Coexisting Metastatic Papillary Carcinoma Thyroid and Clear Cell Neuroendocrine Tumour in Thyroid- A Rare Case Report

Background: Papillary Carcinoma Thyroid is the most common form of differentiated thyroid cancer. Its coexistence with a Clear cell Neuro endocrine tumor (NET) has not been reported yet. Clear cell carcinoma is an epithelial derived tumor, characterised by the presence of clear cells. It may arise in multiple tissues including kidneys, uterus, GIT and ovary. Though these tumours may metastasize in thyroid rarely, they have not been reported to be originating primarily in thyroid gland and metastasising elsewhere. Also calcitonin negative NET of thyroid Gland are extremely rare. In our case, clear cell tumour was an aggressive one with widespread metastasis. It was Calcitonin negative and expressing other NET markers. Clinical Case: 40 year old male, presented to endocrine OPD in September 2018, with complaints of right sided neck swelling of 4 months duration. He gave a history of similar swelling on the right side of neck 2 years ago for which he had undergone right Hemi- thyroidectomy at an outside hospital. The HPE report had mentioned the possibility of clear cell NET. Tumour cells expressed Cytokeratin(CK),Epithelial membrane antigen(EMA), CD 56,c-kit,synaptophysin. There was no expression of TTF-1,Tg,PAX 8,Chromogranin A,calcitonin,CD 5,S-100&P 63. FDG PET scan done in 2018 showed FDG avid 8 x 6.1cm soft tissue mass in the right paratracheal region along with FDG avid nodules in the left lobe. FNAC from the mass showed recurrent carcinoma with extensive hemorrhagic cystic changes. In view of the above mentioned findings, he underwent completion thyroidectomy along with bilateral modified neck dissection(MND) and central compartment clearance(FIGURE 1). HPE report mentioned left thyroid having differentiated papillary carcinoma (pT1a pN1a) with positive lymph node in lateral and central compartment. Microscopic findings of the Tissue specimen from the right modified neck dissection(MND) showed tumor cells in groups and sheets,with clear cytoplasm and fairly uniform nucleus appearance. No papillary or follicular cells, no obvious lymphovascular invasion was seen(FIGURE 2A 2B) Frequent areas of necrosis and loose fibrinous tissue were seen amidst the tumor. Mitotic count was approximately 4-5 /hpf. Immuno histochemistry (IHC)done on the specimen from right MND- patchy Epithelial membrane antigen(EMA) expression, CD 10 weakly expressed, rest markers like TTF-1/ PAX8/ RCC antigen /CEA/ Calcitonin /P 63/High molecular weight cytokeratin (HMWCK)/ CK(MNF)/ CK7/ CK20/ CK 19 were negative(figure 2C). Based on the above findings, it was reported first as CASTLE(Carcinoma with thymus like elements) tumour. Tissue specimen was sent to TATA memorial hospital, Mumbai for review. Extensive IHC profile and molecular studies were done, they suggested that it is more likely to be Ewings sarcoma with epithelial differentiation (IHC - positivity for membranous mic2, EMA, CD56 and c Kit, and presence of EWSR1 rearrangements on molecular testing). Still there was no definite consensus regarding the final diagnosis. Tissue slides were sent abroad to Professor Dr Christopher D.M Fletcher at Harvard Medical School. He termed it as unclassified clear cell malignant neoplasm. Figure 1- GROSS SPECIMEN RIGHT NECK MASS Figure 2AFigure 2BFigure 2A-MICROSCOPY FROM LEFT HEMI THYROID SHOWING DIFFERENTIATED PAPILLARY THYROID CARCINOMA Figure 2B-MICROSCOPY FROM RIGHT MND SHOWING CLEAR CELLS MORPHOLOGY Figure 2C- IHC PANEL ON TISSUE SPECIMEN FROM RIGHT NECK MASS Post surgery, he was put on suppressive doses of levothyroxine and calcium and vitamin D supplements, and advised to follow up regularly. But he was lost to follow up for a year. When he followed up a year later, we did a whole body iodine scan(3mCi- I 131) which showed focal increased tracer uptake in anterior neck region on right of midline with a small mild focus on left, without any uptake elsewhere. His thyroglobulin levels were 0.68 ng/ml (normal range 0- 52) and ATA levels were 48.4 IU/ ml (normal range 0-40). Radioiodine ablation therapy (120 mCi) was given. He remained asymptomatic till feb 2020, when he noticed a painful, rapidly enlarging swelling over the right parieto-occipital region of scalp, which was an osteolytic lesion. MRI brain showed a 3.8x 3.5x 3.1 cm focal lobulated mass in the right parietal region with adjacent bony destruction with dural involvement.(figure 6) and PET scan showed hyper metabolic expansile lesion. He underwent embolization followed by excision of the mass in August 2020. Biopsy from the tumour involving right parietal bone showed metastatic poorly differentiated carcinoma with IHC showing immune reactivity for EMA, Vimentin (focal), CK(MNF -116), and CK - 7, and negative for CK 20/ TTF 1/CK 19/ PAX 8 / CD 45/ CD 99/ CD 117/ Thyroglobulin. His general condition started deterioratingIn November 2020,he presented with enlarging right sided swelling(around 15x 10 cm) over the scalp, at the same location Also,there were multiple,darkly pigmented,nodular, discrete swellings over neck, upper chest, along the surgical scar on skull, all over a span of 25-30 days,(figure 3 and 4). In view of his widespread disease and generalised poor health, he was admitted and PET scan was done which showed metastatic disease with high grade activity in following regions-Lobulated soft tissue scalp lesions with intracranial extension, multiple nodal lesion in bilateral neck, parotids, mediastinal and axillary nodes,multiple liver lesions, marrow lesions and multiple nodular lesions involving both lungs. (Figure 5). Figure 3 Figure 4Figure 5- PET SCAN Fig 6.-FLAIR MRI BRAIN SHOWING METASTASIS Liver biopsy showed tumour cells arranged in solid nests,perivascularly and in pseudo papillae without features suggestive of thyroid cancer. He had persistently low calcium levels during the hospital stay despite adequate calcium and active vitamin D supplementation. He was started on Etoposide-Carboplatin based chemotherapy. Recently admitted for a third cycle of chemotherapy but his chest and scalp lesions have worsened. Conclusion: This is a case report of a clear cell NET along with papillary carcinoma both coexisting in the thyroid gland. Primary Clear cell carcinoma of thyroid is extremely rare. Literature reviewed so far does not show any similar case reported. The possibility of metastasis of clear cell carcinoma from other sites has been excluded based on clinical and IHC findings. This would possibly be the first reported case of Primary clear cell carcinoma of thyroid and also its co-existence with papillary carcinoma.