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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.
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Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria, Australia
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Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria, Australia
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Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria, Australia
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Summary
Adrenocortical carcinoma is a rare disease with poor prognosis whose clinical heterogeneity can at times present a challenge to accurate and timely diagnosis. We present the case of a patient who presented with extensive pulmonary lesions, mediastinal and hilar lymphadenopathy and an adrenal mass in whom the oncological diagnosis was initially uncertain. Through the use of immunohistochemistry, biochemistry and genomic testing, an accurate diagnosis of adrenocortical carcinoma was ultimately made which resulted in more directed treatment being administered. The use of multidisciplinary input and genomics to aid in diagnosis and prognosis of adrenocortical carcinoma is discussed.
Learning points
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Adrenocortical carcinomas can present a diagnostic challenge to clinicians given it is a rare malignancy with significant clinical heterogeneity.
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Specialist multidisciplinary team input is vital in the diagnosis and management of adrenocortical carcinomas.
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Hormonal testing is recommended in the diagnostic workup of adrenal masses, even in the absence of overt clinical signs/symptoms of hormone excess.
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Immunostaining for the highly sensitive and specific steroidogenic factor-1 is vital for accurate diagnosis.
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Genomics can provide prognostic utility in management of adrenocortical carcinoma.
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School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, Australia
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Surgical Services, John Hunter Hospital, Newcastle, New South Wales, Australia
University of Newcastle, Newcastle, New South Wales, Australia
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Department of Endocrinology, John Hunter Hospital, Newcastle, New South Wales, Australia
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Summary
We report concurrent metastatic prostatic adenocarcinoma (PC) and functioning androgen-secreting adrenocortical carcinoma (ACC) in a 77-year-old man. The failure to achieve adequate biochemical castration via androgen deprivation therapy (ADT) as treatment for PC metastases, together with elevated DHEA-S, androstenedione, and discordant adrenal tracer uptake on FDG-PET and PSMA-PET, suggested the presence of a concurrent functional primary adrenal malignancy. On histopathological analysis, scant foci of PC were present throughout the ACC specimen. Castration was achieved post adrenalectomy with concurrent drop in prostate-specific antigen. We outline the literature regarding failure of testosterone suppression on ADT and salient points regarding diagnostic workup of functioning adrenal malignancies.
Learning points
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Failure to achieve castration with androgen deprivation therapy is rare and should prompt careful review to identify the underlying cause.
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All adrenal lesions should be evaluated for hormone production, as well as assessed for risk of malignancy (either primary or secondary).
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Adrenocortical carcinomas are commonly functional, and can secrete steroid hormones or their precursors (androgens, progestogens, glucocorticoids and mineralocorticoids).
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In this case, a co-incident, androgen-producing adrenocortical carcinoma was the cause of failure of testosterone suppression from androgen deprivation therapy as treatment for metastatic prostate cancer. Pathological adrenal androgen production contributed to the progression of prostate cancer.
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Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Victoria, Australia
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Department of Endocrinology, Monash Health, Victoria, Australia
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Department of Endocrinology, Monash Health, Victoria, Australia
Department of Medicine, School of Clinical Sciences, Monash University, Victoria, Australia
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Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Victoria, Australia
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Summary
Insulin autoimmune syndrome (IAS) is a rare cause of non-islet cell hypoglycaemia. Treatment of this condition is complex and typically involves long-term use of glucocorticoids. Immunotherapy may provide an alternative in the management of this autoimmune condition through the suppression of antibodies production by B-lymphocyte depletion. We present a case of a 62-year-old male, with refractory hypoglycaemia initially presenting with hypoglycaemic seizure during an admission for acute psychosis. Biochemical testing revealed hypoglycaemia with an inappropriately elevated insulin and C-peptide level and no evidence of exogenous use of insulin or sulphonylurea. Polyethylene glycol precipitation demonstrated persistently elevated free insulin levels. This was accompanied by markedly elevated anti-insulin antibody (IA) titres. Imaging included CT with contrast, MRI, pancreatic endoscopic ultrasound and Ga 68-DOTATATE position emission tomography (DOTATATE PET) scan did not reveal islet cell aetiology for hyperinsulinaemia. Maintenance of euglycaemia was dependent on oral steroids and dextrose infusion. Complete resolution of hypoglycaemia and dependence on glucose and steroids was only achieved following treatment with plasma exchange and rituximab.
Learning points
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Insulin autoimmune syndrome (IAS) should be considered in patients with recurrent hyperinsulinaemic hypoglycaemia in whom exogenous insulin administration and islet cell pathologies have been excluded.
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Biochemical techniques play an essential role in establishing high insulin concentration, insulin antibody titres, and eliminating biochemical interference. High insulin antibody concentration can lead to inappropriately elevated serum insulin levels leading to hypoglycaemia.
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Plasma exchange and B-lymphocyte depletion with rituximab and immunosuppression with high dose glucocorticoids are effective in reducing serum insulin levels and hypoglycaemia in insulin autoimmune syndrome (IAS).
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Based on our observation, the reduction in serum insulin level may be a better indicator of treatment efficacy compared to anti-insulin antibody (IA) titre as it demonstrated greater correlation to the frequency of hypoglycaemia and to hypoglycaemia resolution.
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.
Search for other papers by Florence Gunawan in
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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.
Diabetes and Metabolism, Garvan Institute of Medical Research, Sydney, New South Wales, Australia
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St Vincent’s Clinical School, UNSW Sydney, Darlinghurst, New South Wales, Australia
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Diabetes and Metabolism, Garvan Institute of Medical Research, Sydney, New South Wales, Australia
St Vincent’s Clinical School, UNSW Sydney, Darlinghurst, New South Wales, Australia
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Summary
Durvalumab is a programmed cell death ligand 1 inhibitor, which is now approved in Australia for use in non-small-cell lung and urothelial cancers. Autoimmune diabetes is a rare immune-related adverse effect associated with the use of immune checkpoint inhibitor therapy. It is now being increasingly described reflecting the wider use of immune checkpoint inhibitor therapy. We report the case of a 49-year-old female who presented with polyuria, polydipsia and weight loss, 3 months following the commencement of durvalumab. On admission, she was in severe diabetic ketoacidosis with venous glucose: 20.1 mmol/L, pH: 7.14, bicarbonate 11.2 mmol/L and serum beta hydroxybutyrate: >8.0 mmol/L. She had no personal or family history of diabetes or autoimmune disease. Her HbA1c was 7.8% and her glutamic acid decarboxylase (GAD) antibodies were mildly elevated at 2.2 mU/L (reference range: <2 mU/L) with negative zinc transporter 8 (ZnT8) and islet cell (ICA) antibodies. Her fasting C-peptide was low at 86 pmol/L (reference range: 200–1200) with a corresponding serum glucose of 21.9 mmol/L. She was promptly stabilised with an insulin infusion in intensive care and discharged on basal bolus insulin. Durvalumab was recommenced once her glycaemic control had stabilised. Thyroid function tests at the time of admission were within normal limits with negative thyroid autoantibodies. Four weeks post discharge, repeat thyroid function tests revealed hypothyroidism, with an elevated thyroid-stimulating hormone (TSH) at 6.39 mIU/L (reference range: 0.40–4.80) and low free T4: 5.9 pmol/L (reference range: 8.0–16.0). These findings persisted with repeat testing despite an absence of clinical symptoms. Treatment with levothyroxine was commenced after excluding adrenal insufficiency (early morning cortisol: 339 nmol/L) and hypophysitis (normal pituitary on MRI).
Learning points:
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Durvalumab use is rarely associated with fulminant autoimmune diabetes, presenting with severe DKA.
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Multiple endocrinopathies can co-exist with the use of a single immune checkpoint inhibitors; thus, patients should be regularly monitored.
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Regular blood glucose levels should be performed on routine pathology on all patients on immune checkpoint inhibitor.
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Clinician awareness of immunotherapy-related diabetes needs to increase in an attempt to detect hyperglycaemia early and prevent DKA.
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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.
