Case 1

A 60-year-old male patient presented with right posterior chest wall pain. CT chest demonstrated a 112 x 63 mm right chest-wall lesion with destruction of the six, seventh and eight ribs and a pathological fracture of the T7 vertebral process. There were multiple bony metastasis on FDG-PET. Fine needle aspiration of the chest demonstrated likely primary thyroid cancer with oncocytic features. Thyroglobulin was >500 mcg/L.

 

He had undergone a right hemithyroidectomy in 2010 which was reported as 7cm “oncocytoma” with no evidence of malignancy. On retrospective interrogation of histopathology from 2010, it was thought there was a single focus of vascular invasion consistent with minimally invasive Hurthle cell carcinoma.  

 

Thyroid ultrasound showed a suspicious hypoechoic nodule with one focus of calcification in the left thyroid bed measuring 1.9x1.6x1.6cm.  He underwent completion left thyroidectomy. Histopathology revealed a 2.4 cm minimally invasive Hurthle cell carcinoma, focal capsular without vascular invasion. Thyroxine was commenced to supress TSH. He underwent  radiation therapy to his posterior chest lesion and had radio-iodine therapy 200 mCi.

 

 

 

Figure 1 – CT demonstrating right seventh rib with large vascular soft tissue component measuring 12 cm in diameter

 

Case 2

A 68-year-old male was investigated for a chronic cough. A chest x-ray and CT chest confirmed multiple cannon-ball lesions with the largest measuring 14 x 8 x 7 cm in the right lobe. There were no other distant metastatic lesions identified on whole body CT and FDG PET scan. An ultrasound of the neck showed no radiological evidence of residual thyroid tissue and no mass lesions at the site of the thyroid bed or lymphadenopathy.

 

He had a background of total thyroidectomy for goitre in 2006. Histopathology was reported as right lobe 140 x 80 x 70 mm, completely occupied by a well-circumscribed light tan nodule with cystic and fibrotic areas consistent with benign follicular adenoma with no evidence of malignancy. Slides were not available for re-evaluation.

 

He underwent a biopsy of his lung lesion confirming metastatic neoplasm with features of thyroid origin with strongly positive PAX8, TTF-1 and thyroglobulin. His thyroglobulin was 1780 mcg/L (<30), consistent with metastatic thyroid carcinoma. After discussions with our cardio-thoracic surgical colleagues, resection of the largest the lesion was not recommended. He received RAI 200mCi and his lesions were all RAI avid.

 

 

Figure 2 – Chest CT demonstrating innumerable bilateral lung metastases, largest in the inferior aspect of the right upper lobe measuring 66 x 73 mm

 

Discussion:

Follicular thyroid carcinoma is the second most prevalent form of thyroid cancer after papillary thyroid carcinoma, accounting for between 5-20% of all thyroid malignancies.[i] Despite locoregional lymphatic spread being rare (1-7%)[ii],  haematogenous spread to lung and bone occurs more often (6-20%).[iii] Although metastatic disease may not be clinically evident for many years, such follicular neoplasms are usually large with evidence of capsule or vascular invasion or considerable cellular pleomorphism.[iv] Whilst minimally invasive follicular carcinomas have an excellent prognosis with cure rates of between 95-100%, widely invasive forms have a poorer prognosis with higher risk of recurrence and metastasis, and higher mortality.[v] The archaic diagnosis of ‘benign metastasising goitre’ arose due to the difficulty in recognising vascular invasion of follicular neoplasms after complete resection.

 

Ultrasound features are helpful in distinguishing papillary thyroid carcinoma (PTC), they are less useful in the diagnosis of follicular thyroid carcinoma. Cytology is also limited in its  ability to distinguish between follicular thyroid carcinoma and benign thyroid adenomas as the same oncogenic drivers are found in follicular thyroid carcinomas and follicular adenomas. Utility of cytological biomarkers or mutations including B-galactose binding protein galectin-3, HMBE-1, PAX-PPARy translocations and RAS mutations is limited in the differentiation between follicular thyroid adenomas and carcinomas pre-operatively.[vi]  Definitive classification of follicular neoplasms predominately requires post-operative histological diagnosis and examination of capsular and vascular invasion.[vii]

 

Despite advances in tumour markers, currently histological analysis of a very large number of tumour capsule samples is required to identify vascular invasiveness and malignant potential. However, minimally invasive carcinomas are often diagnosed with less than a millimetre of tissue differentiating them from adenomas and non-invasive thyroid neoplasm. Yamashima et al  evaluated 14 encapsulated follicular neoplasms with extensive dissection concluded that although labour intensive, multiple sections produced by extensive dissection helped identify minute but definite evidence of angioinvasion.[vii]

 

There is debate internationally as to how much capsule should be examined to ensure a thorough examination, however complete microscopic examination of the tumour capsule is essentially impossible,[viii] and there is a high rate of intra-observer variation at histopathological diagnosis.[ix]  A consensus for adequate sampling has not been established by the College of American Pathologists or the World Health Organization. [x]  Current practice varies between submitting selected sections of the follicular capsule after gross examination for microscopic evaluation to the extreme approach of submitting the entire capsule for microscopic evaluation. With increasing use of molecular diagnostics, we may have a better appreciation of the underlying tumour biology as reflected by the histopathology.

 

In summary, large follicular lesions may harbour small focus of angioinvasion which may have not been sampled for microscopic evaluation. Until histopathological assessment improves, possibly combining immunohistochemistry and molecular diagnostics, yearly thyroglobulin assessment in the medium to long term may be prudent, regardless of if capsular or vascular invasion is identified.

 

Take home point:

• Long-term follow-up with thyroglobulin for late recurrence is warranted for large follicular lesions, regardless of if capsular or vascular invasion is identified.

 

 

[i] Hundahl SA, Cady MP, Cunningham MP, Mazzaferri E, McKee R, Rosai J, Shah JP, Fremgen AM, et al. Initial results from a prospective cohort study of 5583 cases of thyroid carcinoma treated in the United States during 1996. Cancer 2000; 89 (1): 202-217

 

[ii] Alfalah H, Crashaw I, Jany T, et al. Risk factors for lateral cervical lymph node involvement in follicular thyroid carcinoma. World J Surg 2008; 32 (12): 2623-2626

 

[iii] Parameswaran R, Hu JS, Min En N, et al. Patterns of metastasis in follicular thyroid carcinoma and the difference between early and delayed presentation. Ann R Coll Surg Engl 2017; 99 (2): 151-154

 

[iv] Mizukami Y, Nonmura A, Hayashi Y, Ohmura K, Michigishi T, Nogughi M, Nakamura S, Kshizaki T. Late bone metastasis from an encapsulated follicular  carcinoma of the thyroid without capsular and vascular invasion. Pathology international 1996 (46): 457-461

 

[v] DeMay, RM. Follicular lesions of the thyroid. W(h)ither follicular carcinoma? Am J Clin Pathol 2000; 114: 681-683

 

[vi]  Yamashina M. Follicular neoplasms of the thyroid. Total circumferential evaluation of the fibrous capsule. AmJ Surg pathol 1992; 16 (4): 392-400.

 

 

[vii] Staubitz JI, Musholt PB, Musholt TJ. The surgical dilemma of primary surgery for follicular thyroid neoplasms. Best Pract Res Clin endocrinol Metab. 2019; 33 (4): 101292.

 

[viii] Glomski K, Nose V, Faquin C, Sadow PM. Metastatic follicular thyroid carcinoma  and the primary thyroid gross examination: Institutional review of cases from 1990 to 2015. Endorine Pathol 2017; 28: 177-185.

 

 

[ix]  Hirokawa m, Carney JA, Goellner JR, DeLellis RA, Heffess CA, Katoh R, Mashahiko T, Kennichi K. Observer variation of encapsulated follicular lesions of the thyroid gland. Am J Surg Pathol 2002 (26): 1508-1514

 

[x] Seethala RR, Asa SL, Carty SE, et al. College of American Pathologists (CAP) protocol for examination of specimens from

patients with carcinomas of the thyroid gland. Jan;2016 http://www.cap.org/ShowProperty?nodePath=/UCMCon/Contribution%20Folders/WebContent/pdf/cp-thyroid-16protocol-3200.pdf