Poorly differentiated (insular) thyroid carcinoma arising in a long-standing colloid goitre: A cytological dilemma.

Poorly differentiated (insular) thyroid carcinoma (PDITC) is an uncommon thyroglobulin producing neoplasm intermediate in aggressiveness between well-differentiated carcinomas of follicular cell origin and undifferentiated anaplastic carcinoma. Its cytomorphological recognition is essential for planning surgery and subsequent management as it is known for its aggressive behavior, advanced stage at presentation, local recurrences and rapid dissemination. We report a case of PDITC arising in a long-standing goiter, in which presence of microfollicular structures and minimal necrosis resulted in difficulty in distinguishing it from a follicular neoplasm of thyroid.

Introduction

Thyroid carcinomas of follicular origin represent a spectrum from the indolent papillary thyroid carcinoma (PTC) and minimally invasive follicular carcinomas (FC) to the lethal anaplastic carcinomas (AC).[1-10] Poorly differentiated (Insular) thyroid carcinoma (PDITC), first described by Sakamoto et al.,[1] and Carcangia et al.,[2] are rare, aggressive tumors, morphologically and biologically placed between FC/PTC and AC.[1-10]

PDITC, now recognized as a distinct thyroid neoplasm, accounts for 4-7% of thyroid malignancies, is twice as common in males with a mean age of 55.7 years.[3-5] It presents as a rapidly growing, large mass, cold on radioiodine scintigraphy with associated nodal and distant metastasis in 30%.[4] Many cases have radioiodine refractory metastases, resulting in death. Concomitant well-differentiated thyroid carcinoma (WDTC) in both AC and PDITC, suggests progressive dedifferentiation.

Case Report

A 77-year-old female presented with a progressively increasing swelling in the neck of 3-years duration, hoarseness and irregular cough. She had undergone a left hemithyroidectomy elsewhere 40 years earlier, for colloid goiter. An irregular, firm, fixed mass was seen in the right side of neck measuring 8.5 × 6 cm. Indirect laryngoscopy showed right vocal cord paralysis. Computed tomography (CT) scan neck showed a thyroid nodule, 7.8 × 5.8 cm, with internal calcification. CT scan chest showed metastases. Her thyroid profile was normal. Fine needle aspiration cytology (FNAC) of the mass showed high cellularity composed of monomorphic small cells arranged in microfollicles, crowded groups with well-defined borders [Figure 1] and numerous single cells. The cells had scanty, fragile cytoplasm, indistinct cell margins and round nuclei with granular chromatin. Nuclear crowding, occasional grooves and mitoses were seen. Stromal fragments separating the nests [Figure 1] and minimal necrotic debris was seen. A diagnosis of follicular carcinoma was made.

Figure 1

Intact insular aggregates of small cells amidst fibrovascular stroma (Pap, ×100) with (inset) an intact insula enveloped by a single layer of endothelial cells (Pap, ×400)

A right hemithyroidectomy was performed. The enlarged right lobe measured 6.5 × 6 × 4 cm. The anterior surface was bosselated but encapsulated. The tracheal surface showed an irregular raw area (3 × 2 cm) with protruding, grey white tumor tissue. The cut surface showed an infiltrating lobulated, firm, white tumor replacing the entire lobe with a thin rim of thyroid tissue at the periphery.

Microscopically, a widely invasive, cellular tumor with cells arranged in groups, sheets and microfollicles with individual cells having indistinct borders, scanty cytoplasm and round nuclei with finely granular chromatin was seen. Mitoses, vascular emboli and small foci of necrosis were seen. Thin sinusoidal vessels separated the insulae. The tumor extended beyond the thyroid capsule into adjacent skeletal muscle. The residual thyroid showed nodular goiter. No well-differentiated tumor was seen. The congo red stain for amyloid was negative. A diagnosis of PDITC arising in a nodular goiter was made.

Review of the smears showed the groups of cells to be entire, intact insulae, clinging to stroma. They had sharp borders that were encircled by endothelial cells [Figure 1 inset].

In spite of postoperative radioiodine therapy, the metastatic nodules persisted and she succumbed to the disease after 3 years.

Discussion

Most authors concur that PDITC exists but its histological definition is controversial.[4] Some authors define them by predominance of solid, trabecular, insular or sclerotic pattern, whereas others rely on unequivocal high-grade histology. Some include aggressive tall or columnar cell carcinomas in this category.[134] It is included as a distinct entity in the WHO classification,[5] with the aim of uniform terminology and diagnostic criteria considering architectural and high-grade features.[4]

Although PDITC can be diagnosed histologically, cytological diagnosis is problematic.[10] Due to its rarity, lack of experience and subtle cytological findings, most are initially misdiagnosed as follicular neoplasms,[6] as was our case.

The cytological features first described by Pietribiasi et al.,[7] include high cellularity, relatively monomorphic, round, small malignant cells in crowded nests, loosely cohesive groups, microfollicles with or without colloid and as dispersed cells. They have round to oval nuclei with finely granular chromatin, micronucleoli, high nucleocytoplasmic ratio, mitotic figures and necrosis. Atypia is usually mild, but when obvious with abundant necrosis, should prompt a diagnosis of AC.[78] PDITC arising from WDTC may demonstrate cytological features of the latter, with the former becoming evident only on excision. Rarely, thorough sampling shows both components.[6] The background is colloid free and clean, or necrotic. The presence of entire insulae is an uncommon feature, attributed to the use of larger bore needles. A peculiar feature we observed was a single layer of endothelial cells enveloping the insulae [Figure 1, Inset], an as yet undescribed feature in the literature. This corresponded to the thin sinusoids separating the insulae on histopathology. Immunocytochemically, PDITC cells are thyroglobulin and Bcl-2 positive, calcitonin negative and high Ki-67 index. Cell blocks are useful in identifying insulae and for immunohistochemistry.

Presence of microfollicles leads to a misdiagnosis of follicular neoplasm (FN). Smaller tumor cells are key to the diagnosis.[6810] FN cells have coarsely granular chromatin, repetitive follicular pattern, fewer single cells, no necrosis or mitoses. Like PTC, PDITC cells appear relatively monotonous, contain cytoplasmic vacuoles and may possess occasional nuclear grooves, inclusions and possibly, psammoma bodies. In contrast with PTC, metaplastic cytoplasm and papillae are absent. PDITC dedifferentiating from PTC may show overlapping features. Unlike FN and PTC, necrosis is a frequent finding in PDITC.

The dissociated pattern and/or plasmacytoid cells of PDITC can give an impression of medullary thyroid carcinoma (MTC) or non-Hodgkin lymphoma (NHL). PDITC shows necrosis and increased mitoses, a feature generally not observed in MTC. MTC shows red cytoplasmic granularity, salt and pepper chromatin, amyloid and calcitonin positivity. Dispersed small cells, absence of nuclear molding and stretch artefacts, can be seen in PDITC and NHL. Intact insulae and thyroglobulin positivity helps differentiate the two lesions.[6]

Differentiating PDITC from metastasis is clinically important. Metastatic breast, transitional cell, neuroendocrine and prostatic carcinomas can cause confusion. The clinical history and immunocytochemistry for thyroglobulin helps. Small cell carcinoma lung metastasis to the thyroid may be the initial presenting sign of lung cancer.[6] Presence of nuclear molding, streaking and pleomorphism favors the diagnosis of this lesion. Both are TTf-1 and cytokeratin positive but thyroglobulin is strongly expressed in PDITC. Metastatic basaloid squamous cell carcinoma closely resembles PDITC.

In conclusion, cytological features of small cells in insular groups, cellular crowding, numerous single cells, low-grade atypia, mitotic figures, necrosis, thyroglobulin positivity and calcitonin negativity should prompt the pathologist to consider PDITC as this has prognostic implications.