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Department of Biomedical Informatics, University of Colorado, Aurora, Colorado, USA
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Summary
Multiple endocrine neoplasia type 2 (MEN2) is a hereditary cancer syndrome caused by germline-activating pathogenic variants in the RET proto-oncogene. MEN2A is the most common subtype, with a risk for medullary thyroid cancer (MTC), pheochromocytoma (PHEO), and primary hyperparathyroidism (PHPT), whereas MEN2B is less common and associated with MTC and PHEO along with mucosal neuromas. Little is known about the specific RET germline heterozygous variant K666N. This variant has been described in very few families, and in most cases, patients were diagnosed with a very indolent MTC as the only feature. There is one case of MTC and bilateral PHEO. The RET K666N variant is not stratified yet by the American Thyroid Association, and data are limited on pathogenicity; therefore, appropriate screening and treatment of asymptomatic RET K666N carriers are unclear. Here, we report a family with a heterozygous germline RET K666N variant. The proband was identified when she experienced cardiogenic shock and multi-organ failure after an elective hysterectomy and subsequently was found to have PHEO, with genetic testing revealing the RET K666N germline variant. Patient consent was obtained through IRB protocol COMIRB #15-0516.
Learning Points
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The specific RET germline heterozygous variant K666N is rare and described in very few families, and in most cases, patients were diagnosed with a very indolent MTC as the only feature. Our proband is much younger and has PHEO, MTC, and PHPT.
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The RET K666N germline variant appears to be a low penetrance variant for MEN2.
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Summary
Hypoglycemia is one of the paraneoplastic syndrome manifestations that arise from primary and secondary liver cancer. Hypoglycemia usually presents in the late stage of the disease and indicates a poor prognosis. This case series displays the characteristics profile of patients with primary and secondary liver cancer who are presented with hypoglycemia in a tertiary referral hospital in Indonesia. The study included 41 liver cancer patients who were presented with hypoglycemia. Hepatocellular carcinoma was diagnosed in 51.2% of patients, metastatic liver disease in 14.6% of patients, and undiagnosed liver cancer in 34.1% of patients. The mean age was 47.7 years with male predominance (65.9%). Jaundice was found in 58.5% and hepatomegaly in 70.7% of patients. The mean (± S.D.) initial blood glucose was 42.15 ± 17.11 mg/dL and the Child–Pugh score was 9.93 ± 2.11. Based on imaging, tumor diameter was 12.6 ± 6.9 cm, multiple (61%), and involving both lobes (61%). Treatments for hypoglycemia included oral/enteral feeding, intravenous dextrose, and steroids. No treatment was given for the cancer because all patients were in an advanced stage. The treatment resulted in 41.5% blood glucose being controlled, 56.1% refractory, and 2.4% persistent. Mortality was 70.7% and in average occurred 5.76 ± 4.99 days after hypoglycemia. The mainstay of treatment in these cases is treating the tumor with cytoreduction. However, it was difficult to do cytoreduction because the tumor was already in an advanced stage. Beneficial supportive treatments for maintaining normal blood glucose are frequent meals, dextrose infusion, steroids, and glucagon.
Learning points
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Hypoglycemia in liver cancer occurs due to the failure of the liver to fulfill body glucose demand because the liver parenchyma has been largely replaced by the tumor, in addition to the high production of insulin growth factor (IGF).
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Hypoglycemia is often caused by islet cell and non-islet cell tumors, with a higher occurrence in non-islet cell tumors due to paraneoplastic syndrome and the high metabolic requirements of the tumor.
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The mainstay of NICTH treatment is treating the tumor with cytoreduction. However, in an advanced stage, cytoreduction therapy is often challenging to conduct. Beneficial supportive treatments for controlling blood glucose are frequent meals, dextrose infusion, and the injection of steroids and glucagon.
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Steroids play a beneficial role in the treatment of persistent hypoglycemia in hepatocellular carcinoma by stimulating gluconeogenesis and increasing lipolysis. Steroids also have roles in the inhibition of peripheral glucose intake, suppression of big IGF-2 production, and modulation of the GH–IGF axis.
Search for other papers by Katherine Wu in
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St Vincent’s Clinical School, University of New South Wales, Sydney, Australia
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Cancer Genetics Unit, Kolling Institute of Medical Research, Sydney, Australia
Northern Clinical School, University of Sydney Faculty of Medicine and Health, Sydney, Australia
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Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, Australia
Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Sydney, Australia
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Cancer Genetics Unit, Kolling Institute of Medical Research, Sydney, Australia
Northern Clinical School, University of Sydney Faculty of Medicine and Health, Sydney, Australia
Search for other papers by Matti L Gild in
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Summary
RET mutations are implicated in 60% of medullary thyroid cancer (MTC) cases. The RET-selective tyrosine kinase inhibitor selpercatinib is associated with unprecedented efficacy compared to previous multi-kinase treatments. Langerhans cell histiocytosis (LCH) is a clonal histiocytic neoplasm usually driven by somatic BRAF mutations, resulting in dysregulated MAPK signalling. We describe a 22-year-old woman with metastatic MTC to regional lymph nodes, lung and liver. Tumour tissue harboured a somatic pathogenic RET variant p.(M918T) and selpercatinib was commenced. She experienced sustained clinical, biochemical and radiological responses. Two years later, she developed rapidly progressive apical lung nodules, prompting biopsy. Histopathology demonstrated LCH with a rare BRAF variant p.(V600_K601>D). The lung nodules improved with inhaled corticosteroids. We hypothesize that selective pressure from RET blockade may have activated a downstream somatic BRAF mutation, resulting in pulmonary LCH. We recommend continued vigilance for neoplasms driven by dysregulated downstream MAPK signalling in patients undergoing selective RET inhibition.
Learning points
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Patients with RET-altered MTC can experience rapid disease improvement and sustained disease stability with selective RET blockade (selpercatinib).
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LCH is a clonal neoplasm driven by MAPK activation, for which the most common mechanism is BRAF mutation.
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Both MTC and pulmonary LCH are driven by dysregulated MAPK signalling pathway activation.
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We hypothesise that the RET-specific inhibitor selpercatinib may have caused the activation of dormant LCH secondary to selective pressure and clonal proliferation.
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Summary
Struma ovarii is an ovarian teratoma that comprises 2–5% of all ovarian teratomas. Malignant transformation of struma ovarii occurs in less than 5% of all cases, and metastatic disease is even rarer. We report two cases initially diagnosed with benign struma ovarii that presented malignant transformation, specifically highly differentiated follicular carcinoma of the ovary (HDFCO), some years after the first diagnosis. Case 1 concerns a 37-year-old female featuring HDFCO of the right ovary with multiple metastatic foci, who was diagnosed with benign struma ovarii 14 years ago. Case 2 concerns a 26-year-old female diagnosed with HDFCO of the left ovary. This patient was initially diagnosed with benign struma ovarii 6 years ago that recurred 4 years after the diagnosis. Both patients were treated with surgery, adjunctive total thyroidectomy, and radioactive iodine (131I) therapy.
Learning points
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Malignant transformation of struma ovarii is very rare (<5%).
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Diagnosis of HDFCO without extra ovarian dissemination is difficult due to the resemblance of its histological appearance with normal thyroid tissue.
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There is no consensus on the postoperative treatment of malignant struma ovarii (MSO). Clinical and histological features of MSO should be assessed for the postoperative treatment decisions.
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TSH suppression and thyroglobulin level measurements are necessary for patient follow-up.
Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
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Liverpool Diabetes Collaboration, Ingham Institute of Applied Medical Research, Sydney, Australia
South West Clinical School, University of New South Wales, Sydney, Australia
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Summary
Approximately 80% of adrenal incidentalomas are benign, and development into adrenal cortical cancer is extremely rare. This is a major reason behind clinical guidelines recommending surveillance of incidentalomas for a relatively short duration of up to 5 years. Surveillance of lesions less than 1 cm is not routinely recommended. A 70-year-old lady was diagnosed with a non-hyperfunctioning 8 mm right adrenal lesion. She underwent annual biochemical and radiological assessment for 5 years before surveillance was extended to 2-yearly intervals. The lesion was stable in size, and radiological characteristics were consistent with a benign adenoma. Seven years after the initial detection of the adrenal lesion, she developed acute abdominal pain. Imaging revealed a 7 cm right adrenal lesion, which was surgically resected and histologically confirmed to be adrenal cortical cancer. She died 1 year later. Clinical guidelines have moved towards a shortened duration of surveillance of incidentalomas. Even though malignant transformation is a rare event, it is possible that this will result in a delayed diagnosis of adrenal cortical cancer, a highly aggressive malignancy with a poor prognosis. To our knowledge, this is the first published case of an adrenal lesion of less than 1 cm developing into adrenal cortical cancer.
Learning points
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Adrenal incidentalomas are increasingly common.
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Clinical practice guidelines exist to aid in differentiating benign and malignant lesions and assessing functional status.
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Transformation of adrenal incidentalomas to adrenal cortical carcinomas is a rare but recognised event.
Search for other papers by Chi-Ta Hsieh in
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Search for other papers by Jui-Ting Yu in
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Department of Post-Baccalaureate Medicine, National Chung Hsing University, Taichung, Taiwan
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Division of Endocrinology and Metabolism, Department of Internal Medicine, Tungs' Taichung MetroHarbor Hospital, Taichung, Taiwan
Department of Post-Baccalaureate Medicine, National Chung Hsing University, Taichung, Taiwan
Search for other papers by Yao Hsien Tseng in
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Summary
A 69-year-old woman presented with weight loss, fever, dizziness, exertional dyspnea, and drenching night sweats. Imaging showed a thyroid goiter at the left lobe that measured 5.6 × 3.4 × 3.5 cm in size. On computed tomography, she was found to have large adrenal masses. Core needle biopsy of the left thyroid mass revealed the presence of a mucosa-associated lymphoid tissue extranodal marginal zone B cell lymphoma. Non-Hodgkin’s lymphomas (NHL) typically develop in lymph nodes or other lymphatic tissues. There have been cases where the thyroid has been affected, and the secondary involvement of the adrenal gland is common. In reported cases, 7–59% of patients with NHL exhibited symptoms of thyroid dysfunction. Our patient presented no symptoms of thyroid dysfunction or Hashimoto’s thyroiditis. The patient had bilateral adrenal lymphomas that led to adrenal insufficiency. Immunochemotherapy provided a good response in this case, as seen by the rapid improvement in thyroid and adrenal mass on follow-up PET/CT.
Learning points
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Thyroid lymphoma requires a high index of suspicion for diagnosis in patients with a rapidly growing thyroid tumor, even in the absence of chronic inflammatory thyroid disease.
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Depending on the extent of involvement, adrenal lymphoma may rapidly cause adrenal insufficiency.
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In the setting of acute illness, appropriate levels of plasma cortisol are often unclear, necessitating early initiation of glucocorticoid therapy based on clinical suspicion, especially when features like bilateral adrenal masses and elevated ACTH levels are present.
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Treatment modalities include chemotherapy and radiation therapy for localized lesions, together with hormone replacement for organ dysfunction.
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The origin of the tumor influences the clinical outcome of patients with lymphoma simultaneously involving the thyroid and adrenal glands.
Faculty of Medicine and Surgery, Humanitas University, Rozzano, Milan, Italy
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Faculty of Biomedical Sciences, Università della Svizzera Italiana (USI), Lugano, Switzerland
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Summary
Thyroid metastases from nonthyroidal malignancies (NTMs) represent a diagnostic challenge, often displaying heterogeneous clinical manifestations. These metastases are rare but significant, accounting for approximately 2% of thyroid malignancies. Distinguishing them from primary thyroid malignancies is challenging due to the lack of specific ultrasound features, and the ultrasound-based risk stratification systems offer limited utility in such cases. Fine needle aspiration cytology is crucial for definitive diagnosis, yet it may not always provide accurate results. In this case report, we describe a unique instance of thyroid metastases originating from renal cell carcinoma, emphasizing the complexities in diagnosis and the importance of considering oncological conditions when assessing thyroid masses. Awareness of thyroid metastasis from NTMs, particularly in cases of diffuse thyroid hypoechogenicity and hypothyroidism, is essential for clinicians in their diagnostic approach.
Learning points
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Thyroid metastases from nonthyroidal malignancies are diagnostic challenges due to their heterogeneous clinical presentations, often mimicking primary thyroid malignancies.
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Thyroid metastases from nonthyroidal malignancies are relatively rare, but they still account for approximately 2% of thyroid malignancies.
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It is fundamental to consider oncological conditions when assessing thyroid masses, especially in cases of diffuse thyroid hypoechogenicity, hypothyroidism, and history of other tumors.
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Thyroid presentation is quite similar to that of autoimmune hypothyroidism, endocrinologists must be aware of the possibility of thyroid hypofunction due to the massive invasion of the parenchyma.
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Search for other papers by Khalid Aljenaee in
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Summary
Endometrioid carcinomas of the ovary are a subtype of epithelial ovarian tumors, with sertoliform endometrioid carcinomas being a rare variant. We report a case of a previously healthy premenopausal woman presenting with androgenic symptoms in the form of hirsutism and male pattern alopecia. On further testing, she was found to have high levels of luteinizing hormone and total testosterone levels, and imaging revealed a large pelvic abdominal mass in the right ovary. She underwent total hysterectomy with bilateral salpingo-oophorectomy. Microscopy and histopathology confirmed the diagnosis of sertoliform endometrioid carcinoma. Her symptoms improved significantly on follow-up. Androgenic tumors might not be common in premenopausal women; however, it is important to maintain a high level of suspicion in patients presenting with virilizing symptoms especially of rapid progression.
Learning points
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Our 47-year-old patient presented with virilizing symptoms that were rapidly progressing, which raises the suspicion of an underlying androgen secreting neoplasm.
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Sertoliform endometrioid carcinoma (SEC) is an extremely rare variant of endometrioid carcinomas and tend to present at an earlier stage as compared to most endometrioid carcinomas of the ovary.
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Recognition of SEC in virilizing patients is important as it is a well-differentiated, low-grade malignancy with a good prognosis when confined to the ovary.
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Search for other papers by João Sequeira Duarte in
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Summary
Primary thyroid lymphoma (PTL) is a rare malignancy, accounting for less than 5% of all thyroid neoplasms. The follicular subtype is even more rare, accounting for approximately 10% of all PTL cases. We report a case of a 64-year-old woman, who presented with a rapidly growing goitre with mass effect and B symptoms. She had a history of Hashimoto’s thyroiditis and her thyroid ultrasound revealed diffuse goitre with a dominant nodule (56 × 63 × 60 mm) within the right thyroid lobe. Ultrasound-guided percutaneous fine-needle aspiration of the right thyroid nodule was classified as benign, according to Bethesda System, with lymphocytic thyroiditis. A CT scan of the neck showed diffuse enlargement of the thyroid gland extending towards the anterior mediastinum with tracheal deviation and lymphadenopathy within levels VII and right II–IV. The core needle biopsy of the right thyroid nodule revealed a follicular non-Hodgkin’s B cell lymphoma with a Ki67 of 60%. According to the Ann Arbor staging system, she was at stage IIIE. She underwent chemotherapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) with remarkable clinical improvement and is currently in remission 2 years after the diagnosis. PTL is an extremely rare malignancy that usually arises in a lymphocytic thyroiditis background, presenting as a rapidly enlarging goitre, which can lead to compressive symptoms or airway comprise.
Learning points
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Primary thyroid lymphoma (PTL) is a rare malignancy, accounting for less than 5% of thyroid neoplasms.
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PTL should be suspected when a patient presents with a rapidly enlarging goitre, especially in the setting of Hashimoto’s thyroiditis.
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Fine-needle aspiration has a limited capacity for PTL diagnosis due to similar cytomorphological features of lymphoma with thyroiditis. Therefore, in case of clinical suspicion and if fine needle aspiration fails to diagnose PTL, a tissue biopsy should be performed.
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Treatment is dependent on both the stage and histology of PTL. Chemotherapy and local radiotherapy remain the mainstay treatment for PTL.
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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.
