Poorly differentiated carcinoma of the anterior mediastinum in a young male – A diagnostic dilemma
Article Outline
Summary
A 22-year-old male with anterior mediastinal tumour had extensive local and metastatic disease at initial presentation. The diagnosis was based on tru-cut biopsy of the primary lesion and fine needle aspiration cytology of the metastatic deposit along with serum tumour marker studies. The biopsy as well as the cytology smears showed features of a poorly differentiated carcinoma, and both serum alpha-foeto-protein and hCG levels were elevated. A diagnosis of malignant mixed germ cell tumour was suggested. The patient achieved complete remission following cis-platin based chemotherapy and is disease free for the last 12 years.
Keywords: Mediastinum, Germ cell tumour, Malignant, Cis-platin
Introduction
Primary mediastinal malignant nonseminomatous germ cell tumours (NSGCTs) are rare and account for 1–2% of all GCTs in males.1 Mediastinal NSGCTs in 90–100% of the cases present with symptomatic disease.2 The initial problem in the management of these patients is establishing the diagnosis. GCT should be considered particularly in young men presenting with anterior mediastinal mass. Awareness of this possibility, together with estimation of tumour markers like alpha-foeto-protein (AFP) and human chorionic gonadotrophin (HCG) has led to increased frequency of diagnosis of malignant NSGCT.3 Lung cancers are also known to produce these markers.4 On a limited biopsy with features of a poorly differentiated carcinoma it may be difficult to determine the exact histopathological diagnosis. With elevated tumour markers like AFP and HCG; and negative sputum cytology with no tumour on bronchoscopy the diagnosis of malignant GCT has to be based on the age of the patient and location of the tumour. The patient should not be denied the opportunity of remission or cure with current chemotherapeutic regimens.
Case report
A young man of 22 years, a nonsmoker, presented with intense pain in the right sacro-iliac joint and right anterior chest wall swelling of 1-month duration. The patient was diagnosed to have massive right pleural effusion 3 months back and was treated with antitubercular drugs without any improvement. Fine needle aspiration cytology (FNAC) of the sacro-iliac joint was reported elsewhere as suggestive of large cell lymphoma.
On examination the patient had a suffused face with prominent superficial chest veins suggestive of superior vena caval obstruction. There was diffuse swelling of the right chest wall with tenderness. Testicular examination was normal. Chest X-ray (lateral view) revealed a mass in the anterosuperior mediastinum. On CT-scan (thorax) a large isodense mediastinal mass was seen infiltrating the pericardium and encasing the large vessels in the superior mediastinum. The anterior thoracic wall on the right side was infiltrated. The trachea and the main bronchi were markedly compressed and displaced posteriorly (Fig. 1). Loculated effusion in the right lower zone was seen with thickened pleura. CT-scan of the pelvis showed evidence of skeletal metastases to the right ilium and fifth lumbar vertebra. CT-scan of the abdomen and testes was normal. Sputum for cytology did not reveal any malignant cells. There was no evidence of any tumour on bronchoscopic examination.
Figure 1
CT-scan of thorax showing the large mediastinal tumour.
Tru-cut biopsy of the mediastinal mass showed hyperchromatic pleomorphic cells with ample cytoplasm and a diagnosis of poorly differentiated thymic carcinoma was suggested. The patient received radiotherapy and there was a dramatic response. The oncologist suspected non-Hodgkin's lymphoma and requested a review of the histopathology slides, which ruled out the possibility of lymphoma based on morphological features. Meanwhile, the patient developed a rapidly enlarging swelling in the right supraorbital region. CT-scan showed an extradural metastatic deposit in the right frontal and temporal regions with involvement of skull vault. FNAC of the mass showed features of a poorly differentiated carcinoma. In view of the young age of the patient and location of the tumour in the anterior mediastinum a possibility of malignant germ cell tumour was considered. Elevated β-HCG (2600
mIU/ml) and AFP (2100ng/ml) suggested the diagnosis of malignant mixed germ cell tumour.
Further, the patient received 5 cycles of cis-platin, etoposide and ifosfamide (CEI regimen) between February and July 1996 along with G-CSF and other supportive therapy. The patient was closely monitored with regular estimation of tumour markers.
Post-therapy findings
CT-scan (head) showed complete regression of intracranial and extracranial deposits. CT-scan of the thorax showed marked regression of the mediastinal tumour with a small residual mass infiltrating anterior thoracic wall and pericardium. Tru-cut biopsy showed only necrotic material. AFP (2.3ng/ml) and HCG (0.6mIU/ml) had normalized. Due to involvement of the anterior chest wall the patient was considered as a high-risk case for surgery.
Follow-up
The patient is free of the disease for the last 12 years since the diagnosis.
Discussion
Mediastinal malignant NSGCTs are rare and occur almost exclusively in young men and it is defined by Martini5 as “Tumours, which appear in the mediastinum in the absence of a detectable testicular primary tumour and without involvement of the retroperitoneal lymph nodes”. The present case fulfilled these criteria. The mean age at presentation is 24 years and most of the malignant GCT of the mediastinum present with symptomatic disease.2, 6 Tumour extension throughout the mediastinum can produce pericardial and pleural effusion. Superior vena caval syndrome due to vascular compression by rapidly growing tumours occur in 10–20% of the cases. In over 95% of the patients the standard PA and lateral chest X-ray are abnormal. Occasionally patients present with metastatic disease with lungs, liver and bones being the most frequently involved sites. Osseous metastasis is more frequently described in mediastinal disease when compared to its testicular counterpart.7
The age and mode of clinical presentation in this case correlated well with those described in the literature.2, 3, 6 Estimation of serum tumour markers is indispensable in the diagnosis and management of mediastinal germ cell tumours. The importance of identifying these tumours is emphasized in a report of 5 cases by Fox et al.8 involving the mediastinum, lung and lymph nodes without an obvious primary site. The diagnosis of embryonal carcinoma was made after careful review of the histology, tumour marker analysis and subsequent response to therapy. Similarly, in the present case it was the response to radiotherapy, which prompted a review of histopathology slides which was supplemented by FNAC of the metastatic lesion and tumour marker analysis. In young males with poorly differentiated carcinoma and a dominant mass in the mediastinum, a diagnosis of malignant GCT should be considered and serum levels of AFP and HCG should be measured.2, 8 In children and young adults undifferentiated carcinoma of the thymus with t(15, 19) translocation has to be excluded by cytogenetics or RT-PCR. Though, morphologically it may resemble NSGCT, it is not associated with expression of AFP and HCG.9 The most important differential diagnosis in adults is large cell carcinoma in the lung extending or metastasizing to the mediastinum.9 Lung cancers are known to be associated both with expression of AFP and HCG on immunohistochemistry and elevated serum levels.4
All experienced investigators view chemotherapy as the principal mode of therapy in mediastinal NSGCTs.1, 2, 3, 6, 10 The therapeutic outcome is improving with modern cis-platin based chemotherapy. Overall complete remission rates of 50–70% have been achieved in most series. Patients who attain normalization of tumour markers and show incomplete radiographic response are allocated to post-chemotherapy surgery. With this modality of treatment, approximately 50% of the patients are expected to be long-term survivors.1, 2, 3, 6 Disease confined to the mediastinum and necrosis in the post-chemotherapy specimen are important prognostic factors. In contrast, patients with residual carcinoma in resected specimen have a high relapse rate. Patients who do not respond to primary therapy have very poor outcome, as they are rarely curable with salvage therapy.3 Albuquerque et al.10 in their experience with mediastinal NSGCTs describe 14 months survival in patients receiving cis-platin based chemotherapy versus 5.3 months in patients not receiving such therapy. However, because of the advanced disease at presentation even in the group receiving cis-platin based therapy a long-term complete response rate of only 20% could be achieved.
Despite advances in chemotherapy compared to their testicular and retroperitoneal counterparts, mediastinal NSGCT has the worst response and survival with high rate of relapse and hence their optimal management continues to be defined. This impaired prognosis is attributed to advanced disease at presentation, association with haematological malignancies and to the occurrence of sarcomatous elements. It is possible that the mediastinal GCTs arise from cells of different embryologic origin than the retroperitoneal and testicular primaries. The association with haematological abnormalities and Klinefelter's syndrome in patients with this tumour supports this concept.2 It is likely that the development of associated malignancies is an expression multipotent nature of primitive germ cells and is not related to therapy.2
In the present case, with extensive local disease and widespread metastases the patient has achieved complete response to CEI regimen with normalization of tumour markers. Post-chemotherapy surgery was not technically feasible; however, the biopsy showed the presence of necrotic tumour. The patient is on close follow-up and is free of the disease for the last 12 years. Thus, it is important to consider this treatable and potentially curable cancer in selected patients with poorly differentiated carcinomas of the anterior mediastinum.
Conflict of interest statement
The authors have no conflict of interest.
References
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PII: S1755-0017(08)00050-X
doi:10.1016/j.rmedc.2008.07.013
© 2008 Elsevier Ltd. All rights reserved.
