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Journal of Clinical Oncology, Vol 26, No 28 (October 1), 2008: pp. 4686-4688
© 2008 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2008.17.5372
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DIAGNOSIS IN ONCOLOGY

Primary Mediastinal Germ Cell Tumor Evolving Into an Extramedullary Acute Megakaryoblastic Leukemia Causing Cord Compression

Govinda R. Brahmanday

William Beaumont Hospital, Royal Oak, MI

Gabriela Gheorghe

Indiana University School of Medicine, Indianapolis, IN

Ishmael A. Jaiyesimi

William Beaumont Hospital, Royal Oak, MI

Attilio Orazi

Indiana University School of Medicine, Indianapolis, IN

Richard Zekman, Rajul Parikh, Shannon M. Wills

William Beaumont Hospital, Royal Oak, MI

Lawrence H. Einhorn

Indiana University School of Medicine, Indianapolis, IN

In November 2006, a 28-year-old male presented with a 3-week history of pleuritic chest pain. Computed tomography (CT) scan demonstrated a 10.4- x 11.2-cm right-sided anterior mediastinal mass (Fig 1). Positron emission tomography/CT revealed [18F]fluorodeoxyglucose (FDG) maximum standard uptake value (SUVmax, 16.8) in the mediastinum. A CT-guided biopsy revealed a poorly differentiated malignancy with elements of yolk sac components. A few clusters of mature–appearing nucleated RBCs as well as occasional aggregates of poorly differentiated, immature appearing myeloid precursors were seen (Fig 2). Serum beta human chorionic gonadotropin was 82 µ/mL (≤ 4 µ/mL), alpha-feto protein was 10,632 ng/nL (≤ 8.5 ng/nL) and lactate dehydrogenase was 731 U/L (normal range, 100 to 238 U/L). Testicular ultrasound was unremarkable. A diagnosis of primary mediastinal germ cell tumor (PMGCT) was made. After four cycles of standard cisplatin, etoposide, and bleomycin chemotherapy, the tumor markers returned to normal levels. Although a follow-up positron emission tomography/CT scan showed a decrease in FDG uptake (SUVmax of 8.9), the CT scan did not show significant regression in the size of the mediastinal tumor. The patient underwent resection of the mediastinal tumor with negative surgical margins at Indiana University (Indianapolis, IN) approximately 2 months after the completion of chemotherapy. The pathology of the tumor revealed elements of teratoma with highly atypical stromal elements. Immunohistochemistry performed on the resected mediastinal tumor did not reveal any convincing evidence of precursor hematopoietic elements. Approximately 10 months after surgery, the patient noticed intermittent midback pain. He then developed acute onset of lower extremity motor and sensory deficits. A magnetic resonance imaging scan showed an enhancing extradural-extramedullary mass (4.9 x 1.1 cm in sagittal sequence) at T7 through T9 in a right anterolateral location (Fig 3) with significant cord compression. The patient underwent an emergent laminectomy with tumor resection that resulted in incomplete but meaningful recovery of neurological function. The histologic examination of the paraspinal mass revealed poorly differentiated malignant cells associated with numerous multinucleated giant cells resembling abnormal megakaryocytes (Fig 4). Immunohistochemical analysis was performed. The megakaryocytic marker CD42b showed diffuse positivity in the malignant cells (Fig 5). These cells were also positive for CD45RB (leukocyte common antigen), CD43 (Fig 6), CD31, and CD61, the latter also being a megakaryocyte-associated antigen. Additional myeloid markers which included CD117, CD68 (KP-1, PG-M1, CD163), myeloperoxidase, and lysozyme were negative. The lymphoid-associated markers CD20, CD3, CD30 (also germ cell tumor–associated), CD2, CD5, CD79a, and PAX-5 were negative. The germinal cell tumor–associated markers CK7, CK20, PLAP, AFP, beta-HCG, pancytokeratin, and synaptophysin were also negative. The immunohistological profile in conjunction with morphology was consistent with a diagnosis of extramedullary acute megakaryoblastic leukemia. The T-cell receptor–gamma and immunoglobin H gene rearrangement analysis showed no evidence of clonal rearrangements, ruling out lymphoma. Fluorescence in situ hybridization for the presence of isochromosome 12p was negative. The complete blood count and peripheral smear were unremarkable. The bone marrow biopsy was also unremarkable. The patient received radiation therapy to the spine encompassing T5 to T11. Two months after spinal radiation, the patient presented to the hospital with an episode of seizures. Magnetic resonance imaging of the spine and brain suggested leptomeningeal involvement. The cytologic examination supplemented by flow cytometry of the CSF confirmed CSF involvement by leukemic blasts. Bone marrow remained uninvolved by leukemia (or PMGCT). The patient received whole-brain irradiation for the leptomeningeal disease. His chemotherapy is currently on hold, after receiving a few cycles of intrathecal chemotherapy (with methotrexate and cytarabine), due to the interval development of obstructive hydrocephalus.


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An association between PMGCT and hematologic malignancies was first recognized in 1985.1,2 All of the patients who developed hematologic malignancies had a nonseminomatous PMGCT.3 Acute megakaryocytic leukemia is the commonest hematologic malignancy associated with PMGCT.3 So far, less than 20 cases of PMGCT with evolution into acute megakaryocytic leukemia have been reported in the literature.2-10 Most of the reported cases of PMGCT associated with acute megakaryoblastic leukemia (including our patient) have had a yolk sac tumor component. The causal relationship between nonseminomatous PMGCT and leukemia is still elusive. It is quite possible that the nonseminomatous PMGCT, after spreading to the marrow cavity, becomes capable of transforming into leukemia in that microenvironment. Alternatively, it has been suggested that the mesenchyme-like component of yolk sac tumors acts as a pluripotential source for the transformation of primordial germ cells into malignancies typical of nongerminal tissue. A partial confirmation of this hypothesis lies in the presence of hematologic precursors within the PMGCT stroma and vessels within the yolk sac tumor component of these tumors.11 It can be further speculated that expression of hematopoietic growth and differentiation factors in some PMGCT could drive the differentiation of primordial germ cells into hematopoietic progeny. The differentiation factors involved may be responsible for the preferred commitment of the transformed precursors to megakaryocytic and monocytic lineage. Additionally, in a few cases of PMGCT-associated leukemia in which the immunophenotype of the leukemic cells was compared with that of the intratumoral hematopoietic precursors, a comparable result was observed. This suggests a spread of hematopoietic tumor cells from the PMGCT to blood, bone marrow, and/or extramedullary sites.12 The median time for the development of hematologic neoplasia associated with PMGCT is 6 months (range, 0 to 47 months).3 The clinical course of the hematologic neoplasia is very aggressive with a median survival of 5 months (range, 0 to 16 months) after diagnosis.3 Hematologic malignancies occurring in patients with PMGCT are thought to be primary, and not therapy related.11-14 In some cases, immunohistochemical and cytogenetic evidence (especially presence of i12p chromosome) had previously suggested the clonal relationship between the PMGCT and the hematologic malignancy.11-14 As in other previously reported cases, the short interval between the PMGCT and the occurrence of the hematopoietic malignancy argues against a therapy-related origin of the acute megakaryocytic leukemia. There have been two reported cases of PMGCT complicated by acute megakaryotic leukemia, one presenting with an extradural mass and the other with organomegaly.8 However, our patient is the first, to our knowledge, to be ever reported in English literature of a PMGCT evolving into an extramedullary acute megakaryocytic leukemia manifesting as a mass causing cord compression. Furthermore, the aggressive course of the acute megakaryoblastic leukemia involving the CNS with sparing of the bone marrow is striking.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

REFERENCES

1. DeMent SH, Eggleston JC, Spivak JL: Association between mediastinal germ cell tumors and hematologic malignancies: Report of two cases and review of the literature. Am J Surg Pathol 9:23-30, 1985[Medline]

2. Nichols CR, Hoffman R, Einhorn LH, et al: Hematologic malignancies associated with primary mediastinal germ cell tumors. Ann Intern Med 102:603-609, 1985[Abstract/Free Full Text]

3. Hartmann JT, Nichols CR, Droz JP, et al: Hematologic disorders associated with primary mediastinal nonseminomatous germ cell tumors. J Natl Cancer Inst 92:54-61, 2000[Abstract/Free Full Text]

4. Case records of the Massachusetts General Hospital: Weekly clinicopathological exercises—Case 40-1997. A 23-year-old man with a mediastinal embryonal carcinoma and hematologic abnormalities. N Engl J Med 337:1904-1912, 1997[Free Full Text]

5. Domingo A, Romagosa V, Callis M, et al: Mediastinal germ cell tumor and acute megakaryoblastic leukemia. Ann Intern Med 111:539, 1989[Abstract/Free Full Text]

6. Mihál V, Dusek J, Jarosova M, et al: Mediastinal teratoma and acute megakaryoblastic leukemia. Neoplasma 36:739-747, 1989[Medline]

7. Nichols CR, Hoffman R, Glant MD, et al: Malignant disorders of megakaryocytes associated with primary mediastinal germ cell tumors. Prog Clin Biol Res 215:347-353, 1986[Medline]

8. Nichols CR, Roth BJ, Heerema N, et al: Hematologic neoplasia associated with primary mediastinal germ cell tumors. N Engl J Med 322:1425-1429, 1990[Abstract]

9. Vazquez DD, Sancho GMI, Curbera GA, et al: Non-seminomatous germ-cell tumour associated with acute megakaryoblastic leukaemia. Clin and Transl Oncol 9:329-331, 2007[CrossRef]

10. Wang SE, Fligiel S, Naeim F: Acute megakaryocytic leukemia following chemotherapy for a malignant teratoma. Arch Pathol Lab Med 108:202-205, 1984[Medline]

11. Orazi A, Neiman RS, Ulbright TM, et al: Hematopoietic precursor cells within the yolk sac tumor component are the source of secondary hematopoietic malignancies in patients with mediastinal germ cell tumors. Cancer 71:3873-3881, 1993[CrossRef][Medline]

12. Wick MR, Perlman EJ, Orazi A, et al: Pathology and genetics of tumours of the lung, pleura, thymus and heart, in Travis WD, Brambilla E, Muller-Hermelink HK, et al (eds): World Health Organization Classification of Tumors. Lyon, IARC, 2004, pp 198

13. Ladanyi M, Samaniego F, Reuter VE, et al: Cytogenetic and immunohistochemical evidence for the germ cell origin of a subset of acute leukemias associated with mediastinal germ cell tumors. J Natl Cancer Inst 82:221-227, 1990[Abstract/Free Full Text]

14. Neiman RS, Orazi A: Mediastinal nonseminomatous germ cell tumours: Their association with non–germ cell malignancies. Pathol Res Pract 195:589-594, 1999[Medline]


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