Abstract

Hepatocellular carcinoma typically metastasizes within the liver and may involve extrahepatic sites such as the lungs, adrenal glands, and bones at advanced stages. However, hepatocellular carcinoma metastasis to the thyroid is very uncommon and tumor-to-tumor metastasis from a hepatocellular cancer to a thyroid neoplasm is extremely rare. In this report, we present a case of a 70-year-old man with a hepatocellular carcinoma metastasizing to oncocytic thyroid carcinoma, emphasizing the importance of clinical history and of a multidisciplinary approach, as well as the usefulness of site-specific immunohistochemical markers, in diagnosing and managing cases of Rosai’s metastasis, especially when donor and recipient neoplasms share similar histologic features.

Introduction

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and ranks as the fourth leading cause of cancer-related deaths worldwide ¹. It often arises in the context of liver cirrhosis, although cases occurring in non-cirrhotic patients exist, posing challenges for early diagnosis. Risk factors for cirrhosis and subsequent HCC development include infection from hepatotropic viruses, including hepatitis B virus (HBV) and hepatitis C virus, alcohol abuse and alcoholic steatohepatitis, non-alcoholic fatty liver disease and non-alcoholic steatohepatitis, metabolic syndrome, and rarer genetic causes ¹. Dysplastic nodules and dysplastic foci within a cirrhotic background may progress to HCC, which can further metastasize. While HCC frequently exhibits multifocality, either due to multiple HCCs within the same liver or the presence of intrahepatic metastases from the primary tumor, extrahepatic involvement, which negatively impacts prognosis, typically occurs in advanced stages, with the lungs, adrenal glands, and bones being the most commonly involved distant sites. Thyroid metastases from HCC have been rarely reported, and Rosai’s metastases composed of an HCC metastatic to a thyroid neoplasm are extremely uncommon ².

We herein report a case of a Rosai’s metastasis, where the donor tumor was an HCC while the recipient neoplasm was an oncocytic carcinoma of the thyroid, stressing the pivotal role of clinical correlations and the use of an appropriate immunohistochemical panel to reach the correct diagnosis.

Case presentation

A 70-year-old man with a history of chronic HBV hepatitis referred to our center due to the development of Herpes Zoster. In addition to receiving acyclovir treatment, the patient underwent abdominal and neck ultrasounds, which revealed a cirrhotic liver with a 78-mm focal liver lesion and an asymmetric goiter with a 60-mm nodule of uncertain significance in the right thyroid lobe, prompting further characterization with contrast-enhanced computed tomography (CT). The goiter was completely asymptomatic, and, on otorhinolaryngological evaluation, it did not cause functional disorders of swallowing, speech, or laryngeal motility. Total-body CT confirmed both the hypervascular hepatic lesion in S5, with imaging features suggestive of HCC (Fig. 1A) and the thyroid hypervascular nodule with a central avascular core (Fig. 2A). Serum alpha-fetoprotein levels were normal (1.5 UI/ml). Fine-needle biopsy of liver mass confirmed the diagnosis of HCC, while the thyroid fine-needle aspiration proved to be non-diagnostic. The patient underwent wedge resection of liver segments S5-6 and cholecystectomy via a laparotomy approach. The liver specimen showed a solitary grayish 7-cm nodule, which was a moderately differentiated (G2) conventional-type HCC with trabecular-to-solid and pseudo-glandular patterns (Fig. 1B). As microvascular invasion was seen, a pT2 stage was assigned. No satellite nodules or resection margin involvement was identified. Gallbladder and cystic lymph node were free of neoplasia. Features consistent with hepatic cirrhosis were present in the remaining liver. Subsequently, based on the clinico-radiological characteristics of the thyroid nodule, a multidisciplinary team decision to perform a thyroidectomy was made. Grossly, the right thyroid lobe was replaced by a large brownish nodule, which was entirely sampled. Histologic examination featured an encapsulated follicular cell neoplasm almost entirely composed of oncocytic cells, with eosinophilic granular cytoplasm and large nuclei and prominent nucleoli, predominantly arranged in follicular structures, with rare solid areas. Nuclear features of papillary thyroid carcinoma or high-grade features (high mitotic activity or tumor necrosis) were not seen. After complete sampling and histological examination of the main nodule, a microscopic, smaller unencapsulated (“satellite”) nodule outside the capsule of, and close to, the main tumor, with the same cytomorphology observed in the main mass (considered as evidence of capsular invasion) was identified (Fig. 2B), while vascular invasion or extrathyroidal extension were not observed. However, focal sub-centimetric areas, accounting for less than 10% of the entire nodule, composed of more pleomorphic eosinophilic cells with solid and pseudoglandular pattern, were noted (Fig. 3). Given the previous HCC diagnosis, immunohistochemistry for HepPar1, Arginase-1, TTF1, and thyroglobulin was performed. The areas composed of more pleomorphic cells proved to be positive for HepPar1 and Arginase-1 and negative for thyroglobulin and TTF1, whereas the remaining tumor cells showed the opposite immunophenotype (Fig. 4). Therefore, the final diagnosis of minimally invasive oncocytic carcinoma of the thyroid containing an HCC metastasis was made. Two perithyroidal lymph nodes were free of malignant neoplasia (tumour stage: pT3apN0).

The case was discussed multidisciplinary and the proposal of radioactive iodine as adjuvant therapy for the oncocytic carcinoma and/or systemic therapy for HCC was postposed to a post-operative total-body CT scan to guide individualized decision making based on the presence of any measurable or simply evaluable residual disease.

Discussion

Metastases (secondary tumors) to the thyroid are very rare, accounting for 0.36-2.1% of all thyroid malignancies, despite the rich vasculature of the gland ³. The most common primary site is the lung in autopsy series and kidney in surgical specimens ^3-4. A prevalence of primary cancers from the infradiaphragmatic region and of metachronous metastases has been reported ⁵. HCC metastasis to the thyroid seems to be a very rare occurrence, with an incidence rate of 0.8% reported in an autoptic series of HCC patients ^{6, 7}. Tumou-to-tumor metastases with a thyroid neoplasm as the recipient tumour, although very uncommon, have also been reported ³. Nevertheless, tumor-to-tumor metastases where the donor tumour is an HCC and the recipient tumour is a primary thyroid neoplasms are exceptionally rare. While a case of an HCC metastatic to a medullary thyroid carcinoma has been reported ², to the best of our knowledge, this is the first report of an HCC metastatic to an oncocytic thyroid carcinoma.

According to the 2022 WHO classification of Endocrine Tumours, the “oncocytic carcinoma of the thyroid”, formerly known as “Hürthle cell carcinoma”, represents an invasive follicular cell neoplasms composed of at least 75% oncocytic cells characterized by marked accumulation of dysfunctional mitochondria, lacking the nuclear features of papillary thyroid cancer and high-grade features ⁸. Histologically, thyroid metastases from HCC may mimic primary oncocytic thyroid neoplasms, due to their similar cytologic features, including tumor cells with large nuclei, prominent nucleoli, and granular eosinophilic cytoplasm. Additionally, both oncocytic carcinoma of the thyroid and HCC often exhibit a trabecular-to-solid architecture and pseuglandular patterns of HCC may resemble follicular pattern of growth of thyroid carcinomas. The differential diagnosis is even more challenging in the rare event, described here, of a tumor-to-tumor metastasis from HCC colonizing an oncocytic thyroid carcinoma, where HCC foci might mimic the progression to poorly differentiated oncocytic thyroid carcinoma. Therefore, awareness of the patient’s clinical history and, especially in case of a prior or concomitant HCC diagnosis, the usefulness of an appropriate immunohistochemical panel, including hepatocellular (e.g., Hep-Par1 and/or Arginase-1) and thyroid follicular cell (e.g., thyroglobulin and/or TTF1) markers, are imperative to avoid such a diagnostic pitfall and to reach the right diagnosis.

Although fine-needle aspiration cytology has been reported to have high positive and negative predictive values in the setting of metastases to the thyroid ⁴, its intrinsic limitations in diagnosing a tumor-to-tumor metastasis should be acknowledged.

The coexistence of two concurrent neoplasms, along with the tumor-to-tumor metastasis, led to an inaccurate staging of the primary liver tumor in our case. Initially diagnosed as an early-stage HCC suitable to a surgical approach, it was later reclassified as an advanced-stage (stage IV) cancer, likely affecting overall probability of survival ⁹. Although the first choice of treatment for stage IV HCC, in patients with maintained liver function, is systemic therapy, currently there is no evidence supporting the use of systemic therapy after complete resection of a metastasis from HCC. Moreover, it should be highlighted that isolated metastases limited to the thyroid gland have been associated with a more favorable patient outcome compared to multiorgan/widely spread metastatic disease and surgical resection of thyroid metastasis may be of benefit in patients with oligometastastic disease ^3,4. As for the oncocytic thyroid carcinoma, its five-year overall survival has been reported to be 85%, and the presence of distant metastasis at diagnosis is the most important prognostic factor ⁸. Oncocytic thyroid carcinomas are subcategorized as minimally invasive, encapsulated angioinvasive, and widely invasive tumours, and this subclassification has prognostic implications, as clinical recurrence or cancer-related death are very rare event in minimally invasive cancers ^8,10.

Conclusion

This case report stresses the importance of a careful clinico-pathologic correlation and of the crucial role of site-specific immunohistochemical markers to reach the correct diagnosis, especially in the differential of neoplasms with similar histologic features and in oncocytic neoplasms. As thyroid neoplasms seem to be one of the most common “recipient” tumour in case of metastasis of a cancer into another tumour, the possibility of a tumour-to-tumour metastasis presenting as histologically “atypical” areas in an otherwise typical thyroid benign or malignant neoplasm should always be considered, especially in patients with a history of previous cancer. In addition, this report shows that HCC can occasionally manifest atypically, posing challenges for accurate staging and treatment.

CONFLICTS OF INTEREST

Authors declare no potential conflicts of interest.

FUNDING

No funding.

AUTHORS’ CONTRIBUTIONS

Conception: MM and AV. Data Collection: all authors. Figure preparation: AG, AM, AV. Manuscript writing and/or review: all authors.

ETHICAL CONSIDERATION

Written informed consent was obtained from the patient for data publication.

History

Received: September 23, 2023

Accepted: May 25, 2024

Figures and tables

Figure 1.Imaging and histologic features of liver mass. (A) CT scan shows a isodense, hepatic lesion, without calcification, with a pseudo-capsule, hypervascular after the administration of contrast medium with a necrotic central core. (B) Histologically, the surgical specimen showed a moderately differentiated hepatocellular carcinoma, with trabecular and pseudoglandular pattern of growth (hematoxylin and eosin).

Figure 2.Imaging and histologic features of the thyroid nodule. (A) CT scan shows a thyroid hypervascular nodule, without calcification, with sharp margins and a central avascular core. (B) Histologically, a minimally invasive oncocytic carcinoma of the thyroid is seen. Blue sign indicates a smaller, unencapsulated (“satellite”) nodule close to the main tumor with the same cytomorphology observed in the main mass (hematoxylin and eosin).

Figure 3.Tumour-to-tumour metastasis: histologic features. Although hepatocellular carcinoma (in the upper part) and the thyroid neoplasm (in the lower part) show similar cytologic and architectural features (A, haematoxylin and eosin), a higher nuclear pleomorphism and larger nuclei may be observed in the hepatocellular carcinoma (B, haematoxylin and eosin).

Figure 4.Tumor-to-tumor metastasis: immunohistochemical features. The nodular areas of hepatocellular carcinoma within the oncocytic thyroid carcinoma (A, hematoxylin and eosin) are negative for thyroglobulin (B, thyroglobulin immunohistochemistry), whereas they express hepatocellular markers Hep-Par1 (C, Hep-Par1 immunohistochemistry) and Arginase-1 (D, Arginase-1 immunohistochemistry). The primary thyroid cancer shows the opposite immunophenotype.

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