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Poorly differentiated adenocarcinoma of an unknown primary with a thyroid tumour and an aggressive course: thyroid or lung carcinoma?

ABSTRACT: Cancers of unknown primary (CUPs) are challenging for physicians to diagnose and treat. Metastases to the thyroid gland are rare, representing less than 1% of all thyroid malignancies. Here, we report a case of a 69-year-old Asian man who had both thyroid gland and lymph node enlargement in the neck and shoulders but no nodules/tumours in the lung field. The patient died 51 days after his first visit to our office, although pembrolizumab was administered on day 34 based on programmed cell death-ligand 1 (PD-L1) expression. Immunohistochemistry (IHC) with paired box 8 (PAX8) may be useful to diagnostically distinguish poorly differentiated lung adenocarcinomas from napsin A-positive thyroid carcinomas.

SUBMITTER: Ito T

PROVIDER: S-EPMC6467094 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Poorly differentiated adenocarcinoma of an unknown primary with a thyroid tumour and an aggressive course: thyroid or lung carcinoma?

Ito Toshiki T Yoshida Takayuki T Sakai Tomoko T Watanabe Kazumasa K Nishimura Hiroki H Hamada Kunio K Ito Akihide A

Oxford medical case reports 20190416 4

Cancers of unknown primary (CUPs) are challenging for physicians to diagnose and treat. Metastases to the thyroid gland are rare, representing less than 1% of all thyroid malignancies. Here, we report a case of a 69-year-old Asian man who had both thyroid gland and lymph node enlargement in the neck and shoulders but no nodules/tumours in the lung field. The patient died 51 days after his first visit to our office, although pembrolizumab was administered on day 34 based on programmed cell death- ...[more]

PMID: 31007936

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Project description:Background: Radioiodine refractory dedifferentiated thyroid cancer is a major clinical challenge. Anaplastic lymphoma kinase (ALK) mutations with increased ALK activity, especially fusion genes, have been suggested to promote thyroid carcinogenesis, leading to development of poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma. To determine the oncogenic potential of increased ALK activity in thyroid carcinogenesis in vivo, we studied mice with thyrocyte-specific expression of a constitutively active ALK mutant. Methods: Mice carrying a Cre-activated allele of a constitutively active ALK mutant (F1174L) were crossed with mice expressing tamoxifen-inducible Cre recombinase (CreERT2) under the control of the thyroglobulin (Tg) gene promoter to achieve thyrocyte-specific expression of the ALK mutant (ALKF1174L mice). Survival, thyroid hormone serum concentration, and tumor development were recorded. Thyroids and lungs were studied histologically. To maintain euthyroidism despite dedifferentiation of the thyroid, a cohort was substituted with levothyroxine (LT4) through drinking water. Results: ALKF1174L mice developed massively enlarged thyroids, which showed an early loss of normal follicular architecture 12 weeks after tamoxifen injection. A significant decrease in Tg and Nkx-2.1 expression as well as impaired thyroid hormone synthesis confirmed dedifferentiation. Histologically, the mice developed a carcinoma resembling human PDTC with a predominantly trabecular/solid growth pattern and an increased mitotic rate. The tumors showed extrathyroidal extension into the surrounding strap muscles and developed lung metastases. Median survival of ALKF1174L mice was significantly reduced to five months after tamoxifen injection. Reduced Tg expression and loss of follicular structure led to hypothyroidism with elevated thyrotropin (TSH). To test whether TSH stimulation played a role in thyroid carcinogenesis, we kept ALKF1174L mice euthyroid by LT4 substitution. These mice developed PDTC with identical histological features compared with hypothyroid mice, demonstrating that PDTC development was due to increased ALK activity and not dependent on TSH stimulation. Conclusion: Expression of a constitutively activated ALK mutant in thyroids of mice leads to development of metastasizing thyroid cancer resembling human PDTC. These results demonstrate in vivo that increased ALK activity is a driver mechanism in thyroid carcinogenesis.

Dataset Information

Poorly differentiated adenocarcinoma of an unknown primary with a thyroid tumour and an aggressive course: thyroid or lung carcinoma?

Publications

Poorly differentiated adenocarcinoma of an unknown primary with a thyroid tumour and an aggressive course: thyroid or lung carcinoma?

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