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Follicular variant of papillary thyroid carcinoma
A clinicopathologic study of a problematic entity
Article first published online: 9 AUG 2006
Copyright © 2006 American Cancer Society
Volume 107, Issue 6, pages 1255–1264, 15 September 2006
How to Cite
Liu, J., Singh, B., Tallini, G., Carlson, D. L., Katabi, N., Shaha, A., Tuttle, R. M. and Ghossein, R. A. (2006), Follicular variant of papillary thyroid carcinoma. Cancer, 107: 1255–1264. doi: 10.1002/cncr.22138
- Issue published online: 1 SEP 2006
- Article first published online: 9 AUG 2006
- Manuscript Accepted: 13 JUN 2006
- Manuscript Revised: 3 JUN 2006
- Manuscript Received: 13 APR 2006
- follicular variant;
There is continuous debate regarding the optimal classification, prognosis, and treatment of the follicular variant of papillary thyroid carcinoma (FVPTC). The objective of this study was to assess the behavior of FVPTC, especially its encapsulated form, and shed more light on its true position in the classification scheme of well differentiated thyroid carcinoma.
All patients with FVPTC, follicular thyroid adenoma (FTA), and follicular thyroid carcinoma (FTC) who were diagnosed between 1980 and 1995 were reviewed and reclassified according to the currently accepted definition of FVPTC. The tumors were separated into encapsulated and nonencapsulated (infiltrative/diffuse) types. Encapsulated tumors were subdivided further into tumors with or without capsular/vascular invasion. These different subtypes of FVPTC were correlated with outcome and with other clinicopathologic parameters.
After review by 4 pathologists, 78 patients were included in the study. Sixty-one of 78 patients (78%) had encapsulated tumors (18 invasive, 43 noninvasive), and 17 patients had nonencapsulated tumors (infiltrative/diffuse). The gender distribution, age at presentation, and tumor size did not differ between patients with encapsulated and nonencapsulated FVPTC. Patients who had encapsulated FVPTC had a significantly lower rate of marked intratumor fibrosis (18%), extrathyroid extension (5%), and positive margins (2%) compared with patients who had nonencapsulated tumors (88%, 65%, and 50% respectively; P < .0001). Regional lymph node metastases were present in 14 of 78 patients (18%), and no patients had distant metastases. The lymph node metastatic rate was significantly higher in patients who had nonencapsulated tumors (11 of 17 patients; 65%) compared with patients who had encapsulated neoplasms (3 of 61 patients; 5%; P < .0001). In addition, lymph node metastases were not detected in any noninvasive, encapsulated FVPTCs. With a median follow-up of 10.8 years, only 1 patient developed a recurrence, which occurred in an encapsulated FVPTC that had numerous invasive foci. None of the patients with noninvasive, encapsulated FVPTCs developed recurrences, including 31 patients who underwent lobectomy alone, with a median follow-up of 11.1 years.
FVPTC appeared to be a heterogeneous disease composed of 2 distinct groups: an infiltrative/diffuse (nonencapsulated) subvariant, which resembles classic papillary carcinoma in its metastatic lymph node pattern and invasive growth, and an encapsulated form, which behaves more like FTA/FTC. Patients who had noninvasive, encapsulated FVPTCs did not develop lymph node metastases or recurrences and could be treated by lobectomy alone. If the current findings are confirmed, then strong consideration should be given to reclassifying encapsulated FVPTC as an entity that is close to the FTA/FTC class of tumors. Cancer 2006. © 2006 American Cancer Society.
Well differentiated thyroid tumors of follicular cell origin are subdivided into follicular thyroid adenoma (FTA), follicular thyroid carcinoma (FTC), and papillary thyroid carcinoma (PTC). PTC is the most frequent type of thyroid malignancy (>70% of tumors): It often is multifocal, nonencapsulated, and spreads through the lymph nodes.1 In contrast, FTC is unifocal, encapsulated, and metastasizes directly to distant organs with a very low incidence of lymph node metastases.1 The nuclear features of papillary carcinoma (e.g., nuclear clearing, grooves, pseudoinclusions) characterize a carcinoma that belongs to the PTC family.1 The follicular variant of PTC (FVPTC) is the most common subset of papillary carcinoma and is found in 9% to 22.5% of patients with PTC.2–5 This variant is composed entirely or almost completely of follicles, which are lined by cells that have the nuclear features of papillary carcinoma.6 Thus, FVPTC shares with FTA and FTC the presence of follicles. When FVPTC is nonencapsulated and infiltrates the surrounding thyroid parenchyma or diffusely involves the thyroid, the diagnosis of carcinoma usually poses no problem.7 For the encapsulated tumor without invasion of surrounding thyroid tissue, the diagnosis of malignancy relies solely on the presence of the nuclear features of PTC (e.g., nuclear clearing, grooves, pseudoinclusions), which often can be borderline. Therefore, the diagnosis of noninvasive, encapsulated FVPTC versus follicular adenoma is prone to considerable interobserver variability.7, 8 This diagnostic dilemma has very important therapeutic implications. Indeed, if an FVPTC measures ≥1.5 cm, then many physicians in the U.S. will recommend completion thyroidectomy followed by radioactive iodine therapy (RAI).9 Some authors have suggested that patients with encapsulated, noninvasive FVPTC have an excellent prognosis and, thus, believe that only a lobectomy is needed. However, there are no outcome data with long median follow-up from a large number of patients with FVPTC. More important, to our knowledge, there has been no study in which tumor behavior was analyzed according the histologic “subvariants” of FVPTC. (i.e., nonencapsulated [infiltrative/diffuse] vs. encapsulated) that can serve as the basis for a conservative treatment approach of encapsulated, noninvasive FVPTC. In addition, there is some controversy regarding the classification of FVPTC as a member of the PTC group versus the FTA/FTC group. Indeed, Baloch and LiVolsi showed that some encapsulated FVPTCs metastasize to distant sites in the absence of lymph node metastases, mimicking the behavior of FTC.10 Other authors reported that FVPTC has a significantly lower metastatic lymph node rate and more often is encapsulated than classic PTC.11, 12 Recently, several groups have attempted to analyze FVPTC at the molecular and chromosomal levels.13, 14 All of those studies concurred that the molecular profile of the FVPTC seems to be closer to the FTA/FTC group than to classic PTC, supporting further consideration of the classification of FVPTC.
To assess the behavior of FVPTC (especially its encapsulated form) and to shed more light on its true position in the classification scheme of well differentiated thyroid carcinoma, we undertook a clinicopathologic study of all patients with FVPTC who were seen at Memorial Sloan-Kettering Cancer Center between 1980 and 1995. FVPTC tumors were classified according to histologic growth patterns in encapsulated versus nonencapsulated (infiltrative/diffuse) neoplasms. The encapsulated subset was subdivided further according to the presence or absence of invasion in a manner similar to that used to differentiate FTA from FTC.
MATERIALS AND METHODS
The Memorial Sloan-Kettering Cancer Center pathology data base was searched for all tumors that had a diagnosis of FVPTC, FTA, and FTC between January 1980 and December 1995. All tumors with adequate material captured by the computerized data base search were examined microscopically by a head and neck surgical pathologist with expertise in thyroid neoplasia (R.A.G.). Tumors were classified as FVPTC if they were composed completely or almost entirely (99% of the tumor) of follicles lined by cells that had the nuclear features of PTC (i.e., irregular, enlarged, clear nuclei with grooves, pseudoinclusions, and overlapping).6 The presence of tumor necrosis or increased mitotic activity (≥5 per 10 high-power fields) excluded the tumor from the FVPTC category.
The following FVPTCs were included in the study: FVPTC that measured ≥1 cm in greatest dimension with no associated thyroid malignancy except for the presence of 1 or 2 subcentimeter papillary microcarcinomas. For example, FVPTC associated with 3 foci of papillary microcarcinomas were excluded along with FVPTC associated with any non-FVPTC that measured ≥1 cm in greatest dimension. FVPTC associated with any nonpapillary thyroid malignancy also was excluded.
Except for one tumor (reviewed by R.A.G. only), all tumors that were included after the initial review were reexamined microscopically by four board-certified pathologists with special interest in thyroid neoplasia, (R.A.G., G.T., D.L.C., N.K.) to confirm the diagnosis of FVPTC. Histopathologic review was conducted without the pathologist's knowledge of the patients' clinical characteristics or outcome. FVPTCs were subdivided into the following histologic subvariants: 1) encapsulated if the tumor was surrounded totally by a tumor capsule with or without capsular/vascular invasion; 2) infiltrative if there was absent or incomplete encapsulation with invasive tongues of tumor infiltrating nonneoplastic thyroid parenchyma, almost always with prominent fibrosis; or 3) diffuse if 1 lobe or an entire thyroid was involved by a nonencapsulated, diffuse, or multinodular tumor without desmoplasia and with pushing borders or absence of a clear cut delineation between the tumor and the adjacent parenchyma. In view of their lack of total encapsulation, the infiltrative and diffuse variants both were categorized as nonencapsulated. The distribution of the nuclear features characteristic of papillary carcinomas was recorded as either diffuse (i.e., throughout the lesion) or multifocal (i.e., foci that contained papillary carcinoma nuclei were distributed randomly over 30% of the tumor intermixed with areas where the nuclear features were not developed fully or were absent). Tumor size was measured as the greatest dimension of the resected tumor specimen. Mitotic rate was determined by counting 10 high-power fields (×400 magnification) with an Olympus microscope (U-DO model) in the areas of greatest concentrations of mitotic figures. Vascular and capsular invasion were identified according to the criteria outlined in the last Armed Forces Institute of Pathology fascicle on thyroid tumors.6 Capsular invasion was defined as complete penetration of the entire thickness of the tumor capsule. Irregularities of the contour along the inner border of the capsule or nests of tumor embedded within the capsule were not considered capsular invasion. Vascular invasion was defined as invasion of a vessel located within or outside the tumor capsule. The intravascular tumor growth had to be covered by endothelium or attached to the vessel wall. Irregular clusters of nonendothelialized tumor cells that were not attached to the vessel wall represented artefactual dislodgement of tumor during sectioning and did not qualify as vascular invasion. The numbers of foci of vascular invasion in tumor capsule (intracapsular vascular invasion) and outside the tumor capsule (extracapsular vascular invasion) were recorded. The numbers of foci of capsular invasion also were counted. The cytoplasm of the predominant cell type was categorized as either oncocytic or nononcocyctic. The degree of intratumoral fibrosis was recorded as absent, mild, or marked. The presence or absence of tumor extension into the extrathyroid soft tissue stroma as well as the presence of extrathyroid vascular invasion were documented. Finally, microscopic resection margins were categorized as either positive (tumor at the inked margin) or negative (no tumor at the inked margin).
The patient's charts were reviewed for age at diagnosis, gender, type of surgery, and adjuvant therapy (radioactive iodine). Tumor recurrence, both local and metastatic, was established on the basis of clinical examination; radiologic findings on either computer tomography or magnetic resonance imaging studies; findings on follow-up nuclear scanning, including RAI or positron emission tomography scanning; significant rise in serum thyroglobulin; or histologic examination of the recurrent tumor. Dates of initial thyroid surgery, last follow-up, recurrence, and death were recorded. Status at last follow-up was categorized as no evidence of disease, alive with disease, dead of disease, or dead of other causes. The study was approved by the Institutional Review Board of Memorial Sloan-Kettering Cancer Center.
Descriptive statistics were used to summarize study data. Associations between categorical variables were evaluated by using the Fisher exact test or the chi-square test, as appropriate. In all statistical analysis, a 2-tailed P value < .05 was considered statistically significant. Outcomes were classified according to sites of first disease recurrence. Follow-up was calculated from the time of surgery to date of last follow-up.
Reclassification of Follicular Lesions and Identification of Study Patients
The computerized data base search identified 552 follicular neoplasms with adequate material from patients who were seen between 1980 and 1995. After microscopic examination by one of the authors (R.A.G.), 162 FVPTCs were identified. Of these 162 FVPTCs that were identified by our initial histopathologic examination, only 82 patients were retained as potential participants for the study after the elimination of all subcentimeter FVPTCs and FVPTCs that were associated with >2 foci of papillary microcarcinoma or other significant thyroid malignancies (see Material and Methods, above). After rereview by all 4 pathologists, 78 patients finally were included in the study.
Table 1 lists the clinical and pathologic features of the 78 patient who were included in the current study. A median of 12 slides per patient were reviewed. The median tumor size was 2.5 cm, and 9 of 78 FVPTCs (12%) exceeded 4 cm. The neoplasms were encapsulated in 61 of 78 patients (78%), whereas 17 of 78 neoplasms (22%) were nonencapsulated and invaded the surrounding neoplastic tissue in an infiltrative or diffuse pattern (Figs. 1, 2). Table 2 lists the clinical and pathologic features according to the invasive growth patterns of the FVPTCs (encapsulated vs. nonencapsulated). There was no significant difference in tumor size, mitotic rate, presence of a predominantly oncocytic cytoplasm, or vascular invasion between patients with encapsulated FVPTCs and patients with nonencapsulated FVPTCs. In contrast, patients with encapsulated FVPTCs had a significantly lower rate of marked intratumoral fibrosis (18% vs. 88% in nonencapsulated FVPTCs), extrathyroid extension (5% vs. 65%, respectively), and positive margins (2% vs. 50%, respectively; P < .0001). The nuclear features characteristic of papillary carcinomas were present diffusely in 53 of 61 encapsulated FVPTCs (87%) and multifocal in 8 of 61 encapsulated FVPTCs (13%). We did not assess the distribution of PTC nuclei in the nonencapsulated FVPTCs, because the diagnosis of malignancy usually is obvious in these tumors based on the invasive properties of the tumor. The presence of any invasion (capsular or vascular) was observed in 18 of 61 encapsulated FVPTCs (31%; 6 tumors showed both capsular and vascular invasion, 8 tumors showed capsular invasion only, and 4 tumors showed vascular invasion alone). Forty-three of 61 encapsulated FVPTCs (70%) were totally noninvasive.
|Variable||No. of patients (%)||% of total|
|Age, y (median, 43.1 years)|
|Tumor size, cm (median, 2.5 cm)|
|Histologic growth patterns (“subvariants”)|
|Focal (<4 foci)||9||12|
|Extensive (≥4 foci)||5||6|
|Capsular invasion (n = 61 patients)|
|Focal (<4 foci)||8||13|
|Extensive (≥4 foci)||6||10|
|Type of thyroid surgery|
|More than lobectomy but less than total thyroidectomy||3||4|
|Lymph node metastases|
|Characteristic||No. of Patients (%)||P*|
|Encapsulated FVPTC (n = 61 patients)||Nonencapsulated FVPTC (n = 17 patients)|
|Age, y(median, 41.8 years)||.78|
|≤45||33 (54)||10 (59)|
|>45||28 (46)||7 (41)|
|Female||49 (80)||10 (59)||.11|
|Male||12 (20)||7 (41)|
|Tumor size, cm||.19|
|≤4||52 (85)||17 (100)|
|>4||9 (15)||0 (0)|
|Absent||51 (84)||13 (76)|
|Present||10 (16)||4 (24)|
|PTC nuclei in tumor||NA|
|Absent||59 (97)||17 (100)|
|Present||2 (3)||0 (0)|
|Absent||50 (82)||17 (100)|
|Present||11 (18)||0 (0)|
|Absent/mild||50 (82)||2 (12)|
|Marked||11 (18)||15 (88)|
|Absent||58 (95)||6 (35)|
|Present||3 (5)||11 (65)|
|Positive||1 (2)||6 (50)|
|Negative||51 (98)||6 (50)|
|Less than total thyroidectomy||48 (79)||9 (53)|
|Total thyroidectomy||13 (21)||8 (47)|
|Lymph node metastases||<.0001|
|Present||3 (5)||11 (65)|
|Absent||58 (95)||6 (35)|
|Present||0 (0)||0 (0)|
|Absent||61 (100)||17 (100)|
The median age for all 78 patients who were included in this study was 43.1 years (range, 6.5–71.9 years). Fifty-nine of 78 patients (76%) were female. Fifty-four patients underwent a lobectomy, and 21 patients underwent total thyroidectomy. The remaining 3 patients underwent a lobectomy with partial resection of the contralateral lobe (2 patients) and a subtotal thyroidectomy (1 patient). Thirteen patients underwent formal lymph node dissection, including 3 patients who underwent dissection of the central compartment only; 7 patients who underwent uni lateral, modified neck dissection; 1 patient who underwent unilateral, modified neck dissection that included the central compartment; and 2 patients who underwent bilateral, modified neck dissection that included the central compartment. Radioactive iodine was given to only 15 of 78 patients (19%). Regional lymph node metastases were present in 14 of 78 patients (18%), and distant metastases were present in none. Table 2 lists the clinicopathologic features according to the invasive growth pattern (encapsulated vs. nonencapsulated). The lymph node metastatic rate was significantly higher in patients who had nonencapsulated tumors (11 of 17 patients; 65%) compared with patients who had encapsulated neoplasms (3 of 61 patients; 5%; P < .0001). All 43 patients who had noninvasive, encapsulated FVPTC lacked evidence of lymph node metastases. The lymph node metastatic rate was significantly higher in the infiltrative/diffuse group (65%) than in the invasive encapsulated group (3 of 18 patients; 17%; P = .006).Thirty-two patients had lymph node tissue available for microscopic examination. In those 32 patients, the metastatic lymph node rate was significantly higher for patients who had nonencapsulated FVPTC (12 of 13 patients; 92%) than for patients who had encapsulated FVPTC (3 of 19 patients; 16%; P < .0001). Among the patients who underwent lymphadenectomy, the median age in the encapsulated group (45.6 years) was very similar to that in the nonencapsulated group (43 years; P = .72). A similar correlation was found for tumor size, with a similar median size of 2.5 cm for both the encapsulated group and the nonencapsulated group (P = .5). In patients who had assessable lymph node tissue, there was a greater proportion of males in the nonencapsulated group (6 of 13 patients; 46%) than in the encapsulated group (3 of 19 patients; 16%), but this difference was not significant (P = .11). Within the group with invasive, encapsulated FVPTCs, the lymph node metastatic rate was significantly higher (3 of 7 patients; 42%) among patients who had ≥4 foci of invasion (capsular and/or vascular) than among patients who had less invasive foci (0 of 11 patients; P = .04.
All patients who had >1 year of follow-up were included in the outcome analysis. Sixty-nine patients fulfilled this criteria (Table 3) with a median follow-up of 10.8 years (range, 1.2–21 years). All 42 patients who had noninvasive, encapsulated FVPTC were free of disease at follow-up with no recurrence noted and no lymph node metastases. A female patient age 15 years who had encapsulated FVPTC that showed capsular invasion (>4 foci) and 2 foci of vascular invasion developed a recurrence in her neck lymph nodes 2 years after she underwent total thyroidectomy and received RAI therapy. Thirty-one patients with noninvasive, encapsulated FVPTC (with >1 year of follow-up) underwent lobectomy alone and did not receive RAI therapy. None of those 31 patients with noninvasive, encapsulated FVPTC developed a recurrence: This group had a median follow-up of 11.1 years (range, 1.2–21 years), a median tumor size of 2.3 cm (range, 1.1–7 cm), a median age of 43.4 years (range, 11.5–69.1 years), and a male:female ratio of 1:5.2 (5 men and 26 women) (Table 4). Those 31 patients were subdivided according to the American Joint Committee on Cancer tumor, lymph node, metastasis (TNM) staging system (6th edition) as follows: Twenty-one patients had Stage I disease (any T, any N, M0, and younger than age 45 years or T1 [tumor measuring ≤2 cm], N0, M0, and age 45 years or older), 8 patients had Stage II disease (T2 [tumor measuring >2 cm but < 4 cm], N0, M0, and age 45 years or older), and 2 patients had Stage III disease (T3 [tumor measuring >4 cm], N0, M0, and age 45 years or older).
|Histologic subvariant||No. of patients||REC/AWD/DOD: No of patients (%)|
|Encapsulated (n = 55 patients)|
|Invasive||13||1 REC (8)|
|Nonencapsulated (diffuse/infiltrative)||14||0 (0)|
|Median follow-up||11.1 y|
|Median tumor size||2.3 cm|
|Median age||43.4 y|
|Lymph node metastases||Absent|
|AJCC stage (no. of patients)*|
In the current study, we adopted very stringent criteria for the diagnosis of FVPTC. Indeed, we excluded many papillary carcinomas from the FVPTC category if they contained a minor but substantial amount of papillae. The presence of >1% papillary formations eliminated the tumor from the FVPTC category. We also did not include tumors that displayed a high mitotic rate and tumor necrosis. This may explain why we found only 1 diffuse follicular variant in our series. To understand the biologic behavior of FVPTC, we excluded all subcentimeter FVPTCs and allowed only 2 additional foci of papillary microcarcinoma as additional malignancy. In view of this study design, we cannot assess multicentricity in FVPTC. There was no significant disagreement between the pathologists on the study, possibly because of their common training at the same institution. The median age (43.1 years) and the female predominance (76%) of the patient population were in keeping with previous studies on papillary carcinomas that included FVPTCs.2, 15 The encapsulated FVPTCs outnumbered their infiltrative/diffuse counterparts (only 17 tumors were diffuse or infiltrative vs. 61 encapsulated FVPTCs). This rarity of infiltrative/diffuse (i.e., nonencapsulated) FVPTC seems to be concordant with the first detailed article on FVPTCs by Chem and Rosai.16 In their 1977 article, all their cases were infiltrative with an apparently very low incidence since they found only 6 cases of infiltrative FVPTC out of all thyroid carcinoma cases diagnosed at the University of Minnesota Hospitals up to the year 1975. Using a less stringent definition of FVPTC than Chem and Rosai by allowing up to 20% papillary formations, Tielens et al. observed a 5.6% incidence of infiltrative FVPTC among all well differentiated thyroid carcinomas.4
In the current study, patients who had infiltrative/diffuse FVPTC had a significantly greater frequency (P < .0001) of marked intratumoral fibrosis, extrathyroid extension, and positive margins than patients who had encapsulated FVPTC. It is noteworthy that there was no significant difference in vascular invasion between encapsulated FVPTCs and infiltrative/diffuse FVPTCs. This superior potential of nonencapsulated FVPTCs in invading the thyroid and extrathyroid stroma was reflected by its higher rate of total thyroidectomy and especially by its rate of regional lymph node metastases. Indeed, patients with nonencapsulated (infiltrative/diffuse) FVPTCs had a metastatic lymph node rate of 65% compared with 5% for patients with encapsulated FVPTCs (P < .0001). This strong and significant correlation between lymph node metastases and nonencapsulated FVPTC was maintained when only specimens (32 tumors) that contained lymph node tissue were analyzed. This difference in lymph node disease could not be explained by differences in tumor size or age at presentation, because the latter 2 variables were similar between the patients in the encapsulated group and the nonencapsulated group. There was a greater proportion of males in the infiltrative/diffuse group, but this difference did not reach statistical significance (P = .11). In the current study, the metastatic lymph node pattern of encapsulated FVPTCs (5%) was much closer to that reported in follicular carcinomas (on the order of 5–10%), whereas infiltrative/diffuse FVPTCs had a metastatic lymph node pattern within the range reported for classic papillary carcinomas (on the order of 45–65%).11, 4, 2 Our overall lymph node rate in FVPTCs (18%) was slightly higher than that reported by Zhu et al. (13%) but lower than the frequency of lymph node disease reported by Zidan et al. and Tielens et al. (22%).4, 11, 17 The latter difference may be explained by the observation that those investigators allowed up to 20% of papillae in their FVPTCs. Their tumors will be now classified as classic PTC by most authors, because the modern and now universally accepted description of FVPTC indicates that the tumor must be entirely or almost completely follicular in pattern.16, 18 Among the invasive, encapsulated FVPTCs, there was a much higher lymph node metastatic rate in tumors that had ≥4 foci of invasion than in tumors that had fewer invasive foci (42% vs. 0%; P = .04). Indeed, the very few patients who had encapsulated FVPTCs (only 3 patients) that metastasized to lymph nodes all had capsular and vascular invasion with >10 foci of invasion in each patient. A similar correlation between lymph node metastases and extent of invasion was reported in patients who had follicular carcinomas of the oncocytic subtype.19
With regard to prognosis, patients who had invasive tumors, whether encapsulated or not, had a rare but real potential for adverse outcome. One patient who had an encapsulated FVPTC with capsular and vascular invasion developed a recurrence in the cervical lymph nodes 2 years after surgery. With a median follow-up of almost 11 years, overall, 6% of patients who had invasive tumors, whether encapsulated or not, had adverse outcomes, whereas none of the 42 patients who had noninvasive, encapsulated FVPTCs developed recurrences, developed metastases, or died of disease. All 31 patients who had noninvasive, encapsulated FVPTCs and who had adequate follow-up, a median tumor size of 2.3 cm, and underwent lobectomy alone had good outcomes and no lymph node metastases (median follow-up, 11.1 years). These data confirm the view that patients with noninvasive, encapsulated FVPTC have an excellent prognosis.6 Eight of the noninvasive, encapsulated FVPTCs had multifocal distribution of the nuclear features of papillary carcinoma. We classified the entire tumor as FVPTC according to the recommendation of Baloch and LiVolsi with the understanding that some pathologists may count the foci with atypical nuclei and report the lesion as multifocal PTC.10 Other may use alternative terminology, such as tumor as of uncertain malignant potential.20 Whatever position the investigator takes regarding the nuclear features of FVPTC, the current results seem to point to the importance of invasion rather than nuclear features for predicting outcomes in patients who have encapsulated FVPTC. Indeed, encapsulated FVPTC seem to have a behavior much closer to that of follicular tumors (i.e., FTA and FTC) rather than classic PTC. This is reflected by the lack of adverse outcomes in patients with noninvasive lesions and the rarity of lymph node metastases. These morphologic and clinical data are supported by several publications pointing to a molecular profile of FVPTC much closer to the FTA/FTC group than to classic PTC. Zhu et al. reported a low frequency of RET/PTC rearrangement (3%) and a high frequency of ras mutations in FVPTC (43%) very similar to follicular carcinoma.11 BRAF mutations reportedly were absent in FVPTCs and FTCs but present in 53% of classic PTCs.21 The genome-wide profile of FVPTCs assessed by comparative genomic hybridization was identified as very different from classic PTC and closer to the FTA/FTC group.13 It is believed that PAX8-PPARγ rearrangements are restricted to follicular carcinomas and are absent in papillary carcinomas.22 Most recently, Castro et al. reported a similar frequency of PAX8-PPARγ rearrangements in FVPTCs (37.5%), FTCs (45.5%), and FTAs (33.3%).14 Based on their data and on other studies,10 those authors concluded that FVPTC as a whole is not a subgroup of conventional PTC.14 It is noteworthy that some of those molecular studies were composed entirely or in their majority of encapsulated FVPTCs.
The clinical, histologic, and molecular data gathered to date strongly suggest that FVPTC is a heterogeneous disease composed of 2 distinct group of tumors: a nonencapsulated (infiltrative and diffuse) subvariant, which resembles classic PTC in its invasive growth and metastatic lymph node pattern, and encapsulated FVPTC. The latter seems to resemble FTA/FTC in its invasive property, metastatic lymph node pattern, and molecular profile. The lack of adverse outcomes among our 31 patients with noninvasive, encapsulated FVPTC who underwent lobectomy only (with a median follow-up of 11.1 years and a median tumor size of 2.3 cm) strongly suggests that capsular and vascular invasion, and not nuclear features, is the determinant of malignant behavior in encapsulated FVPTC. It is interesting to note that 90% (28 of 31 patients) of our patients with noninvasive, encapsulated FVPTC would have been treated by many experts today with total thyroidectomy and RAI therapy, because these tumors measured ≥1.5 cm in size.9 The total lack of recurrence in our group of patients with noninvasive FVPTC who underwent lobectomy alone suggests that noninvasive, encapsulated FVPTC may be managed by lobectomy only, as recommended by Rosai et al. in the last Armed Forces Institute of Pathology fascicle on thyroid tumors.6 Larger studies with longer follow-up than the current series will be needed to refine therapy for patients with noninvasive, encapsulated FVPTC. If the current findings are confirmed, then strong consideration should be given to reclassifying encapsulated FVPTC as an entity that is close to the FTA/FTC class of tumors (Fig. 3).The same criteria that were used to decide whether follicular tumors are biologically benign or malignant (i.e., capsular and vascular invasion) would be applied to the evaluation of encapsulated FVPTCs. In practical terms, a lack of capsular or vascular invasion should denote a benign clinical behavior in encapsulated FVPTC. If this reclassification is realized, then it will have a major impact on the diagnosis and management of patients with FVPTC. In noninvasive, encapsulated FVPTC, pathologists will be spared the frustrating and subjective exercise of deciding whether a tumor has the nuclear features of papillary carcinoma. More important, countless numbers of patients with noninvasive, encapsulated FVPTC will be spared unnecessary and aggressive therapy with its attached morbidity (i.e., hypoparathyroidism and recurrent nerve injury) and financial costs.
- 1Tumors of the thyroid and parathyroid glands. In: FletcherCDM, editor. Histopathology of Tumors, 2nd ed. London: Churchill Livingstone; 2000: 959–1038..
- 6Follicular carcinomas. Papillary Carcinomas. In: RosaiJ, SobinLH. Tumors of the thyroid gland. Atlas of Tumor Pathology. Washington, DC: Armed Forces Institute of Pathology, 1992: 49–121., , .