Non-hyalinizing trabecular thyroid adenoma: A novel thyroid tumor with diagnostic pitfalls of hyalinizing trabecular adenoma and medullary thyroid carcinoma

doi:10.21203/rs.3.rs-2481761/v1

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Case Report

Non-hyalinizing trabecular thyroid adenoma: A novel thyroid tumor with diagnostic pitfalls of hyalinizing trabecular adenoma and medullary thyroid carcinoma

https://doi.org/10.21203/rs.3.rs-2481761/v1

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Journal Publication

published 20 Jun, 2023

Read the published version in Diagnostic Pathology →

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Background

Only one thyroid follicular cell-derived tumor with a purely trabecular growth pattern has previously been described. This report aims to describe the histological, immunohistochemical, and molecular findings of our second case, propose a novel thyroid tumor, and discuss its diagnostic pitfalls.

Case presentation

A 68-year-old female presented with an encapsulated thyroid tumor composed of thin and long trabeculae. No papillary, follicular, solid, or insular patterns are observed. The tumor cells were elongated or fusiform and arranged perpendicular to the trabecular axis. No nuclear findings of papillary thyroid carcinoma and increased basement membrane material were found. Immunohistochemically, the tumor cells were positive for paired-box gene 8, thyroid transcription factor-1, and negative for thyroglobulin, calcitonin, and chromogranin A. Inter- and intra-trabecular accumulation of type IV collagen-positive materials was not demonstrated. No PAX8/GLIS1, PAX8/GLIS3, BRAF, HRAS, KRAS, NRAS, TERT, CTNB1, PTEN, or RET were detected.

Conclusions

We report our case as a novel disease entity called non-hyalinizing trabecular thyroid adenoma, which has the diagnostic pitfalls of hyalinizing trabecular tumor and medullary thyroid carcinoma.

Thyroid

hyalinizing trabecular tumor

medullary thyroid carcinoma

PAX8/GLIS3 fusion gene

Among thyroid tumors, follicular and papillary growth patterns are the most frequently observed. A trabecular growth pattern is characteristic of hyalinizing trabecular tumor (HTT) and is also present in papillary thyroid carcinoma (PTC), follicular thyroid adenoma (FTA), follicular thyroid carcinoma (FTC), poorly differentiated thyroid carcinoma (PDTC), and medullary thyroid carcinoma (MTC) [1]. Thyroid tumors with trabecular growth patterns are usually mixed with other growth patterns. Recently, we encountered a case of a thyroid follicular cell-derived tumor that was composed of a purely trabecular growth pattern and histologically required differentiation from HTT or MTC. To the best of our knowledge, only one case with unique histological findings has previously been described as a purely trabecular follicular adenoma of the thyroid [2]. Molecular testing was not performed in this case. This report aims to describe the histological, immunohistochemical, and molecular findings of our second case, propose a novel thyroid tumor, and discuss its diagnostic pitfalls.

A 68-year-old female with a thyroid mass was referred to our hospital. Thyroid function tests, including thyroid-stimulating hormone, free T4, free T3, and thyroglobulin, were within normal limits. Ultrasound examination revealed a well-defined, low-echoic, and oval mass measuring 20 × 17 × 18 mm (Fig. 1). It had a homogeneous echo texture and was not associated with any calcification. No peripheral halo signs were present. Doppler imaging revealed an increase in peritumoral blood flow. No so-called “tumor inferno” was found. No lymph node swelling was observed in the neck. This was interpreted as a follicular tumor.

Ultrasound-guided fine-needle aspiration cytology revealed moderate cellularity, composed of discohesive and naked cells. The nuclei were short-spindled in shape and bland (Fig. 2). The nuclei showed a granular chromatin pattern and small nucleoli. No nuclear features characteristic of PTC, such as intranuclear cytoplasmic inclusions, nuclear grooves, or powdery chromatin, were observed. The cytology report was “malignant; MTC.” However, the serum calcitonin level did not increase and the calcitonin stimulation tests did not respond. No germline RET mutations were detected in this study. To make the diagnosis and treatment, a subsequent right lobectomy was performed.

In general, the mass was found to be encapsulated in a thick capsule. The cut surface was solid, whitish-yellow in color, and was associated with focal fibrosis under the capsule (Fig. 3). Microscopically, the tumor was encapsulated and did not show capsular or vascular invasion (Fig. 4a). It was composed of thin and long trabeculae, and other growth patterns, including papillary, follicular, solid, and insular, were not observed. The trabeculae were straight or wigged (Fig. 4b). No follicular structures, lumina, and colloids were observed. The tumor cells were elongated or fusiform and arranged perpendicular to the axis of the trabeculae (Fig. 4c). The cytoplasm was amphophilic and no yellow bodies were observed. The nuclei were oval or short spindles and did not show the nuclear characteristics of PTC, such as intranuclear cytoplasmic inclusions, irregularly shaped nuclei, ground-glass chromatin, and nuclear grooves. A thin fibrovascular stroma was intercalated between the trabeculae. Focally hyalinized or edematous stroma was observed. Amyloid deposition, necrosis, and mitosis were not observed.

Immunohistochemically, the tumor cells were positive for paired-box gene 8 (PAX8) (EPR13510, Abcam, Cambridge, UK) (Fig. 5a) and thyroid transcription factor-1 (TTF-1) (8G7G3/1, Dako, Carpinteria, CA, USA) (Fig. 5b). Thyroglobulin (polyclonal, Histofine, Tokyo, Japan) (Fig. 5c), calcitonin (polyclonal, Dako, Denmark, Glostrup), chromogranin A (polyclonal, Dako, Carpinteria, CA, USA), and carcinoembryonic antigen (CEA; COL-1, Histofine) were negative. Membranous reactivity of MIB-1 (MIB-1, Dako, Glostrup, Denmark) was not observed. No inter- and intra-trabecular accumulation of type IV collagen-positive materials (polyclonal; Abcam, Cambridge, UK) was observed (Fig. 5d). The Ki-67 labeling index (MIB-1, Dako, Glostrup, Denmark) was less than 1%.

In molecular testing, we analyzed common genetic alterations to FTA, FTC, PTC, PDTC, and MTC [3] using the next-generation sequencing custom targeted panel (Ion Torrent Genexus, Thermo Fisher Sci., MA, USA), including point mutations in BRAF, N/K/H-RAS, RET, TERT promoter, EIF1AX, AKT1, CTNB1, PTEN, etc. We also analyzed the presence of PAX8/GLIS1 and PAX8/GLIS3 fusion genes, which are hallmarks of HTT, using RT-PCR (Nikiforova MN et al., PMID: 30648929). No PAX8/GLIS1, PAX8/GLIS3, BRAF, HRAS, KRAS, NRAS, TERT, CTNB1, PTEN, or RET were detected.

No recurrence or metastasis was observed during the 2-year postoperative follow-up.

Trabecular growth patterns have been observed in various thyroid tumors, including HTT, MTC, FTA, FTC, PTC, PDTC, intrathyroidal parathyroid adenoma/carcinoma, and paraganglioma [1]. The growth pattern is not predominant in most cases and is always associated with other growth patterns. The present case showed a trabecular growth pattern throughout the tumor and was characterized by thin and long trabeculae composed of tumor cells arranged perpendicular to their axes. This arrangement can be observed in MTC and HTT [1, 4–6].

MTC is a C cell-derived malignant tumor that produces calcitonin. Several histological variants and growth patterns of MTC have been described, with trabecular growth patterns being common [6]. Most MTCs are nonencapsulated but can be completely encapsulated as FTA [6]. In the present case, cytological findings were suggestive of MTC due to discohesiveness, naked cells, short-spindle nuclei, and granular chromatin pattern. However, calcitonin production was not detected in biochemical or immunohistochemical studies. On such occasions, calcitonin-negative neuroendocrine tumors, which are extremely rare, should be considered [7], but this possibility was denied due to the negativity of chromogranin A and synaptophysin. Furthermore, positivity for both TTF-1 and PAX8 in the present case confirmed that it was not a C-cell-derived tumor but a follicular cell origin [8, 9].

HTT is a non-invasive follicular cell-derived neoplasm characterized by a trabecular growth pattern composed of cells arranged perpendicular to the axis of the trabeculae and inter- and intra-trabecular hyalinization [4]. The growth pattern in the present case was similar to that in HTT. However, another diagnostic criterion for HTT, inter- and intra-hyalinization, was not demonstrated by immunohistochemistry using antibodies against type IV collagen [10]. In addition, other diagnostic features of HTT, such as intranuclear cytoplasmic inclusions [4], yellow bodies [11], cell membranous positivity for MIB-1 [5, 12], and tumor inferno on ultrasound examination [13], were not observed. The presence of a thick capsule is different from that of HTT, which is usually nonencapsulated [3]. Recently, Marchiò et al. described that the presence of the PAX8–GLIS3 fusion in thyroid neoplasms may be used as an ancillary marker for the diagnosis of HTT [14]. This fusion gene was not detected in this case. Based on the above findings, it is clear that the present case did not involve HTT.

In 2015, Ohtsuki et al. reported a case of purely trabecular follicular adenoma with extraordinarily long trabeculae [2]. According to the description, the tumor was encapsulated, had edematous portions, and was composed of long curved or folded trabeculae and did not reveal follicular structures or colloids. Tumor cells were arranged perpendicular to the axis of the trabeculae. Immunohistochemically, the tumor cells were positive for cytokeratin CAM5.2 and thyroglobulin and negative for calcitonin, CEA, and amyloid A. A partial linear pattern was observed for type IV collagen expression. The findings were identical to those of our case except for thyroglobulin immunoreactivity. In the present case, tumor cells were negative for thyroglobulin. Regardless of the reactivity to thyroglobulin, we would consider their case and ours to be the same type of tumor derived from thyroid follicular cells.

According to the 2022 World Health Organization Classification of thyroid neoplasm [15], encapsulated follicular cell-derived tumors without malignant features, such as nuclear findings of PTC, capsular invasion, vascular invasion, necrosis, and mitosis, were diagnosed as FTA and categorized as benign lesions. However, the histological findings were unique and differed considerably from those of FTA. We believe it is difficult to diagnose the present case without follicular growth pattern, colloid, reactivity to thyroglobulin, or RAS mutation as FTA. We would like to report our case as a novel disease entity called non-hyalinizing trabecular thyroid adenoma, which has the diagnostic pitfalls of HTT and MTC.

FTA follicular thyroid adenoma

FTC follicular thyroid carcinoma

HTT hyalinizing trabecular tumor

MTC medullary thyroid carcinoma

PAX8 paired-box gene 8

PDTC poorly differentiated thyroid carcinoma

PTC papillary thyroid carcinoma

TTF-1 Thyroid transcription factor-1

Ethics approval and consent to participate

This case study was approved by the Institutional Review Board of Kuma Hospital (Hyogo, Japan; Kuma Hospital Ethics Committee Approval No. 20200709-1).

Consent for publication

All authors consent to the publication of the manuscript in Diagnostic Pathology.

Availability of data and materials

Data supporting the findings of this study are available from the corresponding author on request.

Competing interests

The authors declare that they have no competing interests.

Funding

The authors received no specific funding for this work.

Authors' contributions

Mitsuyoshi Hirokawa: conceptualization, writing–original draft, and writing–review and editing. Michiko Matsuse, Norisato Mitsutake, Ayana Suzuki, Miyoko Higuchi, Toshitetsu Hayashi, and Hiroshi Kamma: immunohistochemical staining, molecular testing, and writing–review and editing. Akira Miyauchi and Takashi Akamizu: writing, review, and editing. All authors approved the final version of the manuscript.

Acknowledgements

We would like to thank Editage (www.editage.com) for the English language editing.

Volante M, Papotti M. A practical diagnostic approach to solid/trabecular nodules in the thyroid. Endocr Pathol. 2008;19:75–81. https://doi.org/10.1007/s12022-008-9023-5
Ohtsuki Y, Kimura M, Lee GH, Furihata M, Hirokawa M. A purely trabecular follicular adenoma of the thyroid gland, harboring extraordinarily long trabeculae. Biomed Res. 2015;26:380–3
Baloch ZW, Asa SL, Barletta JA, Ghossein RA, Juhlin CC, Jung CK, et al. Overview of the 2022 WHO classification of thyroid neoplasms. Endocr Pathol. 2022;33:27–63. https://doi.org/10.1007/s12022-022-09707-3
Carney JA, Hirokawa M, Lloyd RV, Papotti M, Sebo TJ. Hyalinizing trabecular tumors of the thyroid gland are almost all benign. Am J Surg Pathol. 2008;32:1877–89. https://doi.org/10.1097/PAS.0b013e31817a8f1b
Hirokawa M, Carney JA. Cell membrane and cytoplasmic staining for MIB-1 in hyalinizing trabecular adenoma of the thyroid gland. Am J Surg Pathol. 2000;24:575–8. https://doi.org/10.1097/00000478-200004000-00013
Papotti M, Sambataro D, Pecchioni C, Bussolati G. The pathology of medullary carcinoma of the thyroid: review of the literature and personal experience on 62 cases. Endocr Pathol. 1996;7:1–20. https://doi.org/10.1007/BF02739911
Fernández-Ferreira R, De la Peña-López IR, Zamudio-Coronado KW, Delgado-Soler LA, Torres-Pérez ME, Bourlón-de Los Ríos C, et al. Calcitonin-negative neuroendocrine carcinoma of the thyroid gland: case report and literature review. Case Rep Oncol. 2021;14:112–22. https://doi.org/10.1159/000510807
Gucer H, Caliskan S, Kefeli M, Mete O. Do you know the details of your PAX8 antibody? monoclonal PAX8 (MRQ-50) is not expressed in a series of 45 medullary thyroid carcinomas. Endocr Pathol. 2020;31:33–8. https://doi.org/10.1007/s12022-019-09603-3
Suzuki A, Hirokawa M, Takada N, Higuchi M, Tanaka A, Hayashi T, et al. Utility of monoclonal PAX8 antibody for distinguishing intrathyroid thymic carcinoma from follicular cell-derived thyroid carcinoma. Endocr J. 2018;65:1171–5. https://doi.org/10.1507/endocrj.EJ18-0282
Katoh R, Kakudo K, Kawaoi A. Accumulated basement membrane material in hyalinizing trabecular tumors of the thyroid. Mod Pathol. 1999;12:1057–61
Rothenberg HJ, Goellner JR, Carney JA. Hyalinizing trabecular adenoma of the thyroid gland: recognition and characterization of its cytoplasmic yellow body. Am J Surg Pathol. 1999;23:118–25. https://doi.org/10.1097/00000478-199901000-00014
Takada N, Hirokawa M, Ohbayashi C, Nishikawa T, Itoh T, Imagawa N, et al. Re-evaluation of MIB-1 immunostaining for diagnosing hyalinizing trabecular tumour of the thyroid: semi-automated techniques with manual antigen retrieval are more accurate than fully automated techniques. Endocr J. 2018;65:239–44. https://doi.org/10.1507/endocrj.EJ17-0413
Kobayashi K, Hirokawa M, Jikuzono T, Fukata S, Amino N, Miyauchi A, et al. Hyalinizing trabecular tumor of the thyroid gland: characteristic features on ultrasonography. J Med Ultrason (2001). 2007;34:43–7. https://doi.org/10.1007/s10396-006-0119-6
Marchiò C, Da Cruz Paula A, Gularte-Merida R, Basili T, Brandes A, da Silva EM, et al. PAX8-GLIS3 gene fusion is a pathognomonic genetic alteration of hyalinizing trabecular tumors of the thyroid. Mod Pathol. 2019;32:1734–43. https://doi.org/10.1038/s41379-019-0313-x
Christofer Juhlin C, Mete O, Baloch ZW. The 2022 WHO classification of thyroid tumors: novel concepts in nomenclature and grading. Endocr Relat Cancer. 2022 Dec 22. 2023;30:e220293. https://doi.org/10.1530/ERC-22-0293. Print

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Journal Publication

published 20 Jun, 2023

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Editorial decision: Major revision
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Reviews received at journal
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Reviewers agreed at journal
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Submission checks completed at journal
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You are reading this latest preprint version

Non-hyalinizing trabecular thyroid adenoma: A novel thyroid tumor with diagnostic pitfalls of hyalinizing trabecular adenoma and medullary thyroid carcinoma

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Case presentation

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Background

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