Macrofollicular Variant of Papillary Carcinoma of the Thyroid: A Histologic, Cytologic, and Immunohistochemical Study of 3 Cases and Review of the Literature Open Access

Papillary carcinoma, the most common malignant tumor of the thyroid gland, has a very broad morphologic spectrum.1 In 1991, Albores-Saavedra et al2 described 17 cases of a macrofollicular variant of an encapsulated papillary carcinoma of the thyroid, which can be easily confused with nodular goiter or benign follicular adenoma. According to the definition given by these authors, the macrofollicular variant of papillary carcinoma of the thyroid is characterized histologically by a predominance of macrofollicles (>50% of a cross-sectional area) and clinically by nonaggressive biologic behavior. In recent years, only a few additional cases of this entity have been described, mainly as single case reports.3–5 

Considering the histologic, cytologic, and immunohistochemical features of the macrofollicular variant of papillary carcinoma, there is a broad spectrum of differential diagnoses as follicular adenoma, nodular goiter, or Hashimoto thyroiditis. Cytologic features appear to be discriminatory for the differential diagnosis.

In this study, we describe the clinical and pathologic features of 3 cases of this rare entity, one of them recurring 1 year later as an anaplastic carcinoma, and review the literature.

The cases were retrieved from the surgical pathology files of the University Hospital, Basel, Switzerland. The Papanicolaou-stained cytologic specimens from the presurgical fine-needle aspiration biopsies and the hematoxylin-eosin–stained and elastica-Van Gieson–stained sections of the resected tumors were reviewed. Paraffin blocks were available in all 3 cases, and additional 5-μm-thick sections were prepared for immunohistochemical studies. Immunostaining was performed using the ABC-Elite-Method (Vector, Burlingame, Calif) for thyroid transcription factor-1, p53, cytokeratins 7, 17, 19, and 20, and galectin-3. For each antigen tested, positive and negative control sections were stained simultaneously. The antibodies used, their sources, and their dilutions are provided in Table 1.

A 38-year-old woman presented at physical examination with a nodular, solitary mass in the inferior part of the left thyroid lobe. Ultrasonography detected a solid-cystic nodule, and a fine-needle aspiration biopsy showed atypical epithelial cells with ground-glass, overlapping nuclei, nuclear grooves, and prominent nucleoli (Figure 1). These morphologic features were consistent with a papillary carcinoma of the thyroid. A total thyroidectomy was performed. Macroscopically, the solitary, partially encapsulated nodule in the left thyroid lobe measured 1.4 cm in diameter and was surrounded by normal thyroid tissue. Histologically, it was characterized by a macrofollicular growth pattern (Figure 2), lined by large, cuboidal cells with optically clear, ground-glass, focally overlapping nuclei with nuclear grooves, pseudoinclusions, and prominent nucleoli (Figure 3). The macrofollicles contained dense and eosinophilic colloid. A focal capsule infiltration was detected. The right thyroid lobe showed no evidence of a tumor.

A 72-year-old woman with a multinodular enlargement of the thyroid gland underwent a subtotal bilateral thyroidectomy because of a progressive tracheal compression. A fine-needle aspiration biopsy showed no cytologic features characteristic of papillary carcinoma of the thyroid. Grossly, the thyroid showed several nodules, partially encapsulated, measuring 2 to 10 mm. One nodule (diameter, 1 cm) displayed a diffuse macrofollicular growth pattern. The follicles (diameter, >200 μm) were lined by large, cuboidal cells with optically clear nuclei and nuclear grooves. Diffuse infiltration of the thyroid capsule and infiltration of blood vessels were also detected (Figure 4). A diagnosis of macrofollicular papillary carcinoma of the thyroid was rendered.

The adjacent normal thyroid tissue presented features of a nodular goiter. Five days after this intervention, a complete thyroidectomy was performed.

One year later, at the prior tumor site, the patient developed an undifferentiated, anaplastic carcinoma with capsule, blood vessel, and lymph node infiltration (Figure 5).

A 43-year-old man with a clinical history of goiter presented with a solitary nodule in the right thyroid lobe and an enlarged cervical lymph node on the right neck. Computed tomographic scanning showed no signs of metastases. The cells in a fine-needle aspiration biopsy showed single ground-glass nuclei with nuclear grooves, but these were less prominent than in case 1. A right thyroid lobectomy, a subtotal left thyroid lobectomy, and a neck dissection were performed.

Grossly, the nodule (diameter, 6 cm) consisted of several cysts measuring 7 mm. Histologically, the nodule was completely encapsulated and presented as a macrofollicular growth pattern with cytologic features similar to those of cases 1 and 2. Follicles were lined by large, cuboidal cells with clear nuclei, nuclear grooves, and a fine chromatin pattern. The colloid of these follicles was denser and more eosinophilic than that of the adjacent normal follicles. Capsule or blood vessel infiltration by the tumor could not be detected. The enlarged cervical lymph node showed a metastasis of the macrofollicular variant of papillary carcinoma of the thyroid (Figure 6).

The clinical and pathologic features of the 3 cases are summarized in Table 2.

In all 3 cases, a positivity for cytokeratins 7, 17, and 19, thyroid transcription factor-1, and galectin-3 and a negativity for cytokeratin 20 and p53 were observed. The immunohistochemical results are shown in Table 3.

The macrofollicular variant of papillary carcinoma of the thyroid is a rare entity, first described by Albores-Saavedra et al2 in 1991. According to its definition, more than 50% of the cross-sectional area of the tumor must be composed of macrofollicles (follicles, >250 μm), lined by cells with features characteristic of papillary carcinoma, namely nuclear grooves and optically clear or ground-glass nuclei. Until now, approximately 38 cases of the macrofollicular variant have been reported in the literature.2–7 The main reported features are summarized in Table 4.

Women seem to be more affected than men,2 although recently, several reported cases have concerned men.4,7 In our study, 2 females and 1 male were included.

We detected a regional lymph node metastasis in 1 of 3 cases, whereas Albores-Saavedra et al2 detected a lymph node metastasis in 2 of 17 (11.8%) cases. Evans8 observed metastasis to a regional lymph node in 1 of 14 patients (7.1%). In contrast to the conventional papillary carcinoma, with a reported prevalence of regional lymph node metastases between 35%9 and 50%,10 the low incidence of lymph node metastasis in the macrofollicular variant of papillary carcinoma of the thyroid is probably due to the presence of a well-defined capsule.2 

The mean diameter of the 3 papillary carcinomas in our study was 2.8 cm. In the reported series, the range was 2.3 to 8 cm (Table 1). Considering the 17 cases of Albores-Saavedra et al,2 the macrofollicular variant of papillary thyroid cancer pursues a less aggressive clinical course than the conventional form. The tumor with the smallest diameter (1 cm) recurred as an undifferentiated, anaplastic carcinoma with sarcomatoid differentiation and lymph node infiltration, whereas the other 2 tumors (diameters, 1.4 and 6.0 cm, respectively) showed no signs of recurrence. Carcangiu et al1 and other authors11,12 have reported that many cases of undifferentiated thyroid carcinoma may not arise de novo, but rather as a result of the dedifferentiation of a papillary or follicular carcinoma. Our case could be an example of such a dedifferentiation.

Because of the macrofollicular pattern of this variant of papillary carcinoma of the thyroid, the differential diagnosis with benign diseases such as goiter, macrofollicular adenoma, Graves disease, or hyperplastic nodule may be challenging.

In follicular adenomas, the macrofollicles are lined by flat epithelial cells showing hyperchromatic nuclei, and in Graves disease, colloid and macrofollicles are not abundant.2 

The clear nucleus-Orphan Annie eye13,14 is accepted as one of the important features of papillary carcinoma. Hapke and Dehner13 studied 100 cases of thyroid lesions exclusive of papillary, follicular, or mixed carcinoma. Only 2% (diffuse hyperplasia and follicular adenoma) showed such nuclear morphology; meanwhile, 83% of the papillary carcinomas showed clear or empty nuclei. Other authors1,15,16 have examined the “conventional” follicular variant of papillary carcinoma, and the ground-glass nucleus was one of the diagnostic clues for papillary carcinoma. Pseudoinclusions or nuclear grooving is also supposed to be characteristic of papillary carcinoma.17 However, Scopa et al18 examined 80 nonpapillary thyroid lesions and found nuclear grooves in all but 11 cases (adenomatous hyperplasia and nodular goiter). Since a focal presence of grooves can occur in nonneoplastic thyroid lesions, the quantity of grooved cells (focal or diffuse) and the nuclear shape need to be considered.17–19 In summary, prominent, diffuse, clear, overlapping, “irregular” nuclei with nuclear grooves and pseudoinclusions are elements that strongly favor the diagnosis of papillary carcinoma.

The differential diagnosis of this tumor is even more crucial in frozen sections. Woyke et al5 reported a case in which the diagnosis in frozen section was benign, but a fine-needle aspiration biopsy showed features typical of papillary carcinoma. The cells had large nuclei with powdery chromatin and pseudoinclusions. The cytologic alterations are in fact difficult to appreciate in frozen sections. Cytologic examinations that take place while frozen sections are being prepared are hence a helpful technique to avoid this pitfall. Mesonero et al4 studied fine-needle aspiration biopsies of 16 cases of the macrofollicular variant of papillary carcinoma of the thyroid and suggested ovoid and pear-shaped nuclei, nuclear hypochromasia, and nuclear grooves as cytologic criteria. Less consistently, they found excentric, small nucleoli and nuclear overlap. Hirokawa et al3 considered the presence of large colloid next to ground-glass nuclei important for differentiating between the macrofollicular and conventional variant of papillary carcinoma.

In the literature, the immunohistochemical profile of papillary carcinoma of the thyroid is not absolutely discriminatory. Papillary carcinomas express keratin and thyroglobulin.20 The presence of cytokeratin 19 in papillary carcinoma of the thyroid seems to be useful in the differential diagnosis from normal thyroid gland tissue as well as from benign and malignant follicular neoplasms.21 Thyroid transcription factor-1 is expressed in more than 95% of follicular and papillary thyroid carcinomas as well as in normal thyroid glands.22 In the macrofollicular variant of papillary carcinoma of the thyroid, a positivity was found for cytokeratin and thyroglobulin.2 Galectin-3 is expressed in greater amounts in papillary thyroid cancers but rarely in normal thyroids.23–28 In our study, all 3 cases were positive for cytokeratins 7, 17, and 19, thyroid transcription factor-1, and galectin-3. Like the case reported by Nakamura et al,7 our cases did not show a positivity for p53.

In summary, we report 3 additional cases of the macrofollicular variant of papillary carcinoma of the thyroid. Although this entity has a favorable prognosis, recurrences and metastases may occur. The role of cytologic evaluation in the differential diagnosis is prominent.