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Keywords:

  • macrofollicular variant;
  • papillary thyroid carcinoma;
  • insular component

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

BACKGROUND

The macrofollicular variant of papillary thyroid carcinoma that is the subject of this study has only recently been characterized. Information about its morphologic spectrum and biologic behavior is limited.

METHODS

The authors reviewed 29 examples, including 17 previously reported cases. The clinical and pathologic features of five patients who had the macrofollicular variant of papillary thyroid carcinoma with a minor insular component were analyzed in detail. The insular component in thyroid carcinomas has been associated with aggressive clinical behavior.

RESULTS

The ages of the 5 patients ranged from 31 to 70 years; the mean age was 40 years. Three patients presented with a palpable thyroid nodule and two with a large thyroid mass of long duration. The latter two tumors, which metastasized, were the largest (8 and 11 cm) and showed extrathyroidal and blood vessel invasion. All five tumors were composed predominantly of macrofollicles (>50%) and had a minor insular component that comprised less than 5% of the tumor mass. In most tumors, the macrofollicles were lined by cells with large, clear, grooved nuclei, and all five contained areas of conventional follicular variant of papillary thyroid carcinoma. In the two that metastasized, however, the lining of many macrofollicles consisted of cuboidal cells with small, hyperchromatic, follicular-type nuclei. Only the macrofollicular component was identified in the metastatic deposits in these two patients. All five patients were alive at last follow-up, two with metastases; but follow-up for this study is limited.

CONCLUSIONS

A minor insular component is an additional feature of the macrofollicular variant of papillary thyroid carcinoma that may aid in diagnosis and does not appear to have an adverse effect on the excellent prognosis of patients with these tumors. Cancer 1997; 80:1110-6. © 1997 American Cancer Society.

The macrofollicular variant of papillary thyroid carcinoma was described by Albores-Saavedra et al. in 1991.1 These authors reported 17 patients with thyroid carcinomas characterized microscopically by a predominance of macrofollicles (>50% of a cross-sectional area) and clinically by a low incidence of metastases. Because of this histologic feature, the tumors closely simulated macrofollicular adenoma or adenomatous goiter. Moreover, in some tumors, many macrofollicles were lined by cells with round, hyperchromatic "follicular"-type nuclei that further complicated microscopic interpretation. Galluzzi et al.2 studied the proliferation activity of papillary thyroid carcinomas by immunohistochemistry and concluded that the macrofollicular architecture of the tumors reflected a phase of advanced differentiation with relatively low proliferative activity. Gamboa-Dominguez et al.3 showed that macrofollicular papillary carcinomas are diploid.

In this study, we describe the clinical and pathologic features of 5 patients with macrofollicular variant of papillary thyroid carcinoma associated with minor insular component, a feature that expands the morphologic spectrum of these unusual tumors and provides additional information about their biologic behavior.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

All hematoxylin and eosin-stained sections of the macrofollicular variant of papillary thyroid carcinoma were reviewed to identify those with an insular component. Twenty-nine examples of the macrofollicular variant were found, including 17 that had been previously described.1 The cases were obtained from the surgical pathology files of Parkland Memorial Hospital and Zale-Lipshy University Hospital, Dallas, Texas; Jackson Memorial Hospital, University of Miami Medical Center, Miami, Florida; and the personal files of one of the authors (J.A-S.). Of the 29 macrofollicular papillary thyroid carcinomas, 5 had an insular component. Diagnoses were based on previously published histologic criteria.1 Briefly, for a neoplasm to be classified as the macrofollicular variant, more than 50% of the cross-sectional area of the tumor had to be composed of macrofollicles (follicles >250 μm in diameter). The insular component was characterized by well-defined cell nests (insulae) surrounded by dilated or collapsed capillaries or thin connective tissue septa causing artifactual retraction between the neoplastic cells and the stroma. Some tumors had a well-defined papillary architecture, but this was a focal feature. All tumors were positive for thyroglobulin (Dako, Carpinteria, CA, dilution 1:100), and negative for calcitonin (Dako, dilution 1:100). Clinical and follow-up information was obtained from the patients' charts or through the referring pathologists. For the five patients who had the macrofollicular variant of papillary thyroid carcinoma with an insular component, the following information was included: age at time of presentation, gender, size of the tumor, treatment, extracapsular extension, sites of metastases, and status at last follow-up.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Six of the 29 patients with macrofollicular papillary thyroid carcinomas presented with cervical lymph node metastases, and 2 of these 6 also developed pulmonary metastases. Five thyroid tumors had a minor insular component that comprised less than 5% of the primary cell mass. Metastases were recorded for two of these five patients, but the metastatic deposits did not contain an insular component. All 29 patients were alive, 2 with metastases, 6 months to 9 years after surgical therapy.

The main clinical and pathologic features of the five patients with the macrofollicular variant of papillary thyroid carcinoma with an insular component are shown in Table 1.

Table 1. Macrofollicular Variant of Papillary Thyroid Carcinoma with Insular Component
Case no.Age/Race/GenderSymptomsTumor sizeCapsular invasionMetastasesTreatmentFollow-up
  1. A & W = alive and well; M = male; F = female; W = white; B = black; H = Hispanic.

162/W/MThyroid mass of 8 yrs' duration and enlarged cervical lymph nodes8 × 6 × 2 cmYesLymph nodes, lungs, and boneTotal thyroidectomy and modified neck dissectionAlive with metastases, 5 yrs
231/W/FLeft thyroid nodule of 6 mos' duration4 × 3.5 × 2 cmNoNoLobectomyA & W, 4 yrs
326/W/FPalpable nodule in right lobe of thyroid of 9 mos' duration3 × 3 × 2 cmNoNoLobectomyA & W, 3½ yrs
451/B/MRight neck mass in the thyroid region of 2 yrs' duration5.5 × 4 × 3 cmNoNoLobectomyA & W, 1 yr
570/H/FLarge "goiter" of 10 yrs' duration and pulmonary metastases11 × 8 × 5 cm mass replaced the right thyroid lobeYesLymph nodes and lungsTotal thyroidectomy and resection of anterior cervical lymph nodesAlive with metastases, 6 mos

Macroscopically, the sizes of the 5 tumors ranged from 3 to 11 cm (mean, 5 cm). The two that metastasized were the largest (8 and 11 cm). All were partially or completely encapsulated. The cut surfaces were light to dark brown with occasional hemorrhagic and cystic areas. One of the tumors that metastasized had a large, irregular central scar mimicking a follicular adenoma or a dominant nodule of a colloid goiter (Fig. 1 (125K)).

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Figure 1. The right lobe of the thyroid is replaced by a large, encapsulated, tan mass with a central stellate scar (Case 5).

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Most macrofollicles of the five tumors were lined by cells with large, clear, grooved nuclei characteristic of papillary thyroid carcinoma4, 5 (Figs. 2 (90K) and 3 (106K)). In two cases, however, many macrofollicles were lined by small, round, hyperchromatic nuclei. Foci of conventional follicular variant of papillary thyroid carcinoma were present in all five tumors (Fig. 4 (112K)). A focal but well-defined papillary architecture was observed in only one tumor.

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Figure 2. (A) Both macrofollicles and microfollicles are present in this tumor (Case 1), but the former occupy most of the cross-sectional area. At this magnification, the tumor could be confused with macrofollicular adenoma or nodular goiter (H & E, original magnification ×100).

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Figure 3. Large, irregular, clear nuclei characteristic of papillary carcinoma line a macrofollicle in Case 3 (H & E, original magnification ×250).

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Figure 4. An area of conventional follicular variant of papillary carcinoma is shown (Case 1). The follicles are small and lined by neoplastic cells with large, clear nuclei (H & E, original magnification ×250).

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The insular component comprised less than 5% of each tumor mass. Three types of nuclei were recognized in the insular areas: small, round, hyperchromatic nuclei; large, clear, grooved nuclei (papillary type); and intermediate.6 Hyperchromatic nuclei were present in two tumors (Fig. 5 (152K)). Clear, papillary-type nuclei were found in two tumors (Fig. 6 (221K)). The fifth tumor had collections of intermediate type nuclei in addition to hyperchromatic nuclei. In contrast, the metastatic deposits in lymph nodes, lung, and bone had only a macrofollicular component, and most of the macrofollicles were lined by round, hyperchromatic nuclei. The overall appearance of these metastatic deposits suggested benign thyroid tissue in lymph nodes and lungs (Figs. 7 (157K) and 8 (139K)).

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Figure 5. An insular component of the macrofollicular variant of papillary thyroid carcinoma is shown (Case 5). The cells have round, hyperchromatic (follicular) nuclei (H & E, original magnification ×250).

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Figure 6. An insular component of the macrofollicular variant of papillary thyroid carcinoma is shown (Case 1). The cells show the characteristic clear nuclei of papillary carcinoma (H & E, original magnification ×250).

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Figure 7. This cervical lymph node (Case 1) has been partially replaced by neoplastic macrofollicles, most of which are lined by cuboidal cells with round, hyperchromatic nuclei. The overall appearance of this metastatic deposit suggests benign thyroid tissue in the lymph node (H & E, original magnification ×80).

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Figure 8. A pulmonary metastasis of the macrofollicular variant of papillary thyroid carcinoma is shown (Case 5). The macrofollicles are lined by round, hyperchromatic nuclei (H & E, original magnification ×125).

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DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Although focal, the presence of macrofollicles is a relatively common feature in classical papillary thyroid carcinoma and in the conventional follicular variant. They occur in both primary tumors and metastatic deposits. In the macrofollicular variant, however, more than 50% of the tumor must be composed of macrofollicles. The presence of a minor insular component represents an additional microscopic feature that may aid in diagnosis, since in our experience this feature has most often been observed in carcinomas. Like most variants of papillary thyroid carcinoma, those with a predominant macrofollicular architecture are morphologically heterogenous.

Recognition of this variant of papillary thyroid carcinoma is important because it can be confused with nodular goiter or macrofollicular adenoma. One of the 29 cases we studied was recognized only after the tumor metastasized to regional lymph nodes. Conversely, caution must be exercised to avoid overdiagnosis of carcinoma in cases of colloid or adenomatous goiter, which usually contain many large, distended follicles but lack the cytologic features of papillary carcinoma. Macrofollicles lined by cells with clear nuclei are frequently found in goiter and adenomas and are a source of confusion; however, these nuclei are not enlarged and do not overlap. In the macrofollicular variant of papillary carcinoma, many of the macrofollicles are lined by cells with large, overlapping, clear nuclei that have grooves and pseudoinclusions.4, 5 Moreover, areas of conventional follicular variant of papillary carcinoma are present in all tumors. However, in some tumors, many macrofollicles contain cells with hyperchromatic nuclei, both in the primary tumor and in metastatic deposits. Because the macrofollicles contain abundant colloid and some are lined by follicular-type epithelium, this variant of papillary carcinoma is very difficult to recognize by fine-needle aspiration.7 The differential diagnosis of the macrofollicular variant of papillary carcinoma also includes a rare variant of follicular carcinoma, composed predominantly of macrofollicles and lined by cells with round, hyperchromatic nuclei that have finely granular chromatin. This tumor characteristically has angioinvasive features and metastasizes to lungs and bone.

The macrofollicular variant of papillary carcinoma is an indolent disease characterized by excellent prognosis and a low metastatic rate (6 of 29 cases in our study), as compared with conventional papillary carcinoma8 or the columnar cell variant.9, 10 This is probably due to the presence of a capsule, the well-differentiated character of the neoplastic cells, and the low proliferative activity of the tumor. The long duration of the thyroid mass (8 and 10 years) in the 2 patients with metastases in our study is further evidence of its slow growth. None of the 29 patients in our study with this form of papillary carcinoma have died as a direct result of the tumor, although follow-up is limited. The two tumors that metastasized in this series of five cases were large, had extrathyroidal extension and blood vessel invasion, and occurred in older individuals. Age, tumor size, extrathyroidal extension, and blood vessel invasion are considered to be factors in predicting the survival and determining the prognosis of patients with differentiated thyroid carcinomas.11, 12

The presence of an insular component in the five tumors described herein further supports our experience that this pattern of growth is observed in many carcinomas of follicular cell origin. We have even noted an insular pattern of growth in papillary carcinomas in children younger than 10 years. Although the current series was very small, our findings suggest that a minor insular component does not alter the excellent prognosis of patients with the macrofollicular variant of papillary carcinoma. The insular component of these tumors did not metastasize in any of the five patients. Only the macrofollicular component was observed in the lymph nodes and pulmonary metastases of two patients. We therefore suggest that the insular components of follicular and papillary carcinomas should be quantitated. The results of the current study are in disagreement with those of Sasaki et al.,13 who concluded that the insular component in papillary and follicular carcinomas correlated with poor prognosis regardless of the extent of the insular growth pattern. However, these authors did not include examples of the macrofollicular variant of papillary carcinoma in their series.

The terminology used to describe thyroid carcinomas with an insular component and the prognosis of patients with these tumors have been subjects of controversy. Carcangiu et al.14 proposed the term "insular carcinoma" for these tumors, which they considered poorly differentiated and which exhibited aggressive clinical behavior. Other authors have emphasized various different features of the tumors but employed similar terminology.15-19 Some believe that these carcinomas are poorly differentiated, yet represent an aggressive subset of differentiated thyroid neoplasms.15 Others have expressed the view that they are a subset of anaplastic thyroid malignancy, but with a less aggressive clinical course.18 Ashfaq et al.,6 on the other hand, found that these tumors were morphologically heterogenous and represented variants of papillary and follicular carcinomas with an insular growth pattern of variable extent. These latter authors concluded that the aggressive clinical behavior of these tumors correlated with age and tumor stage rather than with the insular pattern. Ashfaq et al and others16, 18 have emphasized that these tumors retain iodine-concentrating ability, which has therapeutic implications. Jorda et al.20 concluded from the results of multivariate analysis that the insular pattern had no significant correlation with survival. Sasaki et al.13 identified a number of factors, including age, tumor size, and insular pattern, as independent variables for prognosis of follicular and papillary carcinomas with an insular component. In contrast to the patients of Ashfaq et al.,6 those reported by Sasaki et al.13 were older, had larger tumors, and had considerably longer follow-up; these variables may explain the difference in patient survival between the two series. The World Health Organization recognizes an insular component only in follicular carcinomas.21 We believe that more studies with prolonged follow-up are needed to understand better the natural history of thyroid neoplasms with an insular component, including the macrofollicular variant of papillary thyroid carcinoma.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES