Metastatic papillary thyroid carcinoma in the soft tissue of the breast in a male patient: A case report

Introduction

Thyroid cancer is the most common carcinoma of the endocrine glands and accounts for ~1% of all malignancies (1). Papillary thyroid carcinoma (PTC) represents the most frequently identified histological type (80%) (1,2). Due to the improvement of modern imaging methods, the incidence of PTC has increased in the past 15–20 years (predominantly in women). Risk factors for the development of PTC include ionising radiation, Hashimoto's thyroiditis or familial adenomatous polyposis. Familial occurrence is reported to be 4.5%, with a prognosis that is similar to that of sporadic cases. The tumour may also arise around the thyroglossal duct or in the ectopic tissue of the thyroid gland. The first clinical manifestation of PTC is usually a palpable mass in the thyroid area or cervical lymphadenopathy in cases of metastatic disease (3). Histopathological diagnosis is based on the assessment of tumour morphology, nuclear features of tumour cells (nuclear enlargement and overlapping, chromatin characteristics, nuclear groove and pseudoinclusion), and an appropriate immunohistochemical profile, including the markers of thyroid follicular cells [e.g. thyroid transcription factor 1 (TTF1), paired box gene 8 (PAX-8) and thyroglobulin]. Morphologically, up to 15 variants of PTC (classic, follicular, cribriform morular, oncocytic, clear cell, spindle cell, tall cell variants, diffuse sclerosing, columnar, Warthin-like, solid, hobnail, encapsulated, infiltrative or microinvasive variant) have been described, with specific prognostic and predictive markers. The most common histological types include classic PTC, microcarcinoma and follicular variants of PTC. Mutations of the BRAFV600E gene are most often detected by molecular testing (4). The early stage of the tumour is associated with a favourable prognosis, with a >90% 5-year survival rate. Metastases to the cervical lymph nodes do not affect prognosis. Local recurrence is reported in 5–20% of cases. The intermediate risk includes the following histological findings: Tall cell/hobnail/columnar cell variants, vascular invasion, pN1 with more than five positive lymph nodes and microscopic extrathyroidal extension to adipose connective tissue. High-risk cases present with significant extrathyroidal extension (to muscle), incomplete tumour resection or distant metastasis (5). Advanced age (≥55 years) at the time of diagnosis is also a poor prognostic factor. Distant metastasis (to the lungs, bones and central nervous system) develops in 10–15% of cases. Breast metastasis of PTC is extremely rare, particularly in men. To date, to the best of our knowledge, there have been just two male cases reported worldwide (2,6).

The diagnostic process of thyroid gland cancer relies on the clinical findings (palpable mass in the thyroid area or cervical lymphadenopathy in cases of metastatic disease), ultrasound imaging (a lesion with irregular margins, which is higher than wider, the presence of microcalcifications and increased vascularisation), fine-needle aspiration biopsy (FNAB), and subsequent cytological analysis according to The Bethesda System for Reporting Thyroid Cytopathology (7).

The treatment of differentiated carcinomas is surgical, consisting of a total thyroidectomy with subsequent radioiodine therapy, which serves to eliminate any possible residual tumour or distant metastasis. At University Hospital Olomouc (Olomouc, Czech Republic), Olomouc ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up of thyroid cancer are recommended (8).

Case report

In August 2022, a 63-year-old man was referred to the Department of Radiology, University Hospital Olomouc from an external healthcare facility (Hranice, Czech Republic) for a computed tomography (CT) scan of a mediastinal mass described in a previous chest X-ray (Fig. 1). The patient's symptoms included dysphonia and intermittent dysphagia. According to the medical history, the patient was also treated for chronic hypothyroidism and atrial fibrillation that had been complicated by an embolic stroke in the past. No more clinical data was available at the time of the CT examination. Laboratory findings revealed high levels of serum thyroglobulin at 3,847.00 µg/l (normal laboratory reference value, 3.5–77 µg/l), and an elevation of cancer antigen 15-3 at 78.7 kU/l (normal laboratory reference value, 0–25 kU/l), with a normal neuron-specific enolase level of 16.44 µg/l (normal laboratory reference value, 0–30 µg/l). The level of thyroid-stimulating hormone (TSH) was 0.915 mIU/l (normal laboratory reference value, 0.55–4.78 mIU/l) and the antithyroid peroxidase antibody level was 35.6 kU/l (normal laboratory reference value, 0–60 kU/l).

Figure 1. Chest X-ray demonstrating a large mass in the upper mediastinum (solid line arrow). The mass has compressed and dislocated the trachea to the left. The biggest lung parenchyma nodulations are observed bilaterally in the lower lungs zones (dashed line arrow).

Based on the indication of the previous chest X-ray for further evaluation of the mediastinal mass, unenhanced- and parenchymatous-phase chest CT was performed following the intravenous administration of an iodine contrast agent (Ultravist 370; Bayer AG). A large hypodense spherical formation was observed in the upper mediastinum, which was continuous with the right lobe of the thyroid gland and showed peripheral nodular enhancement following the administration of the iodine contrast agent. The mass had compressed and dislocated the trachea to the left (Fig. 2A). Furthermore, the lung parenchyma contained small non-specific nodulations bilaterally, and a follow-up examination in 3–6 months was therefore recommended according to the Fleischner Society if the patient was not already under follow-up elsewhere (9). The samples of the suspicious mediastinal mass subsequently obtained by FNAB were not considered representative for the purposes of histological examination due to the extended necrosis of the tumour, therefore cytology images were not obtained.

Figure 2. CT results. (A) Coronal plane of enhanced CT scan demonstrating a large hypodense mass with peripheral nodular enhancement on the right side of the upper mediastinum (solid line arrow). The mass is continuous with the right lobe of the thyroid gland, and compresses and causes the trachea to deviate to the left. (B) Axial CT scan demonstrating an irregular lobulated formation in the soft tissue of the left breast with homogenous enhancement following the administration of a contrast medium. The lesion is not in a typical male breast cancer localisation (retroareolar/periareolar) and has smooth margins with fat stranding in the surrounding adipose tissue (dashed line arrow). The large mass on the right side of the upper mediastinum is also highlighted (solid line arrow). CT, computed tomography.

In the patient's left breast, an irregular lobulated subcutaneous formation measuring 40×30×50 mm was observed. The breast lesion was homogenously enhanced after the administration of the contrast medium, presenting with smooth margins and fat stranding in the surrounding adipose tissue, without axillary lymphadenopathy at the time of examination. The lesion was relatively distant from the breast gland, it did not exhibit typical male breast cancer (MBC) localisation (retroareolar/periareolar location) and it did not contain spicula; therefore, on the basis of the imaging methods, the lesion was not considered to have originated in the breast (Fig. 2B).

Following the release of the CT findings, the referring physician communicated with the radiologist regarding information provided by the external healthcare facility in Hranice, Czech Republic, where an initial biopsy had been performed on the patient in June 2022. The histopathological analysis from that biopsy confirmed a diagnosis of invasive breast cancer, specifically identified as no special type (NST), which also exhibited focal papillary features (Fig. 3). Immunohistochemically, the cancer cells lacked the expression of oestrogen receptor (ER; 0%) and GATA binding protein 3 (GATA3) (Fig. 4). The index of proliferated Ki-67, a nuclear marker indicating tumour cell proliferation, was 8%.

Figure 3. Histological findings of the metastasis of papillary thyroid carcinoma, with typical nuclear features and post-haemorrhagic changes in the stroma. Magnification (A) ×20, (B) ×40, (C) ×100 and (D) ×200. All images were captured from the same section of the tissue, which was stained with hematoxylin and eosin.

Figure 4. Immunohistochemical markers. Immunohistochemistry results showing absence of (A) gross cystic disease fluid protein 15 (magnification, ×100), (B) GATA binding protein 3 and (C) oestrogen receptor expression in the tumour cells, but positive expression for (D) paired box gene 8, (E) thyroid transcription factor 1 and (F) thyroglobulin (magnification ×100).

However, the findings of a potential thyroid gland tumour, significantly elevated serum thyroglobulin levels (3,847.00 µg/l) and atypical imaging attributes of the mammary lesion were challenging for the multi-specialty board. Given the increasing doubts about the tumour's mammary origin, a second histopathological reading of the breast lesion was requested. The Department of Clinical and Molecular Pathology, University Hospital Olomouc, performed the second histopathological reading. Tissue samples 4-mm thick were fixed in 10% neutral buffered formalin for 24 h at room temperature, before being embedded in paraffin within 24 h. The formalin-fixed and paraffin embedded tissue slides were with an automated stainer using hematoxylin solution and counterstained with eosin Y solution at 65°C for 10 min. Slides were assessed under an Olympus BX46 light microscope (Olympus Corporation) with magnification ×100-400. The tissue blocks were stored at room temperature before immunohistochemical examination. The standardised protocol for immunohistochemistry, including the incubation of sections with primary and secondary antibodies for automated use (Ventana BenchMark ULTRA; Roche Diagnostics), was performed on 4-µm thick formalin-fixed paraffin-embedded tissue samples. An Olympus BX46 light microscope (Olympus Corporation) was used for their analysis.

The results received from the Department of Clinical and Molecular Pathology, University Hospital Olomouc, revealed positive expression of TTF1, PAX-8 and thyroglobulin, and the absence of gross cystic disease fluid protein 15 expression in the tumour cells (Fig. 4). The levels of TSH, anti-thyroid peroxidase antibodies and thyroglobulin antibodies were not elevated in the tissue sample.

Based on the aforementioned findings, the lesion in the left breast was reassessed as a metastasis of a PTC. In November 2022, the patient underwent a total thyroidectomy using the cervical approach, a partial sternotomy and a left-sided breast metastasectomy, with a good postoperative clinical course.

The surgically resected specimen of the left breast measured 90×90×50 mm and contained a lesion measuring 40×35×58 mm. The lesion was characterised by distinct margins, a reddish-pink colour and a soft consistency, with the presence of a focal haemorrhage, and was completely removed. Histologically, the findings were consistent with the core cut biopsy, showing metastasis of a focally necrotising PTC. The tumour cells did not reach the resection margins of the breast tissue.

Postoperative examination of the thyroid gland revealed that the left lobe measured 53×28×25 mm. The resection slices showed a homogenous brown appearance of the thyroid tissue, histologically consistent with normal thyroid gland tissue without a tumour. The right lobe of the thyroid gland measured 105×70×70 mm. The lobe was almost entirely infiltrated by a tumour of a beige-pink colour, with fairly distinct margins and measuring 68×65×85 mm. The tumour was extensively necrotic, with a centrally degraded cavity consisting of soft, brownish necrotic masses. In certain areas, the tumour nearly reached the thyroid gland capsule, but it did not infiltrate it macroscopically. Microscopically, the tumour was described as being composed of thyroid gland tissue, with structures of necrotising papillary carcinoma, with a focal (up to 20%) solid type of growth. Structures of an anaplastic thyroid carcinoma were not found. Blood vessel invasion and extracapsular invasion to the surrounding thyroid tissue were detected, while invasion beyond the thyroid gland was not.

Following surgical treatment, radioiodine therapy was initiated to eliminate possible tumour residues or metastases, and the patient received a single dose of 8.6 GBq radioiodine-131 via oral administration. In January 2023, whole-body scintigraphy with radioiodine-131 was subsequently performed, with findings of bilateral paratracheal tumour residues (Fig. 5). In addition, the CT scan revealed an increase in the quantity and diameter of lung parenchyma nodulations (Fig. 6). Therefore, the lung parenchyma lesions were considered to be metastases. In May 2023, oral lenvatinib (protein kinase inhibitor) therapy was initiated at a dose of 24 mg/day. After 7 days, lenvatinib therapy was discontinued due to deterioration in the patient's health and the patient was admitted to an external healthcare facility. Since August 2023, no new information about the patient's condition had been received, and the patient died during the hospitalisation. Follow-up tools vary according to the histological type, initial treatment, initial risk of persistent/recurrent disease and response to treatment (8). In the present study, physical examination, laboratory examination (serum level of TSH, thyroglobulin and thyroglobulin antibody) and ultrasound examination of the neck every 6–12 months would have been recommended according to the ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up of thyroid cancer (8).

Figure 5. Whole-body scintigraphy with radioiodine-131 revealing paratracheal tumour residuum (solid line arrow).

Figure 6. Unenhanced computed tomography scan in the (A and B) axial planes at different levels demonstrating the increase in the amount and diameter of lung parenchyma nodules bilaterally (solid line arrows). A small amount of pleural effusion is present in the left pleural cavity (dash line arrow).

Discussion

To the best of our knowledge, only two reported cases of metastatic PTC of the male breast are reported in the literature (2,6). In both males, the solitary lesions had presented as a primary manifestation of PTC located in the left breast, as was the case in the present study. An initial pathological misdiagnosis of MBC was also present in both referenced cases.

The incidence of metastasis from differentiated thyroid cancer to the breast is 1–2%. In the case of women generally, the metastasis is typically located in the upper outer quadrant (2). In the present case, the mass was distributed in the upper inner quadrant, fairly distant from the nipple, which is not typical for a primary malignancy arising from the breast in the male population.

MBC accounts for <1% of all breast cancer cases. The risk of developing cancer increases with age; men are often diagnosed later than women, which leads to a worse prognosis as a result of the more advanced disease stage and comorbidities (10,11). The most common type of MBC is invasive carcinoma of NST, and when compared with breast cancer in women, a lobular type of cancer is very rare in men (12). Clinical presentation typically includes a painless, periareolar, eccentric mass (12,13), although bloody discharge from the nipple may be present (13). Mammography images of MBC show a very dense lobulated mass, often with spicules, skin thickening or nipple retraction, and microcalcifications are seen sporadically. Ultrasound examination evaluates tumour size, skin invasion or infiltration to the muscles of the chest wall and regional lymph node involvement. The MBC itself presents as a significantly hypoechoic lesion, often lobulated, with or without acoustic shadowing and visible vascularisation on sonography (14). The positive expression of ER, progesterone receptor and B-cell lymphoma 2 (an apoptosis suppressor gene) (15), and the lack of expression of human epidermal growth factor receptor 2 (16), are often observed in MBC.

The location of the breast lesion in the male patient of the present study was not typical for MBC (peri/retroareolar location). The mass had smooth margins without signs of invasive extension to the surrounding structures of the chest wall, which is not characteristic for MBC; therefore, on the basis of the imaging methods, the lesion was suspected of originating in a location other than the mammary gland.

During histopathological examination, especially when dealing with core-cut biopsy samples, the differential diagnosis can pose certain challenges. Despite the well-defined histological pattern of thyroid cancer in a surgical specimen, the examination of a core-cut biopsy can be limited, so that not all the specific morphological features are identified on a small tumour area. The presence of a solid growth pattern without typical nuclear features can be misleading, so focused immunohistochemical analysis is necessary. The standardized protocol for immunohistochemistry in the present study, including the incubation of sections with primary and secondary antibodies, is provided in Table I. Nuclear positivity of GATA3 expression indicated the mammary origin of the tumour in this case. The lack of ER expression could be explained by the alteration of gene regulation. However, increased GATA3 and PAX-8 expression was also observed in the thyroid cancer. The subsequent immunohistochemical determination of positive expression of TTF1 and thyroglobulin, the specific markers of thyroid differentiation, confirmed the considered diagnosis of metastatic thyroid cancer.

Table I. Immunohistochemistry antibodies.

Table I.

Immunohistochemistry antibodies.

Primary antibody	Supplier	Clone	Catalogue number	Dilution	Incubation temperature, °C	Incubation time, min	Secondary antibody	Supplier	Catalogue number	Dilution	Incubation temperature, °C	Incubation time, min
GATA3	Cell	L50-823	390M-14	1:200	36	32	OptiView	Ventana/	760-700	RTU	36	8+8
	Marque;						DAB	Roche
	Millipor						detection
	Sigma						kit
ER	Ventana;	SP1	790-4325	RTU	36	16	UltraView	Ventana/	760-500	RTU	36	8
	Roche						Universal	Roche
	Diagnostics						DAB
							detection
							kit
TTF1	Biocare	SPT 24	ACR3126C	1:100	36	32	UltraView	Ventana/	760-500	RTU	36	8
	Medical						Universal	Roche
	LLC						DAB
							detection
							kit
Thyroglobulin	Dako; Agilent	DAK-Tg6	M0781	1:200	36	32	UltraView Universal	Ventana/Roche	760-500	RTU	36	8
	Technologies, Inc.						DAB detection
							kit
PAX-8	Abcam	SP348	ab227707	1:100	36	32	UltraView	Ventana/	760-500	RTU	36	8
							Universal	Roche
							DAB
							detection
							kit

[i] RTU, ready-to-use; ER, oestrogen receptor; GATA3, GATA binding protein 3; TTF1, thyroid transcription factor 1; PAX-8, paired box 8.

In terms of differential diagnosis, it is necessary to consider the tall cell variant of papillary breast carcinoma, previously termed breast tumour resembling the tall cell variant of PTC, which has been frequently described in the literature (17–20). The possibility of a second primary tumour must also be considered within the differential diagnosis (21,22), as well as tumour-to-tumour metastasis (23,24), although this is rare.

In conclusion, PTC metastasis to the male breast tissue is extremely rare worldwide, and it may cause diagnostic doubts or incorrect diagnosis followed by an unsuitable medical therapeutic approach. In instances where imaging methods reveal a soft-tissue lesion within the male breast that fails to meet the established criteria for typical MBC manifestations, it is imperative to conduct further assessment and rule out alternative neoplastic origins. Multi-specialty collaboration considering the results of imaging methods, laboratory findings, the biopsy method applied and histopathological analysis involving an appropriate panel of the immunohistochemical profile is pivotal to establishing the definitive and correct diagnosis.

Acknowledgements

Not applicable.

Funding

This study was supported by the Internal Grant of the Palacky University (grant no. IGA_LF_2024_022), the Ministry of Health of the Czech Republic-Conceptual Development of Research Organization (grant no. FNOl, 00098892), and the Ministry of Education, Youth and Sports of the Czech Republic - Conceptual Development of Research Organization (grant no. UPOL, 61989592).

Availability of data and materials

The data generated in the present study are included in the figures and table of this article.

Authors' contribution

VM and LV conceived and designed the study. VM, LV, EM analysed and confirmed the imaging method examination results. DS and MU analysed and confirmed the pathological data. KV provided the surgical aspect to the study. KV, MU and EM revised the manuscript before submission.

Ethics approval and consent to participate

The patient provided written informed consent for the examination, including consent to use documentation anonymously for scientific and statistical purposes.

Patient consent for publication

The patient provided written informed consent for the publication of this case report.

Competing interests

The authors declare that they have no competing interests.

Glossary

Abbreviations

Abbreviations:

References