Thyroid Carcinoma

In 2016 Reynolds and coworkers reported a study of what was initially diagnosed as papillary thyroid carcinoma (PTC) in a  36 year old female with no history of radiation exposure. This patient presented after the ETV6-NTRK3 fusion was reported in the breast (Tognon 2002) but before the same fusion was reported in the salivary glands (Skálová 2010). The study of this patient high lights the value of precision medicine.

Imaging and presentation of thyroid secretory carcinoma

  1. CT scan revealed a mass involving the lower left and right lobes of her thyroid. Enlarged cervical lymph nodes with mediastinal extension were also seen.  Fine needle aspiration indicated PTC.

  2. t= 0 months. A total thyroidectomy was performed months after the FNA. Histology of the resected tumor revealed features of sclerosing and tall cell variants of PTC. Extracapsular extension was present.  Surgical margins were positive. Two of four lymph nodes contained metastatic tumor.

  3. The patient was treated with 159 mCi of radioactive iodine.

  4. t= 14 months FNA of the thyroid bed was deemed suspicious for PTC recurrence.

  5. t= 20 months. Para-tracheal and para-esophageal soft tissue were positive for residual PTC.

  6. At this point, the patient began treatment with the kinase inhibitor sorafenib, which targets PDGFR, VEGFR, c-Raf and b-Raf. B-Raf is commonly mutated in PTC.

  7. In addition to the kinase inhibitor, the patient received 3500 cGy of palliative external beam radiation to the thyroid bed.

  8. The broad spectrum receptor tyrosine kinase inhibitor sunitinib, was also added to the chemotherapeutic regimen.

  9. t= 44 months The patient experienced a second recurrence in the thyroid bed.

  10. t= 53 months Metastasis was seen in the right deltoid.

  11. t = 65 months Metastasis to the soft tissue surrounding the right tibia was seen.  Multiple lung, liver and other soft tissue nodules were identified by imaging.  These lesions were deemed to be metastases.

  12. 107 months (8.9 years) the patient died.

 

Figure 1 Initial manifestation of thyroid secretory carcinoma A. two views of the position of the thyroid B. The initial CT scan.

Histology of thyroid secretory carcinoma

Reynolds and coworkers presented a low magnification H&E image of  of the nodules of the primary tumor with in a fibrous matrix. The tumor nodules exhibit follicular, papillary, microcystic, trabecular, and fused papillary patterns (Fig 1a).

Figure 2 a. low magnification image of the primary tumor from Reynolds (2016). b. cartoon of the thyroid gland c. examples of regions of fibrous thyroid tissue

Reynolds and coworkers noted the presence of papillae with psammoma bodies.  Microcystic features with eosinophilic secretions are also seen in MASC, now known as secretory carcinoma of the salivary gland.  Interestingly, the follicular spaces with colloid and bubbles are also seen in MASC.

Figure 3 secretory features of an ETV6-NTRK3 driven thyroid cancer initially diagnosed as PTC

Other MASC like features such as aprocrine secretions and nuclei with single,  large nucleoli were  seen in the original tumor resected in 2007.  Many of these features remained in metastases resected in 2013 and 2014.

Figure 4 More MASC like features of secretory carcinoma of the thyroid and its metastases

The MASC like nature of this aggressive thyroid cancer, as revealed by H&E staining, prompted immunohistochemistry (IHC) with antibodies used to diagnose MASC and PTC.

The IHC markers revealed a tumor that more resembled MASC than PTC.  MASC markers mammaglobin, GATA-3, and S100 have been reviewed on another site.

Molecular proof of secretory carcinoma

Reynolds and coworkers used fluorescence in situ hybridization (FISH) probes designed to recognize the 5′ end of the ETV6 and 3′ end of the NTRK3 gene.  Presence of the ETV6-NTRK3 gene fusion is indicated by a yellow fluorescence signal.

 

Figure 5 from Reynolds 2016

Secretory carcinoma was further defined by sequencing the fusion junction amplified by PCR.

Figure 6 PCR confirmation of secretory carcinoma TEL is the name of the transcription factor coded by the ETV6 gene.  TrkC is the protein product of the NTRK3 gene.

This particular thyroid Trk fusion junction was also noted  by Leeman-Neill (2014) in PTC from radiation exposed patients and cultured thyroid cells after radiation exposure.

As noted elsewhere on this site, the ETV6-NTRK3 gene fusion was first discovered in mesenchymal tumors.  The concept behind these fusion protein driven cancers is that the promoter of a house keeping gene drives the expression of a rarely expressed protein kinase.  The dimerization of the house keeping protein promotes constitutive activity of the kinase domain.  Is the transcription factor TEL expressed in glandular cells of the thyroid?  ProteinAtlas.org has a nice database of IHC images that can be sorted by antigen and organ.  TEL is indeed expressed in glandular cells of the thyroid

Figure 7 Two examples of TEL expression in normal thyroid

For TEL to be expressed in glandular cells of the thyroid, the ETV6 promoter must be active.  In cells in which the ETV6 promoter is naturally active to produce house keeping amounts of TEL, “house keeping levels” of the growth regulating kinase domain of TRKC would also be produced then the two genes are fused.

Important Information

Awareness of the ETV6-NTRK3 rearrangement in the thyroid was not in existence at the time when the patient first presented.   Trk tests are now available.  Proof of an NTRK gene rearrangement is one component in eligibility for a clinical trial testing a Trk inhibitor.  Phase 1 clinical trial information on this Trk treatment is available on line.

References

Leeman-Neill RJ, Kelly LM, Liu P, Brenner AV, Little MP, Bogdanova TI, Evdokimova VN, Hatch M, Zurnadzy LY, Nikiforova MN, Yue NJ, Zhang M, Mabuchi K, Tronko MD, Nikiforov YE. (2014) ETV6-NTRK3 is a common chromosomal rearrangement in radiation-associated thyroid cancer. Cancer.120(6):799-807 PubMed

Reynolds S, Shaheen M, Olson G, Barry M, Wu J, Bocklage T.(2016)A Case of Primary Mammary Analog Secretory Carcinoma (MASC) of the Thyroid Masquerading as Papillary Thyroid Carcinoma: Potentially More than a One Off. Head Neck Pathol.10(3):405-13 PubMed

Skálová A, Vanecek T, Sima R, Laco J, Weinreb I, Perez-Ordonez B, Starek I, Geierova M, Simpson RH, Passador-Santos F, Ryska A, Leivo I, Kinkor Z, Michal M. (2010) Mammary analogue secretory carcinoma of salivary glands, containing the ETV6-NTRK3 fusion gene: a hitherto undescribed salivary gland tumor entity. Am J Surg Pathol. 2010 May;34(5):599-608 PubMed
Tognon C, Knezevich SR, Huntsman D, Roskelley CD, Melnyk N, Mathers JA, Becker L, Carneiro F, MacPherson N, Horsman D, Poremba C, Sorensen PH.(2002) Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma. Cancer Cell. 2(5):367-76. PubMed