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University of Melbourne, Parkville, Victoria, Australia
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Summary
Acanthosis nigricans (AN) is a common dermatosis associated with hyperinsulinemia and insulin resistance. However, AN has been rarely reported in patients with insulinoma, a state of persistent hyperinsulinemia. We present a case of metastatic insulinoma, in whom AN manifested after the first cycle of peptide receptor radionuclide therapy (PRRT). A 40-year-old man was diagnosed with metastatic insulinoma after 5 months of symptomatic hypoglycemia. Within 1 month post PRRT, the patient became euglycemic but developed a pigmented, pruritic rash which was confirmed on biopsy as AN. We discuss the rare manifestation of AN in subjects with insulinoma, the role of insulin in the pathogenesis of AN, malignant AN in non-insulin-secreting malignancies and association with other insulin-resistant endocrinopathies such as acromegaly.
Learning points
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Acanthosis nigricans (AN) is a common dermatosis which is typically asymptomatic and associated with the hyperinsulinemic state.
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Malignant AN can rapidly spread, cause pruritus and affect mucosa and the oral cavity.
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AN is extremely rare in patients with insulinoma despite marked hyperinsulinemia.
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Peptide receptor radionuclide therapy might have triggered TGF-α secretion in this subject which led to malignant AN.
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Rapid spread or unusual distribution of pruritic AN warrants further investigation to exclude underlying malignancy.
Faculty of Medicine, The University of Queensland, Brisbane, Australia
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Faculty of Medicine, The University of Queensland, Brisbane, Australia
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Department of Radiology, Royal Brisbane and Women’s Hospital, Brisbane, Australia
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Faculty of Medicine, The University of Queensland, Brisbane, Australia
Institute of Health and Biomedical Innovation, Faculty of Health, Queensland University of Technology, Translational Research Institute, Princess Alexandra Hospital, Brisbane Australia
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Summary
A 34-year-old woman presented 18 months post-partum with blurred vision, polyuria, amenorrhoea, headache and general malaise. Comprehensive clinical examination showed left superior temporal visual loss only. Initial investigations revealed panhypopituitarism and MRI demonstrated a sellar mass involving the infundibulum and hypothalamus. Lymphocytic hypophysitis was suspected and high dose glucocorticoids were commenced along with desmopressin and thyroxine. However, her vision rapidly deteriorated. At surgical biopsy, an irresectable grey amorphous mass involving the optic chiasm was identified. Histopathology was initially reported as granulomatous hypophysitis. Despite the ongoing treatment with glucocorticoids, her vision worsened to light detection only. Histopathological review revised the diagnosis to partially treated lymphoma. A PET scan demonstrated avid uptake in the pituitary gland in addition to splenic involvement, lymphadenopathy above and below the diaphragm, and a bone lesion. Excisional node biopsy of an impalpable infraclavicular lymph node confirmed nodular lymphocyte-predominant Hodgkin lymphoma. Hyper-CVAD chemotherapy was commenced, along with rituximab; fluid-balance management during chemotherapy (with its requisite large fluid volumes) was extremely complex given her diabetes insipidus. The patient is now in clinical remission. Panhypopituitarism persists; however, her vision has recovered sufficiently for reading large print and driving. To the best of our knowledge, this is the first reported case of Hodgkin lymphoma presenting initially as hypopituitarism.
Learning points
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Lymphoma involving the pituitary is exceedingly rare and, to the best of our knowledge, this is the first reported case of nodular lymphocyte-predominant Hodgkin lymphoma presenting as hypopituitarism.
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There are myriad causes of a sellar mass and this case highlights the importance of reconsidering the diagnosis when patients fail to respond as expected to appropriate therapeutic intervention.
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This case highlights the difficulties associated with managing panhypopituitary patients receiving chemotherapy, particularly when this involves large volumes of i.v. hydration fluid.
Blacktown Clinical School, School of Medicine, Western Sydney University, Sydney, Australia
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Garvan Institute of Medical Research, Sydney, Australia
St. Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, Australia
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Blacktown Clinical School, School of Medicine, Western Sydney University, Sydney, Australia
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Summary
Cushing’s disease is a rare disorder characterised by excessive cortisol production as a consequence of a corticotroph pituitary tumour. While the primary treatment is surgical resection, post-operative radiation therapy may be used in cases of ongoing inadequate hormonal control or residual or progressive structural disease. Despite improved outcomes, radiotherapy for pituitary tumours is associated with hypopituitarism, visual deficits and, rarely, secondary malignancies. We describe an unusual case of a 67-year-old female with presumed Cushing’s disease diagnosed at the age of 37, treated with transsphenoidal resection of a pituitary tumour with post-operative external beam radiotherapy (EBRT), ketoconazole for steroidogenesis inhibition, and finally bilateral adrenalectomy for refractory disease. She presented 30 years after her treatment with a witnessed generalised tonic-clonic seizure. Radiological investigations confirmed an extracranial mass infiltrating through the temporal bone and into brain parenchyma. Due to recurrent generalised seizures, the patient was intubated and commenced on dexamethasone and anti-epileptic therapy. Resection of the tumour revealed a high-grade osteoblastic osteosarcoma. Unfortunately, the patient deteriorated in intensive care and suffered a fatal cardiac arrest following a likely aspiration event. We describe the risk factors, prevalence and treatment of radiation-induced osteosarcoma, an exceedingly rare and late complication of pituitary irradiation. To our knowledge, this is the longest reported latency period between pituitary irradiation and the development of an osteosarcoma of the skull.
Learning points:
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Cushing’s disease is treated with transsphenoidal resection as first-line therapy, with radiotherapy used in cases of incomplete resection, disease recurrence or persistent hypercortisolism.
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The most common long-term adverse outcome of pituitary tumour irradiation is hypopituitarism occurring in 30–60% of patients at 10 years, and less commonly, vision loss and oculomotor nerve palsies, radiation-induced brain tumours and sarcomas.
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Currently proposed characteristics of radiation-induced osteosarcomas include: the finding of a different histological type to the primary tumour, has developed within or adjacent to the path of the radiation beam, and a latency period of at least 3 years.
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Treatment of osteosarcoma of the skull include complete surgical excision, followed by systemic chemotherapy and/or radiotherapy.
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Overall prognosis in radiation-induced sarcoma of bone is poor.
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Newer techniques such as stereotactic radiosurgery may reduce the incidence of radiation-induced malignancies.
Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia
Department of Endocrinology and Diabetes, Royal North Shore Hospital, Sydney, New South Wales, Australia
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Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia
Department of Endocrinology and Diabetes, Royal North Shore Hospital, Sydney, New South Wales, Australia
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Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia
Department of Endocrinology and Diabetes, Royal North Shore Hospital, Sydney, New South Wales, Australia
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Summary
Struma ovarii is a rare, usually benign ovarian tumour with malignancy occurring in <5% of cases. Metastases, particularly seeding to bone, are extremely rare. Presentation is variable but often features local pain and/or ascites and hyperthyroidism may occur. It is not established how to best treat and follow patients with extensive disease. Case reports of radioiodine (I131) ablative therapy following thyroidectomy have shown reduced recurrence. We describe the case of a 33-year-old woman who presented with bone pain and was diagnosed with skeletal metastases with features of follicular thyroid carcinoma. However, thyroid pathology was benign. She recalled that 5 years prior, an ovarian teratoma was excised, classified at that time as a dermoid cyst. Retrospective review of this pathology confirmed struma ovarii without obvious malignant features. The patient was found to have widespread metastases to bone and viscera and her thyroglobulin was >3000 µg/L following recombinant TSH administration prior to her first dose of I131. At 25 months following radioiodine treatment, she is in remission with an undetectable thyroglobulin and clear I131 surveillance scans. This case demonstrates an unusual presentation of malignant struma ovarii together with challenges of predicting metastatic disease, and demonstrates a successful radioiodine regimen inducing remission.
Learning points:
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Malignant transformation of struma ovarii (MSO) is extremely rare and even rarer are metastatic deposits in bone and viscera.
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MSO can be difficult to predict by initial ovarian pathology, analogous to the difficulty in some cases of differentiating between follicular thyroid adenoma and carcinoma.
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No consensus exists on the management for post operative treatment of MSO; however, in this case, three doses of 6Gbq radioiodine therapy over a short time period eliminated metastases to viscera and bone.
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Patients should continue to have TSH suppression for ~5 years.
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Monitoring thyroglobulin levels can predict recurrence.
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Summary
Denosumab is a fully human MAB that acts as a potent anti-resorptive by inhibiting activation of osteoclasts by inhibiting the receptor activator of nuclear factor-kappa B (RANK) ligand. Hypocalcaemia has been reported as one of the serious adverse sequelae of use of denosumab. We present a case of refractory hypocalcaemia following administration of a single dose of denosumab in a patient with metastatic castrate-resistant prostate cancer. The patient’s serum calcium and vitamin D concentrations and renal function were normal prior to denosumab administration. Serum alkaline phosphatase (ALP) level was however elevated pre-morbidly consistent with known bone metastases. The patient was treated with high-dose oral and IV calcium without any appreciable response in serum calcium. During his 30-day hospital admission, he demonstrated disease progression with development of new liver metastases and bone marrow involvement. Normocalcaemia was not achieved despite 1 month of aggressive therapy. Given the patient was asymptomatic and prognosis guarded, he was eventually discharged for ongoing supportive care under the palliative care team.
Learning points:
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Denosumab is a potent anti-resorptive therapy and hypocalcaemia is one of the known adverse effects.
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Serum calcium and vitamin D concentrations must be replete prior to administration of denosumab to reduce the risk of hypocalcaemia.
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Denosumab has been proven to be more effective than zoledronic acid in preventing skeletal-related adverse effects in patients with metastatic castrate-resistant prostate cancer.
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Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Victoria, Australia
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Summary
We report a case of a 67-year-old man with type 2 diabetes presented with diabetic ketoacidosis, two weeks after his first dose of nivolumab therapy for non–small-cell lung carcinoma. He was started on empagliflozin two days prior in the setting of hyperglycaemia after the initiation of nivolumab therapy. Laboratory evaluation revealed an undetectable C-peptide and a positive anti-glutamic acid decarboxylase (GAD) antibody. He was treated with intravenous fluids and insulin infusion and was subsequently transitioned to subcutaneous insulin and discharged home. He subsequently has developed likely autoimmune thyroiditis and autoimmune encephalitis.
Learning points:
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Glycemic surveillance in patients receiving immune checkpoint inhibitors is recommended.
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Early glycemic surveillance after commencement of anti-programmed cell death-1 (PD-1) inhibitors may be indicated in selected populations, including patients with underlying type 2 diabetes mellitus and positive anti-glutamic acid decarboxylase (GAD) antibody.
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Sodium-glucose co transporter-2 (SGLT2) inhibitors should be used with caution in patients on immunotherapy.
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Department of Medicine, Monash University, Melbourne, Australia
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Summary
Insulinomas are rare neuroendocrine tumours that classically present with fasting hypoglycaemia. This case report discusses an uncommon and challenging case of insulinoma soon after upper gastrointestinal surgery. A 63-year-old man presented with 6 months of post-prandial hypoglycaemia beginning after a laparoscopic revision of Toupet fundoplication. Hyperinsulinaemic hypoglycaemia was confirmed during a spontaneous episode and in a mixed-meal test. Localisation studies including magnetic resonance imaging (MRI), endoscopic ultrasound (EUS) and gallium dotatate positron emission tomography (68Ga Dotatate PET) were consistent with a small insulinoma in the mid-body of the pancreas. The lesion was excised and histopathology was confirmed a localised well-differentiated neuroendocrine pancreatic neoplasm. There have been no significant episodes of hypoglycaemia since. This case highlights several key points. Insulinoma should be sought in proven post-prandial hyperinsulinaemic hypoglycaemia – even in the absence of fasting hypoglycaemia. The use of nuclear imaging targeting somatostatin and GLP1 receptors has improved accuracy of localisation. Despite these advances, accurate surgical resection can remain challenging.
Learning points:
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Hypoglycaemia is defined by Whipple’s triad and can be provoked by fasting or mixed-meal tests.
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Although uncommon, insulinomas can present with post-prandial hypoglycaemia.
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In hypoglycaemia following gastrointestinal surgery (i.e. bariatric surgery or less commonly Nissen fundoplication) dumping syndrome or non-insulinoma pancreatogenous hypoglycaemia syndrome (NIPHS) should be considered.
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Improved imaging techniques including MRI, endoscopic ultrasound and functional nuclear medicine scans aid localisation of insulinomas.
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Despite advances in imaging and surgical techniques, accurate resection of insulinomas remains challenging.
School of Medicine and Dentistry, James Cook University, Douglas, Queensland, Australia
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School of Medicine and Dentistry, James Cook University, Douglas, Queensland, Australia
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Summary
Autoimmune hypophysitis (AH) has been previously described in a typical demographic population, primarily women in the reproductive age group and perinatal period. The era of immune modulation using anti-cytotoxic T-lymphocyte-associated antigen 4 biological therapy (ipilimumab) against advanced cancers like metastatic melanomas has now resulted in a new form of hypophysitis being increasingly recognised under a spectrum of immune-related adverse events. Drug-related AH often presents with subtle symptoms and a pituitary mass, with the potential for fatality necessitating wide awareness and a high index of clinical suspicion given that it is usually treatable. We describe below two cases of AH within the last three months at our centre, which were treated with different regimens and produced good endocrine outcomes.
Learning points
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AH is a new and defined clinical entity occurring as a side effect of ipilimumab, which enhances immune-mediated destruction of metastatic melanoma.
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It can present insidiously and have life-threatening complications related to hypocortisolism, hence a high index of clinical suspicion must be exerted by treating physicians, and seems to result in resolution of pituitary masses and variable improvements of pituitary function.
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Clinical improvement, radiological resolution of pituitary masses and variable normalisation of pituitary function are possible with early treatment with high-dose oral or i.v. steroids and hormone replacement therapy, although duration and dosing protocols are unclear at this stage.
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Ipilimumab should continue to be prescribed as treatment for metastatic melanoma; however, close clinical observation of patient's progress must be maintained while they are on this drug.
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Predictive factors for onset of AH remain unclear and it is imperative that AH is distinguished from pituitary metastases.
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Further studies are required to determine the safety of continuing therapy with ipilimumab in patients who have developed AH while on treatment.
