Renal Medullary Carcinoma and Sickle Cell Trait: A Push for Early Diagnosis and Intervention Report of Two Cases.

Renal medullary carcinoma (RMC) is a rare but highly aggressive neoplasm that primarily affects young African Americans with sickle cell trait. Most patients present with macroscopic hematuria and have metastases at diagnosis. Chemotherapy, biologics directed against the more common renal cell carcinomas and radiation have all shown limited efficacy in treating patients with advanced RMC. We report two patients with RMC. Both had Stage IV disease. One underwent radical nephrectomy followed by radiation and biologic drug therapy but died five months later; the other underwent multiple cycles of chemotherapy plus anti-angiogenesis treatment but died 15 months after diagnosis. Review of the literature suggests that early diagnosis and surgical intervention while the tumor is confined to the kidney offer the best prospect for long term survival. Since newborn screening for sickle cell is now mandated in the US, the at-risk population for RMC could be identified and followed by yearly urine dipstick testing for microscopic hematuria. Those who test positive can be further evaluated to rule out RMC.

Case report of severe Cushing's syndrome in medullary thyroid cancer complicated by functional diabetes insipidus, aortic dissection, jejunal intussusception, and paraneoplastic dysautonomia: remission with sorafenib without reduction in cortisol concentration.

BACKGROUND: Normalization of cortisol concentration by multikinase inhibitors have been reported in three patients with medullary thyroid cancer-related Cushing's syndrome. Aortic dissection has been reported in three patients with Cushing's syndrome. Diabetes insipidus without intrasellar metastasis, intestinal intussusception, and paraneoplastic dysautonomia have not been reported in medullary thyroid cancer. CASE PRESENTATION: An adult male with metastatic medullary thyroid cancer presented with hyperglycemia, hypernatremia, hypokalemia, hypertension, acne-like rash, and diabetes insipidus (urine volume >8 L/d, osmolality 190 mOsm/kg). Serum cortisol, adrenocorticoitropic hormone, dehydroepiandrostenedione sulfate, and urinary free cortisol were elevated 8, 20, 4.4, and 340 folds, respectively. Pituitary imaging was normal. Computed tomography scan revealed jejunal intussusception and incidental abdominal aortic dissection. Sorafenib treatment was associated with Cushing's syndrome remission, elevated progesterone (>10 fold), normalization of dehydroepiandrostenedione sulfate, but persistently elevated cortisol concentration. Newly-developed proximal lower limb weakness and decreased salivation were associated with elevated ganglionic neuronal acetylcholine receptor (alpha-3) and borderline P/Q type calcium channel antibodies. CONCLUSION: Extreme cortisol concentration may have contributed to aortic dissection and suppressed antidiuretic hormone secretion; which combined with hypokalemia due cortisol activation of mineralocorticoid receptors, manifested as diabetes insipidus. This is the first report of paraneoplastic dysautonomia and jejunal intussusception in medullary thyroid cancer, they may be related to medullary thyroid cancer's neuroendocrine origin and metastasis, respectively. Remission of Cushing's syndrome without measurable reduction in cortisol concentration suggests a novel cortisol-independent mechanism of action or assay cross-reactivity. Normalization of dehydroepiandrostenedione sulfate and elevation of progesterone suggest inhibition of 17-hydroxylase and 21-hydroxylase activities by sorafenib.

The effect of chronic lymphocytic thyroiditis on patients with thyroid cancer.

BACKGROUND: The purpose of this study was to investigate the association between chronic lymphocytic thyroiditis (CLT) and malignant tumors of the thyroid. METHODS: A retrospective review of 647 patients who underwent thyroid surgery at the Department of Breast and Thyroid Surgery in Anhui Provincial Hospital, China in 2012 was performed. The clinicopathological characteristics of patients with thyroid malignancies and CLT were collected. CLT was diagnosed by histopathological method. RESULTS: Among 647 patients, 144 patients had thyroid malignancies and 108 patients had been diagnosed with CLT. Moreover, in total, 44 patients had thyroid malignancies coexistent with CLT: forty-one (93.2%) patients had been diagnosed with the papillary thyroid cancer (PTC); two (4.5%) patients suffered from medullary carcinoma; and one (2.3%) patient suffered from lymphoma. The morbidity of thyroid malignancies in patients with CLT was significantly higher than that in patients without CLT (40.7% versus 18.6%; P <0.001). A female preponderance was observed in the patients with CLT compared with those without CLT (P <0.001). There was no statistically significant difference in the tumor size (P = 0.073), multifocality (P = 0.0871), neck lymph node metastasis (P = 0.350), age (P = 0.316), microcarcinoma (P = 0.983) and tumor-node-metastasis (TNM) stage (P = 0.949) between the patients of thyroid malignancies with CLT and without CLT. CONCLUSIONS: Female predominance was observed in patients with CLT. CLT may have no effect on the progression of thyroid malignant tumor. Nevertheless, the influences of CLT on the prognosis of the thyroid carcinoma still need to be investigated with a larger sample size.

Coincidence of primary hyperparathyroidism and nonmedullary thyroid carcinoma.

The incidence of primary hyperparathyroidism (pHPT) combined with nonmedullary thyroid carcinoma (NMTC) has been reported between 2-13%. To date, it remains controversial whether these 2 pathologies occur coincidental or are caused by specific risk factors or genetic changes. The aim of this study was to evaluate the clinical and histological characteristics of NMTC associated with pHPT. We reviewed prospective database records of 1 464 unselected, consecutive patients who were treated for pHPT in our institution between 1986 and 2012 and identified 41 NMTC (2.8%). The collective consisted of 35 papillary (PTC) and 6 follicular (FTC) thyroid carcinomas. Our collective of 41 NMTC including 34 single adenomas and 7 multiglandular diseases consisted of 33 females and 8 males. Patients with FTC demonstrated significant lower preoperative PTH levels compared to PTC. Interestingly, NMTC were predominantly located on the right side. FTC had significant larger tumors as well as demonstrated increased extrathyroidal growth and lymph node metastases. In 71% pHPT and NMTC were diagnosed synchronously. The comorbidity of pHPT and NMTC occurs in about 3%. As pHPT is often operated by a focal minimally invasive approach, we advocate a mandatory preoperative thyroid ultrasound for all patients with pHPT to be able to identify synchronous thyroid disease.

Thyroid cancer detection with dual-isotope parathyroid scintigraphy in primary hyperparathyroidism.

BACKGROUND: Thyroid cancer cells have been shown to take up (99m)Tc-sestamibi. The role for (99m)Tc-sestamibi scintigraphy (Tc-MIBI) in the diagnosis of thyroid cancer in patients with primary hyperparathyroidism (PHPT) is unclear. Our aim was to determine whether dual-isotope parathyroid scintigraphy is useful in identifying thyroid cancer. METHODS: A prospective database of 3,187 patients who underwent neck exploration for PHPT was reviewed to identify patients who had concurrent thyroid resection. Patients with benign and malignant thyroid disease were comparatively analyzed. RESULTS: A total of 470 patients underwent both thyroidectomy and parathyroidectomy (reoperations in 21%). Benign disease (n = 391, 83%) was more common than malignancy [papillary thyroid cancer (n = 75) and medullary thyroid cancer (n = 5); 1 had both]. Dual-isotope scintigraphy obtained in 374 patients (80%) had a sensitivity of 67% and a positive predictive value of 66% for parathyroid adenoma localization in these patients with thyroid disease. False-positive scintigraphy occurred in 22% with benign and 45% with malignant thyroid disease (P = 0.002). On Tc-MIBI imaging, 54 (86%) of 63 patients with malignancy had hot nodules, compared to 248 (81%) of 308 patients with benign disease (P = 0.49). On I-123 imaging, 34 (54%) of 63 patients with malignancy had cold nodules, compared to 42 (14%) of 304 patients with benign disease (P < 0.001). A dual-isotype phenotype of both Tc-MIBI-Hot and I-123-Cold had sensitivity 52%, specificity 88%, positive predictive value 47%, and negative predictive value 90% for detecting a thyroid malignancy. CONCLUSIONS: A Tc-MIBI-Hot/I-123-Cold phenotype is very specific for detecting thyroid malignancy. Patients with this imaging phenotype should strongly be considered for preoperative ultrasound-guided biopsy. Patients found intraoperatively to have false-positive parathyroid scintigraphy should be evaluated for thyroid cancer.

[Hirschsprung's disease and medullary carcinoma of the thyroids: two diseases in a monogenetic disorder]. / La enfermedad de Hirschsprung y el carcinoma medular de tiroides: dos enfermedades en una alteración monogénica.

INTRODUCTION: The most common gene involved in Hirschsprung's disease (HD) is protooncogene RET. More than 100 mutations of this gene have been described associated with HD. The mutations that change a cysteine with another aminoacid (mainly in exons 10 and 11) give a risk of familial medullary thyroid carcinoma (FTMC) and MEN 2A. These mutations are found in 5% of patients with HD and have an autosomal dominant inheritance. The FTMC is aggressive and the prophylactic thyroidectomy is the best treatment. We present our results in screening for RET protooncogene mutations associated with TMC in patients with HD. PATIENTS AND METHODS: We have treated 40 patients with HD in the last 15 years. We have classified the patients into two groups: A) high risk of RET protooncogene mutation associated with FTMC (family history of HD, long-segment and/or associated syndromes) and B) low risk (rectosigmoid involvement). We have identified the exons 7, 8, 9, 10, 11, 13, 14 and 15 of the RET protooncogene in 12 of 15 children from group A and 6 from 25 from group B. RESULTS: We have found the p.Cys620Ser mutation (exon 10) in a girl from group A (long-segment). In the family study, we have found the same mutation in her mother, her oncle and her cousin. CONCLUSION: The comprehensive management of children with HD requires screening for RET protooncogene mutations associated with FTMC. In the first-degree relatives of children with a mutation risk, screening is required.

Medullar thyroid carcinoma in mediastinum initially presenting as Ectopic ACTH syndrome. A case report.

A rare case with ectopic adrenocorticotrophic hormone syndrome (EAS) caused by medullar thyroid carcinoma (MTC) in mediastinum was reported. This 49 year-old male patient initially presented with serious and intractable hypokalemia. Endocrine evaluations showed increased levels of adrenocorticotrophic hormone (ACTH) and urinary free cortisol, which could not be suppressed more than 50% by high-dose dexamethasone suppression test. Computed tomography (CT) scan detected a 5×5×5 cm mass at the bottom of thyroid in anterior mediastinum. The patient underwent total thyroidectomy with central compartment and ipsilateral modified radical neck dissection. Pathological examination showed an infiltrating thyroid medullary carcinoma with abundant amyloid deposition, meanwhile immunohistochemical positive for ACTH. After surgery, serum levels of kalium, as well as cortisol and ACTH returned to normal range. During follow-up, the patient's clinical manifestation of Cushing syndrome relieved.

A high level of carcinoembryonic antigen as initial manifestation of medullary thyroid carcinoma in a patient with subclinical hyperthyroidism.

Carcinoembryonic antigen (CEA), a tumor marker with a glycoprotein structure, is frequently used in follow-up gastrointestinal malignancies. CEA levels may also increase in neuroendocrine tumors, including medullary thyroid carcinoma (MTC), and in some benign diseases. Patients whose blood tests show high CEA levels should have additional tests regarding MTC. Although MTC comprises only 3%-11% of all thyroid cancers, it should be tested because it has a poor prognosis and may accompany multiple endocrine neoplasia. We present the case of a 76-year-old man with subclinical hyperthyroidism with sporadic MTC who presented with initial high serum CEA levels. He underwent total thyroidectomy and left modified neck dissection. Pathologic specimens stained strongly for CEA. The patient's blood was analyzed for mutations in exons 10, 11, 13, 14, 15, and 16, but the RET proto-oncogene revealed no mutations. The patient was regularly followed by measurement of serum CEA levels and performance of positron emission tomography-computed tomography. Seventeen months after surgery, the patient has remained well and showed no signs of tumor recurrence.

Mixed Medullary-follicular-derived carcinomas of the thyroid gland.

Tumors of the thyroid are subclassified based on the cell of origin and commonly include follicular-derived tumors and C-cell-derived tumors. The most common follicular-derived tumors are papillary carcinoma and follicular carcinoma, whereas the malignant C-cell-derived tumor is medullary thyroid carcinoma. Rare cases in the literature describe patients who have follicular-derived and C-cell-derived tumors in the same thyroid gland. These can be synchronous but anatomically separate carcinomas, or they can show some mixing of the 2 components. The mixture may be at an interface, as in collision tumors, or can be throughout the entire lesion, as in true mixed medullary-follicular-derived carcinomas. The clinical, histologic, and molecular features of these mixed tumors and the classification guidelines are reviewed.

Renal medullary carcinoma and its association with sickle cell trait: a case report and literature review.

Renal medullary carcinoma (rmc) is a rare and aggressive renal malignancy that usually presents at an advanced stage, has a poor prognosis, and is associated with sickle cell trait. We present a case of rmc including radiologic and pathology findings, treatment, and outcome. A review of the literature is also presented, with an emphasis on the association of rmc with sickle cell trait, which was an unknown diagnosis in our patient preoperatively.

Thyroid carcinoma risk in patients with hyperthyroidism and role of preoperative cytology in diagnosis.

AIM: The aim of this study was to determine the frequency of thyroid carcinoma in patients with hyperthyroidism and evaluate the role of preoperative ultrasonography (US) guided thyroid fine needle aspiration biopsy (FNAB) in diagnosis of thyroid carcinoma in these patients. METHODS: Three hundred twenty-five hyperthyroid patients--119 with toxic multinodular goiter (TMNG), 47 with autonomous functioning toxic nodule (AFTN) and 159 with Graves Disease (GD)--were included in this study. All patients were evaluated with US and in all patients with nodules, US guided FNAB was carried out. RESULTS: Among 159 patients with GD, 62 were without nodules. Totally, 583 nodules in 263 patients were sampled by FNAB. Cytologic results of nodules were as follows: 87.7% benign, 6.2% inadequate, 4.3% suspicious and 1.9% malignant. Postoperatively, 42 (12.9%) patients were diagnosed as thyroid carcinoma histopathologically. Thyroid carcinoma was detected postoperatively in all patients with malignant cytology, in 47.8% of patients with suspicious cytology and in 44.4% of patients with inadequate cytology. Moreover, in 13 patients with benign cytology and in 3 Graves patients without any nodule ultrasonographically, incidental thyroid carcinoma was found (5.7%). Consequently, thyroid malignancy rates were 16% in TMNG, 6.4% in AFTN and 12.6% in GD. CONCLUSION: Thyroid carcinoma is common in hyperthyroidism and FNAB is a reliable method in diagnosis of thyroid malignancy in these patients. Additionally, incidental thyroid carcinoma prevalence is also high in patients with hyperthyroidism. We suggest that it is reasonable to evaluate nodules with FNAB in hyperthyroid patients prior to radioactive iodine treatment or surgical intervention.

The Y606C RET mutation causes a receptor gain of function.

CONTEXT: Medullary thyroid carcinoma (MTC) is the most common feature of multiple endocrine neoplasia type 2A (MEN2A) and occurs in almost all patients affected by germline RET mutations. OBJECTIVE: We identified and characterized an activating germline RET point mutation (G>A substitution leading to the heterozygous missense mutation Y606C in exon 10), in a 58-year-old female affected by MTC. DESIGN: The RET/Y606C and RET/C620Y, obtained by site-directed mutagenesis, as well as the RET/wild-type (wt) were cloned in an expression vector and transiently transfected in NIH3T3 fibroblasts. In vitro cell model was used to evaluate the effect of Y606C mutation on the RET downstream signalling pathways through Western blot analysis. RESULTS: We found that the cysteine insertion, due to the Y606C mutation, results in increased receptor dimerization, which is accompanied by an increased tyrosine phosphorylation of the Y905 residue in the RET/Y606C, demonstrating that the Y606C mutation is associated with constitutive receptor activation. As RET activation results in an intracellular signalling cascade involving extracellular signal-regulated kinases (ERKs), we investigated ERK activity in our transfected cells. Results demonstrated a significant increase in ERK2 phosphorylation in the RET/Y606C vs. the RET/wt and RET/C620Y transfected cells, suggesting an up-regulation of RET signalling. CONCLUSIONS: All these findings demonstrate that the Y606C mutation is associated with RET constitutive activation and thus has to be considered of pathogenetic relevance in the development of MTC.

Renal medullary carcinoma: ultrastructural studies may benefit diagnosis.

Renal medullary carcinoma is a recently described highly aggressive malignancy that in most instances exhibits a constellation of clinical and light microscopic features sufficiently distinctive to enable a quick and confident diagnosis. Presented are three examples where, because of unusual elements in the clinical presentation, electron microscopic examination proved beneficial in establishing the diagnosis.

Medullary thyroid carcinoma metastatic to the pituitary gland: an unusual site of metastasis.

We present a case of metastatic medullary thyroid carcinoma involving the pituitary gland of a 23-year-old woman with multiple endocrine neoplasia type 2b who presented with diabetes insipidus and visual loss. The diagnostic features, including cytomorphology and immunohistochemistry, used to differentiate pituitary adenoma from metastatic medullary carcinoma are discussed. Pituitary metastases and tumor-to-tumor metastases in this region are also highlighted.

Ectopic Cushing's syndrome due to CRH secreting liver metastasis in a patient with medullary thyroid carcinoma.

Ectopic production of CRH by a medullary thyroid carcinoma or its metastases is a rare cause of ectopic Cushing's syndrome (ECS). We report a 45-year old male with medullary thyroid carcinoma (MTC), who, 24 years following the initial diagnosis, presented with clinical and biochemical evidence of an ACTH dependent Cushing's syndrome. Rapid deterioration of his clinical condition and elevated cortisol levels were observed. Computed tomographic imaging of the abdomen revealed extensive liver metastases. The patient underwent fine needle aspiration biopsy of a liver lesion and immunohistochemistry showed that the cells expressed calcitonin, carcino-embryonic antigen and synaptophysin. Further analysis revealed that the material also expressed CRH. This is an unusual case of a CRH-secreting liver metastasis from a medullary thyroid carcinoma 24 years after the initial diagnosis of MTC.

A Model Linking Sickle Cell Hemoglobinopathies and SMARCB1 Loss in Renal Medullary Carcinoma.

Renal medullary carcinoma (RMC) is a highly aggressive malignancy that predominantly afflicts young adults and adolescents with sickle hemoglobinopathies. It is characterized by complete loss of expression of the chromatin remodeler and tumor suppressor SMARCB1 Despite therapy, the outcomes of patients with RMC remain very poor, highlighting the need to understand the etiology of this cancer, and develop new diagnostic, preventive, and therapeutic strategies. A key knowledge gap in RMC biology is why sickle hemoglobinopathies predispose to the development of this cancer. We propose a model wherein the extreme conditions of hypoxia and hypertonicity of the renal medulla, combined with regional ischemia induced by red blood cell sickling, activate DNA repair mechanisms to drive deletions and translocations in SMARCB1, which is localized in a fragile region of chromosome 22. This mechanism would explain the linkage between RMC and sickle hemoglobinopathies, as well as the age dependence and predilection of RMC toward the right kidney.Significance: This perspective proposes an integrated and testable model of renal medullary carcinoma pathogenesis. Insights provided by this model can additionally inform other malignancies arising from the renal medulla and/or associated with loss of the SMARCB1 tumor suppressor gene. Clin Cancer Res; 24(9); 2044-9. ©2018 AACR.