A rare highly aggressive tumour: lymphoepithelioma-like thymic carcinoma

Abstract

Lymphoepithelioma-likethymic carcinoma is a rare neoplasm that presents with compressive symptoms or as an incidental radiological finding of an anterior mediastinal mass. It is an aggressive carcinoma with a high rate of invasion, metastasis and recurrence. Its diagnosis usually carries a poor prognosis largely due to propensity for late diagnosis. To date, guidance for treatment remains limited. This is a case of lymphoepithelioma-like thymic carcinoma in a young male adult who presented initially with back pain. Despite prompt initiation of chemotherapy with cisplatin, doxorubicin and cyclophosphamide, he had a complicated hospital course leading to demise within 2 months of diagnosis.

Background

Thymic carcinoma is a rare but important cause of anterior mediastinal masses and accounts for 15%-20% of all thymic neoplasms. It is found more commonly in Asia and fewer than 500 cases are diagnosed in the USA per year.¹ Thymic carcinomas typically present with compressive mass symptoms and occasionally are diagnosed incidentally through radiography. Clinical presentation can be similar to other causes of anterior mediastinal mass, such as lymphoma, making diagnosis challenging. Because tumour growth in the mediastinum can be asymptomatic, thymic carcinomas often are diagnosed in advanced or metastatic stages, conferring a poor prognosis. Moreover, certain subtypes, such as the lymphoepithelioma-like subtype, are particularly aggressive, highlighting the importance of increased clinical suspicion, prompt diagnosis and initiation of chemotherapy. We present a rare case of lymphoepithelioma-like thymic carcinoma in a previously healthy young man who presented with seemingly benign back pain.

Case presentation

A previously healthy African-American male aged 26 years presented to our hospital 1 month after developing low back pain, which later spread to his neck and chest. This was associated with low-grade fevers, chills, night sweats, malaise, unintentional 18-lb weight loss and appearance of multiple firm and non-tender masses on the right side of his neck. Past medical history was unremarkable. He used alcohol and marijuana daily and carries a two pack-year smoking history. Family history was significant for his mother having non-Hodgkin’s lymphoma at age 59.

Two days prior to admission, he developed vomiting and diarrhoea, prompting his presentation to an outside hospital. There, he was found to have an anterior mediastinal mass on chest X-ray and CT. He was transferred to our institution for further management.

On presentation, the patient’s vital signs were normal. His neck exam demonstrated significant cervical and supraclavicular lymphadenopathy. He also had tenderness to palpation of both flanks, the lower lumbar spine and the right iliac spine. Rest of examination was unremarkable.

Investigations

Routine laboratory exams were notable for hypercalcaemia 14.5 mg/dL and an elevated lactate dehydrogenase (LDH) 1847 U/L. Alpha-fetoprotein (AFP) and B-human chorionic gonadotropin (β-hCG) were normal. A CT scan with intravenous contrast revealed an anterior mediastinal mass in addition to right hilar and subcarinal lymphadenopathy (figure 1).

Figure 1.

Axial section from a contrast-enhanced CT showing an anterior mediastinal mass (block arrow) with right hilar and subcarinal lymphadenopathy (arrows).

These findings raised concern for lymphoma and MRI of the cervical and thoracic spine revealed metastatic disease involving the cervical, cardiophrenic and perihepatic lymph nodes, as well as the cervical and thoracic vertebrae (figure 2).

Figure 2.

Sagittal short tau inversion recovery (STIR) images of the cervical and thoracic spine showing metastatic lesions.

Flexible bronchoscopy was attempted to obtain a tissue diagnosis. However, no endobronchial lesion was found. Subsequently, right supraclavicular lymph node biopsy was performed. Biopsy findings (figure 3) showed nests and sheets of undifferentiated tumour cells with large vesicular nuclei, prominent nucleoli and scant-to-moderate amounts of amphophilic cytoplasm. The cells demonstrated brisk mitotic activity and small foci of necrosis (figure 3). Immunohistochemistry showed tumour cells that were positive for cytokeratin 8/18, cytokeratin AE1/AE3, EBER (an Epstein-Barr virus (EBV)-encoded RNA) and CD5, suggesting thymic cell origin. The cells were negative for c-kit (CD117) expression.

Figure 3.

Sections from supraclavicular lymph node biopsy; upper left (H&E stain), upper right (cytokeratin 8/18), lower left (CD5), lower right (Epstein-Barr virus-encoded RNA).

Bone marrow biopsy (figure 4) revealed marrow infiltrated by nests of highly pleomorphic neoplastic cells with similar immunoprofile to the lymph node biopsy cells. The morphological and immunophenotypical findings were consistent with EBV-positive, undifferentiated, non-keratinising lymphoepithelioma-like carcinoma, possibly nasopharyngeal or thymic in origin. Nasal endoscopy with adenoid biopsy was negative for a neoplastic process. He was thus diagnosed with EBV-associated lymphoepithelioma-like thymic carcinoma.

Figure 4.

Bone marrow biopsy showing a diffuse infiltrate of large pleomorphic neoplastic cells with positive Epstein-Barr virus-encoded RNA immunostain.

Differential diagnosis

The differential diagnosis of anterior mediastinal mass consists of thymic mass, including thymomas, thymic carcinomas, carcinoids and thymolipomas; lymphoma; germ cell tumour; metastases from a primary lung cancer; non-neoplasms such as intrathoracic thyroid and thymic cysts and lymphangioma. Any of these can manifest with compressive symptoms such as chest pain, shortness of breath, dysphagia, cough, phrenic nerve palsy and superior vena cava syndrome.²

The patient’s rapid progression of systemic symptoms, including fevers, weight loss and night sweats, neck lymphadenopathy and family history of non-Hodgkin’s lymphoma put lymphoma high on the differential. Malignant germ cell tumour and thymic carcinoma were also in high suspicion given the constellation of symptoms. In contrast, thymomas present indolently and do not usually metastasize hematogenously or lymphatically as in this patient, so thymoma was low on the differential. Thymic carcinoids are associated with multiple endocrine neoplasia type 1,² which was not seen in this patient, so this also was lower on our differential.

Differentiating between lymphoma, germ cell tumour and thymic carcinoma ultimately requires core biopsy for flow cytometry. Prior to this step, however, AFP, LDH and β-hCG levels can be used to help distinguish between potential causes of germ cell tumours if germ cell tumour is on the differential. Benign germ cell tumours, or teratomas, typically have normal AFP levels. Among malignant germ cell tumours, seminomas typically have a normal AFP and occasionally an elevation of β-hCG, while the majority of non-seminomatous germ cell tumours demonstrate elevated AFP or elevated β-hCG.³ Our patient had a normal AFP and β-hCG level, making non-seminomatous germ cell tumour unlikely, although not ruling out seminomatous germ cell tumour. Teratoma was considered but ruled out given the patient’s systemic symptoms. Definitive diagnosis of the mediastinal germ cell tumours ultimately requires tissue biopsy.

Tissue biopsy was used to diagnose our patient with an EBV-associated lymphoepithelioma-like thymic carcinoma. He presented with distant hematogenous metastases to the bone and lymphatics, which is consistent with stage IVb thymic carcinoma based on the Masaoka-Koga staging system. This is the most advanced stage of the disease and is the presentation of approximately half of patients at the time of diagnosis.¹

Treatment

Based on the advanced nature of the patient’s thymic carcinoma, he was promptly started on systemic chemotherapy with a combination of cisplatin, doxorubicin and cyclophosphamide.

Outcome and follow-up

Our patient underwent chemotherapy with cisplatin, doxorubicin and cyclophosphamide. His treatment course was complicated by hypercalcaemia, poorly controlled pain, pulmonary embolism, pathologic fracture and finally, delirium and recurrent fevers. While undergoing treatment for hypercalcaemia and infection, patient was also initiated on a morphine drip for palliation of pain. He had a rapid clinical decline with acute encephalopathy and ultimately succumbed to hypoxic respiratory failure and sepsis, only 2 months after his initial presentation and having completed three cycles of chemotherapy.

Discussion

The thymic epithelial neoplasms include benign thymomas, malignant thymomas, thymic carcinoids and thymic carcinomas. Collectively, thymic epithelial neoplasms generally occur in the fourth and fifth decades of life.³ They typically present with compressive symptoms related to the mass, such as cough, chest pain, phrenic nerve palsy or superior vena cava syndrome. Occasionally, they may appear as incidental radiographic findings in asymptomatic patients, or as a collection of symptoms pointing to a paraneoplastic syndrome. Imaging usually shows a mediastinal mass in the anterosuperior region that is characterised by necrotic, cystic or calcified features.⁴

Thymic carcinomas constitute 15%–20% of all thymic neoplasms. Compared with malignant thymomas, thymic carcinomas demonstrate high likelihood of capsular invasion and metastasis. Histologically, they are divided into low-grade and high-grade subtypes. Our patient’s subtype, lymphoepithelioma-like, is high-grade and the most frequent subtype of thymic carcinomas, comprising 12%–32% of all thymic carcinomas.^{5 6}

C-kit (CD117), a tyrosine kinase receptor, is notably overexpressed in thymic carcinoma as well as in a variety of other malignancies. It is present in 73%–86% of thymic carcinomas and only 0%–5% of benign thymomas.^{7 8} C-kit expression is frequently tested given its association with poorer disease-related and progression-free survival.⁹ Interestingly, the patient in this case had c-kit-negative thymic carcinoma.

Lymphoepithelioma-like thymic carcinomas are characterised by a diffuse histological growth pattern consisting of sheets and islands of large tumour cells with large vesicular nuclei, prominent nucleoli and a dense surrounding lymphoid infiltrate.⁶ It is particularly aggressive with a high rate of metastasis and recurrence.⁶ It is associated with pleural, diaphragmatic and pericardial involvement in 20%–25% of cases, extrathoracic metastases in 67% and lymphatic metastases in 46%. Hematogenous spread to multiple organs including the liver, kidneys and brain has also been reported.^{10 11} Rarely, lymphoepithelioma-like thymic carcinoma has been associated with paraneoplastic syndromes.¹²

As with lymphoepithelial-like tumours in other parts of the body, multiple studies have implicated EBV in the pathogenesis of lymphoepithelioma-like subtype of thymic carcinoma.^13–15 Notably, lymphoepithelioma-like thymic carcinoma has similar histopathological characteristics as undifferentiated nasopharyngeal carcinoma, for which EBV is a known etiologic agent. The involvement of EBV in the pathogenesis of thymic epithelial tumours, as well as the exact mechanism through which this occurs, remains controversial. Some evidence suggests a central tumourigenic role of the virus, with infection of the tumour progenitor cell. The presence or absence of the virus does not appear to have a role in prognostication.¹⁶

The prognosis of lymphoepithelioma-like thymic carcinoma is very poor due to its propensity for late diagnosis, metastasis and recurrence. The associated 5-year survival for thymic carcinoma is 30%–50%.⁵ Median survival after diagnosis is between 18.7 and 36 months.^{5 17} The main factors influencing prognosis are the stage of disease, resectability of the tumour and histological grade.^{6 18}

Surgery, with or without neoadjuvant chemoradiotherapy depending on resectability, is the first-line treatment for patients with thymic carcinoma. For patients with unresectable or metastatic thymic carcinoma, radiation and/or chemotherapy may be used for palliation. There is no established standard chemotherapy regimen, although the National Comprehensive Cancer Network recommends carboplatin/paclitaxel as first-line therapy. The ADOC regimen (cisplatin, doxorubicin, vincristine and cyclophosphamide) also appears effective.² Our patient, who had an unresectable stage IVb thymic carcinoma, was treated with a combination of cisplatin, doxorubicin and cyclophosphamide.

Learning points.

• Consider underlying malignancy in patients who present with persistent back pain and constitutional symptoms.

• The differential diagnosis of an anterior mediastinal mass consists of thymic mass, including thymomas, thymic carcinomas, carcinoids and thymolipomas; lymphoma; germ cell tumour; metastases from a primary lung cancer and non-neoplasms such as intrathoracic thyroid; thymic cysts and lymphangioma.

• Thymic carcinoma presents with constitutional symptoms such as fevers, weight loss and night sweats similar to lymphoma.

• Thymic carcinoma is highly aggressive and needs rapid diagnosis and treatment for best outcomes. Despite best measures, thymic carcinoma carries an overall poor prognosis. Palliation of symptoms and holistic care should be at the core of the treatment plan.