Clinical Overview > Topic
Search for other papers by A La Greca in
Google Scholar
PubMed
Search for other papers by D Dawes in
Google Scholar
PubMed
Search for other papers by M Albuja-Cruz in
Google Scholar
PubMed
Search for other papers by C Raeburn in
Google Scholar
PubMed
Search for other papers by L Axell in
Google Scholar
PubMed
Search for other papers by L Ku in
Google Scholar
PubMed
Search for other papers by C Klein in
Google Scholar
PubMed
Search for other papers by C Marshall in
Google Scholar
PubMed
Department of Biomedical Informatics, University of Colorado, Aurora, Colorado, USA
Search for other papers by L Fishbein in
Google Scholar
PubMed
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
-
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.
-
The RET K666N germline variant appears to be a low penetrance variant for MEN2.
Search for other papers by Katherine Wu in
Google Scholar
PubMed
Search for other papers by Shejil Kumar in
Google Scholar
PubMed
Search for other papers by Ed Hsiao in
Google Scholar
PubMed
Search for other papers by Ian Kerridge in
Google Scholar
PubMed
St Vincent’s Clinical School, University of New South Wales, Sydney, Australia
Search for other papers by Min Ru Qiu in
Google Scholar
PubMed
Search for other papers by Rhonda Siddall in
Google Scholar
PubMed
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 Roderick Clifton-Bligh in
Google Scholar
PubMed
Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, Australia
Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Sydney, Australia
Search for other papers by Anthony J Gill in
Google Scholar
PubMed
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
Google Scholar
PubMed
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
-
Patients with RET-altered MTC can experience rapid disease improvement and sustained disease stability with selective RET blockade (selpercatinib).
-
LCH is a clonal neoplasm driven by MAPK activation, for which the most common mechanism is BRAF mutation.
-
Both MTC and pulmonary LCH are driven by dysregulated MAPK signalling pathway activation.
-
We hypothesise that the RET-specific inhibitor selpercatinib may have caused the activation of dormant LCH secondary to selective pressure and clonal proliferation.
Search for other papers by Andreia Amado in
Google Scholar
PubMed
IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Rua Júlio Amaral de Carvalho 45, 4200-135 Porto, Portugal
Faculdade de Medicina da Universidade do Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal
Search for other papers by Elisabete Teixeira in
Google Scholar
PubMed
IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Rua Júlio Amaral de Carvalho 45, 4200-135 Porto, Portugal
Faculdade de Medicina da Universidade do Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal
Search for other papers by Sule Canberk in
Google Scholar
PubMed
IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Rua Júlio Amaral de Carvalho 45, 4200-135 Porto, Portugal
Instituto de Ciências Biomédicas de Abel Salazar, Universidade do Porto, R. Jorge de Viterbo Ferreira 228, 4050-313 Porto, Portugal
Search for other papers by Sofia Macedo in
Google Scholar
PubMed
Search for other papers by Bárbara Castro in
Google Scholar
PubMed
Search for other papers by Hugo Pereira in
Google Scholar
PubMed
Search for other papers by João Varanda in
Google Scholar
PubMed
Search for other papers by Susana Graça in
Google Scholar
PubMed
i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, R. Alfredo Allen 208, 4200-135 Porto, Portugal
IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Rua Júlio Amaral de Carvalho 45, 4200-135 Porto, Portugal
Faculdade de Medicina da Universidade do Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal
Search for other papers by Amélia Tavares in
Google Scholar
PubMed
Search for other papers by Carlos Soares in
Google Scholar
PubMed
Search for other papers by Maria João Oliveira in
Google Scholar
PubMed
Search for other papers by Manuel Oliveira in
Google Scholar
PubMed
IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Rua Júlio Amaral de Carvalho 45, 4200-135 Porto, Portugal
Faculdade de Medicina da Universidade do Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal
Search for other papers by Paula Soares in
Google Scholar
PubMed
IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Rua Júlio Amaral de Carvalho 45, 4200-135 Porto, Portugal
Faculdade de Medicina da Universidade do Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal
Centro Hospitalar Universitário São João, Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal
Search for other papers by Manuel Sobrinho Simões in
Google Scholar
PubMed
i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, R. Alfredo Allen 208, 4200-135 Porto, Portugal
IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Rua Júlio Amaral de Carvalho 45, 4200-135 Porto, Portugal
Faculdade de Medicina da Universidade do Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal
Search for other papers by Antónia Afonso Póvoa in
Google Scholar
PubMed
Summary
We report a 61-year-old male patient without personal history of thyroid carcinoma or radiation exposure. In 2011, he presented with a cervical mass whose biopsy diagnosed a papillary thyroid carcinoma (PTC) in a lymph node metastasis (LNM). Total thyroidectomy with lymphadenectomy of central and ipsilateral compartment was performed. Histopathology identified a 2 mm follicular variant of PTC and LNM in 25/25 lymph nodes. The patient was treated with 150 mCi of radioactive iodine (RAI), followed by levothyroxine suppressive therapy. In 2016, a retrotracheal mass was diagnosed, suggesting local recurrence; patient was submitted to surgical excision and RAI therapy (120 mCi). Due to seizures, in 2019, a brain CT was performed that diagnosed brain metastases. The patient underwent debulking of the main lesion. Histopathology analysis confirmed a metastatic lesion with variated morphology: classical PTC and follicular pattern and hobnail and tall cell features. Molecular analysis revealed BRAFV600E in LNM at presentation and BRAFV600E and TERT promoter (TERTp) mutations in the recurrent LNM and brain metastasis. Based upon this experience we review the reported cases of subcentimetric PTC with brain metastases and discuss the molecular progression of the present case.
Learning points
-
Papillary microcarcinoma (PMCs) usually have very good prognosis with low impact on patient survival.
-
PMCs presenting in elderly patients with LNM at diagnosis may carry a guarded outcome.
-
Brain metastasis although rare indicate aggressive phenotypic features.
-
Patient risk stratification of PMCs based on histopathological analysis and genetic testing may have a significant impact on prognosis providing therapeutic markers, that may predict disease progression and overall outcome.
Search for other papers by R Casey in
Google Scholar
PubMed
Search for other papers by S Prendeville in
Google Scholar
PubMed
Search for other papers by C Joyce in
Google Scholar
PubMed
Search for other papers by D O'Halloran in
Google Scholar
PubMed
Summary
We present the case of a 30-year-old female who was diagnosed with hereditary phaeochromocytoma secondary to a rare gene mutation in exon 8 of the RET oncogene. This genetic mutation was picked up as part of an extended genetic screen using a method known as next generation sequencing. Detection of this genetic mutation prompted further screening for the manifestation of multiple endocrine neoplasia type 2A (MEN2A). The patient subsequently underwent a thyroidectomy with histology confirming C-cell hyperplasia.
Learning points
-
Genetic analysis is an important step in the diagnostic work up of phaeochromocytoma.
-
Extended genetic analysis is important when there is a strong suspicion of hereditary phaeochromocytoma.
-
Mutations in exon 8 of the RET gene are associated with phaeochromocytoma as part of MEN2A syndrome.
