Problems and controversies in the histopathology of thyroid carcinomas of follicular cell origin.
Abstract: Context.--Despite past and recent efforts, many problems and controversies remain in the classification of thyroid carcinomas of follicular cell origin. These controversies have an impact on the prognosis and therapy of patients with thyroid carcinoma as well as on the development of robust cutting-edge research aimed at better outcome and quality of life.

Objective.--To focus on 3 contentious areas with significant clinical value: the follicular variant of papillary thyroid carcinoma, the extent of invasion in follicular carcinoma, and the poorly differentiated thyroid carcinomas.

Data Sources.--The published English language literature was reviewed.

Conclusions.--Recent data show that prognosis and therapy for many disease entities can be better delineated if a meticulous microscopic examination is performed. An accurate assessment of the extent of invasion (especially vascular) is crucial. Proliferative grading (ie, mitosis and necrosis) is of high prognostic value and should be looked for in every specimen. In addition, molecular data gathered to date can help reassess these tumors at the histologic level. Classification proposals based on personal experience rather than adequate and careful clinical follow-up should be discouraged.
Article Type: Report
Subject: Thyroid cancer (Diagnosis)
Thyroid cancer (Genetic aspects)
Thyroid cancer (Care and treatment)
Thyroid cancer (Prognosis)
Histology, Pathological (Practice)
Evidence-based medicine (Practice)
Author: Ghossein, Ronald
Pub Date: 05/01/2009
Publication: Name: Archives of Pathology & Laboratory Medicine Publisher: College of American Pathologists Audience: Academic; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2009 College of American Pathologists ISSN: 1543-2165
Issue: Date: May, 2009 Source Volume: 133 Source Issue: 5
Topic: Event Code: 200 Management dynamics
Accession Number: 230151989
Full Text: The famed French Canadian pathologist Pierre Masson used to say: "No classification is more difficult to establish than that of thyroid [carcinomas]. Their pleomorphism is almost the rule; very few are adapted to a precise classification." (1) Dr Masson's statement is still valid, 37 years later, despite the major technical advances that pathologists have accomplished in the last 4 decades. Indeed, the problems and controversies that exist in the classification of thyroid carcinomas of follicular cell origin have an impact on the prognosis and therapy of our patients as well as on the development of robust cutting-edge research aimed at better outcomes and quality of life. In this article, we will focus on 3 problems that have a major impact on management and prognosis.

FOLLICULAR VARIANT OF PAPILLARY THYROID CARCINOMA

The follicular variant of papillary thyroid carcinoma (FVPTC) is the most common subset of papillary thyroid carcinoma (PTC) 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 the presence of follicles with follicular thyroid adenoma (FTA) and follicular thyroid carcinoma (FTC). When FVPTC is nonencapsulated and infiltrates the surrounding thyroid parenchyma or diffusely involves the thyroid, the diagnosis of carcinoma usually poses no problem. 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 (eg, nuclear clearing, overlapping, 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 FVPTC measures more than 1.5 cm, many physicians in the United States will recommend completion thyroidectomy followed by radioactive iodine (RAI) therapy. (9) Some authors have suggested that patients with encapsulated, noninvasive FVPTC have an excellent prognosis and thus believe that only a lobectomy is needed.6 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 to the histologic "subvariants" of FVPTC (ie, nonencapsulated [infiltrative/diffuse] vs. encapsulated), which can serve as the basis for a conservative treatment approach for 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 LiVolsi10 showed that some encapsulated FVPTCs metastasize to distant sites in the absence of lymph node metastases, thus mimicking the clinical behavior of FTC. Other authors reported that FVPTC has a significantly lower metastatic lymph node rate and is more often encapsulated than classic PTC. (11,12) Recently, several groups have attempted to analyze FVPTC at the molecular and chromosomal levels. (11,13,14) All these studies concurred that the molecular profile of FVPTC seems to be closer to that of the FTA/FTC group than to that of the classic PTC, supporting further consideration for the classification of FVPTC.

[FIGURE 1 OMITTED]

To assess the clinical 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 (New York, New York) between 1980 and 1995. (15) The follicular variant of papillary thyroid carcinomas was classified according to histologic growth patterns as encapsulated versus non-encapsulated (infiltrative/diffuse) neoplasms (Figures 1 and 2). 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.

The encapsulated FVPTCs outnumbered their infiltrative/diffuse counterparts (only 17 tumors were diffuse or infiltrative versus 61 encapsulated FVPTCs). The rarity of infiltrative/diffuse (ie, nonencapsulated) FVPTCs is concordant with the first detailed article on FVPTCs by Chem and Rosai. (16)

In our study, patients who had infiltrative/diffuse FVPTC had a significantly greater frequency (P < .001) of marked intratumoral fibrosis, extrathyroidal extension, and positive margins than did patients who had encapsulated FVPTC.15 This superior potential of nonencapsulated FVPTCs for invading the thyroid and extrathyroidal stroma was reflected by the higher rate of total thyroidectomy and especially by the 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 < .001). This difference in lymph node disease could not be explained by differences in tumor size, sex, or age at presentation because the latter 2 variables were similar between the patients with encapsulated tumor and those with nonencapsulated tumor. In our study, the metastatic lymph node rate of encapsulated FVPTCs (5%) was much closer to that reported for follicular carcinomas (on the order of 5%-10%), whereas infiltrative/diffuse FVPTCs had a metastatic lymph node rate within the range reported for classic papillary carcinomas (on the order of 45%-65%). Our overall metastatic lymph node rate for FVPTCs (18%) was slightly higher than that reported by Zhu et al (11) (13%) but lower than the frequency of lymph node disease reported by Zidan et al17 and Tielens et al (4) (22%). The latter difference may be explained by the fact that the investigators allowed up to 20% of papillae in their FVPTCs. (4) Their tumors will now be classified as classic PTC by most authors, because the modern and universally accepted description of FVPTC indicates that the tumor must have an entirely or almost completely follicular pattern. (18) Among the invasive, encapsulated FVPTCs, the lymph node metastatic rate was much higher in tumors that had 4 foci of invasion than in those 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 each patient having more than 10 foci of invasion. A similar correlation between lymph node metastases and extent of invasion has been reported in patients with follicular carcinomas of the oncocytic sub-type. (19)

Regarding prognosis, patients who had invasive tumors, whether encapsulated or not, had a rare but real potential for an adverse outcome. (15) One patient with an encapsulated FVPTC with capsular and vascular invasion had a recurrence in the cervical lymph nodes 2 years after surgery. With a median follow-up of almost 11 years, 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 had recurrences/metastases or died of disease. All 31 patients who had noninvasive, encapsulated FVPTC and underwent lobectomy alone had good outcomes and no lymph node metastases (median follow-up, 11.1 years; median tumor size, 2.3 cm). 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, (10) with the understanding that some pathologists may count the foci with atypical nuclei and report the lesion as multifocal PTC. (10) Others 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 seems to have a clinical behavior much closer to that of follicular tumors (ie, FTA and FTC) than to classic PTC. This is reflected by the lack of adverse outcomes in patients with noninvasive lesions and by the rarity of lymph node metastases. These morphologic and clinical data are supported, as mentioned earlier, by several studies pointing to a molecular profile of FVPTC that is much closer to that of the FTA/FTC group than to classic PTC.

[FIGURE 2 OMITTED]

Indeed, Zhu et al (11) have shown a low frequency (3%) of rearrangement during transfection (RET/PTC rearrangement) and a high frequency of rat sarcoma viral oncogene homolog (RAS) mutations in FVPTC (43%), very similar to observations with follicular carcinoma. Adeniran et al (21) confirmed these findings and showed that within PTC, RAS mutations occur only in FVPTC and are associated with a low level of lymph node metastases. Moreover, v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations were found to be absent in FVPTC and FTC but present in 53% to 56% of classic PTCs. (21,22) PAX8-PPAR[gamma] rearrangement was thought to be restricted to follicular carcinomas and absent in papillary carcinomas. (23) However, Castro et al14 reported a similar frequency of PAX8-PPAR[gamma] rearrangement in FVPTCs (37.5%), FTCs (45.5%), and FTAs (33.3%).

The clinical, histologic, and molecular data gathered to date strongly suggest that FVPTC is a heterogeneous disease composed of 2 distinct groups 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 properties and metastatic lymph node pattern. 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--are the determinants of malignant behavior in encapsulated FVPTC. It is interesting to note that 90% (28 of 31) of our patients with noninvasive, encapsulated FVPTC would have been treated by most experts today with total thyroidectomy and RAI therapy because their tumors were at least 1.5 cm in size. (9) The lack of disease 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 (6) in the last fascicle on thyroid tumor published by the Armed Forces Institute of Pathology. Larger studies with longer follow-up than that of 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 (Figure 3). The same criteria that were used to decide whether follicular tumors are biologically benign or malignant (ie, capsular and vascular invasion) would be applied to the evaluation of encapsulated FVPTCs. In practical terms, lack of capsular or vascular invasion should denote a benign clinical behavior for encapsulated FVPTC. If this reclassification is realized, then it will have a major impact on the diagnosis and management of patients with FVPTC. For 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 (ie, hypoparathyroidism and recurrent nerve injury) and financial costs.

[FIGURE 3 OMITTED]

EXTENT OF INVASION IN FOLLICULAR CARCINOMA: MINIMALLY INVASIVE VERSUS WIDELY INVASIVE TUMORS

Follicular carcinomas of the thyroid gland, including their oncocytic variant (the so-called Hurthle cell carcinoma), are subdivided into minimally invasive and widely invasive tumors. (6) The minimally invasive carcinoma, also termed encapsulated, is totally surrounded by a fibrous capsule and displays capsular invasion and/or foci of vascular invasion. It is unusual for these foci of invasion to be detected grossly. (6) In contrast, widely invasive follicular and Hurthle cell carcinoma are defined by extensive areas of invasion at both the macroscopic and microscopic level. (6) This classification correlates very well with outcome, such that minimally invasive tumors have an overall excellent prognosis, whereas widely invasive tumors have a much poorer outcome. (6) However, some encapsulated, minimally invasive follicular carcinomas recur and metastasize. (24,25) Identifying these cases at the time of diagnosis is crucial because a minimally invasive tumor will be treated by lobectomy alone, followed by observation in some centers, even if the follicular tumor is of the oncocytic (Hurthle cell) category. This approach runs the risk of undertreating those few minimally invasive tumors with a poor outcome. Many surgeons are at variance with this minimalist surgical approach and will perform a total thyroidectomy for any minimally invasive follicular carcinoma, especially of the oncocytic category, and will most likely overtreat a large number of cases.

[FIGURE 4 OMITTED]

[FIGURE 5 OMITTED]

We attempted to identify prognostic factors of recurrence in a series of 50 encapsulated Hurthle cell carcinomas treated at Memorial Sloan-Kettering Cancer Center. (26) Seven of 50 patients (14%) had disease recurrence. All patients with a recurrence had many foci of vascular invasion ([greater than or equal to]4) (Figures 4 through 6). In univariate analysis, a decrease in relapse-free survival correlated with the presence of at least 4 foci of vascular invasion (P < .001) (Figure 7), a tumor size greater than 4 cm (P = .04), the presence of a mild to moderate mitotic rate (1-4 mitoses/10 high-power fields, X400) (P = .01), and a solid/trabecular growth pattern (P = .009). Extensive capsular invasion, sex, and age did not confer a statistically higher recurrence rate. The finding of a solid/trabecular growth and a mild to moderate mitotic rate correlated with the presence of numerous foci ([greater than or equal to] 4) of vascular invasion (P = .01 and P = .005, respectively). The correlation between extent of vascular invasion and adverse outcome was reported in a small study of encapsulated non-Hurthle cell follicular carcinomas (27) and in larger studies of follicular carcinomas in general without emphasis on its oncocytic variant. (28,29) It is remarkable that the number of foci of vascular invasion that we determined would place patients at high risk of disease recurrence ([greater than or equal to] 4 vessels) is very close to that reported by Lang et al (28) in 1986 (>4 foci). On the basis of the above data, we believe that encapsulated follicular carcinoma, including encapsulated Hurthle cell carcinomas, cannot be all assembled under the "minimally invasive" category, a term that denotes limited invasion and, more importantly, excellent prognosis. Indeed, some follicular carcinomas have extensive vascular invasion, which implies a high risk for recurrence. Some have suggested naming encapsulated follicular tumors with extensive vascular invasion as "widely invasive." (28,30) Others find this designation quite arbitrary and prefer using descriptive terms such as encapsulated follicular carcinomas with extensive vascular invasion. (27) Whatever the designation, we believe it is important to avoid the use of the term minimally invasive for these aggressive encapsulated follicular neoplasms with extensive angioinvasion. Indeed, disease in patients may be undertreated because of the use of the "minimally invasive" terminology in the pathology report.

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Consequently, the number of foci of vascular invasion should be mentioned in the pathology reports on follicular carcinomas, with a note regarding the increased risk of recurrence if at least 4 foci of vascular invasion are observed. A diligent search for vascular invasion is highly recommended in the presence of a solid growth pattern and mitoses because these characteristics are highly associated with extensive angioinvasion. These recommendations will rationalize the management and prognostication of patients with follicular carcinomas.

[FIGURE 11 OMITTED]

POORLY DIFFERENTIATED THYROID CARCINOMAS

Thyroid carcinomas of follicular cell origin represent a spectrum of tumors ranging from the indolent, well-differentiated, papillary carcinomas and minimally invasive follicular carcinomas to the almost universally lethal anaplastic carcinomas. In between these 2 extremes is a group of tumors having an intermediate position at the histologic and prognostic levels. (6) These neoplasms were termed poorly differentiated thyroid carcinomas (PDTCs) in their original description in the early 1980s. (31,32) Most authors concur that this entity exists but its histologic definition is subject to controversy. (1,33-36) For some authors, these tumors are defined on the basis of a solid/trabecular or sclerotic "scirrhous" growth pattern, (32) whereas others suggest relying on "histologic" grading (ie, nuclear atypia, necrosis, and mitoses). (37) Some pathologists also have included aggressive variants of papillary thyroid carcinoma, such as the tall cell and columnar cell variants (defined by their cell type and not their mitotic rate or necrosis), in the category of PDTC. (38,39)

In a study performed at Memorial Sloan-Kettering Cancer Center, we defined PDTC on the basis of the presence of necrosis and/or a high mitotic rate, irrespective of growth pattern and cell type (Figure 8). (40) We chose histologic grading (which includes mitoses and necrosis) to define this aggressive group of thyroid tumors because, to our knowledge, these features were shown to define clinical behavior independently of architectural grade (ie, growth pattern) and cell type in various tumor systems, including papillary thyroid carcinoma. (37) Therefore, we performed a detailed clinicopathologic correlation of 58 patients with PDTC. The study demonstrated that patients with PDTCs, defined on the basis of tumor necrosis and/ or high mitotic rate ([greater than or equal to] 5 mitoses per 10 high-power fields), have an overall survival rate of 60% at 5 years, a rate in between that of patients with well-differentiated thyroid carcinomas and with anaplastic carcinomas (Figure 9). Poorly differentiated thyroid carcinomas, defined mainly on the basis of growth pattern alone (such as the tumors reported in the large Italian study by Volante et al (36)), also occupy an intermediate prognostic position in the spectrum of thyroid carcinoma progression; however, survival of patients is much better when their definition is applied to PDTCs than when our definition is applied on the basis of mitoses and necrosis. This discrepancy is due to the fact the patient population in the Italian study was clinically heterogeneous and divisible into 3 subgroups based on a numeric scoring system, with tumor necrosis as the most influential parameter; the other 2 parameters were high mitotic rate and older age. Indeed, the overall survival curve of their most favorable subgroup overlapped that of patients with well-differentiated papillary and follicular carcinomas. (36) The overall survival of patients with most aggressive disease (those whose neoplasms contained at least tumor necrosis) in their study (36) is closer to that of the patients in our study, whose tumors were defined by necrosis and/or a high mitotic rate. This finding has important clinical implications. In agreement with the most recent Turin proposal for the definition of PDTC, (41) pathologists should not diagnose PDTC on the basis of solid growth pattern alone. Most importantly, a tumor with a predominant papillary and/or follicular pattern displaying tumor necrosis and/or a high mitotic rate should not be diagnosed as "follicular carcinoma" or as "moderately differentiated papillary carcinoma." This may mislead clinicians in believing that they are dealing with a relatively indolent, well-differentiated thyroid carcinoma. The importance of PDTC defined on the basis of mitoses and/or necrosis is emphasized by our own data showing that this tumor is the major cause of RAI-refractory, fluorodeoxyglucose positron emission tomographypositive incurable thyroid carcinomas.42 Interestingly, we also found that 71% of the primary PDTCs that became RAI refractory were initially diagnosed by the primary pathologist as better differentiated tumors on the basis of the presence of papillary and/or follicular architecture or the presence of typical PTC nuclear features (Figure 10). (42) These carcinomas were reclassified in our study as PDTCs on the basis of tumor necrosis and/or high mitotic activity. The importance of tumor necrosis in primary tumors is validated by the fact that it was the only independent variable (along with extrathyroidal extension) that was associated with decreased overall survival in RAI-refractory thyroid carcinomas (Figure 11). Tumor necrosis is therefore superior to histotype in predicting survival in this group of patients. Within PDTC, the extent of invasion (extrathyroidal, capsular invasion) and the lack of tumor capsule correlated with worse outcome. (40) Minimally invasive PDTCs seem to behave in an indolent fashion, although this is difficult to confirm because of the rarity of these cases. (40) In our opinion, data in the literature are insufficient to assess the prognostic value of tumors with focal PDTC. Finally, the number of chromosomal abnormalities in PDTC is intermediate between that of well-differentiated and anaplastic thyroid carcinoma, mirroring its intermediate position at the morphologic and prognostic levels.43 This is also true of the Ki-67 proliferative rate and p53 immunopositivity of PDTC. (44) These markers cannot, however, be used on their own to diagnose PDTC. Kinase pathway mutations known to be involved in thyroid carcinoma development, such as BRAF; RAS; and phosphatidylinositol 3-kinase, catalytic, [alpha]-polypeptide (PIK3CA), were shown to be present in 51% of PDTCs defined on the basis of tumor necrosis and/or high mitotic rate. (45) This obviously raises hope for better outcome in patients whose carcinomas are often refractory to current modalities. Indeed, therapies targeted against some of these mutations are now available in clinical trials.

CONCLUSION

Thyroid carcinomas of follicular cell origin are in need of continuous reclassification. The prognosis and treatment of many disease entities can be better delineated if a meticulous microscopic examination is performed. An accurate assessment of the extent of invasion (especially vascular) is crucial. Proliferative grading (ie, mitosis and necrosis), neglected by previous generations of pathologists, is of high prognostic value and should be looked for in every specimen. In addition, molecular data gathered in the last 20 years can help reassess these tumors at the histologic level, as in the case for FVPTCs. Finally, classification proposals based on personal experience rather than adequate and careful clinical follow-up should be discouraged. It is time for the new generation of academic pathologists to practice evidence-based medicine rather than being the "dogmatic" histopathologists of the past.

Accepted for publication January 8, 2009.

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Ronald Ghossein, MD

From the Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York.

The author has no relevant financial interest in the products or companies described in this article.

Presented in part at the Surgical Pathology of Neoplastic Diseases course, Memorial Sloan-Kettering Cancer Center, New York, New York, May 12-16, 2008.

Reprints: Ronald Ghossein, MD, Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065 (e-mail: ghosseir@mskcc.org).
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