment independently decrease locoregional recurrence risk in childhood and adolescent differentiated thyroid cancer.

UNLABELLED: We sought to assess whether extensive surgical treatment, postsurgical radioiodine therapy, or both decrease the risk of locoregional recurrence (LR) after curative primary treatment in children and adolescents diagnosed with differentiated thyroid cancer (DTC) at age

Results of a phase I clinical study using dendritic cell vaccinations for thyroid cancer.

OBJECTIVE: We assessed the feasibility and efficacy of dendritic cell (DC) therapy for advanced thyroid papillary and follicular cancer. DESIGN: Six Japanese patients (2 men and 4 women; aged 46-72 years, mean 60 years), who were diagnosed as advanced thyroid cancer with refractory distant metastases (papillary, n=5; follicular, n=1), were enrolled. Patients were first vaccinated weekly for 4 weeks with 10(7) autologous tumor lysate-pulsed monocyte-derived mature DCs followed by fortnightly vaccinations for 8 weeks (total=8 vaccinations). Lowdose (350 KIU) interleukin-2 was also administered for 3 days at each vaccination. Clinical response, adverse effects, delayed-type hypersensitivity skin testing (DTH), and IFN-( ) production by peripheral CD3(+) lymphocytes were evaluated. MAIN OUTCOME: Of the 6 patients, disease was assessed as stable in 2 and as progressive in 4. No adverse events were observed. Results of DTH and IFN-( ) production in peripheral lymphocytes did not correlate to the clinical response. CONCLUSIONS: DC immunotherapy could be administered to patients with thyroid papillary or follicular cancer without substantial side effects.

Follicular variant papillary thyroid carcinoma arising in struma ovarii.

Struma ovarii is a rare monodermal ovarian teratoma in which thyroid tissue is the predominant or exclusive element. Malignant transformation is known to occur, usually as classical papillary thyroid carcinoma (PTC). However, the recognition of follicular variant PTC raises the possibility of similar malignancy arising in struma ovarii. We examined 13 cases of struma ovarii to determine if these lesions can exhibit histological, immunohistochemical, and/or molecular features of follicular variant PTC. Ten of these had atypical histology, cytologic features of PTC, and all ten showed diffuse positivity for CK19; eight of these were also positive for HMBE-1. Mutational analysis for BRAF identified no V600E mutations. However, seven of the ten cases with features of follicular variant PTC exhibited a rearranged in transformation (RET)/PTC rearrangement by reverse transcriptase polymerase chain reaction (RT-PCR). The three cases considered to be benign based on histologic and cytologic criteria were negative for CK19 and HBME-1 by immunohistochemistry, and had no evidence of BRAF mutation or ret/PTC-1 and ret/PTC-3 rearrangements. These results indicate that follicular variant PTC can occur in struma ovarii and that such lesions exhibit the same morphologic and immunohistochemical profile as follicular variant PTC in thyroid. The application of molecular testing to verify the diagnosis can be valuable, as these lesions may harbor ret/PTC gene rearrangements.

Fine needle aspiration of follicular variant of papillary thyroid carcinoma presenting with pleural effusion: a case report.

BACKGROUND: Malignant pleural effusion in association with mesothelioma, bronchogenic carcinoma and breast carcinoma is common, although less frequently reported with other malignancies. We report a follicular variant of papillary thyroid carcinoma (FVPTC), diagnosed on fine needle aspiration cytology (FNAC) of thyroid and lymph nodes and subsequently proved to have metastasized to the pleural cavity. CASE: A 46-year-old man presented with history of breathlessness, thyroid swelling, pleural effusion and bilateral cervical lymphadenopathy. FNAC of the thyroid swelling and the lymph nodes showed features of FVPTC with cervical lymph node metastasis. Pleural fluid examination led to suspicion of pleural involvement by metastatic deposit, confirmed by subsequent pleural biopsy. CONCLUSION: Thyroid malignancies presenting with pleural effusion are rare. In this case, although pleural fluid cytology suggested involvement of pleura, a definitive diagnosis could be rendered only on pleural biopsy. An ancillary aid, such as immunocytochemistry, could have helped establish pleural involvement on routine pleural fluid cytology alone. This case emphasizes the possible existence of rare cases of FVPTC that may be associated with a dismal prognosis. In our case, initial diagnosis of FVPTC could be made only on correlating FNA features of thyroid aspirate with those of lymph node aspirate.

Extremely Well-Differentiated Papillary Thyroid Carcinoma Resembling Adenomatous Hyperplasia Can Metastasize to the Skull: A Case Report.

We describe herein histologic, immunohistochemical, and molecular findings and clinical manifestations of a rare case of an extremely well differentiated papillary thyroid carcinoma (EWD-PTC). Similarly, it is also difficult to diagnose follicular variant papillary thyroid carcinoma (FVPTC), whose diagnosis is still met with controversy. A recently reported entity of well-differentiated tumor of uncertain malignant potential (WDT-UMP) is added to the diagnostic spectrum harboring EWD-PTC and FVPTC. We report this case, because EWD-PTC is different from FVPTC in its papillary architecture, and also from WDT-UMP in its recurrence and metastatic pattern. These morphologically deceptive entities harbored diagnostic difficulties in the past because the diagnosis depended solely on histology. However, they are now diagnosed with more certainty by virtue of immunohistochemical and molecular studies. We experienced a case of EWD-PTC, which had been diagnosed as adenomatous hyperplasia 20 years ago and manifested recurrence with lymph node (LN) metastasis 7 years later. After another 7 years of follow-up, a new thyroid lesion had developed, diagnosed as FVPTC, with LN metastasis of EWD-PTC. One year later, the patient developed metastatic FVPTC in the skull. Immunohistochemically, the EWD-PTC was focally positive for CK19, negative for galectin-3, and focally negative for CD56. Molecular studies revealed BRAF-positivity and K-RAS negativity. The FVPTC in the left thyroid showed both BRAF and K-RAS negativity. In conclusion, EWD-PTC and FVPTC share similar histologic features, but they are different tumors with different molecular biologic and clinical manifestations. A large cohort of EWD-PTC should be included in further study.

Primary Thyroid Carcinoma with Low-Risk Histology and Distant Metastases: Clinicopathologic and Molecular Characteristics.

BACKGROUND: Distant metastases (DM) are a rare occurrence in well-differentiated thyroid carcinoma. The aim of this study was to analyze the clinical, pathologic, and molecular features of primary thyroid carcinoma with low-risk histology that develop DM. METHODS: A detailed clinicopathologic review and targeted next-generation sequencing were performed on a cohort of well-differentiated thyroid carcinoma lacking gross extrathyroidal extension, extensive vascular invasion, or significant lymph node metastases but exhibiting DM. RESULTS: Primary well-differentiated thyroid carcinoma with low-risk histologic features and DM was a rare occurrence, accounting for only 3% of metastatic non-anaplastic thyroid carcinoma. All 15 cases meeting the inclusion criteria harbored DM at presentation. The majority (11/15) of these tumors were follicular variant of papillary thyroid carcinoma (PTC), especially the encapsulated form (n = 8). The remaining patients harbored encapsulated Hürthle cell carcinoma (n = 2), encapsulated follicular carcinoma (n = 1), and an encapsulated papillary carcinoma classical variant (n = 1). Of the 12 encapsulated carcinomas, 10 had capsular invasion only and no vascular invasion. Ninety-two percent of the tumors exhibited extensive intra-tumoral fibrosis. Among the eight tumors that were subjected to next-generation sequencing analysis, a RAS mutation was the main driver (5/8), and TERT promoter mutation was highly prevalent (6/8). In four cases, TERT promoter mutations were associated with RAS or BRAF mutations. BRAF-mutated classical variant of papillary carcinoma also presented with DM but was less common (1/8). In 11/15 cases, the clinician was able to diagnose distant disease based on the clinical presentation. In 3/4 incidental cases that were genotyped, TERT promoter mutations were found. CONCLUSIONS: When DM occur in primary thyroid carcinoma with low-risk histology, they are almost always found at presentation. The majority are encapsulated follicular variant of PTC with capsular invasion only. TERT promoter mutations occur at a higher rate than that seen in PTC in general and may help explain the aggressive behavior of these histologically deceptive primary carcinomas.

Role of Ultrasound in Predicting Tumor Invasiveness in Follicular Variant of Papillary Thyroid Carcinoma.

BACKGROUND: Follicular variant of papillary thyroid carcinoma (FVPTC) is traditionally divided into infiltrative and encapsulated types. Adding to this classification, noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) represents a reclassification of a subset of cases (encapsulated tumors without lymphovascular or capsular invasion). The purpose of this study was to assess the role of ultrasound (US) in predicting tumor invasiveness in FVPTC. METHODS: From January 2014 to May 2016, preoperative US examinations were performed on 151 patients with 152 FVPTCs who underwent surgery. Based on a pathologic analysis, the FVPTCs were categorized into three groups: NIFTP, invasive encapsulated FVPTC (iE-FVPTC), or infiltrative FVPTC (I-FVPTC). Each nodule was categorized based on the US pattern according to the Korean Thyroid Imaging Reporting and Data System (K-TIRADS) and the American Thyroid Association (ATA) guidelines. The correlation between tumor invasiveness and the K-TIRADS or ATA category was investigated using Spearman's rank correlation coefficient. RESULTS: Among the 152 FVPTCs, there were 48 (31.6%) NIFTPs, 60 (39.5%) iE-FVPTCs, and 44 (28.9%) I-FVPTCs. US characteristics of the FVPTCs differed significantly according to tumor invasiveness (p ≤ 0.030). Tumor invasiveness showed a significant positive correlation with K-TIRADS (tumors of all sizes: r = 0.591, p < 0.001; tumors ≥1.0 cm: r = 0.427, p < 0.001) and ATA categories (tumors of all sizes: r = 0.532, p < 0.001; tumors ≥1.0 cm: r = 0.466, p < 0.001). According to both K-TIRADS and ATA guidelines for all-sized tumors, the most common subtype was NIFTP in low-suspicion nodules (52.6% and 51.6%), iE-FVPTC in intermediate-suspicion nodules (52.7% and 54.2%), and I-FVPTC in high-suspicion nodules (82.5% and 69.4%). After surgery, lymph node metastases were confirmed in two (4.2%) NIFTP cases, three (5.0%) iE-FVPTC cases, and eight (18.2%) I-FVPTC cases (p = 0.001). The results of the BRAF mutation analysis were not significantly different between the groups (p = 0.507). CONCLUSIONS: Increasing tumor invasiveness from NIFTP to iE-FVPTC to I-FVPTC is positively correlated with the level of suspicion on US using both K-TIRADS and ATA guidelines.

2-Deoxy-2-[18F]fluoro-D-glucose-positron emission tomography and positron emission tomography/computed tomography diagnosis of patients with recurrent papillary thyroid cancer.

OBJECTIVE: 2-Deoxy-2-[F-18]fluoro-D-glucose positron emission tomography (FDG-PET) has an established role in restaging of various cancers, including papillary and undifferentiated thyroid carcinoma, but detection rates are variable in the published literature. We were therefore prompted to review our experience with FDG-PET in detection of recurrent papillary thyroid cancer (PTC). METHODS: This is a retrospective study (April 1, 1995-March 31, 2005) of 21 patients with histologic diagnosis of PTC who had PET examinations. The group included seven men and 14 women, with age range of 26-75 years (average 50 +/- 16). The PET scan request was triggered by rising levels of thyroglobulin (Tg) in the presence of a negative iodine-131 scan. RESULTS: Recurrent/metastatic disease was identified by PET in 16 (76%) of the 21 patients with PTC. The sensitivity and specificity of FDG-PET for disease detection in this cohort were 88.2% [95% confidence interval (CI), 65.7-96.7] and 75% (95% CI, 30.1-95.4), respectively. The Tg levels were 1.0-10.4 ng/ml (average, 4.52 ng/ml) in the patients with negative PET scans and 1.0-38 ng/ml (average, 16.8 ng/ml) in patients with positive scans. The lesions were located in the cervical lymph nodes (8), thyroid bed (4), lungs (4), and mediastinal lymph nodes (2). CONCLUSION: Our study confirms the feasibility of PET in detection of residual/recurrence of PTC, with sensitivity of 88.2% (95% CI, 65.7-96.7) and specificity of 75% (95% CI, 30.1-95.4). Detectable levels of Tg, even in the presence of negative I-131 scan or anatomic imaging, should prompt restaging with FDG-PET.

Cyclooxygenase-2 in normal, hyperplastic and neoplastic follicular cells of the human thyroid gland.

This study was undertaken to investigate cyclooxygenase-2 (COX-2) expression in follicular cells of the human thyroid. COX-2 expression was studied immunohistochemically in a total of 174 samples. COX-2 immunoreactivity was confined to the cell cytoplasm with the nuclei remaining unlabelled. COX-2 expression was observed in five cases (17.2%) of normal follicular cells and in one case (16.6%) of solid cell nests. Follicular carcinoma expressed COX-2 more frequently than follicular adenoma (93.4% vs 21.1%) (p

[Follicular thyroid carcinoma: metastasis to unusual skin locations]. / Carcinome vésiculaire de la thyroïde avec métastases cutanées de localisations inhabituelles.

INTRODUCTION: Cutaneous metastasis of thyroid cancer is rare. When it occurs, it usually affects the scalp and neck. We report here a case where follicular thyroid carcinoma metastasized to unusual skin locations. CASE: An 82-year-old woman was followed after a total thyroidectomy for follicular thyroid carcinoma. Assessment after 2 years showed the presence of a small cervical residue, pulmonary metastases, and a high thyroglobulin level. Two sets of internal radiation therapy with iodine 131 (100 mCi each) followed. Response to treatment was poor, and cutaneous and subcutaneous nodules appeared on the abdomen, back, and front left thigh. Biopsy of these lesions showed that they were malignant, and testing with anti-thyroglobulin antibodies confirmed the diagnosis of cutaneous metastasis of follicular thyroid carcinoma. DISCUSSION: Although the rare cutaneous metastases of follicular thyroid carcinoma usually occur on the scalp, firm nodular cutaneous lesions that are painless and resist standard treatment in patients with a history of thyroid cancer should suggest the possibility of metastasis.