“Hybrid” Thyroid Carcinoma 313Clinical Research

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IPATIMUP—Institute ofMolecular Pathology andImmunology of the Universityof Porto (PC, EF, MS-S);Medical Faculty of the Universityof Porto (EF, MS-S);and Hospital S. João, Porto,Portugal (EF, JM, MS-S).

Address correspondence toDr. M. Sobrinho-Simões,IPATIMUP, R Roberto Friass/n 4200-465 Porto-Portugal.E-mail: ssimoes@ipatimup.pt

Endocrine Pathology, vol. 13,no. 4, 313–320, Winter 2002© Copyright 2002 by HumanaPress Inc. All rights of anynature whatsoever reserved.1046–3976/02/13:313–320/$20.00

Follicular, Papillary, and “Hybrid” Carcinomasof the Thyroid

Patrícia Castro, PHD, Elsa Fonseca, MD, PHD, João Magalhães, MD,and Manuel Sobrinho-Simões, MD, PHD

AbstractThe existence of well-differentiated thyroid tumors sharing the clinicopathologic fea-tures of follicular and papillary carcinoma is discussed using the so-called diffuse (multin-odular) form of the follicular variant of papillary carcinoma as a paradigm. Although theconcept of a “hybrid carcinoma” of the thyroid is intellectually very appealing, we con-clude that there is not (yet) enough reliable genotypic or phenotypic evidence to supportutilization of such a term.Key Words: Follicular variant of papillary carcinoma; “hybrid” carcinoma; clinicopatho-logic features; well-differentiated carcinomas.

3. Well differentiated carcinomas, not oth-erwise specified (NOS). This designationhas been created to encompass neo-plasms derived from the thyroid follicu-lar epithelium that display signs ofcapsular and/or vascular invasion and arecomposed of cells with nuclei that arelarger, clearer, and more irregular thanthe nuclei of follicular carcinomas with-out reaching the florid appearance ofPTC nuclei [1,3,4].

4. Poorly differentiated carcinomas display-ing trabecular, insular, and/or solidpattern(s) of growth that are composedof neoplastic cells with “intermediate”-type nuclei that resemble those of PTC.

We did not include in this heteroge-neous group of lesions the so-called cribri-form-morular variant of PTC despite itspeculiar etiopathogenesis via APC/β cateninalterations [5] because there are not enoughfollow-up data on the relatively few casesidentified to date. We also did not con-sider the malignant tumors composed ofoxyphilic (Hürthle) cells as good candidatesfor hybrid carcinomas. Most researchers

IntroductionSeveral possibilities occur when one

thinks of “hybrid” carcinomas of the thy-roid follicular epithelium:

1. The so-called follicular variant of papil-lary carcinoma. Is it a mere morphologicvariant of papillary thyroid carcinoma(PTC) or a “real” clinicopathologic vari-ant that lies somewhere in between fol-licular and papillary carcinoma andshould therefore be separated from clas-sic PTC?

2. Other variants of papillary carcinomathat are identified by the typical appear-ance of the nuclei of the neoplastic cellsin tumors with a trabecular and/or solidpattern of growth. This applies, e.g., tothe trabecular variant of papillary carci-noma encompassing, according to someresearchers, the hyalinizing trabecularadenoma and the hyalinizing trabecularcarcinoma of the thyroid [1]. It alsoapplies to the solid variant of papillarycarcinoma that occurs frequently in chil-dren both sporadically and in postirra-diation settings [1,2].

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would agree that such tumors should bedivided according to their nuclear charac-teristics into two categories—oxyphilic(Hürthle) cell variants of follicular andpapillary carcinoma [6–8]—but manyetiopathogenic issues remain unclarified,namely the reported high frequency ofRET rearrangement in both benign andmalignant Hurthle cell tumors [9] and theconsistent lack of PAX8/peroxisomeproliferator-activated receptor γ (PPARγ)translocation in Hürthle cell follicular car-cinomas [10]. Curiously, it is not rare tosee neoplastic papillae in Hürthle cell fol-licular tumors, thus demonstrating themajor nosologic importance of the nuclearfeatures over that of growth pattern [1,2,8].

Definition and Problems

As a working definition of hybrid carci-noma, we use here that of Baloch andLiVolsi [11]: hybrid carcinomas are tumorsthat show features of both follicular andpapillary carcinoma. They tend to occuras solitary, encapsulated lesions that oftendisplay vascular invasion and have somenuclear features suggesting PTC. Accord-ing to Baloch and LiVolsi [11], such tumorsonly rarely occur as multifocal lesions orgive rise to nodal metastases.

This option rules out the possibility ofusing the dual metastatic pattern (lymphnode and blood-borne metastases) as themajor criterion for considering a neoplasmas a hybrid carcinoma. For instance, PTCsthat give rise to both types of metastasessuch as the diffuse sclerosing variant shouldnot be considered as hybrid carcinomas.

The definition of Baloch and LiVolsi[11] emphasizes the phenotypic features ofthe neoplasms and creates room to explorethe existence of a hybrid oncogenic path-way: PTCs are usually diploid or near dip-loid tumors displaying RET and TRK

rearrangements and/or overexpression ofother tyrosine kinase receptors such asc-MET and EGFR, whereas follicular car-cinomas occur usually as aneuploid tumorsdisplaying RAS mutations and PAX8/PPARγ rearrangements [10,12–19]. It isalso known that the two pathways mayinteract (e.g., RET and TRK tyrosinekinase oncogenes cooperate with RAS inthe neoplastic transformation of thyroidcells) [20], thus reinforcing the possibilityof a hybrid carcinogenic pathway.

Taking all this into account it is tempt-ing to posit from a conceptual standpointthat PTC with a DNA aneuploid content,foci of trabecular/solid growth pattern, andunequivocal signs of vascular invasiveness[21] may represent hybrid carcinomas.The same holds true for PTC arising froma preexisting follicular tumor (adenoma ornodular goiter) [22] provided one couldprove such tumors share molecular alter-ations of papillary and follicular carcinomaand are more prone to give rise to blood-borne metastases than classic PTC.

Since the aforementioned conditionscannot be fulfilled, at least for the present,we decided, in accordance with Baloch andLiVolsi [11], to focus the discussion on thefollicular variant of PTC (FVPTC).

Follicular Variant of PTC

FVPTC was described by Lindsay in1960 and was thought, for a while, toresemble closely the classic form of PTCin biologic and clinic behavior [1,2,23,24].Oversimplifying the issue, it was advancedthat the FVPTC, like most PTCs, was aslowly growing neoplasm that tended togive rise to lymph node metastases [1,2,23].In 1985, Carcangiu et al. [25] pointed outthat, at variance with common PTC, somecases of the FVPTC were prone to give riseto lung metastases. This finding was con-

“Hybrid” Thyroid Carcinoma 315

firmed in a large series from the LisbonCancer Institute (Limbert E, personal com-munication). Moreover, it was observedthat the growth pattern of the encapsulatedform of FVPTC—there is also a poorly cir-cumscribed, infiltrative form that sharesmost of the microscopic features of classicPTC—mimicked that of follicular carci-noma: pushing borders, capsular and vas-cular invasion, and blood-borne metastases,occasionally in the absence of lymph nodemetastases [1,2,23–26]. Curiously, Selzeret al. [27] had already reported in 1977that carcinomas with a mixed follicular/papillary pattern had a prognosis and meta-static pattern intermediate between thepure papillary and follicular carcinomas.

The coexistence of encapsulated lesionsdisplaying prominent signs of vascularinvasion and frequent metastases in thelungs and bones is particularly evident ina subset of cases of the follicular variant ofPTC that have been designated as diffuse,multinodular, or aggressive forms (Table 1)[28–31].

Immunohistochemical study of FVPTC,regardless of whether it is the encapsulatedor diffuse/multinodular subtype, has

shown that this variant is much more simi-lar to follicular carcinoma than to classicPTC. This holds true regarding thecytokeratin profile; E-cadherin/cateninscomplex; and sugars, mucins, and histo-blood group antigens, as far as one canjudge from the available evidence (nega-tively biased by the rarity of studiesaddressing specifically the features ofFVPTC) [32–35].

A few cytogenetic studies have disclosedthe occurrence of trisomies of chr #7, #10,and #17 [36] monosomy or LOH of chr#22 [37,38] and translocation 3;5 [38] insome cases of FVPTC, thus suggesting thatsuch cases may lie, from a cytogeneticstandpoint, somewhere in between papil-lary and follicular carcinoma.

When these data are considered alongwith the clinicopathologic features (growthpattern, vascular invasion, and distantmetastases), it seems logical to concludethat some cases of FVPTC, namely thosethat display signs of clinical and biologicaggressiveness, may qualify as good candi-dates for hybrid carcinomas of the thyroid.

The critical evaluation of this conclu-sion needs the combined efforts of surgi-

Table 1. Summary of Clinicopathologic Data and Comparison Between Diffuse/Multinodular FVPTC, Common PTC, and Encapsulated FVPTCa

Common PTC Diffuse/multinodular FVPTC Encapsulated FVPTC(n = 25) p Valueb (n = 10) p Valuec (n = 8) p Valued

Gender (male; female) 8; 17 NS 1; 9 NS 0; 8 NSMean age (yr ± SEM)e 42.5 ± 3.3 0.008 26.8 ± 3.3 0.008 40.3 ± 2.3 NSTumor size (cm ± SEM)e 2.0 ± 0.2 NS 2.5 ± 0.3 NS 2.3 ± 0.4 NSMulticentricity (%) 24.0 0.002 80.0f 0.0007 0 NSExtrathyroid extension (pT; %) 12.0 0.0006 70.0 0.003 0 NSLymph node metastasis (%) 36.0 0.019 80.0 0.004 12.5 NSVenous invasion (%) 20.0 0.0009 80.0 0.0007 0 NS

aNS, not significant.bComparison of diffuse/multinodular FVPTC and common PTC.cComparison of diffuse/multinodular FVPTC and encapsulated FVPTC.dComparison of common PTC and common FVPTC.eIn two cases of diffuse/multinodular FVPTC, the tumoral tissue involved the whole thyroid lobe.fAll comparisons were performed using χ2 test with Yates correction except in this comparison in which Mann-Whitney test was used.Adapted from Ivanova et al. [31].

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cal pathologists and molecular biologists.It will be necessary to compare, usingthoroughly classified lesions, the clinico-pathologic, immunohistochemical, andmolecular characteristics of the three mainsubtypes of FVPTC (encapsulated, poorlycircumscribed, and diffuse/multinodular)

with those of classic PTC. It will also beinteresting to explore, apart from putativedifferences in cytoskeletal proteins, adhe-sion molecules, matrix-degrading enzymes,and so on, the molecular mechanismsinvolved in the development of FVPTC:Are RET and TRK rearrangements equallydistributed in every subtype of PTC? Whatabout RAS mutations and PAX8/PPARγtranslocation? Are there any differencesbetween FVPTC and classic PTC regard-ing the overexpression of tyrosine kinasereceptors? Finally, it will be interesting toknow whether some cases of FVPTC con-sistently exhibit the trisomies and/ortranslocations that are the hallmark of sometypes of follicular tumors of the thyroid [39].

The Problem of Nuclear Features

We have excluded from this discussionthe issue of the putative diagnostic mean-ing of the nuclear appearance whenever itis somewhat papillary looking. We also didnot discuss whether or not it is easy andreproducible to classify the nuclear featuresof a given neoplasm as “suggestive” of PTC.Such appearance is seen in some cases ofFVPTC, namely of the diffuse/multinodu-lar subtype [28,29,31]. It is also observedin many poorly differentiated carcinomasthat partly correspond to neoplasms thatLjungberg et al. [40] have grouped underthe designation “Differentiated thyroidcarcinomas, intermediate type.” The nucleiof these lesions superficially resemble thoseof PTC. Nevertheless, the mean sizes ofthe nuclei of “insular” and “solid” subtypesof poorly differentiated carcinoma (202and 207 µm3, respectively) are similar tothose of follicular adenomas and follicularcarcinomas (207 and 219 µm3, respec-tively) and much lower than those of PTC(258 µm3) [41,42], thus demonstratinghow subjective (and fragile) our histo-

Fig. 1. This case was selected to illustrate the strategy we follow in our institute.It is an encapsulated lesion of about 1.5 cm in a 39-yr-old woman. The capsule isthick and there are unequivocal signs of capsular and vascular invasiveness (A)(×400) and (B) (×100).

“Hybrid” Thyroid Carcinoma 317

pathologic evaluation is [43]. Further, theetiopathogenesis of the typical nuclear fea-tures of PTC remains partially unclarified,and it is therefore difficult to progress in

the understanding of the mechanismsunderlying the appearance of papillary-looking nuclei.

The correct identification of PTC nucleifor diagnostic purposes is probably the big-gest problem being faced in thyroid pathol-ogy. This issue is thoroughly dealt with inthree articles published in January 2002 byBaloch and LiVolsi [11], Chan [44], andRenshaw and Gould [45]. The latterinvestigators concur with the strategy sug-gested by Rosai et al. [1] and Williamset al. [4]: whenever in doubt regarding thenuclear features of an encapsulated tumordisplaying unequivocal signs of invasive-ness, the neoplasm should be classifiedas “well-differentiated thyroid carci-noma, NOS.”

We do not particularly like this solutionand use it as rarely as possible (Fig. 1).However, and for the time being, we thinksuch a pragmatic option may be moreappropriate than jumping to a diagnosisof “hybrid” carcinoma without havingenough molecular and clinicopathologicevidence.

Conclusion

The idea of a “hybrid” carcinoma in thethyroid, sharing the molecular pathwaysand the clinicopathologic features of folli-cular and papillary carcinoma, is veryappealing from a conceptual standpoint.However, we think there is not enoughreliable genotypic evidence nor solid phe-notypic data to support utilization of sucha term in daily routine. In cases in whichone is challenged by a well-differentiatedmalignant neoplasm that does not entirelyfit into the categories of follicular or papil-lary carcinoma, the designation “well-dif-ferentiated carcinoma, NOS” is preferableto that of “hybrid” carcinoma.

Fig. 1. (continued) The nuclei of most of the neoplastic cells are large and slightlymore irregular than the nuclei of normal follicular cells (C) (×200). In some areasthe nuclei are larger, clearer, and more irregular than those in the bulk of thetumor (D) (×200) and thus should be considered of the “intermediate” or papil-lary-looking type. Despite this, and taking into consideration all the morphologicfeatures, we classified the tumor as “follicular carcinoma, angioinvasive.” If thenuclear features were consistently more impressive toward the papillary side, wewould consider the diagnosis of “well-differentiated carcinoma, angioinvasive”.

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Acknowledgment

This work was presented in part at the11th Annual Meeting of the EndocrinePathology Society, February 23, 2002.

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