Ellena CottonFaculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK Specialist Medicine, Manchester University Foundation Trust, Manchester, UK
A young woman carrying germline DICER1 mutation was discovered to have a pituitary microprolactinoma when she became amenorrhoic. The mutation was identified as a result of family screening following the early death of the patient’s daughter with ovarian cancer. The patient was in follow-up screening for thyroid disease, and investigations were initiated when she became amenorrhoic. MR scan revealed a 6 mm diameter pituitary microadenoma and raised prolactin. The prolactin was efficiently suppressed with low-dose cabergoline, and her menstrual cycles resumed. Dicer is an RNase enzyme, which is essential for processing small non-coding RNAs. These molecules play pleiotropic roles in regulating gene expression, by targeting mRNA sequences for degradation. DICER1 plays different roles depending on cell context, but is thought to be a functional tumour suppressor gene. Accordingly, germline mutation in one DICER1 allele is insufficient for oncogenesis, and a second hit on the other allele is required, as a result of postnatal somatic mutation. Loss of DICER1 is linked to multiple tumours, with prominent endocrine representation. Multinodular goitre is frequent, with increased risk of differentiated thyroid cancer. Rare, developmental pituitary tumours are reported, including pituitary blastoma, but not reports of functional pituitary adenomas. As DICER1 mutations are rare, case reports are the only means to identify new manifestations and to inform appropriate screening protocols.
DICER1 mutations lead to endocrine tumours.
DICER1 is required for small non-coding RNA expression.
DICER1 carriage and microprolactinoma are both rare, but here are reported in the same individual, suggesting association.
Endocrine follow-up of patients carrying DICER1 mutations should consider pituitary disease.
Secondary amenorrhoea and galactorrhoea represent a common endocrine presentation. We report a case of an oestrogen-producing juvenile granulosa cell tumour (JGCT) of the ovary in a 16-year-old post-pubertal woman with hyperprolactinaemia amenorrhoea and galactorrhoea which resolved following surgical resection of the tumour. This patient presented with a 9-month history of secondary amenorrhoea and a 2-month history of galactorrhoea. Elevated serum prolactin at 7081 mIU/l and suppressed gonadotropins (LH <0.1 U/l; FSH <0.1 U/l) were detected. Serum oestradiol was significantly elevated at 7442 pmol/l with undetectable β-human chorionic gonadotropin. MRI showed a bulky pituitary with no visible adenoma. MRI of the abdomen showed a 4.8 cm mass arising from the right ovary with no evidence of metastatic disease. Serum inhibin B was elevated at 2735 ng/l. A right salpingo-oophorectomy was performed, and histology confirmed the diagnosis of a JGCT, stage International Federation of Gynaecology and Obstetrics 1A. Immunohistochemical staining for prolactin was negative. Post-operatively, oestrogen and prolactin levels were normalised, and she subsequently had a successful pregnancy. In summary, we present a case of an oestrogen-secreting JGCT with hyperprolactinaemia manifesting clinically with galactorrhoea and secondary amenorrhoea. We postulate that observed hyperprolactinaemia was caused by oestrogenic stimulation of pituitary lactotroph cells, a biochemical state analogous to pregnancy. To the best of our knowledge, this is the first report of hyperprolactinaemia as a result of excessive oestrogen production in the context of a JGCT.
Hyperprolactinaemia with bilateral galactorrhoea and secondary amenorrhoea has a wide differential diagnosis and is not always caused by a prolactin secreting pituitary adenoma.
Significantly elevated serum oestradiol levels in the range seen in this case, in the absence of pregnancy, are indicative of an oestrogen-secreting tumour.
JGCTs are rare hormonally active ovarian neoplasms mostly secreting steroid hormones.
Serum inhibin can be used as a granulosa cell-specific tumour marker.
JGCTs have an excellent prognosis in the early stages of the disease.
Mercedes RobledoHereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO) and ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain
Ronald de KrijgerDepartment of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands Department of Pathology, Reinier de Graaf Hospital, Delft, The Netherlands
Pheochromocytomas (PCC) and paraganglioma (PGL) are rare neuroendocrine tumors arising from chromaffin cells of the neural crest. Mutations in the RET-proto-oncogene are associated with sporadic pheochromocytoma, familial or sporadic medullary thyroid carcinoma (MTC) and multiple endocrine neoplasia type 2. In the past, only few cases of pigmented PCCs, PGLs, and one case of pigmented MTC have been reported in the literature. Herein, we present the case of a 77-year old woman with a history of Tako-tsubo-cardiomyopathy and laboratory, as well as radiological, high suspicion of pheochromocytoma, who underwent left-sided adrenalectomy. The 3 cm tumor, which was located on the upper pole of the left adrenal, appeared highly pigmented with dark red to black color. Histologic examinations revealed highly pleomorphic cells with bizarre, huge hyperchromatic nuclei, that immunohistochemically were positive for chromogranin A and synaptophysin, focally positive for HMB45 and negative for melan A. These clinical and pathological features led to the diagnosis of the rare variant of a melanotic ‘black’ pheochromocytoma. In our case a somatic RET mutation in exon 16 (RET c.2753T>C, p.Met918Thy) was detected by targeted next generation sequencing. In summary, this case represents a rare variant of catecholamine-producing tumor with distinct histological features. A potential relationship between the phenotype, the cellular origin and the genetic alterations is discussed.
Pheochromocytoma is a rare neuroendocrine tumor.
Pigmentation is seen in several types of tumors arising from the neural crest. The macroscopic black aspect can mislead to the diagnosis of a metastasis deriving from a malignant melanoma.
RET mutation are seen in catecholamine and non-catecholamine producing tumors of the same cellular origin.
A previously healthy 32-year-old woman developed cyclical mood swings after being prescribed cabergoline for a pituitary microprolactinoma. These mood swings persisted for over 2 years, at which point she developed an acute manic episode with psychotic features and was admitted to a psychiatry unit. Cabergoline was discontinued and replaced with aripiprazole 10 mg/day. Her manic episode quickly resolved, and she was discharged within 6 days of admission. The aripiprazole suppressed her prolactin levels for over 18 months of follow-up, even after the dose was lowered to 2 mg/day. There was no significant change in tumor size over 15 months, treatment was well tolerated. However, after 9 months of taking 2 mg aripiprazole, she developed brief manic symptoms, and the dose was returned to 10 mg daily, with good effect.
Dopamine agonists such as cabergoline, which are a standard treatment for microprolactinomas, can have serious adverse effects such as psychosis or valvular heart disease.
Aripiprazole is a well-tolerated atypical antipsychotic that, unlike other antipsychotics, is a partial dopamine agonist capable of suppressing prolactin levels.
Adjunctive, low-dose aripiprazole has been utilized to reverse risperidone-induced hyperprolactinemia.
This case report demonstrates how aripiprazole monotherapy, in doses ranging from 2 to 10 mg/day, was effective in suppressing prolactin in a woman with a microprolactinoma who developed psychiatric side effects from cabergoline.
A 21-year-old woman presented with amenorrhea, bilateral galactorrhea and fatigue. Visual acuity and visual fields were normal. Laboratory examination demonstrated hyperprolactinemia. Magnetic resonance imaging (MRI) of the pituitary showed a 19×17×12-mm sellar mass with supra- and parasellar extension, causing compression of the pituitary stalk and optic chiasm. Further examinations confirmed mild hyperprolactinemia, strongly elevated TSH (>500 mU/l), low free thyroxine (FT4), hypogonadotropic hypogonadism and secondary adrenal insufficiency. Hydrocortisone and l-T4 replacement therapy was started. Three months later, the galactorrhea had disappeared, thyroid function was normalized and MRI revealed regression of the pituitary enlargement, confirming the diagnosis of pituitary hyperplasia (PH) due to primary hypothyroidism. Subsequently, the menstrual cycle returned and the hypocortisolism normalized. This case demonstrates that severe primary hypothyroidism may have an unusual presentation and should be considered in the differential diagnosis of pituitary enlargement associated with moderate hyperprolactinemia.
One should always try to find one etiology as the common cause of all the clinical findings in a pathologic process.
Amenorrhea, galactorrhea and fatigue may be the only presenting clinical manifestations of primary hypothyroidism.
Not every patient with galactorrhea, hyperprolactinemia and a pituitary mass has a prolactinoma.
Primary hypothyroidism should always be considered in the differential diagnosis of hyperprolactinemia associated with pituitary enlargement and pituitary hormone(s) deficiency(ies).
When PH due to primary hypothyroidism is suspected, thyroid hormone replacement should be started and only regression of pituitary enlargement on MRI follow-up can confirm the diagnosis.
Examination of thyroid function in patients with a pituitary mass may avoid unnecessary surgery.
We report three patients who developed symptoms and signs of ocular neuromyotonia (ONM) 3–6 months after receiving gamma knife radiosurgery (GKS) for functioning pituitary tumours. All three patients were complex, requiring multi-modality therapy and all had received prior external irradiation to the sellar region. Although direct causality cannot be attributed, the timing of the development of the symptoms would suggest that the GKS played a contributory role in the development of this rare problem, which we suggest clinicians should be aware of as a potential complication.
GKS can cause ONM, presenting as intermittent diplopia.
ONM can occur quite rapidly after treatment with GKS.
Treatment with carbamazepine is effective and improve patient's quality of life.
Sunita M C De SousaDepartment of Endocrinology, St Vincent's Hospital, Sydney, New South Wales, Australia Hormones and Cancer Group, Garvan Institute of Medical Research, 384 Victoria Street, Sydney, New South Wales, 2010, Australia
Ann I McCormackDepartment of Endocrinology, St Vincent's Hospital, Sydney, New South Wales, Australia Hormones and Cancer Group, Garvan Institute of Medical Research, 384 Victoria Street, Sydney, New South Wales, 2010, Australia
Pituitary hyperplasia (PH) occurs in heterogeneous settings and remains under-recognised. Increased awareness of this condition and its natural history should circumvent unnecessary trans-sphenoidal surgery. We performed an observational case series of patients referred to a single endocrinologist over a 3-year period. Four young women were identified with PH manifesting as diffuse, symmetrical pituitary enlargement near or touching the optic apparatus on MRI. The first woman presented with primary hypothyroidism and likely had thyrotroph hyperplasia given prompt resolution with thyroxine. The second and third women were diagnosed with pathological gonadotroph hyperplasia due to primary gonadal insufficiency, with histopathological confirmation including gonadal-deficiency cells in the third case where surgery could have been avoided. The fourth woman likely had idiopathic PH, though she had concomitant polycystic ovary syndrome which is a debated cause of PH. Patients suspected of PH should undergo comprehensive hormonal, radiological and sometimes ophthalmological evaluation. This is best conducted by a specialised multidisciplinary team with preference for treatment of underlying conditions and close monitoring over surgical intervention.
Normal pituitary dimensions are influenced by age and gender with the greatest pituitary heights seen in young adults and perimenopausal women.
Pituitary enlargement may be seen in the settings of pregnancy, end-organ insufficiency with loss of negative feedback, and excess trophic hormone from the hypothalamus or neuroendocrine tumours.
PH may be caused or exacerbated by medications including oestrogen, GNRH analogues and antipsychotics.
Management involves identification of cases of idiopathic PH suitable for simple surveillance and reversal of pathological or iatrogenic causes where they exist.
Surgery should be avoided in PH as it rarely progresses.
Ectopic hormone secretion is a well-recognised phenomenon; however, ectopic prolactin secretion is exceptionally rare. Hoffman and colleagues reported the first ever well-documented case of ectopic prolactin secretion secondary to a gonadoblastoma. We report a lady who presented with galactorrhoea and a large ovarian tumour that was found to secrete high levels of prolactin.
Aim of this case report is to highlight the occurrence of this condition.
Lack of awareness can often lead to a diagnostic conundrum.