SCLEROSING MUCOEPIDERMOID CARCINOMA WITH EOSINOPHILIA OF THYROID

BACKGROUND                                               
Sclerosing mucoepidermoid carcinoma with eosinophils of thyroid (SCEME) is a rare thyroid carcinoma. Although it is believed to take a slow, indolent approach to grow, the carcinoma can cause complications due to involvement of large part of the thyroid and neck. Apart from the involvement of thyroid gland, SCEME is also known to metastasize to different body parts, further complicating the prognostic outcome. The interesting part of the clinical picture is sclerosis and fibrosis of the involved part of the thyroid gland, and Hashimoto’s Thyroiditis (HT) in non-involved portion of the thyroid. The stroma shows infiltration of eosinophils, lymphocytes and plasma cells.
SCEME has been found to be associated mostly with papillary thyroid cancer (PTC), and few cases with follicular or anaplastic thyroid cancer. There are two opposing views regarding the origin of SCEME, first one being a follicular cell origin. Other authors have suggested a primary involvement of salivary gland and secondary involvement of thyroid and neck. There is no research conducted so far on SCEME and neither any mouse models exist. However, the spontaneous granulomatous autoimmune thyroiditis (SAT) mouse model comes close to mimicking SCEME.
SAT model was first described by Dr. Helen Braley-Mullen’s lab using NOD.H2h4 strain of mice. The NOD.H2h4 mice on K-haplotype spontaneously develop autoimmune thyroiditis (mimicking Hashimoto’s thyroiditis), when given sodium iodide in drinking water. This mouse strain has been described to be suitable for the study of two autoimmune diseases- Hashimoto’s thyroiditis and Sjogren’s syndrome, two components which form part of SCEME. The infiltrate in the thyroids is typically that of mononuclear cells where CD4 T cells are predominant. Their lab also described another version of SAT model with knockdown of interferon-gamma from the thyroid. Interestingly this version of SAT has extensive infiltration of eosinophils, along with CD4 T cells. This model however does not lead to thyroid cancer, but leads to thyroid cell hyperplasia.
The role of HT in contributing towards development of thyroid cancer has always been controversial. However, many clinical studies suggest better prognosis, when HT is found associated with thyroid cancer. Work done in SAT mouse model has demonstrated the secretion of various pro-inflammatory cytokines by infiltrating CD4 T cells. These cytokines however can contribute to the cancer cell death due to the TNF-alpha cell death pathway along with ROS cell death pathway, which might explain better thyroid cancer prognosis. Therefore loss of these cytokines coupled with HT might shift the infiltrate from lymphocytic heavy to high in eosinophils. This shift in the infiltrate might be responsible for hyperplasia and fibrosis. This event coupled with the active transformation pathways such as those of PTC might lead to SMECE.

HYPOTHESIS
It is therefore possible that local loss of inflammatory cytokine expression (TNF-alpha or IFN-gamma etc) in thyroid coupled with loss of tumor suppressors (such as cell death pathway regulators) and activation of transformation pathways leads to the development of SCEME.

 SIGNIFICANCE
SCEME is a rare thyroid neoplasm with a unique phenotype. Although described as indolent tumor, few cases have been associated with metastatic spread. This particular metastatically spreading SCEME has been termed as aggressive. However, till date no explanations have been forthcoming regarding the origin of the tumor, which is important to develop targeted therapeutic strategies. So far the treatment strategies involve surgical intervention which is beneficial in the absence of metastatic spread or recurrence of the neoplasm. Since a part of SCEME resembles the SAT-mouse model, this writeup is an attempt to explore the biology of SCEME. So far the influence of pro-inflammatory cytokines on the development and progression of thyroid cancers have not been explored properly. One PTC type associated with the pro-inflammatory cytokines is RET/PTC3 oncogene mediated PTC. RET/PTC3 oncogene is known to express various pro-inflammatory cytokines but this does not make this tumor aggressive. My unpublished work suggests that these cytokines are also responsible for ROS and TNF-alpha mediated cell death of the cancer cells. Speculating further we also feel that infiltrating T cells from HT would weaken the thyroid cancer progression. pRb and p53 are tumor suppressors ubiquitously involved in cancers and in epidermoid carcinomas as well. Combining all these together would be able to help us understand SCEME’s origins.

Comments

Post a Comment

Popular posts from this blog

Overdiagnosis and Thyroid cancer incidence

If you read about thyroid cancer, everyone agrees that its incidence is on the rise. In recent months, there has been lots of press coverage as how this increased thyroid incidence is due to overdiagnosis. To illustrate the overdiagnosis with an example, we need to take a look at South Korea. There was a huge increase in the incidence of thyroid cancer in South Korea which was blamed on overdiagnosis . But a recent review article on this topic cautions; not so fast . Thyroid cancers form about 2.1% of total cancer diagnoses worldwide, with women disproportionately affected, accounting for about 77% of the cases. The phenomenon of more women patients than men is unique to thyroid pathology and is also seen in Hashimoto's thyroiditis and Graves' disease. Majority of thyroid cancers are termed differentiated with two main subtypes, papillary thyroid cancers (PTC) and follicular thyroid cancers (FTC). The increased incidence of the thyroid cancer is mainly attributed to increas...
Read more

SCLEROSING MUCOEPIDERMOID CARCINOMA WITH EOSINOPHILIA OF THYROID

  SCLEROSING MUCOEPIDERMOID CARCINOMA WITH EOSINOPHILIA OF THYROID (Failed Beheard application 😉) Research background and summary  What rare disease do you study?  A: SCLEROSING MUCOEPIDERMOID CARCINOMA WITH EOSINOPHILIA OF THYROID The general disease area of the rare disease you study. e.g. Immune/inflammatory disorder, metabolic disorder, neurodegenerative disorder, etc...  A: CANCER BIOLOGY/ INFLAMMATION Specific Aims (Less than 1000 words) This section should include background, hypothesis, specific aims, and significance.  A: BACKGROUND Sclerosing mucoepidermoid carcinoma with eosinophils of thyroid (SCEME) is a rare thyroid carcinoma. Although it is believed to take a slow, indolent approach to grow, the carcinoma can cause complications due to involvement of large part of the thyroid and neck. Apart from the involvement of thyroid gland, SCEME is also known to metastasize to different body parts, further complicating the prognostic outcome. The interest...
Read more

Metabolic pathways and energy sources for tumors

Warburg's effect is quoted many times to describe the faulty metabolic pathways in tumor cells. Tumor cells which are rapidly dividing are known to create a hypoxic microenvironment which does not support glucose oxidation. Under these circumstances, glycolysis becomes a dominant metabolic pathway to generate energy for the rapidly dividing tumor cells. However, this may not be the complete story. In recent years, there has been a tremendous amount of work being done to explore the metabolic pathways involved in various tumors. All this now depicts a newer reality where glycolysis instead of being "The pathway" is now thought to be one of the pathways used by the tumor cells. Of interest are the protein metabolic pathways such as glutamine and proline pathways, The nucleic acid metabolic pathways and my present interest, the fatty acids pathways.  If we consider that alternative pathways such as fatty acid oxidation, protein metabolic pathways,  then all the proteins ...
Read more

LKB1 conundrum: LKB1 in thyroid cancer

LKB1 conundrum: LKB1 in thyroid cancer LKB1 is a known tumor suppressor. first identified in Peutz Jeghers Syndrome, characterized by general hamartomatous polyposis leading to the formation of multiple tumors at several sites in the body. Loss or inactivation of LKB1 has been shown in lung cancer and other organ systems confirming its role as a tumor suppressor. LKB1 is known to act as a tumor suppressor through various different mechanisms. One of the important mechanisms being activation of downstream tumor suppressor, AMPK. AMPK in turn inhibits mTOR which is important for regulation of metabolic pathways in tumor cells. However, recent evidence suggests that AMPK might not be a tumor suppressor but promote tumor growth under certain contexts. There are reports suggesting both AMPK and mTOR to be active in tumors without compromising the action of one another. This is turn also applies to the protein upstream of AMPK, i.e. LKB1. Therefore both LKB1-AMPK have now been termed as cont...
Read more

LKB1 conundrum: LKB1 in thyroid cancer

LKB1 conundrum: LKB1 in thyroid cancer LKB1 is a known tumor suppressor. first identified in  Peutz Jeghers Syndrome , characterized by general hamartomatous polyposis leading to the formation of multiple tumors at several sites in the body. Loss or inactivation of LKB1 has been shown in  lung cancer  and  other   organ systems  confirming its role as a tumor suppressor. LKB1 is known to act as a tumor suppressor through various different mechanisms. One of the important mechanisms being activation of downstream tumor suppressor, AMPK. AMPK in turn inhibits mTOR which is important for regulation of metabolic pathways in tumor cells. However,  recent evidence  suggests that AMPK might not be a tumor suppressor but  promote tumor growth  under certain contexts. There are reports suggesting both AMPK and mTOR to be active in tumors without compromising the action of one another. This is turn also applies to the protein upstream of AMPK, ...
Read more