Solid papillary thyroid carcinoma with Hashimoto’s thyroiditis: description of a further case with challenging cytological features

Abstract

Solid papillary thyroid carcinoma (SV-PTC) is a rare variant which is mainly observed in young patients with a history of exposure to ionising radiations. Neoplasms belonging to such category generally carry RET-PTC (REarranged during Transfection- Papillary Thyroid Carcinoma) fusions and seem to have a slightly worse prognosis with respect to classical and follicular variants of papillary thyroid carcinoma (PTC), though consistent prognostic and survival data are scarce. SV-PTC should be differentiated from trabecular-insular poorly differentiated thyroid carcinomas, which occur in a different age group and carry a dismal prognosis. These latter tumours do not show the typical nuclear features of PTC and show tumour necrosis with an high mitotic activity. In this report a further case of SV-PTC is described which was associated to Hashimoto’s thyroiditis, a finding never described in the cytological literature up to now for SV-PTC; this association created further differential diagnostic problems. The neoplasm displayed RET-PTC1 fusion.

Background

Solid variants account for ~3% of all papillary thyroid carcinoma (PTC) cases.¹ These are formed by differentiated thyreocytes which have the nuclear features of classic PTC but generally show minor (<50%) or absent papillary architecture, both in fine-needle aspirates and in tissue samples. Two major case series have been published in the histopathological literature.^{2 3} Four extensive case series of solid papillary thyroid carcinoma (SV-PTC)^4–7 have been published in the cytopathological literature, plus some case reports.^8–11 Several of these cases occur in the paediatric age and may have a history of ionising radiation exposure.^{1–3 11} Epidemiological data are not always coherent: some authors underline a slightly worse prognosis of SV-PTC as compared with classical PTC and its follicular variants.

In this report we describe a further case of SV-PCT carrying a RET-PTC fusion and in which an association with Hashimoto’s thyroiditis was documented cytohistologically and clinically.

Case presentation

A 21-year-old man with chronic thyroiditis presented for an endocrinological check-up. During the clinical interview, he declared to suffer from slight tachycardia and shortness of breath while training in a body-building fitness programme. He displayed diffuse muscular hypertrophy and admitted the chronic assumption of anabolising hormones plus off-label testosterone tablets. An ultrasound examination of the thyroid performed at the time of the initial consultation disclosed an unhomogeneous gland structure, in keeping with chronic thyroiditis. His TSH was 2.6 UI/mL under L-thyroxin therapy. At a difference with an ultrasound examination performed 1 year before, a hypoechogenic solid nodule with innumerable microcalcifications, measuring 15×15 mm, was now found in the apical paraisthmic region of the left lobe (figure 1). An ultrasound-guided fine needle aspiration biopsy (FNAB) was performed on this nodule (three passes with a 25 gauge needle) and several smears were obtained, which were stained with May-Grümwald-Giemsa (MGG) and Papanicolaou (PAP). Needle washings were also performed and kept in CytoLyt solution. A liquid-based cytological preparation was also obtained, which was stained with PAP.

Figure 1.

Transversal ultrasound scan of the thyroid gland showing a hypoechogenic solid nodule with innumerable fine calcifications.

The cytological picture was very cellular. Numerous epithelial cell sheets and clusters could be noticed in a background containing abundant lymphoid cells in various degrees of maturation and mature plasma cells. Both normal Hürthle-type cells and atypical thyreocytes could be seen: these latter also displayed oxyphilic morphology and were present as large syncytial sheets or three-dimensional clusters with ragged borders and architectural disorder, without an evident follicular or papillary aggregation (figure 2). They had irregularly shaped, oval nuclei, larger than those of usual PTC, with marked anysonucleosis, granular chromatin and frequent nuclear grooves or infoldings. Their cytoplasms were granular and cyanophylic on PAP staining (figures 3A and 4). Occasional mitotic figures could be observed. The neoplastic cells showed diffuse immunocytochemical expression of CK 19 (figure 3B). The background also showed numerous dystrophic microcalcifications.

Figure 2.

Fine-needle aspiration biopsy sample. Direct smear showing a sheet of atypical epithelial cells with evident phenomena of anisocytosis and anisonucleosis. The cells show irregular chromatin structure, with folded nuclear membrane and dense, granular bluish cytoplasms. Numerous lymphoid cells can be seen in the background as well as some normal looking thyreocytes, (lower centre) May-Grümwald-Giemsa, ×40, original magnification.

Figure 3.

(A) Fine needle aspiration biopsy sample: liquid-based cytology sample, showing an epithelial cell cluster with ragged borders. The cells show pleomorphic nuclei, with folded nuclear membranes and evident chromocentres, with dense cytoplasms, mostly of polygonal shape. More than occasional lymphoid cells can be seen in the background. Papanicolaou, ×630, original magnification. (B) (inset) immunocytochemical staining, showing diffuse cytoplasmic expression of CK19 by the neoplastic cells (alkaline phospatase, ×630, original magnification).

Figure 4.

Fine needle aspiration biopsy sample. Direct smear showing an irregular 3-D three dimensional cluster of neoplastic cells showing pleomorphic nuclei with irregular chromatin structure, folded nuclei and some intranuclear inclusions (right half of picture). A mitotic figure may be seen in the upper left portion of the picture. Notice the absence of branching phenomena, or of papillary or follicular structures. The cytoplasms are well defined, granular, cyanophylic and tend to the polygonal shape. Papanicolaou, ×630, original magnification.

Investigations

Two MGG-stained smears and the needle washings were sent for molecular pathological examination. Next generation sequencing was performed by using a Ion Ampliseq Colon & Lung Cancer Panel (Life Technology, Ion Torrent PGM). PCR was also performed for RNA study; a RET-PTC1 fusion was found. A diagnosis of positive for malignancy (Tir 5 according to the 2014 modification of the Italian consensus for classification and reporting of thyroid cytology)¹² was formulated. Further comments to the cytological diagnosis indicated the possibility of a non-classical variant of PTC.

Treatment

Total thyroidectomy was performed. One left neck lymph node was also excised. The thyroid weighed 40 g and showed a left apical nodular area of firm consistency, 15 mm in diameter, with a gritting cut surface.

Outcome and follow-up

Histopathological findings

The nodular area of the left lobe showed a neoplastic proliferation of thyreocytes with solid-trabecular and syncytial growth. The solid cell nests were separated by thin fibrocapillary septa and/or by thicker fibrous bands. (figure 5). The neoplasm was immersed in a florid lymphoid proliferation with formation of lymphoid follicles. The neoplastic cells nests were formed by medium sized thyreocytes having the classic nuclear features of PTC and oxyphylic differentiation (figures 6–7).

Figure 5.

Surgical sample. Low-power microscopic magnification, showing a neoplastic cell growth with solid and syncytial pattern. The neoplastic cell solid nests are separated by thin fibrovascular septa. There is no definite papillary or follicular pattern and a lymphoid infiltrate is evident in the background. H&E, ×100, original magnification.

Figure 6.

Surgical sample. Medium-power microscopic magnification, showing a neoplastic growth with trabecular and solid pattern to which a lymphoplasmacellular infiltrate is intimately admixed. Notice the irregularly-cleft nuclei and the granular, eosinophylic cytoplasms of the neoplastic cells. H&E, ×400, original magnification.

Figure 7.

Surgical sample. High-power microscopic magnification, showing the nucleo-cytoplasmic features of the epithelial component. Notice the presence of distinct nuclear atypia, somewhat superior to that of ordinary variants of papillary thyroid carcinoma and the well-defined, granular, eosinophylic cytoplasms. An accompanying lymphoid infiltrate is admixed to the neoplastic cell population. H&E, ×630, original magnification.

Well-formed papillary or follicular structures were almost completely absent (both being <5% of the neoplasm). The neoplastic cells expressed diffusely TTF1, PAX8 (figure 8A,B), CK19, CK7, Galectin3 and HBME1. The Ki67 proliferation rate was 2%. There was no necrosis. A histopathological diagnosis of SV-PTC (pT1a, pN0) was made.

Figure 8.

(A) Surgical sample. Immunohistochemical stain for TTF1 showing diffuse expression by the neoplastic cells. The stain also enhances the solid and alveolar pattern of growth of the neoplasm. Immunoperoxidase, ×200, original magnification. (B) Surgical sample. Immunohistochemical stain, showing expression of PAX8 in most neoplastic nuclei. Immunoperoxidase, ×400, original magnification.

Discussion

SV-PTC is a rare variant of thyroid carcinoma with solid-trabecular or syncytial growth, having the classic nuclear features of PTC but with scant or absent papillary architecture. The extent of the solid growth should be >50% of its total volume.^1–4 SV-PTC should be considered a further variant of PCT, differing from all of the other ones because of its peculiar pattern of growth. Nikiforov et al ³analysed a series of 20 cases of SV-PCT, with a survival rate of 90% after a mean follow-up of 18.7 years, slightly worse than that observed for classic PTC (93,5% with a mean follow-up of 16.6 years). RET/PCT rearrangement was demonstrated in 3/7 SV-PCT (43%), of which two cases were RET/PTC1 and 1 was RET/PTC3.

Numerous SV-PTCs have been reported in the cytopathological literature.4–11 13–16 In FNAB samples, they were found to have syncitial, microfollicular or dyshesive growth in more or less one-third of the cases each.⁵

Despite the numerous reports, it is surprising that the association with Hashimoto’s thyroiditis is only present in an histopathological series examining exclusively paediatric cases from Japan and Ukraine, in which it was respectively demonstrated in 25.9% and 29.4% of tumours with dominant solid-trabecular growth.¹⁷ To our knowledge, the current case seems to be the first one observed in the cytological literature in which this association has been described preoperatively.

We were perplexed by this case because, despite the evident lymphocytic infiltration, which indicated concurrent Hashimoto’s disease, this neoplasms, unlike the so-called ‘Warthin-like’ PTC,^18–25 did not display lymphocytic infiltration of the papillary stalks of the carcinomatous component, as these latter were completely absent. In this aspect, the deep mingling of the lymphoid component with the carcinomatous component was, instead, somewhat more reminiscent of some lymphoepithelial carcinomas of other organs. Moreover, due to the characteristic nuclear features of the neoplasm and to the absence of mitotic figures or necrosis, the possibility of a poorly differentiated thyroid carcinoma had already been excluded. So, the possibility of a solid variant of PTC or that one of a tall cell variant was left open, the latter one due to the oxyphylic appearance of the cytoplasms and the higher than average degree of atypia of the neoplastic cells.15 16 26 27 A final comment to the cytopathological diagnosis was issued, stating that a non-classical variant of PTC could not be excluded.

Based on the criteria exposed in the literature, we believe that the diagnosis of the SV-PTC could be entertained in cases showing solid-trabecular/syncytial pattern of growth, as the one here described. SV-PTC could also be considered in cases with dyshesive pattern, in which the absence of papillary stalks and of ‘branching’ features in the cell clusters could lead to a correct diagnosis. SV-PTC cases with microfollicular pattern may be more difficult to differentiate from the Follicular Variant of Papillary Carcinoma (FVPC), with frequent nuclear overlapping and clear-cut nuclear features of PTC, as opposed to weaker nuclear criteria addressing for FVPC, being the major differential criteria.

Molecular pathology studies of the SV-PTC have found RET/PTC1 or RET/PTC3 rearragements, as the current case, or B-RAF (B-Raf protein) mutations, with at least two novel mutations: 1) the B-RAFVK600-1E¹³ and 2) B-RAFV600 delinsAL.¹⁴

Moreover, 43% of the SV-PCT studied by Prasad et al ²⁸ showed ETV6/NTRK3 fusions (as in secretory breast and salivary gland carcinoma). NTRK fusions in SV-PCT become, in this way, the second most common molecular pathological abnormality in this neoplasm.

Interestingly, in a recent Japanese study,²⁹ the expression of two cancer-stem cell markers: ABCG2 (ATP binding cassette 2) and multidrug resistance associated protein 1 was statistically more frequent in SV-PTC as compared with usual PTC and was significantly associated to adverse clinical outcomes.

We believe that the study of more extensive case series may still add significant prognostic information on this singular subtype of PTC.

Learning points.

• Solid papillary thyroid carcinoma (SV-PTC) is a rare variant of papillary thyroid carcinoma that may raise diagnostic problems on fine needle aspiration biopsy samples if associated to lymphocytic thyroiditis.

• Some SV-PTC may host, besides to RET-PTC fusions, supplementary genetic alterations, like novel or uncommon BRAF mutations and 43% of them also show ETV6-NTRK3 fusions:

• the prognosis of SV-PTC may be slightly worse than classical variant/usual papillary thyroid carcinoma.

• SV-PTC associated to lymphocytic thyroiditis seems to be more frequent in Asian paediatric patients with or without a previous history of radiation to the neck.