Macrofollicular Variant Of Papillary Thyroid Carcinoma Research Articles

Macrofollicular Variant of Papillary Thyroid Cancer: A Clinicopathologic and Molecular Review

Context: The macrofollicular variant of papillary thyroid carcinoma (MFVPTC) is a rare entity; this variant is a well-differentiated tumor with predominance of macrofollicles lined by cells showing the nuclear features of papillary thyroid carcinoma (PTC). It is claimed to be clinically nonaggressive with a low incidence of metastasis. It is very important to correctly recognize this entity, it might clinically represents a dangerous source of diagnostic error, since it can be easily misinterpreted as a benign disease such as goiter, macrofollicular adenoma, Grave's disease, or hyperplastic nodule. The objective of this article was to provide an update overview of the clinical, cytologic, histologic, and immunohistochemistry (IHC) as well as the molecular characteristics of MFVPTC. Evidence Acquisition: This rare subtype of papillary thyroid carcinoma was first described in 1991. We performed a comprehensive online literature review since its first description up to this date. Results: MFVPTC is a rare variant of papillary thyroid carcinoma that can be extremely difficult to diagnose preoperatively; however, IHC stains and molecular studies might help to differentiate this neoplasm from other thyroid entities. Conclusions: This review highlights the diagnostic difficulties that both clinicians and pathologists face when dealing with follicular variants of papillary thyroid carcinoma. While IHC and gene mutation studies are helpful in narrowing down the differential diagnosis, these techniques need further improvements in order to increase their diagnostic accuracy.

A Noninvasive Encapsulated Macrofollicular Variant of Papillary Thyroid Carcinoma Presenting with Gross Lymph Node Metastasis: A Case Report and Literature Review

Dear Editor:The follicular variant of papillary thyroid carcinoma (FV-PTC) without vascular or capsular invasion is considered tohave virtually no metastatic potential or recurrence risk (1).The macrofollicular variant of papillary thyroid carcinoma(MFV-PTC) is a very rare variant of FV-PTC the behavior ofwhich appears to be similar to FV-PTC (2). However, morerecently, this phenomenon has been challenged by reports ofsystemic metastases and recurrent and fatal cases (3). We re-port a case of encapsulated noninvasive MFV-PTC that pre-sented with gross lymph node metastases, and briefly reviewthe literature. A right thyroid nodule was incidentally foundby a computed tomography scan in an 80-year-old male.Subsequently, a 3.7cm·3.6cm·3.3cm heterogeneous iso- tohyperechogenic thyroid nodule in the right lobe and a2.2cm·2cm·1.3cm right jugular lymph node, both withcalcifications, were detected by ultrasonography. Fine-needleaspiration biopsy of both lesions was performed under ultra-sonography guidance and showed malignant cells consistentwith PTC. The patient underwent a total thyroidectomy withcentral and right (levels 3–4) lymph node dissection. Thethyroidectomy specimen revealed a 3.7cm·3.2cm·2.9cmencapsulated white solid nodule in the right lobe (Fig. 1),which was entirely submitted for histological evaluation. Onhistology, the nodule was completely surrounded by a thickand focally calcified capsule, without evidence of vascular orcapsular invasion. The nodule was predominantly macro-follicular, with minor areas composed of smaller follicles. Thecells lining the macrofollicles were often attenuated withoutsignificant nuclear atypia (Fig. 1). In contrast, the cells liningthe smaller follicles were more cuboidal and had the typicalnuclear features of PTC (Fig. 1). Numerous intratumoral cal-cifications and psammoma bodies were observed (Fig. 1).Insular/solid growth, necrosis, or mitotic activity was notobserved. Two lymph node metastases were found. Thelargest one (2.4cm) was composed predominantly ofmacrofollicles, akin to the primary tumor (Fig. 1). Im-munohistochemistry was supportive of malignancy, withthe tumor cells being diffusely positive for galectin-3, andfocallypositiveforHBME-1(HectorBattiforamesothelin-1)inthe non-macrofollicular areas only. The proliferative index(Ki-67) in the primary tumor and in the larger metastasis wasvery low ( 50%) was composed ofmacrofollicles (>250lm), corresponding to the arbitrarydefinition of an MFV-PTC (2). Interestingly, that feature wasalso retained in the larger lymph node metastasis, but not inthe smaller one. In the literature, although several cases ofMFV-PTC have presented with lymph node metastasis, mostof these cases were either infiltrative and/or associated withvascular invasion (2). In the largest series of MFV-PTC of 29patients, 6 developed lymph node and 2 developed lungmetastasis (2). The metastases occurred in older patients whohad insular components, extrathyroidal extension, and vas-cular invasion. In our case, although the patient was elderly,no other risk factors were identified. To the best of ourknowledge, there are two other documented cases of encap-sulatedMFV-PTCwithoutcapsularorvascularinvasionwithlymph node and/or systemic metastasis (3). In comparison,we found no well-documented cases of conventional encap-sulated noninvasive FV-PTC with lymph node metastases. Inthe study by Liu et al. (1), the only encapsulated FV-PTC withlymph node metastasis had several foci of lymphovascularinvasion. Moreover, observing that most cases of FV-PTCwith metastatic disease had obvious invasion, Lloyd et al. (4)recommend caution in making a diagnosis of FV-PTC in theabsence of the major histopathologic features or obvious

Macrofollicular variant of papillary carcinoma, a potential diagnostic pitfall: A report of two cases including a review of literature

Macrofollicular variant of papillary thyroid carcinoma (MFVPTC) is one of the rarest histologic types of papillary carcinoma. This tumor may mimic an adenomatoid/colloid nodule or follicular neoplasm (macrofollicular type) both on histology and cytology. There are very few articles describing the cytologic features of MFVPTC. We report the cytologic findings of two surgically confirmed MFVPTC. The first case showed abundant thin colloid with moderate amount of follicular cells arranged in a honeycombed and syncytial pattern. Some but not all the follicular cells showed enlarged round to ovoid nuclei, overlapping nuclei, few nuclear grooves and rare intranuclear inclusions. The second case showed abundant thin colloid and predominantly benign appearing follicular cells with few overlapping nuclei, enlarged round to ovoid nuclei and rare nuclear grooves. No intranuclear inclusions were identified. A review of the literature was done and the cytologic findings of MFVPTC including our two cases were tabulated. The cytologic findings showed moderate to abundant thin with focally thick colloid in 75% of cases and sheet like arrangement of follicular cells in 76%. Although nuclear features such as chromatin clearing, overlapping and grooves were present in majority of cases, the quantity varied from rare to focal. Small to prominent nucleoli were present in all of the evaluable cases. Intranuclear inclusions were seen only in 45% of patients. Hence, the cytologic features of macrofollicular variant of papillary carcinoma though present can be subtle and intranuclear inclusions may not be present always.

Lymph node metastasis from undiagnosed occult papillary thyroid cancer

To the Editor A 57-year-old woman was referred to our Endocrine Unit 3 years after she underwent total thyroidectomy for a large non-toxic multinodular goiter with tracheal deviation. At that time histology was negative for malignancy. She had no family history of thyroid disease. At the time of our observation no palpable neck mass was present, but neck ultrasound imaging study revealed a left lateral solid cervical mass (8 9 13 9 14 mm), with features of a lymph node, strongly hypoechoic, lacking in homogeneity, containing several microcalcifications and lack of visibility of the hilum (Fig. 1). The patient gave informed consent to the study and US-FNAB of this mass with thyroglobulin assay in the wash-out liquid were performed. Thyroglobulin (Tg) value of[30.000 ng/ml in the wash-out liquid of the needle and the presence of epithelial follicular cells in the specimen suggested the presence of proliferating thyroid cells [1, 2]. The patient was then submitted to a modified neck dissection. At pathology, neck mass resulted a lymphatic metastasis from occult classic papillary thyroid carcinoma (PTC) because of the presence of lymphatic tissue partially substituted by atypical thyroid cells, with nuclear grooves and ground glass cytoplasma. After surgery the patient received a therapeutic I dose (3,700 Mbq) using the thyroid hormone withdrawal method. In this hypothyroid protocol, levothyroxine treatment was withdrawn for 4 weeks, while triiodothyroxine was given for 2 weeks and then withdrawn for 2 weeks. Serum thyrotropin (TSH) and thyroglobulin (Tg) were then measured. TSH levels were 120 mcUI/ml and Tg was \1 ng/ml. The whole body scan (WBS) after therapy showed only minimal thyroid bed uptake. She is actually on therapy with L-tiroxine at the dose of 900 mcg/week, with TSH 0.5 mcUI/ml, Tg \ 0.2 ng/ml and TgAb \ 10 UI/ml. In this case, neck ultrasound study revealed a loco-regional metastasis from a nodule with no previously evidence of malignancy. This rare event could be the consequence of the presence of a focus of papillary microcarcinoma (microPTC) undiagnosed because of goiter dimension and multiple nodules presence. Papillary thyroid microcarcinomas (PTCs) are found in approximatively in 6–36 % of the population at autopsy. Only fewer than 2 % of microPTCs come to clinical attention [3]. Despite the very low mortality rates, locoregional recurrence is a common clinical problem. Some microPTCs have lymph node metastasis (16–64 %) and multiple tumor formation (23–33 %) at presentation, which are both associated with a less favorable outcome, including distant metastases and increased mortality [3]. In this case, pathological revision of thyroid did not found any focus of carcinoma. This event was reported in 0.17 % of patients previously diagnosed as affected from benign nodular goiter [4]. In this cases a nodular goiter previously diagnosed as non-malignant, after showed a malignant behavior. This was described in rare macrofollicular variant of PTC and in some rare lesions with nuclei less clear than those of conventional papillary carcinoma [4]. In our case, the lesion was described as lymph node metastasis from a classic PTC. We cannot exclude that thyroid microcarcinoma may have developed subsequently on the small thyroid remnant. For this reason, we decided to submit the patient to radioiodine ablation. In 2009, ATA recommended (recommendation 44) periodic serum thyroglobulin assay and neck ultrasonography during followup of patients with thyroid cancers managed with subtotal A. Carbone P. Bellitti R. Bruno (&) Unita Operativa Complessa di Endocrinologia, Ospedale di Tinchi, Matera, Italy e-mail: roccobruno1@virgilio.it

Three cases of macrofollicular variant of papillary thyroid carcinoma

The macrofollicular variant of papillary thyroid carcinoma (MFPTC) is a well-established entity with characteristic large follicles containing pale colloid and lined by cells with nuclear features of papillary thyroid carcinoma (PTC). In this study, we present three cases of MFPTC, along with a brief review of the literature. For all three of our cases, the histology of the resected specimen showed predominantly macrofollicular structures lined by cells with nuclear characteristics of PTC. Immunohistochemically, the three cases show positivity for galactin-3, cytokeratin-19, and HBME-1. These cases will help us in understanding the distinction from other benign and malignant follicular lesions of the thyroid, which is of utmost importance. The key to diagnosis is a high-power examination of any macrofollicular lesion of the thyroid.

Two Patients with Highly Aggressive Macrofollicular Variant of Papillary Thyroid Carcinoma

The macrofollicular variant of papillary thyroid carcinoma (MFV-PTC) is an unusual type of thyroid carcinoma with histological features that can be confused with nodular goiter or follicular adenoma. It generally has a good prognosis and low incidence of metastases. We report two patients with highly aggressive MFV-PTC including bone metastases, one of whom died of their disease. The first patient was a 59-year-old woman with an occipital mass diagnosed histologically as papillary thyroid carcinoma (PTC), follicular variant. There were multiple bone lesions on computed tomography. Ten years earlier a biopsy of a thyroid nodule had been negative for malignant cells. Thyroidectomy showed a 3-cm nodule in the thyroid, diagnosed as MFV-PTC. Iodine 131 whole body scan showed uptake in the skull, ribs, thoracic and lumbar spine, and pelvic bones. The second patient was an 81-year-old man with a history of right thyroid nodule treated by total thyroidectomy with a postoperative diagnosis of adenomatous goiter. Three years later he developed a right shoulder mass, histologically diagnosed as follicular variant of PTC. The original thyroidectomy specimen was reviewed and reclassified as MFV-PTC. The patient developed new bone and lung metastases. Three treatments with (131)I were not effective. He died of metastatic thyroid cancer. To our knowledge these are the first cases of MFV-PTC reported with bone metastasis. Although MFV-PTC usually has a good prognosis these cases highlight the importance of careful histopathological examination for MFV-PTC in thyroidectomy specimens that may appear to be seemingly benign nodular thyroid disease.

Macrofollicular Variant of Papillary Thyroid Carcinoma: A Case and Control Analysis.

The planimetric, flow cytometric, and immunohistochemical characteristics of the macrofollicular variant of papillary thyroid carcinoma (MFVPTC) have not been reported before. The clinical, morphological, immunohistochemical, planimetric, and flow cytometric characteristics of six cases of the MFVPTC and six of the follicular variant of papillary thyroid carcinoma (FVPTC) were analyzed. Patients had undergone surgical treatment. The mean age was 38 (range 29-64 yr), and five were women. Tumors had a mean size of 3.2 cm (range 0.3-4.5 cm). Half were originally diagnosed as goiter. Macrofollicles had a mean diameter of 345.5 um, perimeter of 1237 um, and area of 13,779 um(2), with nuclear changes of PTC. Mean follow-up was 107 mo (range 12-277), and neither lymph node metastases nor recurrence were seen. Differences in diameter, perimeter, and area between the macrofollicular and follicular variants were found. Follicular neoplastic cells were thyroglobulin and 5-100 protein positive in macrofollicles and normofollicles. All were negative to cytokeratin and to high-mol-wt keratin. All tumors were diploid. There were no significant differences in follow-up, DNA content, nor immunohistochemical reactivity. Differences in diameter (p < 0.00006), perimeter (p < 0.0001), and area (p < 0.001) were observed. It is important to recognize this variant because it could be misdiagnosed as benign thyroidal lesions.