Oncogenic Osteomalacia: Challenges in Diagnosis.

To report a case of osteomalacia induced by a mesenchymal tumour in the head and neck region, in view of its rarity and classical late diagnosis. To review the literature on the usage of fluorodeoxyglucose-positron emission tomography-computed tomography (FDG PET-CT) and octreotide scanning in the localisation of the culprit tumour. An elderly male presented with a 7-year history of chronic muscle pain and weakness, to the extent of functional disability. FDG PET-CT was done which showed uptake in the region of the right anterior ethmoids. Endoscopic excision of the mass was done. However, the patient did not improve significantly. Subsequently, a DOTA-1-NaI3-octreotide (DOTANOC) scan was done which revealed a tumour in the region of the right medial rectus, excision of which was done. This time, the patient improved clinically and biochemically. The histopathology was phosphaturic mesenchymal tumour. A steady but definitive symptomatic improvement was noted in the postoperative period along with reversal of the deranged biochemical parameters, confirming the diagnosis of oncogenic osteomalacia. Octreotide-based PET-CT seems to be the most sensitive imaging modality in localising the tumours that cause oncogenic osteomalacia. However, FDG-based PET-CT still would be a good choice in centres where SSTR-based imaging facilities are not available.

Paraneoplastic Manifestation of Primary Squamous Cell Cancer of the Thyroid Gland.

Paraneoplastic manifestation (PNM) of cancers is a non-metastatic, non-invasive systemic effect of malignancies due to chemokines and hormones produced by the primary neoplasm. Squamous cell cancers (SCCs) are known to present with PNM. Primary SCC of thyroid accounts for <1% of all thyroid malignancies and carries a very poor prognosis. We present a rare case of SCC arising from the thyroid gland who presented with fever, leukemoid reaction and hypercalcemia as part of PNM. A 67-year-old male patient presented with two months history of intermittent high-grade fever, weakness, loss of weight and appetite. Examination revealed a large (~10 cm) hard swelling over the right side of the neck. Investigations revealed neutrophilic leukocytosis, elevated C-reactive protein (CRP) and procalcitonin and hypercalcemia with a normal thyroid-stimulating hormone (TSH). The fever workup was negative for infection. Fine-needle aspiration cytology (FNAC) and core biopsy of the thyroid mass revealed malignant cells with squamous differentiation. An extensive search for possible other primary was ruled out by triple endoscopy. The combination of fever, neutrophilic leukocytosis, hypercalcemia and squamous malignancy was consistent with a diagnosis of PNM of SCC. A fluorodeoxyglucose-positron emission tomography (FDG-PET) CT scan showed a heterogeneously enhancing mass lesion in the right lobe of the thyroid with some retrosternal extension. He underwent total thyroidectomy with bilateral central compartment neck dissection. Final histopathology revealed moderately differentiated SCC of the thyroid. Concurrent chemoradiation was given. Despite continued chemotherapy, he succumbed to illness within six months of diagnosis. Primary SCC of thyroid (PSCCT) is a rare malignancy. It is a highly aggressive tumor having a poor prognosis with a median survival time of about 9-12 months and less clearly defined therapy due to its rarity. Paraneoplastic manifestation of PSCCT is known. As fever, leukemoid reaction and hypercalcemia can be a paraneoplastic manifestation, one should think of PSCCT.

An Interesting Case of Thyrotoxicosis.

Ectopic thyroid tissue can be present in the embryonal path of descent of the thyroglossal duct anywhere from the foramen caecum to the thyroid gland. However, for such ectopic thyroid tissue to be hyperfunctioning is quite rare. Here, we discuss a 56-year-old female patient who presented with persistent thyrotoxicosis for over 7 years. She had undergone thyroidectomy in 1982 for thyrotoxicosis and was rendered hypothyroid (thyroid-stimulating hormone of 75 µIU/mL). Whole-body technetium scan was done twice which did not show any uptake in the neck or other parts of the body and an empirical dose of 15 mCi of radioiodine therapy was also given to treat the thyrotoxicosis. She continued to be thyrotoxic and was on carbimazole 30 mg/day along with beta-blockers. In 2021, an Iodine131 whole-body scan revealed small remnant thyroid tissue and an ectopic thyroid tissue in a thyroglossal cyst. In such cases of persistent or recurrent thyrotoxicosis despite standard treatments, an ectopic location should be sought after and treated.

Dorsal vertebral body tumor and non-compressive quadriparesis - A rare case report of a phosphaturic mesenchymal tumor.

Background: Phosphaturic mesenchymal tumors cause renal phosphate wasting leading to hypophosphatemia manifesting as bone pain and fractures. About 95% of these tumors involve the extremities and the appendicular skeleton, with spinal tumors being exceedingly rare. We describe a case of non-compressive quadriparesis, caused by a thoracic vertebral body phosphaturic mesenchymal tumor (PMT). Case Description: A 34-year-old gentleman presented with a 3-year history of gradually progressive quadriparesis, predominantly involving proximal muscles. Magnetic resonance imaging neither showed evidence of compressive lesions nor myelopathy. On routine biochemistry, he was found to have hypophosphatemia and phosphaturia, with serum phosphorus levels of 1.84 mg/dl, and fractional excretion of phosphorus >5%. A DOTATOC positron emission tomography scan suggested the possibility of a PMT in the D10 vertebral body with a corresponding hyperdense/sclerotic focus on non-contrast computed tomography. After instituting phosphate replacement therapy and complete surgical excision of the hyperdense focus, he made a full neurological recovery. His phosphate levels normalized without the need for supplements. Histopathological examination showed spindle cells with positive staining for Vimentin, a mesenchymal cell marker. At 5 years of follow-up, the patient continues to be asymptomatic with a full return to normal function and no residual weakness. Conclusion: PMTs involving the spine are a rare reversible cause of non-compressive quadriparesis. Early diagnosis and excision of the lesion correct the hypophosphatemia and result in complete neurological recovery.

Thyroglobulin Levels in Patients who have Undergone Hemithyroidectomy for Differentiated Thyroid Cancer. An Assessment of Levels and Trends at a Tertiary Referral Centre.

Subramanian Kannan Serum thyroglobulin (Tg) and thyroglobulin antibody (TgAb) levels are used to monitor patients with differentiated thyroid cancer (DTC) after total thyroidectomy with or without radioiodine (RAI) ablation. However, they are also measured in patients who are treated with thyroid lobectomy (TL)/hemithyroidectomy (HT). Data on the levels of Tg and its trend in those undergoing TL/HT is sparse in India. We reviewed retrospective data of DTC patients who underwent TL/HT and were followed-up with postoperative Tg levels between 2015 and 2020. Out of 247 patients, 17 had undergone either TL or HT, which included papillary thyroid cancer ( n = 12), follicular thyroid cancer ( n = 4), and noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) in 1 patient. All patients with DTC had tumor size < 4 cm (T1/2, clinical N0, Mx). The median follow-up was 15 months (range, 1-125) and the median Tg level was 7.5 ng/mL (interquartile range [IQR]; 3.6, 7.5) and ranged from 0.9 to 36.7 ng/mL. The median thyroid-stimulating hormone (TSH) level was 2.03 IU/L (IQR; 1.21, 3.59) and it ranged from 0.05 to 8.54 IU/L. As of last follow-up, none of them underwent completion thyroidectomy; however, eight patients had a decline in Tg ranging from 8 to 64%, four patients had increase in Tg ranging from 14 to 145%, three patients had stable Tg, and one of them had an increase in TgAb titers. As per American Thyroid Association (ATA) response-to-treatment category, six patients had indeterminate response, five patients had biochemical incomplete response, four patients had excellent response, and two did not have follow-up Tg and TgAb levels. While absolute values of Tg were well below 30 ng/mL in almost all patients with HT/TL, the Tg trends were difficult to predict, and only 23% of patients were able to satisfy the criteria for "excellent response" on follow-up. We suggest keeping this factor in mind in follow-up and while counselling for HT in patients with low-risk DTC.

Systematic Review and Meta-Analysis to Identify the Immunocytochemical Markers Effective in Delineating Benign from Malignant Thyroid Lesions in FNAC Samples.

Conventional cytology-based diagnosis for thyroid cancer is limited with more than 30-45% of nodules categorized as indeterminate, necessitating surgery for confirming or refuting the diagnosis. This systematic review and meta-analysis were aimed at identifying immunocytochemical markers effective in delineating benign from malignant thyroid lesions in fine needle aspiration cytology (FNAC) samples, thereby improving the accuracy of cytology diagnosis. A systematic review of relevant articles (2000-2021) from online databases was carried out and the search protocol registered in PROSPERO database (CRD42021229121). The quality of studies was assessed using QUADAS-2. Review Manager 5.4.1 from Cochrane collaboration and MetaDisc Version 1.4 was used to conduct the meta-analysis. Bias in the studies were visually analyzed using funnel plots, and statistical significance was evaluated by Egger's test. Systematic review identified 64 original articles, while meta-analysis in eligible articles (n = 41) identified a panel of 5 markers, Galectin-3, HBME-1, CK-19, CD-56, and TPO. Assessment of the diagnostic performance revealed that Gal-3 (sensitivity: 0.81; CI: 0.79-0.83; specificity: 0.84; CI: 0.82-0.85) and HBME-1 (sensitivity: 0.83; Cl: 0.81-0.86; specificity: 0.85; CI: 0.83-0.86) showed high accuracy in delineating benign from malignant thyroid nodules. Efficacy analysis in indeterminate nodules showed Gal-3 and HBME-1 have high specificity of 0.86 (CI 0.84-0.89) and 0.82 (CI 0.78-0.86), respectively, and low sensitivity of 0.76 (CI 0.72-0.80) and 0.75 (CI 0.70-0.80), respectively. Diagnostic odds ratio (DOR) of Galectin-3 and HBME-1 were 39.18 (CI 23.38-65.65) and 24.44 (CI 11.16-53.54), respectively. Significant publication bias was observed for the markers Galectin-3 and CK-19 (p < 0.05). The panel of 5 markers identified from this meta-analysis are high-confidence candidates that need to be validated in thyroid cytology to establish their efficacy and enable clinical applicability.

Molecular Markers in the Diagnosis of Thyroid Cancer in Indeterminate Thyroid Nodules.

The Bethesda System for the Reporting of Thyroid Cytology recognises six diagnostic categories of thyroid nodule cytology with an incremental risk of malignancy. Although the Bethesda system created a much-needed handhold by standardising the cytological diagnosis and management of thyroid nodules worldwide, the system does not provide a clear answer to the heterogeneous group of nodules with indeterminate cytology. Improvement in the assessment of indeterminate fine-needle aspiration (FNA) results with molecular testing allows better risk stratification and reduces the need for diagnostic thyroid surgery. The molecular markers are classified as a "rule out" test, which has a high negative predictive value and helpful in cases with a low pre-test probability of cancer to rule out thyroid cancer. The "rule in" test has a high positive predictive value and helps in confirming malignancy in those with a high pre-test probability of cancer. This review summarises the commonly used molecular studies in thyroid FNAC aspirates and their current role in clinical practice.

Development of a Low-cost NGS Test for the Evaluation of Thyroid Nodules.

Ultrasound-guided fine needle aspiration cytology (FNAC) is the preferred method of identifying malignancy in palpable thyroid nodules using the Bethesda reporting system. However, in around 30-40% of FNACs (Bethesda categories III, IV, and V), the results are indeterminate and surgery is required to confirm malignancy. Out of those who undergo surgery, only 10-40% of patients in these categories are found to have malignancies, thus proving surgery to be unnecessary for some patients or to be incomplete in others. While molecular testing on thyroid FNAC material is part of the American Thyroid Association (ATA) guidelines in evaluating thyroid nodules, it is currently unavailable in India due to cost constraints. In this study, we prospectively collected FNAC samples from sixty-nine patients who presented with palpable thyroid nodules. We designed a cost-effective next-generation sequencing (NGS) test to query multiple variants in the DNA and RNA isolated from the fine needle aspirate. The identification of oncogenic variants was considered to be indicative of malignancy, and confirmed by surgical histopathology. The panel showed an overall sensitivity of 81.25% and a specificity of 100%, while in the case of Bethesda categories III, IV, and V, the sensitivity was higher (87.5%) and the specificity was established at 100%. The panel could thereby serve as a rule-in test for the diagnosis of thyroid cancer and therefore help identify patients who require surgery, especially in the indeterminate Bethesda categories III, IV, and V.

Is Paget Disease of Bone more Common in South India? Clinical Characteristics, Therapeutic Outcome and follow-up of 66 Patients from Tamil Nadu.

INTRODUCTION: Paget disease of bone (PDB) is a disorder of altered bone remodeling mainly characterized by increased osteoclastic activity. While the exact Indian prevalence remains unknown, a clustering of published cases suggests South Indian predominance. OBJECTIVE: To study the clinico-biochemical profile and therapeutic response of patients with PDB and briefly review the epidemiology of PDB from an Indian perspective. MATERIALS AND METHODS: Retrospective data was collected from the charts of patients who have been seen in endocrine out-patient clinics in Tamil Nadu over a 12-year period. Published literature on PDB from India was reviewed. RESULTS: A total of 66 patients (71% males) predominantly from Tamil Nadu were studied. The mean age at presentation was 67 ± 8 years. Polyostotic involvement was seen in 89% and familial occurrence of PDB in 5 patients. Symptoms at presentation mainly included bone pain (51%) and skeletal deformities (18%). Scalp vein sign (21%) and sensorineural hearing loss (64%) were also noted. Incidental PDB detection by raised serum alkaline phosphatase (SAP) levels was observed in 17% and by abnormal fluorodeoxyglucose-positron emission tomography (FDG-PET) scan in 6% of cases. Mean SAP at presentation was 606 ± 438 IU/L (Normal, 76-140). Major skeletal site involvement includes pelvis (62.1%) and spine (34.8%). Mean (range) follow-up of the cohort was 3.4 yrs (1-12 yrs). In all, 64 subjects received zoledronate and two received alendronate, and mean (SD) SAP at 1-year was 73 ± 42 IU/L. All but two showed remission at the end of 1 year. Two had pathological fractures and two had sarcomas. A review of epidemiology of PDB in Indian literature clearly showed a South Indian predilection for unclear reasons. CONCLUSION: In our cohort of PDB, male gender, polyostotic involvement, and hearing impairment were noted in more than two-thirds of patients and single-dose intravenous zoledronate was effective in normalizing SAP in almost all patients. PDB is intriguingly more common in South India and this needs more exploration.

Approaching Indeterminate Thyroid Nodules in the Absence of Molecular Markers: "The BETH-TR Score".

CONTEXT: Given the lack of easy access to molecular markers for indeterminate thyroid nodules (Bethesda (BETH) category III, IV), the clinician can either decide to get a second opinion from an expert high-volume thyroid cytopathologist, redo the FNAC after a period of 3-6 months, or send the patient for a diagnostic hemithyroidectomy. Reviewing the sonographic risk features is also one way of triaging these nodules. The ACR-TIRADS (TR) is an objective method of sonographic risk assessment and is superior to other forms of sonographic classification. AIM: We propose combining the scoring of the TR category and BETH category (both expressed as a numerical value and summated) and look at the score which could potentially guide the clinician in deciding whom to send for surgery. SETTINGS AND DESIGN: Observational prospective collection of consecutive patient data from the thyroid FNAC clinic. STATISTICAL ANALYSIS USED: The BETH categories were represented numerically and summated with the TR category. The categorical outcome variables of benign and malignant nodules and the summated score was analyzed using the Kruskal-Wallis test. RESULTS: We analyzed 450 FNAC data, out of which 403 were thyroid nodule aspirates. Out of these nodules, 96 of them underwent surgery and 64% of these nodules were malignant on final histopathology (malignant = 62 and benign = 34). The mean size of the benign nodules was 3.6 ± 2.2 cm compared to 2.8 ± 1.8 cm of the malignant nodules. After excluding those with BETH 1 (n = 4), the mean BETH-TR score for benign nodules was 6 ± 1.4 and malignant nodules 9.4 ± 2.1 (P < 0.0001). The BETH-TR score progressively increased from 7.3 ± 0.92 in follicular thyroid cancers (FTC) to 8.6 ± 1.4 in follicular variant papillary thyroid cancer (FVPTC) to 10 ± 1.3 in classic papillary thyroid cancers (PTC). Among the indeterminate nodules (BETH III and IV; n = 40), the BETH-TR score of benign nodules was 6.75 ± 1 and malignant nodules was 7.5 ± 0.72 (P value = 0.01). A BETH-TR score ≥7 gave a sensitivity of 92% specificity of 74% and correctly identified malignant nodules in 86% of cases (likelihood ratio 3.5; ROC area: 0.8841; CI 0.79-0.94). CONCLUSION: A combined sonocytological BETH-TR score is one way to triage the management of indeterminate thyroid nodules. A BETH-TR score ≥7 gave a sensitivity of 92% specificity of 74% and correctly identified malignant nodules in 86% of cases.

Neonatal Severe Primary Hyperparathyroidism: A Series of Four Cases and their Long-term Management in India.

CONTEXT: Neonatal severe primary hyperparathyroidism (NSPHPT) is an extremely rare autosomal recessive disorder, requiring a high index of suspicion. Infants affected with this disorder present with severe life-threatening hypercalcemia early in life, requiring adequate preoperative medical management followed by surgery. AIMS: We report four newborns with NSPHPT who were managed over 10 years. SUBJECTS AND METHODS: Demography, clinical presentation, treatment, and follow-up data were retrospectively studied with descriptive analysis to highlight the utility of long-term medical management, surgery, and genetic testing reported in the literature. STATISTICAL ANALYSIS USED: Descriptive Analysis. RESULTS: We had three males and one female infant with a mean age of diagnosis at 28.7 days, calcium 29.2+/-2.8 mg/dL, and parathormone (PTH) 1963+/-270.4 pg/mL. All four infants presented with failure to thrive, hypotonia, and respiratory distress. All infants were treated medically followed by total parathyroidectomy plus transcervical thymectomy, with an additional hemithyroidectomy in one of them. Imaging was negative in all four cases. Three babies became hypocalcemic while the fourth infant had a drop in PTH and is on the tab. cinacalcet 30 mg/day. CaSR mutation was positive in three infants. CONCLUSIONS: Diagnosing NSPHPT needs expert clinical acumen. It requires emergency medical management to control calcium levels. The crisis may present later, necessitating parathyroidectomy in these cases once the child is fit for surgery. Surgery offers a cure for this unusual lethal hypercalcemia while the role of cinacalcet needs a special mention. Sound knowledge in endocrinology with parathyroid embryology and morphology is of paramount importance. Our case series might add a few insights into managing this unusual genetic disorder.

Identifying the Burden and Predictors of Diabetes Distress among Adult Type 2 Diabetes Mellitus Patients.

BACKGROUND: Diabetes is a psychologically challenging medical condition. Diabetes distress (DD) refers to the unique, often hidden emotional burdens and worries that the patient experiences when managing diabetes. OBJECTIVE: The objective of the study was to find the burden and identify the predictors of DD in adult Type 2 diabetes mellitus (T2DM) patients. MATERIALS AND METHODS: Two hundred and fifty T2DM patients were recruited for this study from the endocrine outpatient department from February to April 2019. DD was measured using the Diabetic Distress Scale. RESULTS: The prevalence of DD was 19.6%. The risk of DD was 4.25 times more in those aged ≤45 years as compared to those aged >45 years. Patients with hemoglobin A1c (HbA1c) >8% had 8.8 times more DD. Patients on insulin had more DD (5.4 times) as compared to patients who were on oral antidiabetic drugs. Patients with a history of treatment interruption had 11 times more risk of DD as compared to patients who did not. CONCLUSIONS: DD was found to be high among patients aged ≤45 years, illiterates, patients on insulin, patients with a history of treatment interruption, and those with HbA1c >8%. Patients with high DD were found to have higher HbA1c levels.

Is 3-4 Weeks Required for TSH to Rise Post Thyroidectomy? A prospective Study and Discussion of its Implications on Patient Care.

CONTEXT: In patients with differentiated thyroid cancer (DTC), for the purpose of radioiodine (131I) whole-body scan and treatment of remnant, or residual tumor, or metastatic disease, thyroid hormone withdrawal remains the standard approach for raising thyroid-stimulating hormone (TSH) levels to ensure adequate radioiodine uptake. Thyroid hormone is withdrawn 3-4 weeks prior radioiodine therapy (RAIT) to allow the serum-TSH concentration to rise to above 25-30 mU/L. AIMS: We studied the time taken for TSH to rise in 40 patients after total thyroidectomy operated for DTC. SETTINGS AND DESIGN: Prospective observational study. METHODS AND MATERIALS: 40 patients with proven differentiated thyroid cancer attending a tertiary care center were studied. STATISTICAL ANALYSIS USED: Data was analyzed by using SPPSS software for windows (version 15, SPSS Inc., Chicago, USA). RESULTS: After performing preoperative TSH in all patients excluding preoperative TSH elevation, it was planned to collect weekly postoperative samples till TSH ≥30. The mean (standard deviation, SD) age of the cohort was 40 (13) years with 35 females (88%) and their mean (SD) preoperative TSH was 3.6 (1.35) mIU/L. At the end of the first week postoperatively, the mean TSH of the cohort was 24.25 (6) with 8 patients (20%) achieving the cut-off of TSH ≥30 mIU/L and 30 patients (75%) achieving TSH level ≥20 mIU/L. At the end of the second week, the mean TSH was 53 (17) with all patients (100%) achieving a TSH level >30 mIU/ml. CONCLUSIONS: An iodine whole-body scan can be performed in 10-14 days after total thyroidectomy instead of the usual wait time of 4 weeks. This could improve patient QOL and avoid complications related to prolonged hypothyroidism.