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Endocrinology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
Institute of Metabolism and System Research, University of Birmingham, Birmingham, UK
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Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
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Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
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Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
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Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
Department of Endocrinology and Diabetes, University Hospital of Wurzburg, Wurzburg, Germany
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Summary
The spectrum of endocrine-related complications of COVID-19 infection is expanding; one of the most concerning of which is adrenal haemorrhage due to the risk of catastrophic adrenal crisis. In this study, we present a case that highlights the challenging management of a large, indeterminate unilateral adrenal mass during pregnancy and draws attention to a rare yet probably underestimated complication of COVID-19. During hospitalization for severe COVID-19 pneumonia, a 26-year-old woman was incidentally found to have a 12.5 cm heterogeneous left adrenal mass. Soon after the discovery, she became pregnant and upon referral, she was in the seventh week of gestation, without clinical or biochemical features of hormonal excess. The uncertainty of the diagnosis and the risks of malignancy and surgical intervention were discussed with the patient, and a period of radiological surveillance was agreed upon. An MRI scan performed 3 months later showed a size reduction of the adrenal lesion to 7.9 cm, which was against malignancy. A Doppler ultrasound showed a non-vascular, well-defined round lesion consistent with an adrenal haematoma, likely a complication of the recent COVID-19 infection. The multidisciplinary team recommended further radiological follow-up. The patient then spontaneously had miscarriage at 12 weeks gestation. Subsequent radiological surveillance showed a further size reduction of the adrenal lesion to 5.5 cm. The patient conceived again during follow-up, and the repeated Doppler ultrasound showed stable appearances of the adrenal mass, and thus, it was agreed to continue radiological monitoring after delivery. The pregnancy was uneventful, and the patient delivered a healthy baby. An MRI scan performed after delivery showed a stable but persistent lesion consistent with a likely underlying adrenal lesion.
Learning points
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Unilateral adrenal haemorrhage can occur as a complication of COVID-19 and should be considered in the differential diagnosis of heterogeneous adrenal masses if there is a history of recent infection.
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Management of large indeterminate adrenal masses during pregnancy poses several challenges and should be led by an experienced multidisciplinary team.
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Underlying adrenal tumours may trigger non-traumatic haemorrhages, especially if exacerbated by stressful illness.
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Summary
A 33-year-old female presented in 2013 with left flank pain. Ultrasound and MRI pelvis showed a complex mass 9 × 7 cm arising from the left ovary suggestive of ovarian torsion. She underwent a laparoscopic cystectomy, but the patient was lost to follow-up. Three years later, she presented with abdominal distension. Ultrasound and CT scan revealed a solid left ovarian mass with ascites and multiple peritoneal metastasis. Investigations showed elevated CA 125, CA 19-9. Ovarian malignancy was suspected. She underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy on November 2016. The histopathology confirmed a well-differentiated thyroid cancer of ovarian origin with features of a papillary follicular variant without evidence of ovarian cancer and the thyroglobulin (Tg) level was elevated, more than 400 consistent with the diagnosis of malignant struma ovarii. The follow-up post-surgery showed normalization of CA 125, CA 19-9 and Tg. The patient underwent total thyroidectomy on January 2017. The histology was benign excluding thyroid cancer metastases to the ovary. She was started on thyroxine suppression, following which she received two ablation doses 131iodine (131I) each 5.3 GBq. The Tg remains slightly elevated at less than 10. 131I WBS showed no residual neck uptake and no distant avid metastasis. She was planned for molecular analysis which may indicate disease severity. We describe a case of malignant struma ovarii with widespread metastatic dissemination and a good response to surgery and 131I treatment without recurrence after 5 years of follow-up. The Tg remains slightly elevated indicating minimal stable residual disease.
Learning points
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Malignant struma ovarii is a rare disease; diagnosis is difficult and management is not well defined.
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Presentation may mimic advanced carcinoma of the ovary.
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Predominant sites of metastasis are adjacent pelvic structures.
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Thyroidectomy and 131iodine therapy should be considered. The management should be similar to that of metastatic thyroid cancer.
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Summary
The Covid-19 vaccination has been rapidly implemented among patients with cancer. We present two cases of patients with endocrine tumours who developed lymphadenopathy following a Covid-19 vaccination. In the case of a patient with multiple endocrine neoplasia (MEN) 1 syndrome, an 18-fluorodeoxyglucose (18FDG)-PET/CT showed positive axillary lymph nodes. Further work-up with fine needle aspiration showed a reactive pattern following a Covid-19 vaccination in the ipsilateral arm shortly before the 18FDG-PET/CT. A second patient, in follow-up for thyroid cancer, developed clinical supraclavicular lymphadenopathy after a Covid-19 vaccination. Follow-up ultrasound proved the lesion to be transient. These cases demonstrate lymphadenopathy in response to a Covid-19 vaccination in two patients susceptible to endocrine tumours and metastatic disease. With growing evidence about the pattern and occurrence of lymphadenopathy after mRNA Covid-19 vaccination, recommendations for scheduling and interpretation of imaging among cancer patients should be implemented to reduce equivocal findings, overdiagnosis, and overtreatment, while maintaining a good standard of care in oncological follow-up.
Learning points
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Reactive lymphadenopathy is very common after an mRNA vaccination against Covid-19 and should be part of the differential diagnosis in patients with endocrine tumours who recently received a Covid-19 mRNA vaccination and present with an ipsilateral lymphadenopathy.
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A good vaccine history is essential in assessing the risk for lymphadenopathy and if possible, screening imaging in patients with endocrine tumours should be postponed at least 6 weeks after the previous vaccination.
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For now, a multidisciplinary care approach is recommended to determine the necessary steps in the diagnostic evaluation of lymphadenopathy in the proximity of a Covid-19 vaccination.
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Department of Pathological Anatomy, ZNA Hospitals, Antwerpen, Belgium
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Summary
Pituitary carcinoma is a rare type of malignancy and only accounts for 0.1–0.2% of all pituitary tumours. Most pituitary carcinomas are hormonally active and they are mostly represented by corticotroph and lactotroph carcinomas. Corticotroph carcinoma can present as symptomatic Cushing’s disease or can evolve from silent corticotroph adenoma which is not associated with clinical or biochemical evidence of hypercortisolism. We hereby present a case of a bone-metastasized corticotroph pituitary carcinoma masquerading as an ectopic adrenocorticotropic hormone (ACTH) syndrome in a patient with a history of a non-functioning pituitary macro-adenoma. Our patient underwent two transsphenoidal resections of the primary pituitary tumour followed by external beam radiation therapy. Under hydrocortisone substitution therapy she developed ACTH-dependent hypercortisolism without arguments for recurrence on pituitary MRI and without central-to-peripheral ACTH-gradient on inferior petrosal sinus sampling, both suggesting ectopic production. Ultimately, she was diagnosed with an ACTH-secreting vertebral metastasis originating from the primary pituitary tumour. This case report demonstrates the complex pathophysiology of pituitary carcinoma and the long diagnostic work-up. Certain features in pituitary adenoma should raise the suspicion of malignancy.
Learning points
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The diagnosis of pituitary carcinoma can only be made based on documented metastasis, therefore, due to the often long latency period between the detection of the primary tumour and the occurrence of metastasis, the diagnostic work-up most often spans over multiple years.
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Pituitary carcinoma including corticotroph carcinoma is very rare in contrast to pituitary adenoma and only accounts for 0.1–0.2% of all pituitary tumours.
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Histopathology in pituitary adenoma should certainly accomplish the following goals: accurate tumour subtyping and assessment of tumoural proliferative potential.
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Repeated recurrence of pituitary adenoma after surgical resection, a discrepancy between biochemical and radiological findings, resistance to medical and radiation therapy, and silent tumours becoming functional are all hallmarks of pituitary carcinoma.
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Silent corticotroph adenomas are non-functioning pituitary adenomas that arise from T-PIT lineage adenohypophyseal cells and that can express adrenocorticotropic hormone on immunohistochemistry, but are not associated with biochemical or clinical evidence of hypercortisolism. Silent corticotroph adenomas exhibit a more aggressive clinical behaviour than other non-functioning adenomas.
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Treatment options for corticotroph carcinoma include primary tumour resection, radiation therapy, medical therapy, and chemotherapy. Sometimes bilateral adrenalectomy is necessary to achieve sufficient control of the cortisol excess.
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Summary
An adrenocorticotropic hormone (ACTH)-producing pheochromocytoma (PCC)/paraganglioma is the cause of ectopic Cushing’s syndrome (CS) in 5.2% of cases reported in the literature. We present a previously healthy 43-year-old woman admitted to our hospital with cushingoid features and hypertensive urgency (blood pressure = 200/120 mmHg). Her 24-h urinary free cortisol was >4270 nmol/day (reference range (RR) = 100–380 nmol/day) with a plasma ACTH of 91.5 pmol/L (RR: 2.0–11.5 pmol/L). Twenty-four-hour urinary metanephrines were increased by 30-fold. Whole-body CT demonstrated a 3.7-cm left adrenal mass with a normal-appearing right adrenal gland. Sellar MRI showed a 5-mm sellar lesion. MIBG scan revealed intense uptake only in the left adrenal mass. She was managed pre-operatively with ketoconazole and phenoxybenzamine and underwent an uneventful left laparoscopic adrenalectomy, which resulted in biochemical resolution of her hypercortisolemia and catecholamine excess. Histology demonstrated a PCC (Grading System for Adrenal Pheochromocytoma and Paraganglioma score 5) with positive ACTH staining by immunohistochemistry. A PCC gene panel showed no mutations and there has been no evidence of recurrence at 24 months. This case highlights the difficult nature of localizing the source of CS in the setting of a co-existing PCC and sellar mass.
Learning points
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An adrenocorticotropic hormone (ACTH)-producing pheochromocytoma (PCC) is an important item to be considered in all patients presenting with ectopic Cushing’s syndrome (CS).
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In exceptionally rare cases, patients with ectopic CS may present with multiple lesions, and a systematic approach considering all potential sources is crucial to avoid misdiagnosis.
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CS with a large adrenal mass but lacking contralateral adrenal atrophy should raise suspicion of an ACTH-dependent process.
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In patients with clinical suspicion of PCC, clinicians should be mindful of the use of steroids and beta-blockers without appropriate alpha blockade as they may precipitate an adrenergic crisis.
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Summary
Autonomous thyroid adenomas are caused by activating mutations in the genes encoding the thyroid-stimulating hormone receptor (TSHR) or mutations in the Gas subunit of the TSHR. Nodules with suspicious sonographic features should be submitted to fine-needle aspiration. Additional molecular testing may be performed to characterize the thyroid nodule’s malignant potential further. We present a patient who underwent whole-transcriptome RNA-sequencing that indicated a TSHR I568T mutation after an ultrasound showed suspicious sonographic features and fine-needle aspiration was ‘suspicious for malignancy’. The patient underwent thyroid resection and was found to have a locally invasive classical papillary thyroid carcinoma. Most reports of TSHR I568T mutation have been seen in patients with benign thyroid conditions. While there is insufficient data to suggest that the TSHR I568T mutation causes aggressive thyroid malignancy, we believe clinicians who identify the presence of this mutation on genome sequencing should be cautious about the possibility of locally invasive thyroid malignancy, especially when associated with Bethesda V cytopathology.
Learning points
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Germline and somatic activating mutations in the genes coding for the thyroid-stimulating hormone receptor (TSHR) have been frequently reported in familial and sporadic autonomous thyroid adenomas and non-autoimmune hyperthyroidism.
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Most reports of TSHR I568T mutation have been detected in patients with benign thyroid conditions.
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We present a patient who underwent whole-transcriptome RNA-sequencing that indicated a TSHR I568T mutation and subsequently underwent thyroid resection and was found to have a locally invasive classical papillary thyroid carcinoma.
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Clinicians who identify the presence of TSHR I568T mutation on genome sequencing should be cautious about the possibility of locally invasive thyroid malignancy, especially when associated with Bethesda V cytopathology.
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Summary
Thyroid eye disease (TED) is the most common extra-thyroidal manifestation in Graves’ disease (GD). Additional/concurrent/synchronous pathologies may be present, especially in elderly patients who present with atypical features such as non-axial (or eccentric) proptosis, absence of lid lag and restricted superior extra-ocular movements. A 70-year-old female presented with progressive proptosis of her left eye and diplopia. She was diagnosed with GD a year prior and initiated on carbimazole. On examination, she had eccentric proptosis, restricted superior extra-ocular movements and a palpable mass in the supero-temporal quadrant of the left eye. Her T3 (1.33 ng/mL) and T4 (8.85 µg/dL) were normal with carbimazole. Thyroid-stimulating hormone (TSH)-receptor antibody was positive (3.15 IU/L, reference range <1.75). MRI revealed an enhancing lesion infiltrating the left superior rectus, with concurrent characteristic muscle belly involvement bilaterally. Orbital biopsy showed atypical lymphoid cells (CD20+), suggesting marginal zone lymphoma. CT thorax and abdomen, fluorodeoxyglucose-positron emission tomography and bone marrow examination were normal. The patient was administered orbital radiotherapy for her localised lymphoma and carbimazole was continued. TED is the most common cause of orbital involvement overall and in GD. However, additional or alternative pathology may be present which requires evaluation. MRI can be a useful adjunct in these patients. Orbital lymphoma needs to be staged with workup for disseminated disease. Radiotherapy is the treatment of choice for localized disease. The index case provides evidence for synchronous presentation of dual pathology and highlights the importance of astute clinical examination as well as keeps a low threshold for MRI in selected cases.
Learning points
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Thyroid eye disease can co-exist with other ocular pathology, especially in elderly individuals.
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Eccentric proptosis, absent lid lag and restriction of eye movements (suggesting tendon involvement) should alert towards the presence of alternative pathology.
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Orbital imaging using MRI not only has greater sensitivity in diagnosing radiologically bilateral disease in patients who have unilateral involvement clinically but is also useful to identify concurrent neoplasms.
The Faculty of Medicine, Technion, Haifa, Israel
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The Faculty of Medicine, Technion, Haifa, Israel
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Severe hypocalcaemia in breast cancer with bone metastasis is a rare finding usually associated with an advanced stage of the disease. We report a case of a 45-year-old woman with a history of local ductal carcinoma in situ (DCIS) of the breast, who presented with muscle tremors and general weakness. Hypocalcaemia was evident, with a positive Chvostek sign and a serum calcium level of 5.9 mg/dL (1.47 mmol/L), phosphorus 5.9 mg/dL (normal range: 2.3–4.7 mg/dL) with normal levels of albumin, magnesium and parathyroid hormone. High oral doses of alpha calcitriol and calcium with i.v. infusion of high calcium doses were instituted, altogether sufficient to maintain only mild hypocalcaemia. A whole-body CT revealed bone lesions along the axial skeleton. A biopsy from a bone lesion revealed a metastasis of breast carcinoma. With this pathological finding, leuprolide (GNRH analogue) and chlorambucil (alkylating agent) were initiated, followed by prompt tapering of infused calcium down to full discontinuation. Serum calcium was kept stable close to the low normal range by high doses of oral alpha calcitriol and calcium. This course raises suspicion that breast metastases to the skeleton caused tumour-induced hypocalcaemia by a unique mechanism. We assume that hypocalcaemia in this case was promoted by a combination of hypoparathyroidism and bone metastasis.
Learning points
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Severe hypocalcaemia can a presenting symptom for breast cancer relapse.
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Summary
In July 2017, a 35-year-old woman was referred to our care for treatment of a large pituitary mass with an unusually high growth rate. She presented with right-sided ptosis and diplopia (n. III palsy), increasing retrobulbar pain and vertigo. Although laboratory investigations were consistent with acromegaly, she exhibited no clear phenotypic traits. During transsphenoidal surgery aimed at biopsy, typical adenomatous tissue was encountered, upon which it was decided to proceed to debulking. Histopathological analysis demonstrated a poorly differentiated plurihormonal Pit-1-positive adenoma with focal growth hormone (GH) and prolactin positivity, positive SSTR2 staining and a Ki-67 of 20–30%. Postoperative magnetic resonance imaging (MRI) examination revealed a large tumour remnant within the sella invading the right cavernous sinus with total encasement of the internal carotid artery and displacement of the right temporal lobe. As a consequence, she was treated additionally with radiotherapy, and a long-acting first-generation somatostatin analogue was prescribed. Subsequently, the patient developed secondary hypocortisolism and diabetes mellitus despite adequate suppression of GH levels. In September 2019, her symptoms recurred. Laboratory evaluations indicated a notable loss of biochemical control, and MRI revealed tumour progression. Lanreotide was switched to pasireotide, and successful removal of the tumour remnant and decompression of the right optic nerve was performed. She received adjuvant treatment with temozolomide resulting in excellent biochemical and radiological response after three and six courses. Symptoms of right-sided ptosis and diplopia remained. Evidence for systemic therapy in case of tumour progression after temozolomide is currently limited, although various potential targets can be identified in tumour tissue.
Learning points
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Poorly differentiated plurihormonal Pit-1-positive adenoma is a potentially aggressive subtype of pituitary tumours.
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This subtype can express somatostatin receptors, allowing treatment with somatostatin analogues.
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A multidisciplinary approach involving an endocrinologist, neurosurgeon, pituitary pathologist, neuroradiologist, radiation oncologist and medical oncologist is key for the management of patients with aggressive pituitary tumours, allowing the successful application of multimodality treatment.
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Temozolomide is first-line chemotherapy for aggressive pituitary tumours and carcinomas.
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Further development of novel targeted therapies, such as peptide receptor radionuclide therapy (PRRT), vascular endothelial growth factor (VEGF) receptor-targeted therapy, tyrosine kinase inhibitors, mammalian target of rapamycin (mTOR) inhibitors and immune checkpoint inhibitors, is needed.
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Department of Medicine, University College Dublin, Dublin, Ireland
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Department of Medicine, University College Dublin, Dublin, Ireland
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Summary
Thyroid dysfunction is among the most common immune-related adverse reactions associated with immune checkpoint inhibitors. It most commonly manifests as painless thyroiditis followed by permanent hypothyroidism. This usually causes mild toxicity that does not interfere with oncological treatment. In rare instances, however, a life-threatening form of decompensated hypothyroidism called myxoedema coma may develop. We present a case of myxoedema coma in a woman in her sixties who was treated with a combination of CTLA-4 and PD-1 immune checkpoint inhibitors; for stage four malignant melanoma. She became hypothyroid and required thyroxine replacement after an episode of painless thyroiditis. Six months after the initial diagnosis of malignant melanoma, she presented to the emergency department with abdominal pain, profuse diarrhoea, lethargy and confusion. She was drowsy, hypotensive with a BP of 60/40 mmHg, hyponatraemic and hypoglycaemic. Thyroid function tests (TFTs) indicated profound hypothyroidism with a TSH of 19 mIU/L, and undetectable fT3 and fT4, despite the patient being compliant with thyroxine. She was diagnosed with a myxoedema coma caused by immune-related enteritis and subsequent thyroxine malabsorption. The patient was treated with i.v. triiodothyronine (T3) and methylprednisolone in the ICU. While her clinical status improved with T3 replacement, her enteritis was refractory to steroid therapy. A thyroxine absorption test confirmed persistent malabsorption. Attempts to revert to oral thyroxine were unsuccessful. Unfortunately, the patient’s malignant melanoma progressed significantly and she passed away four months later. This is the first reported case of myxoedema coma that resulted from two distinct immune-related adverse reactions, namely painless thyroiditis and enterocolitis.
Learning points
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Myxoedema coma, a severe form of decompensated hypothyroidism is a rare immunotherapy-related endocrinopathy.
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Myxedema coma should be treated with either i.v. triiodothyronine (T3) or i.v. thyroxine (T4).
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Intravenous glucocorticoids should be co-administered with thyroid hormone replacement to avoid precipitating an adrenal crisis.
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Thyroid function tests (TFTs) should be monitored closely in individuals with hypothyroidism and diarrhoea due to the risk of thyroxine malabsorption.
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A thyroxine absorption test can be used to confirm thyroxine malabsorption in individuals with persistent hypothyroidism.
