Case Report
Mixed medullary and follicular cell derived thyroid carcinoma-series of three cases
https://doi.org/10.21203/rs.3.rs-2816244/v1
This work is licensed under a CC BY 4.0 License
posted
You are reading this latest preprint version
Papillary thyroid carcinoma and medullary thyroid carcinoma are two distinct types of thyroid carcinoma. Mixed thyroid carcinoma is a rare form of thyroid cancer accounting for less than 0.5% of thyroid malignancies. We present a series of mixed PTC and MTC with details of their clinic-radiological, pathological diagnosis and follow up.
Follicular cell derived carcinoma
papillary thyroid carcinoma
medullary thyroid carcinoma
Mixed medullary and follicular cell derived carcinoma (MMFCC) is a primary malignant epithelial neoplasm of the thyroid gland showing morphological and immunophenotypical evidence of coexisting follicular and C cell derived tumor cell population within the same lesion. Mixed PTC and MTC (MMPTC) is a subtype of MMFCC with morphologic and immunophenotypic distinct Papillary thyroid carcinoma (PTC) and medullary thyroid carcinoma (MTC) components.
PTC is derived from follicular cells of endodermal origin. PTC comprises 75-80% of differentiated thyroid carcinoma [1]. MTC arises from parafollicular cells derived from ultimobranchial body of neural crest [2]. It accounts for 5-8% of thyroid carcinoma. MTC can occur in either hereditary or sporadic setting with hereditary cases presenting at a younger age [3]. MMPTC is a rare form of thyroid cancer accounting for less than 0.5% of thyroid malignancies. It usually presents either as a solitary nodule or is incidentally discovered. Ultrasonography (USG) does not have specific findings for MMPTC. Depending on the predominant component fine needle aspiration (FNAC) may suggest either medullary carcinoma or papillary carcinoma [4]. We present a series of MMPTC with their clinicoradiological and FDG-PET findings, IHC explaining their probable histogenetic origin and possible molecular mechanisms responsible for their development.
Case 1: A 34 year old male with swelling in front of neck of 2 months duration in 2017. USG of thyroid showed multiple hypoechoic nodular lesions with small calcifications in both lobes and significant lymph nodes. On FNAC differential diagnosis of anaplastic carcinoma was considered and so pre surgery serum calcitonin test was not done. On gross examination of total thyroidectomy specimen both lobes showed lesion. Correlating histopathology with IHC, a diagnosis of MMPTC was rendered (Fig 1: a-c). Post surgery, the calcitonin level was < 2 pg/ml. Patient was administered 100 mCi of radioiodine therapy. Post therapy scan revealed the presence of significant remnant thyroid tissue in the neck with no locoregional or distant metastasis (Fig 2a). The first follow-up whole body iodine scan done after 6 months suggested complete ablation of the remnant thyroid tissue with serum thyroglobulin level of 0.265 ng/ml (Fig 2b). He is alive as on date with no new symptoms.
Case 2: A 28 year old female presented with swelling in front of neck of 2 months duration in May 2016. FNAC done at the hospital where she presented initially was reported as follicular neoplasm, Bethesda IV and was referred to our centre for further management. A right hemithyroidectomy done revealed MMPTC on histopathology which was confirmed on IHC. As per NCCN guidelines ultrasound of the neck was done which revealed no significant finding and hence only completion thyroidectomy was done which showed no residual tumor. Patient received 100 mCi of radioactive iodine therapy following surgery. The therapy dose scan revealed the presence of significant remnant thyroid tissue in the neck with no locoregional or distant metastasis (Fig 1: d-f). A follow-up whole body iodine scan in 2017 suggested complete ablation of the remnant thyroid tissue. The TG level was < 0.04 ng/ml. A follow-up whole body MIBI scintigraphy scan in December of 2017 and 2019 were negative. The serum calcitonin level increased from 38 pg/ml (prior to completion thyroidectomy) to 103 pg/ml in 2019. In December 2020, the serum calcitonin got further elevated to 1579 pg/ml. A FNAC and histopathology with IHC from right cervical lymph node dissection specimen in January 2021 showed metastatic deposits of MMPTC. Ga68 DOTANOC scan in April 2021 showed multiple somatostatin receptor (SSTR) positive lytic sclerotic metastatic lesions involving axial and appendicular skeleton. Multiple non SSTR avid soft tissue density metastatic nodules were seen in bilateral lungs (Fig 2: c, f and g). Serum calcitonin on follow up remain elevated however at present, her condition is stable.
Case 3:A 52year male with swelling in front of neck in 2018. USG neck showed single heterogeneous nodule measuring 41 x 32 mm in right lobe of thyroid suggestive of malignancy. FNAC from right lobe of thyroid was reported as Bethesda VI and possibilities of medullary carcinoma or papillary thyroid carcinoma were considered. FNAC in correlation with HPE and IHC performed on total thyroidectomy confirmed the diagnosis of MMPTC with node negative disease (Fig 1: g-i). About 100 mCi of RIT was given in 2018 post surgery. Therapy dose scan did not reveal any abnormal radioiodine avid lesion in the neck or elsewhere in the entire torso. A first follow-up whole body iodine scan did not reveal any abnormal uptake. TG level was also within normal limits. In May 2019, patient underwent C7 corpectomy with cage placement with screws for a MRI and biopsy confirmed cervical spine metastasis. Ga68 DOTANOC scan in July 2019 showed multiple SSTR positive lytic metastatic skeletal lesions in head of right humerus, right 1st rib, C7, D4, L3, L4 & L5 vertebrae and right ischium (Fig 2: d, e, h and i). Peptide Receptor Radionuclide Therapy (PRRT) at a dose of 150 mCi of Lu-177 DOTATATE was administered. Therapy dose scan revealed tracer localization in all the sites mentioned in the PET scan (Fig 2). In Jan 2020, palliative RT with a dose of 2800 cGy in 7 fractions, using 6 MV photons was given to C6/D4 vertebrae followed by spinal decompression to manage the persistent neck pain. His follow-up F-18 FDG PET-CT scan in March 2021 revealed persistence of disease with new lytic lesion in left 2nd rib. He is currently on Cabozantinib (Tyrosine kinase inhibitor) and follow-up.
The thyroid carcinomas are divided based on the proposed cell of origin as follicular cell derived neoplasm or parafollicular cell (C-cell) derived [3, 4]. The thyroid follicular cells secrete thyroglobulin (TG) and the C-cells secrete hormone calcitonin [3]. Papillary and medullary carcinomas thyroid account for 75-80% and 5 to 8% of thyroid carcinomas respectively. Mixed thyroid carcinomas are very rare and account for <0.5% of thyroid carcinomas [1]. Concomitant presence of PTC and MTC in the same patient is a rare event with only a few reports documented in literature. In 1981, the first MTC with PTC case was reported by Lamberg et al. High rates of concurrent PTC with MTC was later reported by Biscolla et al. in 2004 (13.8%) and Kim et al. in 2010 (19%). in patients with MTC. Among these, most of them were papillary thyroid microcarcinomas with separate MTC and PTC components. There is considerable difference in cell of origin, histopathological appearance, genetic alteration, management and follow up of these patients [5].
In practice, the concurrent occurrence of medullary and papillary thyroid carcinoma can be seen as synchronous, but anatomically distinct MTC and PTC or as collision tumor where each merge with one another; or as true mixed medullary-follicular-derived carcinomas where medullary carcinoma and follicular-derived carcinoma are intimately intermixed is rare [3].
Several theories have been proposed for concurrent occurrence of MTC and PTC in literature.
Collision effect theory has been proposed which was supported by “coincidental occurrence” of RET and BRAF mutations separately in medullary and follicular components of mixed thyroid carcinomas, respectively leading to concurrent occurrence of embryologically and genetically divergent tumors [6]. Another potential theory proposed by Volante et al. is hostage theory which assumes that hyperplastic follicular foci are formed due to stimulation of non neoplastic follicular cells entrapped by MTC cells by trophic factors. Additionally the acquired genetic defects in these hyperplastic follicular cells during proliferation may lead to neoplastic transformation [1]. Common stem cell theory proposed by Ljungberg et al. postulated that a common progenitor cell, possibly in the ultimobranchial body undergoes divergent differentiation giving rise to both parafollicular and follicular cell lines which explains the presence of same receptors, immunohistochemical markers (TG and calcitonin) and similar pattern of molecular alterations in both tumors despite their different embryologic origins [1, 5]. Common tumorigenic stimulus such as radiation exposure promotes the malignant transformation of both endodermal and neural crest-derived cell lines [4].
Correlating the findings in our cases with the theories proposed indicate the likelihood of collision effect theory in first case, hostage theory in second case and stem cell theory in third case.
Most studies hypothesize common genetic behavior underlying thyroid malignancies. RET proto-oncogene contribute to oncogenesis in MTC and PTC by tyrosine kinase activation via point mutation or rearrangement. However the role of RET oncogene showed conflicting results in cases of simultaneous PTC and MTC [6, 7]. Germline point mutations of RET is seen in MTC. Sporadic mutations in the RET protooncogene is seen in 30% to 50% of MTC. Somatic BRAF point mutation is seen most commonly associated with PTC; however point mutations/rearrangements of the tyrosine kinase receptors and NTRK1 are more characteristic and are documented in about 20% to 40% of cases. BRAFV600E and RAS mutations remain the main driver mutations in PDTC. In collision tumors RET and BRAF genes both play a role in the tumorigenesis [3].
F-18 FDG PET/CT in normal PTC is less sensitive but has specificity, PPV and accuracy hence can be useful for those patients with negative diagnostic radioiodine scan with elevated serum thyroglobulin or anti-thyroglobulin antibody levels. Ga 68 DOTA PET- CT on the other hand has an important role in PTC mixed with MTC, considering its good results in lesion detection. In individuals with a higher calcitonin production in a mixed carcinoma thyroid, 68Ga-DOTA PET/CT could be a valuable imaging method, while F18-FDG PET/CT could be more tailored for those tumors with a relatively greater CEA secretion [8]. PRRT using 177Lu-octreotate could be considered as a treatment in those patients with high uptake on 68Ga DOTA PET-CT scan (Krennings uptake grade 3 and more) and positive SSTR expression in tumor histology. Since this high uptake score is present in a very limited number of patients, this treatment is only suitable in such selective group of MTC patients only like in our third case [9].
PTC has a relatively better 10 year survival as compared to MTC. MTC has worse prognosis and is difficult to cure with high chances of recurrence. Disease related fatal outcome is seen in 20% of MMPTC. Prognosis of MMPTC depends on the medullary component [4].
Owing to high chances of recurrence, rarity of the tumors and paucity of literature on management, an aggressive approach at initial presentation is recommended. The effectiveness of external radiotherapy and chemotherapy remains controversial; however surgically unresectable lesions may be treated with palliative radiotherapy.
Knowledge of this less known variant and judicious use of IHC is essential to make a correct diagnosis and avoid diagnostic dilemma. More work is needed at molecular level to understand these tumors.
Ethical approval: The study was approved by institutional ethics committee.
Informed consent was obtained.
Competing interests: The authors declare no competing interests.
Authors' contributions:
Dr Daphne Fonseca - Conceptualization, wrote the main manuscript, collected and analyzed data, supervised the project, prepared figures, and reviewed the manuscript.
Dr Sahithi Shilpa Arya - wrote the main manuscript, collected and analyzed data, supervised the project, prepared figures, and reviewed the manuscript.
Dr Prathyusha B - Collected and analyzed data, prepared figures and reviewed the manuscript.
Dr Madhu Vijay P - Collected and analyzed data, prepared figures and reviewed the manuscript.
Dr Suseela Kodandapani - Supervised the project and reviewed the manuscript.
Dr Chandrasekhar Rao - provided follow up, supervised the project and reviewed the manuscript.
Dr Zakir Ali A - Supervised the project, prepared figures and reviewed the manuscript.
Funding: None
Availability of data and materials: Not applicable.
No competing interests reported.
posted
You are reading this latest preprint version