IgG4-related disease is a novel disease entity characterized by diffuse lymphoplasmacytic infiltration rich in IgG4-positive plasma cells and fibrosis into multiple organs. There is still controversy over whether some thyroid diseases are actually IgG4-related disease. The objective of this study was to elucidate the clinicopathological features of Graves’ disease with diffuse lymphoplasmacytic infiltration in the thyroid.
Patients and Methods
Among 1,484 Graves’ disease patients who underwent thyroidectomy, we examined their histopathological findings including the degree of lymphoplasmacytic and fibrotic infiltration and levels of IgG4-positive plasma cells in the thyroid. Their clinical pictures were defined by laboratory and ultrasonographic evaluation.
A total of 11 patients (0.74%) showed diffuse lymphoplasmacytic infiltration in the stroma of the thyroid gland. Meanwhile, other patients showed variable lymphoid infiltration ranging from absent to focally dense but no aggregation of plasma cells in the thyroid gland. Based on the diagnostic criteria of IgG4-related disease, 5 of the 11 subjects had specifically increased levels of IgG4-positive plasma cells in the thyroid. Fibrotic infiltration was present in only 1 patient developing hypothyroidism after anti-thyroid drug treatment for 4 years, but not in the other 10 patients with persistent hyperthyroidism. Obliterative phlebitis was not identified in any of the 11 subjects. Thyroid ultrasound examination showed 1 patient developing hypothyroidism who had diffuse hypoechogenicity, but the other hyperthyroid patients had a coarse echo texture.
In our study, Graves’ disease patients with persistent hyperthyroidism who had diffuse lymphoplasmacytic infiltration rich in IgG4-positive plasma cells in the thyroid showed no concomitant fibrosis or obliterative phlebitis.
Anaplastic thyroid cancer (ATC) is one of the most aggressive malignancies in humans, often demonstrating resistance to multimodal therapeutic approaches. The median survival of ATC patients after initial diagnosis was reported to be < 6 months due to the rapid progression of disease by dissemination and/or invasion. There have been several reports describing possible effective chemotherapies, but these studies might be biased by the nature of retrospective accumulations of clinical experiences, and thus reliable data concerning the efficacies of the treatment efforts are required.
In 2009, we established the research organization Anaplastic Carcinoma Research Consortium Japan (ATCCJ) to investigate this highly malignant disease. Using this nationwide organization, we conducted a prospective clinical study to investigate the feasibility, safeness, and efficacy of chemotherapy with weekly paclitaxel for ATC patients. This trial is registered on the clinical trials site of the University Hospital Medical Information Network Clinical Trials Registry Web site (UMIN000008574). The study was started in 2012, and enrollment was closed in March 2014 after accumulating 71 patients from 28 registered institutes. The follow-up data will be available in April 2015.
Important information concerning the management of this disease is expected to be revealed by this study. The concept and design of the study are described herein.
Anaplastic thyroid cancer; Chemotherapy; Prospective study; Feasibility; Protocol; Paclitaxel
A family with germline tandem V804M/Y806C mutations in the RET proto-oncogene was reported. The in vitro study results showing that these mutations were on the same allele and that RET with these mutations had a moderate transforming activity were confirmed by the clinical features of the offspring as a natural experiment. Thus, the tandem double RET mutations are pathogenetic for MEN 2B.
RET; Tandem mutations; Multiple endocrine neoplasia 2B; De novo mutation; Medullary thyroid carcinoma
Patients with metastases to the thyroid from renal cell carcinoma (RCC) that need surgical management are not many and unfamiliar to clinicians and thyroid endocrinologists. Therefore, little information is available on ultrasonographic features of metastatic carcinoma in the thyroid. The strategic value of ultrasound in preoperative surgical planning for patients with thyroid nodules has become increasingly appreciated. The purposes of this article are to clarify the ultrasound characteristics of metastatic carcinoma to the thyroid from RCC by evaluating many patients in one institute, and to investigate the role of ultrasonography in preoperative diagnosis.
Ten patients with these carcinomas who had undergone surgical management were investigated clinically and ultrasonographically. Ultrasonographic features to be evaluated were the form of involvement in the thyroid, size, shape, pattern, calcifications, vascularity, and tumor thrombus. Clinical features were previous history of RCC, serum thyroglobulin levels, cytology, preoperative diagnosis, and surgery.
Ultrasonographic features of these carcinomas were more likely to involve a solitary, irregular, and solid without calcifications, and prominent intra-tumoral vascularity and tumor thrombus in the vein. These patients tended to be older, and to have relatively late recurrence in the thyroid, RCC in the right kidney as the primary site, and relatively low serum thyroglobulin levels.
Metastatic carcinomas to the thyroid from RCC presented highly characteristic features on ultrasonography. These ultrasonographic features combined with cytological findings and previous medical history of RCC can provide the optimal process for the preoperative diagnosis of such patients.
Thyroid; Ultrasonography; Metastatic carcinoma; Renal cell carcinoma; Diagnosis; Tumor thrombus
Thyroid nodules with cystic content or mixed sponge-like aspect on ultrasonography and a concordant cytology are strongly predictive of benignity.
We present 8 patients with honeycomb-like papillary thyroid carcinoma with multiple small cysts on ultrasonography.
The patients were 6 women and 2 men aged between 30 and 57 years. The tumors of these patients showed honeycomb-like multiple small cysts that were aggregated in some area of the thyroid gland on ultrasonography. Histopathological examination indicated a well-differentiated type of papillary thyroid carcinoma with multiple small cysts and a small solid lesion. The cysts were lined with papillary carcinoma cells, and normal thyroid tissue lay between the cysts.
There is a peculiar type of papillary thyroid carcinoma that histopathologically shows honeycomb-like multiple small cysts in the thyroid gland. Ultrasonography can be used to identify characteristic features of honeycomb-like multiple small cysts in the thyroid gland in such patients.
One should be aware of this peculiar type of papillary thyroid carcinoma with honeycomb-like multiple small cysts on ultrasonography, although thyroid nodules with cystic lesions are generally regarded as benign in clinical management.
Thyroid; Papillary carcinoma; Cyst; Honeycomb; Ultrasonography
Background: We showed previously that subclinical low-risk papillary thyroid microcarcinoma (PTMC) could be observed without immediate surgery. Patient age is an important prognostic factor of clinical papillary thyroid carcinoma (PTC). In this study, we investigated how patient age influences the observation of low-risk PTMC.
Methods: Between 1993 and 2011, 1235 patients with low-risk PTMC chose observation without immediate surgery. They were followed periodically with ultrasound examinations. These patients were enrolled in this study. We divided them into three subsets based on age at the beginning of observation: young (<40 years), middle-aged (40–59 years), and old patients (≥60 years). Observation periods ranged from 18 to 227 months (average 75 months).
Results: We set three parameters for the evaluation of PTMC progression: (i) size enlargement, (ii) novel appearance of lymph-node metastasis, and (iii) progression to clinical disease (tumor size reaching 12 mm or larger, or novel appearance of nodal metastasis). The proportion of patients with PTMC progression was lowest in the old patients and highest in the young patients. On multivariate analysis, young age was an independent predictor of PTMC progression. However, none of the 1235 patients showed distant metastasis or died of PTC during observation. Although only 51 patients (4%) underwent thyrotropin (TSH) suppression based on physician preference, the PTMC of all patients enrolled in this TSH suppression study, except one, were clinically stable. To date, 191 patients underwent surgery for various reasons after observation. None showed recurrence except for one in the residual thyroid, and none died of PTC after surgery.
Conclusions: Old patients with subclinical low-risk PTMC may be the best candidates for observation. Although PTMC in young patients may be more progressive than in older patients, it might not be too late to perform surgery after subclinical PTMC has progressed to clinical disease, regardless of patient age.
We previously reported that the Ki-67 labeling index (LI) in primary tumors and the thyroglobulin (Tg)-doubling time (DT) were potent prognostic indicators in patients with papillary thyroid carcinoma (PTC).
To elucidate the relationship between these two factors.
A total of 390 patients with PTC who underwent total thyroidectomy between 1998 and 2004 and in whom the Tg-DT was calculated were enrolled. We determined the Ki-67 LI in primary tumors and compared these values with the patients' clinicopathological factors, postoperative Tg status, Tg-DT, and prognosis. Tg status was categorized by postoperative serum Tg values: biochemically persistent disease (BPD), equivocal state, and biochemical remission.
The Ki-67 LI was ≤5% in 312 patients (80%), 5%-10% in 48 patients (12%), and >10% in 30 patients (8%). Ki-67 LI was significantly associated with BPD (p < 0.0001). The proportion of BPD patients increased with the higher Ki-67 LI category: 24, 67, and 87%, respectively. The Ki-67 LI had a significant inverse correlation with the Tg-DT (Spearman's ρ = −0.5267, p < 0.0001). Of the 378 patients without distant metastasis at surgery, 68 patients had recurrence, and 6 of the 390 patients died of PTC during the follow-up (mean 88 months). On multivariate analyses, the Ki-67 LI remained an independent predictor of disease-free survival and disease-specific survival when Tg-DT and Tg status were excluded from the analyses.
Evaluation of the Ki-67 LI in primary tumors may allow the prediction of the postoperative Tg status, Tg-DT and prognosis of patients with PTC.
Published by S. Karger AG, Basel
Papillary thyroid carcinoma; Ki-67 labeling index; Thyroglobulin-doubling time; Biochemically persistent disease; Prognosis
Minimally invasive follicular thyroid carcinoma (MI-FTC) is characterized by limited capsular and/or vascular invasion with good long-term outcomes. However, some cases of MI-FTC show a poor prognosis because of severe distant metastasis (i.e., metastatic MI-FTC). Nonetheless, no method has been established for predicting the prognosis of MI-FTC. This study was conducted to identify novel prognostic factors for metastatic MI-FTC by the use of microRNA (miRNA). Thirty-four patients with MI-FTC were categorized into two groups: the metastatic group, M(+) (n=12) and the non-metastatic group, M(−) (n=22). In the M(+) group, distant metastasis was recognized after the initial operation established the diagnosis of MI-FTC. In the M(−) group, no distant metastasis was recognized postoperatively for ≥10 years. Using laser micro-dissection followed by quantitative real-time PCR and PCR arrays, we performed a comprehensive expression profiling of 667 miRNAs in formalin-fixed, paraffin-embedded samples from the initial MI-FTC operation. Furthermore, we assessed the potential use of miRNAs as novel biomarkers for the metastatic potential of MI-FTC by logistic regression analysis. Comprehensive quantitative analysis of miRNA expression in MI-FTC samples revealed that the miR-221/222 cluster (i.e., miR-221, miR-222 and miR-222*), miR-10b and miR-92a were significantly upregulated in the M(+) group compared with the M(−) group. Interestingly, the expression levels of these miRNAs were also shown to be upregulated in widely invasive FTC (WI-FTC; n=13) that has distant metastasis and worse prognosis, indicating a close similarity in the miRNA expression between metastatic MI-FTC and WI-FTC. Logistic regression analysis revealed that miR-10b made a significant contribution to prognosis (OR 19.759, 95% CI 1.433–272.355, p= 0.026). Our findings suggest that miR-10b is a potential prognostic factor for evaluating the metastatic potential of MI-FTC at an initial operation stage.
microRNA; minimally invasive follicular thyroid carcinoma; thyroid surgery; metastasis; prognostic factor
Subclinical hyperthyroidism is usually associated with Graves' disease or toxic nodular goiter. Here we report a family with hereditary subclinical hyperthyroidism caused by a constitutively activating germline mutation of the thyrotropin receptor (TSHR) gene.
The proband was a 64-year-old Japanese woman who presented with a thyroid nodule and was found to be euthyroid with a suppressed serum TSH. The nodule was not hot. Although antibodies to thyroid peroxidase and thyroglobulin antibodies were present, TSHR antibodies were not detected by TSH-binding inhibition or by bioassay. Two of her middle-aged sons, but not her daughter, also had subclinical hyperthyroidism without TSHR antibodies. Without therapy, the clinical condition of the affected individuals remained unchanged over 3 years without development of overt hyperthyroidism.
A novel heterozygous TSHR point mutation causing a glutamic acid to lysine substitution at codon 575 (E575K) in the second extracellular loop was detected in the three family members with subclinical hyperthyroidism, but was absent in her one daughter with normal thyroid function. In vitro functional studies of the E575K TSHR mutation demonstrated a weak, but significant, increase in constitutive activation of the cAMP pathway.
Although hereditary nonautoimmune overt hyperthyroidism is very rare, TSHR activating mutations as a cause of subclinical hyperthyroidism may be more common and should be considered in the differential diagnosis, especially if familial.
There are some important prognostic factors for papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC). In this paper, clinicopathological features significantly affecting patient prognosis are described based on our data as well as others. Distant metastasis at diagnosis is the most important prognostic factor for both PTC and FTC. Other than that, preoperative and intraoperative findings are important to evaluate the biological behavior of PTC. Extrathyroid extension, large lymph-node metastasis, and extranodal tumor extension that can be evaluated preoperatively or intraoperatively are significant prognostic factors for PTC patients. In contrast, pathological findings are important not only for diagnosis of FTC, but also for the evaluation of its biological character. Grade of invasiveness (minimally or widely invasive) and degree of differentiation (well differentiated or including a poorly differentiated component) greatly affect the prognosis of FTC patients.
Thyroid carcinoma showing squamous differentiation throughout the entire lesion is diagnosed as squamous cell carcinoma of the thyroid (SCCT) in the WHO classification. This entity is a rare disease and shows a dire prognosis; however, squamous differentiation is more frequently detected in only a portion of papillary thyroid carcinoma. In this paper, we present our experience of 10 patients (8 primary lesions and 2 with recurrence in the lymph nodes) with papillary thyroid carcinoma having an SCC component (PTC-SCC). Only 3 of 8 primary lesions (38%) and none of the 2 recurrent nodes were preoperatively diagnosed as or suspected of having SCC components. All 10 patients underwent locally curative surgery. To date, 3 patients have died of carcinoma, and 2 had distant metastasis at diagnosis or had an undifferentiated carcinoma component. The other 7 are currently alive 5 to 43 months after diagnosis. Systemic adjuvant therapy after the detection of recurrence was effective for 2 patients. It is possible that some PTC-SCC patients without distant metastasis who undergo locally curative surgery can survive for a prolonged period and adjuvant therapies can be effective for local and distant recurrences.
We previously reported that depressive personality (the scores of hypochondriasis, depression and psychasthenia determined by the Minnesota Multiphasic Personality Inventory (MMPI)) and daily hassles of Graves' disease (GD) patients treated long trem with antithyroid drug (ATD) were significantly higher in a relapsed group than in a remitted group, even in the euthyroid state. The present study aims to examine the relationship among depressive personality, emotional stresses, thyroid function and the prognosis of hyperthyroidism in newly diagnosed GD patients.
Sixty-four untreated GD patients responded to the MMPI for personality traits, the Natsume's Stress Inventory for major life events, and the Hayashi's Daily Life Stress Inventory for daily life stresses before and during ATD treatment.
In the untreated thyrotoxic state, depressive personality (T-scores of hypochondriasis, depression or psychasthenia greater than 60 points in MMPI) were found for 44 patients (69%). For 15 (23%) of these patients, the scores decreased to the normal range after treatment. However, depressive personality persisted after treatment in the remaining 29 patients (46%). Normal scores before treatment were found for 20 patients (31%), and the scores were persistently normal for 15 patients (23%). The remaining 5 patients (8%) had higher depressive personality after treatment. Such depressive personality was not associated with the severity of hyperthyroidism. Serum TSH receptor antibody activity at three years after treatment was significantly (p = 0.0351) greater in the depression group than in the non- depression group. The remission rate at four years after treatment was significantly (p = 0.0305) lower in the depression group than in the non- depression group (22% vs 52%).
The data indicate that in GD patients treated with ATD, depressive personality during treatment reflects the effect of emotional stress more than that of thyrotoxicosis and that it aggravates hyperthyroidism. Psychosomatic therapeutic approaches including antipsychiatric drugs and/or psychotherapy appears to be useful for improving the prognosis of hyperthyroidism.
Subcutaneous or intrastrap muscular (SIM) recurrence is rare in papillary thyroid carcinoma (PTC) patients, and its clinical significance remains unclear. We analyzed 29 patients with PTC who showed SIM recurrence in order to elucidate this issue. The incidence of patient age 55 years or older at initial surgery, extrathyroid extension, and clinically detected lymph node metastasis was 83%, 35%, and 46%, respectively. After surgical dissection, 17% of patients showed repeated SIM recurrence. Distant recurrence was detected in 45% of patients and was more likely to occur in patients with high-risk clinicopathological features. In all but one patient in this series, distant recurrence was detected at the same time or after the detection of SIM recurrence. Three patients died of PTC, but none of these patients died of the development of recurrent SIM lesions. These findings suggest that although SIM recurrence is a rare event and is not fatal, it is a predictor of distant recurrence especially in patients with high-risk clinicopathological features. Careful followup is recommended for such patients.
Papillary thyroid carcinoma (PTC) frequently metastasizes to the lymph node in lateral compartment, which can often be detected on preoperative ultrasonography (N1b). However, PTC located in one lobe showing contralateral but not ipsilateral N1b is not common. We analyzed the clinicopathological features and prognosis of 13 patients with PTC limited in one lobe showing contralateral but not ipsilateral N1b. Sizes of the primary lesions ranged from 0.8 cm to 3.0 cm and only 2 tumors showed extrathyroid extension. Metastatic lateral node measured from 0.6 to 3.1 cm. Ten patients showed pathological central node metastasis and 5 had minute PTC lesions in the contralateral lobe. However, 3 patients did not show either of these. None of the patients have developed carcinoma recurrence or died of carcinoma to date. Taken together, PTC located in one lobe with contralateral but not ipsilateral N1b is rare and generally shows an indolent behavior. Although most patients had central node metastasis and/or minute PTC lesions in the contralateral lobe, it is also possible for carcinoma cells to metastasize directly from primary lesions to the contralateral lateral node. Total thyroidectomy with central node dissection and therapeutic MND of the contralateral compartment may be an acceptable surgical design and bilateral MND might not be mandatory.
We report the case of a 50-year-old man presenting symptoms of autonomic dysreflexia associated with Charcot spine following complete C8 spinal cord injury. After posterior lumbar interbody fusion of L2/3 with simultaneous posterior instrumentation from L1 to L5, the patient recovered from the symptoms of autonomic dysreflexia. Although the patient began to faint when he sat up and transferred after surgery, it began to be resolved by continuous urinary catheterization, setting a limit to activity and prescription of alpha-, beta-stimulants. Within a few weeks after performing these treatment strategies, he could return to active wheelchair life, and no recurrence of any symptoms was noted at the 6-year follow-up. Although there are only a small number of cases with Charcot spine presenting autonomic dysreflexia, surgical stabilization of the affected lesion for patients with this condition should be recommended.
Charcot spine; Autonomic dysreflexia; Spinal fusion surgery
Thyroid transcription factor-1 (TTF-1, NKX2-1) is a homeodomain-containing transcriptional factor that binds to and activates the promoters of thyroid and lung-specific genes, such as thyroglobulin, thyroid peroxidase, and thyroid stimulating hormone receptor. TTF-1 is known to play a key role in the development of the thyroid. However, the precise mechanism of TTF-1 gene transcription in human thyroid cells has not been studied. The expression of transcriptional activity in various lengths of the 5′-flanking region of the human TTF -1 gene was studied in TTF-1 positive and negative human thyroid cell lines. Increased transcriptional activity was observed in thyroid cell lines containing plasmids that coded for a sequence proximal to the transcription start site of exon 1 of the TTF-1 gene. However, we did not observe any difference in promoter activity in the region up to −2.6 kb from the proximal transcription start site of the TTF-1 gene between TTF-1 positive and negative cells. These results suggest that the proximal 5′-flanking region of the human TTF -1 gene does not contain sufficient cis-active regulatory information to direct gene expression in thyroid cells, and that other cis- or trans-acting factors participate in the thyroid specific gene expression of TTF-1.
thyroid; TTF-1; transcription; human cell line; stem cell
Papillary carcinoma is a prominent malignancy originating from follicular cells. This disease generally shows an indolent character, but patients demonstrating certain clinicopathological features have a dire prognosis. At present, Western countries adopted almost routine total thyroidectomy with radioactive iodine (RAI) ablation, while limited thyroidectomy with extensive prophylactic lymph node dissection has traditionally been performed for most patients in Japan. Recently, accurate evaluation of carcinoma stage can be performed on preoperative imaging studies, especially on ultrasonography. It is therefore important to treat papillary carcinoma patients depending on clinicopathological features rather than in a stereotyped fashion. In this paper, appropriate extension of thyroidectomy and lymph node dissection is discussed based on Western and recently published Japanese guidelines and the experience in Kuma Hospital.
The clinical significance of nodal metastasis in well-differentiated follicular carcinoma (WD-FC) of the thyroid remains a controversial issue. This study aimed to clarify clinical and pathological characteristics of WD-FC with nodal metastasis, based on the new WHO classification. We examined 249 WD-FC cases diagnosed between 1983 and 2004 in our hospital. Poorly differentiated follicular carcinoma was not included in this study. Of the 249 WD-FC cases, 9 (3.6%) revealed nodal metastasis. The incidences of nodal metastasis in minimally invasive and widely invasive cases were 2.0 and 9.8%, respectively. In four patients, nodal metastasis was detected in the ipsilateral lymph nodes during the initial surgery. A total of 6 patients presented with nodal metastasis 2–10 years after the initial operation, and 3 patients with bilateral and large nodal metastases were relatively young. No patients succumbed to the carcinoma. Primary lesions of WD-FC with nodal metastasis were microscopically conventional, and there were no findings predicting nodal metastasis. We hypothesized that the incidence of nodal metastasis in WD-FC, based on the new WHO classification, was lower compared with previous reports. Younger individuals may be at a higher risk of large bilateral nodal metastasis. The presence of nodal metastasis did not affect the long-term outcome of follicular carcinoma.
thyroid; follicular carcinoma; metastasis; lymph node
Metastasis to regional lymph nodes is a common step in the progression of cancer. Recent evidence suggests that tumor production of CXCR4 promotes lymph node metastasis. Nitric oxide (NO) may also increase metastatic ability in human cancers.
Nitrite/nitrate levels and functional CXCR4 expression were assessed in K1 and B-CPAP papillary thyroid carcinoma (PTC) cells after induction and/or inhibition of NO synthesis. CXCR4 expression was also analyzed in primary human PTC. The relationship between nitrotyrosine levels, which are a biomarker for peroxynitrate formation from NO in vivo, CXCR4 expression, and lymph node status was also analyzed.
Production of nitrite/nitrate and functional CXCR4 expression in both cell lines was increased by treatment with the NO donor DETA NONOate. The NOS inhibitor L-NAME eliminated this increase. Positive CXCR4 immunostaining was observed in 60.7% (34/56) of PTCs. CXCR4 expression was significantly correlated with nitrotyrosine levels and lymph node metastasis in human PTC.
Our data indicate that NO stimulates CXCR4 expression in vitro. Formation of the NO biomarker nitrotyrosine was also correlated with CXCR4 expression and lymph node metastasis in human PTC. NO may induce lymph node metastasis via CXCR4 induction in papillary thyroid carcinoma.
Purpose of review
The global incidence of small papillary thyroid carcinoma (PTC) is increasing remarkably, mostly due to the increased use of imaging studies worldwide. The issue of how to manage low-risk small PTC has become urgent. In this review, we focus on how to treat low-risk papillary thyroid microcarcinomas (PMCs; i.e., PTCs measuring ≤10 mm).
Studies of large numbers of patients with low-risk PMC clarified that most of the PMCs did not grow or grew very slowly and were harmless. Active observations of these patients discriminated rare progressive cases from the majority. Surgery performed after the detection of progression signs was not too late, and surgery immediately after the detection and diagnosis of low-risk PMC may be overtreatment for most patients. Interestingly, low-risk PMCs in elderly patients were most unlikely to progress, in sharp contrast to clinical PTC. The reason for this phenomenon remains unknown.
Active observation without immediate surgery can be a leading alternative to the classical surgical treatment in the majority of the patients with low-risk PMC. It is not too late to perform surgery after the detection of progression signs for these patients.
nonsurgical treatment; observation; papillary thyroid carcinoma; papillary thyroid microcarcinoma; prognosis