a follicular variant of papillary thyroid carcinoma in struma ovarii. case report with unique...

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A follicular variant of papillary thyroidcarcinoma in struma ovarii. Case report withunique molecular alterations

DOI: 10.1111/j.1365-2559.2009.03401.x

Sir: Struma ovarii (SO) is a rare monodermal form ofovarian teratoma in which >50% of the tumour iscomposed by thyroid tissue.1 The histological appear-ance of SO mimics that of several thyroid lesions.2

When the morphological features of SO correspond tonormal thyroid tissue, goitre or adenoma, they areconsidered as benign SO (BSO).1,3 When the morpho-logical features are those of classical papillary thyroidcarcinoma (cPTC), follicular variant of PTC (FVPTC) orfollicular thyroid carcinoma (FTC), they are consideredas malignant SO (MSO).1,4,5 The percentage of PTCwithin MSO varies from 70%5 to 85% of cases;1 in theformer series, 44% of the tumours were cPTC and 26%were classified as FVPTC.5

The differential diagnosis between BSO and MSOmay be extremely difficult. This holds particularly truefor MSO with a follicular growth pattern due to theabsence of a well-defined capsule, making it almostimpossible to identify capsular or vascular invasion.1

Furthermore, focal ‘PTC-like’ nuclear changes are often

present, increasing the diagnostic difficulties withregard to FVPTC.1,6

We report a case of SO in a 38-year-old woman whopresented with a pelvic mass diagnosed as an ovariancyst. The histological examination showed a predom-inantly follicular patterned tumour depicting neoplasticcells with large, roundish and clear nuclei withevenly distributed chromatin and absent or inconspic-uous nucleoli (Figures 1 and 2). The follicles wereoften irregular and of variable size and frequentlycontained variably stained colloid (Figure 2). Focally,there were foci composed of clear cells and somepapillary structures (Figures 1 and 2). In some foci, thenuclei of the neoplastic cells were larger, clearer, moreirregular and grooved, displaying the appearance ofPTC nuclei (Figure 2). The results of the immunohis-tochemical study are summarized in Table 1 andFigure 3. A diagnosis of MSO with FVPTC phenotypewas made.

DNA sequences of H-RAS (exon 2), N-RAS (exon 2)and BRAF (exon 15) genes were analysed, as describedby Castro et al.,7 from the tumour and adjacent normaltissue. No mutations were detected in exons 15 and 2 ofBRAF and HRAS, respectively. In exon 2 of NRAS, aCAA fi CGA change was detected in codon 61(Q61R)(Figure 4). Fluorescence in situ hybridization for PAX8-PPARc and RET ⁄ PTC fusion genes was done on isolatednuclei.7 A PAX8-PPARc rearrangement was detected in16% of 200 analysed nuclei (Figure 4). No RET ⁄ PTCrearrangement was detected. The final diagnosis wasMSO with a FVPTC phenotype depicting a NRASmutation (Q61R) and a PAX8-PPARc rearrangement.

Figure 1. Papillae and follicles (top) in ovarian stroma (bottom)

(H&E). The two inserts show a greater detail of papillae and follicles

(H&E).

482 Correspondence

� 2009 The Authors. Journal compilation � 2009 Blackwell Publishing Ltd, Histopathology, 55, 465–488.

Table 1. Antibodies, dilutions,suppliers, and results ofimmunohistochemistystaining

Antigen

Antibody

Dilution ResultsClone and Source

Thyroid transcription factor-1 8G7G3 ⁄ 1, Dako 1:50 +

Thyroglobulin DAK-Tg6, Dako 1:6000 +

Chromogranin A DAK-A3, Dako 1:600 )

Synaptophysin SY38 ⁄ BioGenex 1:50 )

Progesterone receptor SP2, LabVision 1:500 )

Cytokeratin-19 b170, Novocastra 1:50 +

HBME-1 HBME-1, Dako 1:50 +

Galectin-3 9C4, Novocastra 1:500 +

A B

C D

Figure 2. A, An area of the tumour composed of clear cells (H&E). B, Follicles with thick and clear colloid (H&E). C,D, Papillary carcinoma-like

nuclei in follicular and papillary structures (H&E).

Correspondence 483


Very few cases of SO have been studied for thegenetic alterations frequently detected in ‘cervical’thyroid carcinoma;3,8–10 and neither RAS mutation(s)nor PAX8-PPARc rearrangement(s) have been detectedpreviously.

Thyroid tumours are characterized by a close geno-type–phenotype relationship.11,12 RET ⁄ PTC1 and theBRAFV600E mutation tend to concentrate in cases ofcPTC; RET ⁄ PTC3 and, perhaps, BRAFVK600-1E appearto be associated with the solid variant of PTC;12 theBRAFK601E mutation is typical of FVPTC, whereasN-RAS and PAX8-PPARc rearrangements have beenreported in tumours displaying a prominent folliculargrowth pattern follicular thyroid adenoma (FTA), FTCand FVPTC.7,12 At variance with cPTC, FVPTC shows ahigh percentage of RAS mutations (43%) and PAX8-PPARc rearrangement (37%).7,12

A similar genotype–phenotype association emergesfrom the study of the genetic alterations in SO. APubmed search disclosed four articles reporting mole-cular alterations in SO (Table 2). Overall, in the 14 BSOreported to date, no BRAF or RAS mutations have beenfound, and only one case presented a RET ⁄ PTCrearrangement.3,8,10 Out of 17 MSO, 29% had a BRAFmutation and 41% had a RET ⁄ PTC rearrange-ment.8–10 Every MSO presenting a cPTC phenotypehad the BRAFV600E, and the two cases with FVPTCphenotype presenting BRAF mutations had BRAFK601E

and BRAFTV599–600M.10 The prevalence of RET ⁄ PTCrearrangements in MSO was high (50%),8–10 and everyMSO positive for RET ⁄ PTC had a FVPTC phenotype.8

All molecular alterations mentioned above weremutually exclusive, as they occur in ‘cervical’PTC.3,8–10,12,13 The presence of RAS mutations and ⁄ or

A B

C D

Figure 3. A,B, Galectin 3 strong and diffuse immunoreactivity in follicles (A) and papillae (B). C, Cytokeratin 19 reactivity (H&E). D, HBME-1

reactivity (H&E).

484 Correspondence


Table 2. Molecular alterations described in struma ovarii cases

Study Case Histology BRAF RAS RET ⁄ PTC

Elisei et al.3 1 BSO ND ND RET ⁄ PTC3

Flavin et al.9 2 MSO cPTC V600E ND WT

Schmidt et al.10 3 BSO WT WT WT

4 BSO WT WT WT

5 BSO WT WT WT

6 BSO WT WT WT

7 BSO WT WT WT

8 BSO WT WT WT

9 BSO WT WT WT

10 BSO WT WT WT

11 BSO WT WT WT

12 BSO WT ND ND

13 BSO ND WT WT

14 MSO FVPTC TV599-600M WT WT

15 MSO FVPTC WT WT WT

16 MSO FVPTC WT WT WT

17 MSO FVPTC K601E WT WT

18 MSO cPTC V600E WT WT

19 MSO cPTC* V600E WT WT

Boutross-Tadross et al.8 20 BSO WT ND WT

21 BSO WT ND WT

22 BSO WT ND WT

23 MSO FVPTC WT ND RET ⁄ PTC 1







30 MSO FVPTC WT ND WT



*Metastasis with cPTC phenotype.ND, Not done; WT, wild-type; BSO, benign struma ovarii; MSO, malignant struma ovarii; FVPTC, follicular variant of papillarythyroid carcinoma; cPTC, classical papillary thyroid carcinoma.

Correspondence 485


PAX8-PPARc rearrangement has not been reported inany SO despite their prevalence in FTA, FTC andFVPTC.7 The detection in the present MSO with aFVPTC phenotype of a RAS mutation and a PAX8-PPARc rearrangement fits with the results obtained in‘cervical’ FVPTC.7

The detection of molecular alterations does notusually provide crucial diagnostic information indoubtful cases because only the BRAF mutationappears to be, at least in ‘cervical’ PTC, 100%predictive of malignancy.11,12

Besides its impact on the differential diagnosis itremains to be seen if such molecular alterations haveprognostic or therapeutic importance. Only scant

information on the prognosis of MSO is available:metastasis is reported in up to a quarter of patients5

and recurrence can affect up to 35% of them,6 but nowell-defined prognostic criteria have been established.Elisei et al.3 have reported a SO that was classified asBSO by histology and displayed a RET ⁄ PTC3 rear-rangement; the authors suggested that the presence ofthe rearrangement indicates the possibility of subse-quent malignant evolution,3 but this claim remains tobe proven.14 It is also unknown if the presence of thePAX8-PPARc rearrangement in MSO may be associ-ated with vascular invasiveness, as reported in ‘cervi-cal’ FVPTC and FTC.7,15

acknowledgements

This study was supported by Fundacao CalousteGulbenkian through a PhD grant to R.C. and thePortuguese Foundation for Science and Technologythrough a Post-Doc grant to P.C. (Ref. SFRH ⁄ BPD ⁄26553 ⁄ 2006). We thank also the Portuguese Foun-dation for Science and Technology for partial fundingof this study through a research project (PTDC ⁄ SAU-OBD ⁄ 69787 ⁄ 2006).

Ricardo Celestino1,2,3

Joao Magalhaes1,3,4

Patricia Castro1

Marie Triller5

Joao Vinagre1,2,3

Paula Soares1,3

Manuel Sobrinho-Simoes1,3,4

1Institute of Pathology and Molecular Immunology,

University of Porto (IPATIMUP),2Biomedical Sciences Institute Abel Salazar,

University of Porto (ICBAS),3Department of Pathology, Medical Faculty,

University of Porto,4Department of Pathology, Hospital Sao Joao,

Porto, Portugal, and5Cabinet de Pathologie Tolbiac, Paris, France

1. Tavassoli F, Devilee P. World Health Organization classification of

tumours. Pathology and genetics of tumours of the breast and female

genital organs. Lyon: IARC Press, 2003.

2. Devaney K, Snyder R, Norris HJ, Tavassoli FA. Proliferative and

histologically malignant struma ovarii: a clinicopathologic study

of 54 cases. Int. J. Gynecol. Pathol. 1993; 12; 333–343.

3. Elisei R, Romei C, Castagna MG et al. RET ⁄ PTC3 rearrangement

and thyroid differentiation gene analysis in a struma ovarii

fortuitously revealed by elevated serum thyroglobulin concen-

tration. Thyroid 2005; 15; 1355–1361.

C A A

C G A

Arginine (mutant)

Glutamine (Wild type) A

B

Figure 4. A, Mutation of NRAS gene in codon 61 consisting of a

CAA fi CGA change that leads to substitution of glutamine by an

arginine (Q61R). B, Representative result obtained in the fluorescence

in situ hybridization analysis for PAX8-PPARc rearrangement. Green

dots are the bacterial artificial chromosome (BAC) probes for PPARc,

red dots are BAC probes for PAX8; the nuclei are stained with 4¢-6-

diamidino-2-phenylindole. Nuclei in which the two probes were fused

or touching were scored as positive for fusion gene (arrow).

486 Correspondence


4. DeLellis RA, Lloyd RV, Heitz PU, Eng C. WHO classification of

tumours. Pathology and genetics of tumours of endocrine organs.

Lyon: IARC Press, 2004.

5. Makani S, Kim W, Gaba AR. Struma Ovarii with a focus of

papillary thyroid cancer: a case report and review of the

literature. Gynecol. Oncol. 2004; 94; 835–839.

6. Yassa L, Sadow P, Marqusee E. Malignant struma ovarii. Nat.

Clin. Pract. Endocrinol. Metab. 2008; 4; 469–472.

7. Castro P, Rebocho AP, Soares RJ et al. PAX8-PPARgamma

rearrangement is frequently detected in the follicular variant of

papillary thyroid carcinoma. J. Clin. Endocrinol. Metab. 2006; 91;

213–220.

8. Boutross-Tadross O, Saleh R, Asa SL. Follicular variant papillary

thyroid carcinoma arising in struma ovarii. Endocr. Pathol. 2007;

18; 182–186.

9. Flavin R, Smyth P, Crotty P et al. BRAF T1799A mutation

occurring in a case of malignant struma ovarii. Int. J. Surg.

Pathol. 2007; 15; 116–120.

10. Schmidt J, Derr V, Heinrich MC et al. BRAF in papillary thyroid

carcinoma of ovary (struma ovarii). Am. J. Surg. Pathol. 2007; 31;

1337–1343.

11. Trovisco V, Vieira DCI, Soares P et al. BRAF mutations are

associated with some histological types of papillary thyroid

carcinoma. J. Pathol. 2004; 202; 247–251.

12. Sobrinho-Simoes M, Maximo V, Rocha AS et al. Intragenic

mutations in thyroid cancer.Endocrinol. Metab. Clin. North Am.

2008; 37; 333–362, viii.

13. Soares P, Trovisco V, Rocha AS et al. BRAF mutations and

RET ⁄ PTC rearrangements are alternative events in the etio-

pathogenesis of PTC. Oncogene 2003; 22; 4578–4580.

14. Rhoden KJ, Unger K, Salvatore G et al. RET ⁄ papillary thyroid

cancer rearrangement in nonneoplastic thyrocytes: follicular cells

of Hashimoto’s thyroiditis share low-level recombination events

with a subset of papillary carcinoma. J. Clin. Endocrinol. Metab.

2006; 91; 2414–2423.

15. Nikiforova MN, Lynch RA, Biddinger PW et al. RAS point

mutations and PAX8-PPAR gamma rearrangement in thyroid

tumors: evidence for distinct molecular pathways in thyroid

follicular carcinoma. J. Clin. Endocrinol. Metab. 2003; 88; 2318–

2326.

Underreporting of placental abnormalities

DOI: 10.1111/j.1365-2559.2009.03402.x

Sir: The placenta provides important evidence in caseswhere perinatal malpractice is claimed, and therefore itis essential that all clinically significant diagnoses bepresent and accurate in the final pathology report.1 Weretrospectively examined the completeness and qualityof diagnoses in the final pathology reports of aconsecutive series of 100 cases that had been examinedin a standard manner2 and reported by pathologistswith no special training in placental pathology. Thecases were submitted from live births on the basis ofspecific clinical indications.3

The original haematoxylin and eosin-stained slides,along with submitted clinical information, were exam-ined for the presence of selected diagnostic abnormal-ities.2 The review diagnoses were then compared with

the original report, and each discrepancy was classifiedas underreporting or as misdiagnosis. The clinicaldiagnosis was also reviewed to determine whether ornot it was confirmed by the original pathologicaldiagnoses. Paired and unpaired observations werecompared using McNemar’s and Fisher’s exact tests,respectively; the two results were combined usingGoodman’s weighted version of Fisher’s inverse v2

method to obtain a single P-value.4

The slide review showed that there was at least onediagnostic abnormality present in 91 of the casesexamined, with a maximum of five diagnostic catego-ries affecting any one case. At least one diagnosis wasmissed in the original report in 81 of these 91 cases(89%) (Table 1). Underreporting varied markedlyamong diagnostic categories, and several categoriesshowed statistically significant differences in the rela-tive frequency of underreporting. In contrast, misdiag-nosis was uncommon, occurring in only five cases(5%).

The 100 original final reports were completed byseven pathologists. The frequency with which at leastone placental abnormality went unreported variedfrom 85% to 100% of each pathologist’s cases (differ-ence not significant by v2, P = 0.82). There was no

Table 1. Underreporting of placental abnormalities (100cases)

Diagnostic category

Abnormalitypresent* Unreported†

n n (%)

Abnormal weight 40 31 (78)5,6

Abnormal maturation 39 37 (95)2,3,7

Acute chorioamnionitis 38 10 (26)1,2,6,8

Pre- or post-term gestation 37 23 (62)3,5,9

Meconium staining 32 20 (63)4,7

Villous oedema 29 29 (100)1,4,9

Acute or chronic villitis 8 8 (100)8

Chorangiosis 4 3 (75)

Any category 91 81 (89)‡

*Presence of abnormality verified by review.

†Pathological diagnosis absent from original report.

‡At least one diagnosis absent from original report.1–9Similarly numbered rows have a statistically significantdifference in percent of unreported diagnoses; 1,2,3P < 0.001;4,5,6,7P < 0.005; 8P = 0.008; 9P = 0.017.

Correspondence 487


a follicular variant of papillary thyroid carcinoma in struma ovarii. case report with unique...

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