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Open access

Ali A Zaied, Halis K Akturk, Richard W Joseph and Augustine S Lee

Summary

Nivolumab, a monoclonal antibody against programmed cell death-1 receptor, is increasingly used in advanced cancers. While nivolumab use enhances cancer therapy, it is associated with increased immune-related adverse events. We describe an elderly man who presented in ketoacidosis after receiving nivolumab for metastatic renal cell carcinoma. On presentation, he was hyperpneic and laboratory analyses showed hyperglycemia and anion-gapped metabolic acidosis consistent with diabetic ketoacidosis. No other precipitating factors, besides nivolumab, were identified. Pre-nivolumab blood glucose levels were normal. The patient responded to treatment with intravenous fluids, insulin and electrolyte replacement. He was diagnosed with insulin-dependent autoimmune diabetes mellitus secondary to nivolumab. Although nivolumab was stopped, he continued to require multiple insulin injection therapy till his last follow-up 7 months after presentation. Clinicians need to be alerted to the development of diabetes mellitus and diabetic ketoacidosis in patients receiving nivolumab.

Learning points:

  • Diabetic ketoacidosis should be considered in the differential of patients presenting with metabolic acidosis following treatment with antibodies to programmed cell death-1 receptor (anti-PD-1).

  • Autoimmune islet cell damage is the presumed mechanism for how insulin requiring diabetes mellitus can develop de novo following administration of anti-PD-1.

  • Because anti-PD-1 works by the activation of T-cells and reduction of ‘self-tolerance’, other autoimmune disorders are likely to be increasingly recognized with increased use of these agents.

Open access

Ploutarchos Tzoulis, Richard W Corbett, Swarupini Ponnampalam, Elly Baker, Daniel Heaton, Triada Doulgeraki and Justin Stebbing

Summary

Five days following the 3rd cycle of nivolumab, a monoclonal antibody, which acts as immune checkpoint inhibitor against the programmed cell death protein-1, for metastatic lung adenocarcinoma, a 56-year-old woman presented at the hospital critically ill. On admission, she had severe diabetic ketoacidosis (DKA), as evidenced by venous glucose of 47 mmol/L, blood ketones of 7.5 mmol/L, pH of 6.95 and bicarbonate of 6.6 mmol/L. She has had no personal or family history of diabetes mellitus (DM), while random venous glucose, measured 1 week prior to hospitalisation, was 6.1 mmol/L. On admission, her HbA1c was 8.2% and anti-GAD antibodies were 12 kIU/L (0–5 kU/L), while islet cell antibodies and serum C-peptide were undetectable. Nivolumab was recommenced without the development of other immune-mediated phenomena until 6 months later, when she developed hypothyroidism with TSH 18 U/L and low free T4. She remains insulin dependent and has required levothyroxine replacement, while she has maintained good radiological and clinical response to immunotherapy. This case is notable for the rapidity of onset and profound nature of DKA at presentation, which occurred two months following commencement of immunotherapy. Despite the association of nivolumab with immune-mediated endocrinopathies, only a very small number of patients developing type 1 DM has been reported to date. Patients should be closely monitored for hyperglycaemia and thyroid dysfunction prior to and periodically during immunotherapy.

Learning points:

  • Nivolumab can induce fulminant type 1 diabetes, resulting in DKA.

  • Nivolumab is frequently associated with thyroid dysfunction, mostly hypothyroidism.

  • Nivolumab-treated patients should be monitored regularly for hyperglycaemia and thyroid dysfunction.

  • Clinicians should be aware and warn patients of potential signs and symptoms of severe hyperglycaemia.

Open access

Marina Tsoli, Anna Angelousi, Dimitra Rontogianni, Constantine Stratakis and Gregory Kaltsas

Summary

Parathyroid carcinoma is an extremely rare endocrine malignancy that accounts for less than 1% of cases of primary hyperparathyroidism. We report a 44-year-old woman who presented with fatigue and diffuse bone pain. Laboratory findings revealed highly elevated serum calcium and parathyroid hormone (PTH) levels and a 4.5 × 3 × 2.5 cm cystic lesion in the lower pole of the right thyroid lobe that was shown histologically to be a parathyroid carcinoma. Ten years later, the patient developed brain and pulmonary metastases and recurrence of PTH-related hypercalcemia. Treatment of hypercalcemia along with localized radiotherapy and various chemotherapy regimens failed to induce a biochemical or radiological response. In conclusion, parathyroid carcinoma is a rare neoplasia that may develop metastases even after prolonged follow-up, for which there is no evidence-based treatment besides surgery. Different chemotherapeutic schemes did not prove to be of any benefit in our case highlighting the need for registering such patients to better understand tumor biology and develop specific treatment.

Learning points:

  • Metastases can develop many years after parathyroid cancer diagnosis.

  • Surgery is the only curative treatment for parathyroid carcinoma.

  • Chemotherapy and radiotherapy prove to be ineffective in parathyroid cancer treatment.

  • Patient registering is required in order to delineate underlining pathology and offer specific treatment.

Open access

Tsung-Chun Huang, Yu-Kai Cheng, Tsung-Wei Chen, Yung-Chang Hsu, En-Wei Liu and Hsin-Han Chen

Summary

Thyroid cancer with cranial metastasis in a pregnant woman is very rare. In the literature, most cases are diagnosed early from neurogenic signs or symptomatic thyroid gland. Pregnancy also contributes to a hesitation toward early surgical and medical treatments. We reported a scalp tumor in a physically healthy 37-year-old pregnant female with a follicular thyroid carcinoma (FTC) with lung, bone and cranial metastasis in initial presentation. Silent neurogenic and physical examinations make an early diagnosis very challenging. Resection of scalp and intracranial tumor, a thyroidectomy, post-operative radioactive iodine therapy and tyrosine kinase inhibitors were employed as treatment. The scalp tumor was confirmed as a metastatic follicular thyroid carcinoma via positive immunoreactivity for thyroglobulin and thyroid transcription factor 1 in tumor cells. Blood examination revealed an elevated thyroglobulin level (>5335 ng/mL). The patient was discharged without any neurological deficit. An asymptomatic scalp tumor in a pregnant woman with a normal thyroid disease history needs differential diagnosis from intracranial origin. Rapid progression and an elevated thyroglobulin level are the indicators that further image study is needed. Aggressive surgical excision of resectable thyroid gland and metastatic tumor are essential for a longer survival rate. There is nothing to indicate that a post-partum operation will worsen prognosis.

Learning points:

  • Follicular thyroid cancer with cranial metastasis in initial presentation can be asymptomatic.

  • Follicular thyroid cancer with cranial metastasis in a pregnant woman can be treated after delivery.

  • Rapid enlargement of scalp tumor is indicated for further image study even in a patient without any neurological deficit.

Open access

Jin-Ying Lu, Po-Ju Hung, Pei-Lung Chen, Ruoh-Fang Yen, Kuan-Ting Kuo, Tsung-Lin Yang, Chih-Yuan Wang, Tien-Chun Chang, Tien-Shang Huang and Ching-Chung Chang

Summary

We report a case of follicular thyroid carcinoma with concomitant NRAS p.Q61K and GNAS p.R201H mutations, which manifested as a 13.5 cm thyroid mass with lung, humerus and T9 spine metastases, and exhibited good response to radioactive iodine treatment.

Learning points

  • GNAS p.R201H somatic mutation is an activating or gain-of-function mutation resulting in constitutively activated Gs-alpha protein and downstream cAMP cascade, independent of TSH signaling, causing autonomously functioning thyroid nodules.

  • NRAS p.Q61K mutations with GNAS p.R201H mutations are known for a good radioactive iodine treatment response.

  • Further exploration of the GNAS-activating pathway may provide therapeutic insights into the treatment of metastatic follicular carcinoma.

Open access

Reiner Jumpertz von Schwartzenberg, Ulf Elbelt, Manfred Ventz, Knut Mai, Tina Kienitz, Lukas Maurer, Thomas Rose, Jens C Rückert, Christian J Strasburger and Joachim Spranger

Parathyroid carcinoma is a rare disease leading to severe hypercalcemia due to hyperparathyroidism. Surgery is the primary treatment option. A more progressive form of the disease is characterized by parathyrotoxicosis, and subsequent hypercalcemia is the most common cause of death. We report a case presenting with severe hypercalcemia due to parathyrotoxicosis from parathyroid carcinoma treated for the first time using the monoclonal antibody denosumab as a rescue therapy and present long-term follow-up data. The 71-year-old patient presented with severe hypercalcemia due to metastatic parathyroid carcinoma. Despite undergoing treatment with bisphosphonates, cinacalcet hydrochloride, and forced diuresis, the patient`s condition deteriorated rapidly due to resistant hypercalcemia. Surgery performed because of spinal metastasis and forced diuresis lowered calcium levels, albeit they remained in the hypercalcemic range and significantly increased when forced diuresis was stopped. Considering a palliative situation to overcome hypercalcemia, we decided to administer denosumab, a monoclonal antibody that binds to the receptor activator of nuclear factor-kappa B ligand. After a single subcutaneous administration of 60 mg denosumab, calcium levels normalized within one day. Subsequent denosumab injections led to permanent control of serum calcium for more than 2 years despite rising parathyroid hormone levels and repeated surgeries. Together with recent cases in the literature supporting our observation, we believe that denosumab is relevant for future trials and represents an effective tool to control hypercalcemia in patients with advanced stages of parathyroid cancer.

Learning points

  • Severe hypercalcemia is the most common cause of death in patients with parathyroid carcinoma.

  • The monoclonal antibody denosumab rapidly lowered severely elevated serum calcium levels due to parathyrotoxicosis.

  • Denosumab was effective in the long-term treatment of hypercalcemia despite progression of parathyroid carcinoma.

Open access

Maura Bucciarelli, Ya-Yu Lee and Vasudev Magaji

Summary

Ectopic ACTH secretion from breast cancer is extremely rare. We report a case of a 30-year-old woman with a history of breast cancer, who presented with psychosis and paranoid behaviour. CT of the head showed white matter disease consistent with posterior reversible encephalopathy syndrome (PRES). Despite using mifepristone with multiple antihypertensives including lisinopril, spironolactone and metoprolol, she was hypertensive. Transaminitis did not allow mifepristone dose escalation and ketoconazole utilization. Etomidate infusion at a non-sedating dose in the intensive care unit controlled her hypertension and cortisol levels. She was transitioned to metyrapone and spironolactone. She was discharged from the hospital on metyrapone with spironolactone and underwent chemotherapy. She died 9 months later after she rapidly redeveloped Cushing's syndrome and had progressive metastatic breast cancer involving multiple bones, liver and lungs causing respiratory failure.

Learning points

  • Cushing's syndrome from ectopic ACTH secreting breast cancer is extremely rare.

  • Cushing's syndrome causing psychosis could be multifactorial including hypercortisolism and PRES.

  • Etomidate at non-sedating doses in intensive care setting can be effective to reduce cortisol production followed by transition to oral metyrapone.

Open access

K Nadarasa, M Bailey, H Chahal, O Raja, R Bhat, C Gayle, A B Grossman and M R Druce

Summary

We present the case of a patient with metastatic parathyroid carcinoma whose hypercalcaemia was medically managed through two pregnancies. The diagnosis was made when the patient presented with chronic knee pain and radiological findings consistent with a brown tumour, at the age of 30. Her corrected calcium and parathyroid hormone (PTH) levels were significantly elevated. Following localisation studies, a right parathyroidectomy was performed with histology revealing parathyroid carcinoma, adherent to thyroid tissue. Aged 33, following biochemical recurrence of disease, the patient underwent a second operation. A subsequent CT and FDG–PET revealed bibasal pulmonary metastases. Aged 35, the patient was referred to our unit for treatment of persistent hypercalcaemia. The focus of treatment at this time was debulking metastatic disease using radiofrequency ablation. Despite advice to the contrary, the patient conceived twice while taking cinacalcet. Even though there are limited available data regarding the use of cinacalcet in pregnancy, both pregnancies continued to term with the delivery of healthy infants, using intensive medical management for persistent hypercalcaemia.

Learning points

  • Parathyroid carcinoma is a rare cause of primary hyperparathyroidism.

  • Hypercalcaemia during pregnancy can result in significant complications for both the mother and the foetus.

  • The use of high-dose cinacalcet in pregnancy has been shown, in this case, to aid in the management of resistant hypercalcaemia without teratogenicity.

Open access

S Solomou, R Khan, D Propper, D Berney and M Druce

Summary

A 33-year-old male was diagnosed with a metastatic neuroendocrine carcinoma of uncertain primary. He defaulted from follow-up without therapy and some months later developed episodic severe hypoglycaemia, which was found to be associated with inappropriately elevated insulin and C-peptide levels. It was considered likely that the neuroendocrine tumour was the source of the insulin secretion. Diazoxide and somatostatin analogue were used to control hypoglycaemia. Much later in the course of the disease, he developed metabolic derangement, increased skin pigmentation and psychological disturbance, without frankly Cushingoid physical findings. Investigations revealed highly elevated cortisol levels (the levels having previously been normal) with markedly raised ACTH levels, consistent with the co-secretion of ACTH and insulin by the tumour. Treatment with metyrapone improved his psychological state and electrolyte imbalance. Unfortunately, despite several cycles of first-, second- and third-line chemotherapy from the start of the first hormonal presentation onwards, imaging revealed widespread progressive metastatic disease and the patient eventually passed away. This case highlights the importance of keeping in mind the biochemical heterogeneity of endocrine tumours during their treatment.

Learning points

  • The clinical presentation of insulin-secreting tumours includes symptoms of neuroglycopaenia and sympathetic overstimulation.

  • Tumour-associated hypoglycaemia can be due to pancreatic insulinomas, and although ectopic hormone production occurs in a number of tumours, ectopic secretion of insulin is rare.

  • A possible switch in the type of hormone produced can occur during the growth and progression of neuroendocrine tumours and, when treating neuroendocrine tumours, it is important to keep in mind their biochemical heterogeneity.

Open access

Mauro Boronat, Juan J Cabrera, Carmen Perera, Concepción Isla and Francisco J Nóvoa

Summary

A man underwent total thyroidectomy for goiter when he was 62 years old. The pathology report informed on a 5.5 cm oncocytic follicular adenoma and a 3.5 mm papillary microcarcinoma. Due to the papillary tumor, he was treated with ablative radioiodine therapy and suppressive doses of levothyroxine. After uneventful follow-up for 9 years, increased levels of serum thyroglobulin were detected. Further imaging studies including a whole body scan (WBS) after an empirical dose of 200 mCi 131I were negative. Two years later, a 99mTc SestaMIBI WBS and a 2-[18F]-fluoro-2-deoxy-d-glucose positron-emission tomography showed a well-delimited focal uptake in the right femur. A bone biopsy of the lesion demonstrated metastasis of follicular thyroid carcinoma. Retrospective histological reexamination of available material from the primary oncocytic thyroid tumor failed to reveal definitive traits of malignancy.

Learning points

  • Oncocytic follicular thyroid tumors are a relatively uncommon variant of follicular thyroid neoplasms mostly composed of distinctive large oxyphilic cells (Hürthle cells).

  • Criteria for the distinction between benign and malignant oncocytic neoplasms are not different from those used in the diagnosis of ordinary follicular tumors.

  • Some cases of apparently benign oncocytic neoplasms have been found to develop malignant behavior.

  • Search to rule out vascular and capsular invasion should be particularly exhaustive in histological assessment of oncocytic thyroid tumors.

  • Even so, long-term surveillance remains appropriate for patients with large apparently benign oncocytic tumors.