An HIV-associated mediastinal germ cell tumour complicated by acute myeloid leukaemia.INTRODUCTION
The introduction of highly active antiretroviral therapy (HAART) has revolutionised HIV medicine resulting in a substantial reduction in HIV-related mortality. With the improved life expectancy in this patient group, data from cancer and AIDS registries suggest that the spectrum of non-AIDS-defining cancers reported is broadening and compared with the general population some cancers are significantly increased in HIV-positive patients [1,2].
It has also been reported that testicular germ cell tumours (GCT) also occur more frequently in HIV-1 infection [3-7]. Primary GCT may arise anywhere along the midline, from sacrum sacrum: see spinal column. , testes, ovaries, retroperitoneum and mediastinum mediastinum /me·di·as·ti·num/ (me?de-ah-sti´num) pl. mediasti´na [L.]
1. a median septum or partition.
2. to the pineal or suprasellar regions. Histologically they comprise seminomatous and/or teratomatous teratomatous
pertaining to or of the nature of teratoma. elements. Extragonadal GCT (EGCT) carry a poorer prognosis than their gonadal gonadal
pertaining to or arising from a gonad. See also testicular, ovarian.
cords formed by epithelial cells which migrate from the mesonephric tubules in the embryo to the gonadal ridge and establish the indifferent counterparts and patients with a primary mediastinal mediastinal /me·di·as·ti·nal/ (-as-ti´n'l) of or pertaining to the mediastinum.
of or pertaining to the mediastinum. non-seminomatous germ cell tumour (MNSGCT) are defined as poor risk in the IGCCCG prognostic category with a 48% 5-year survival . Although there are increasing data relating to the outcome of patients with HIV-related GCT , only two case reports describe patients with HIV disease and M-GCT [10,11].
We report on a case of a primary M-NSGCT in an HIV-positive male who responded to chemotherapy with the excision of a post-chemotherapy necrotic primary mass only for his remission to be complicated by the development of acute leukaemia.
A 37-year-old heterosexual White male presented with a 1-month history of retrosternal chest pain, non-productive cough, dyspnoea dyspnoea
dyspnea. and significant weight loss. He had been diagnosed as being HIV-positive 14 months previously and commenced HAART (abacavir, lamivudine and efavirenz).
On examination he was cachectic cachectic /ca·chec·tic/ (kah-kek´tik) pertaining to or characterized by cachexia.
Affected by or relating to cachexia. with an ECOG performance status of 3 and had no palpable lymphadenopathy. There was reduced air entry in his left chest and physical signs consistent with superior vena cava superior vena cava
n. Abbr. SVC
A large vein formed by the union of the two brachiocephalic veins and the azygos vein that receives blood from the head, neck, upper limbs, and chest, and empties into the right atrium of the heart. (SVC) obstruction. He had bilateral gynaecomastia, no palpable abdominal organomegaly and normal testes. Serum tumour marker evaluations showed lactate dehydrogenase (LDH) 1099 IU/l (normal range 150-500 IU/l), betahuman chorionic chorionic
pertaining to the chorion.
a circular band of cells of placental origin that invade the endometrium and form the endometrial cups in the mare. gonadotrophin (hCG) 1880 IU/l (normal range, 0-4 IU/l), alpha-fetoprotein (AFP) 33,000 ng/ml (normal range, 0-13 ng/ml). Baseline renal and hepatic function tests were normal on admission, and full blood count showed Hb 10.9g/dl, WCC 7.5?109/l, platelets 592x[10.sup.9]/l. His CD4 cell count was 141/[mm.sup.3] with an undetectable HIV-1 plasma viral load.
Computerised tomography (CT) scan of his brain, chest, abdomen and pelvis demonstrated a large right-sided mediastinal mass, 17x13x19cm, encasing the aorta and pulmonary vessels. There was marked compression of the superior vena cava and the right main bronchus and a right pleural effusion. The liver was enlarged with no focal lesion identified within it. He had a normal testicular ultrasound scan.
Biopsy of the mediastinal mass suggested a GCT with immature teratomatous elements. He underwent a right pleurocentesis and in view of his poor clinical condition commenced urgent 'low-dose' 2-day etoposide/cisplatin (EP) chemotherapy that was repeated 7 days later over 3 days. The compressive symptoms, however, worsened over the first 4 days following treatment start, requiring, initially, stent insertion in the SVC and, subsequently, the left brachiocephalic vein left brachiocephalic vein
A vein that receives the left vertebral, internal thoracic, superior intercostal, inferior thyroid, and other veins. .
He subsequently commenced POMB/ACE (cisplatin, vincristine vincristine /vin·cris·tine/ (vin-kris´ten) an antineoplastic vinca alkaloid; used as the sulfate salt in the treatment of various neoplasms, including Hodgkin's disease, acute lymphocytic leukemia, non-Hodgkin's lymphoma, Kaposi's , methotrexate, bleomycin alternating 2-weekly with actinomycin-D, cyclophosphamide, etoposide) chemotherapy  and received six cycles in total.
The first cycle of POMB was given at full dose. However, despite pleurocentesis and administration of prolonged intravenous folinic acid rescue to counteract methotrexate toxicity, the patient developed confluent blisters on his lower limbs that healed spontaneously with regular dressings. This may be due to the development of significant lower limb oedema after administration of the first POMB chemotherapy, secondary to poor mobility, reduced serum albumin (20g/l) and the SVC obstruction contributing to the third space fluid collection. Following that cycle, he also developed neutropenic sepsis requiring standard broad spectrum antibiotics and granulocyte granulocyte /gran·u·lo·cyte/ (gran´u-lo-sit?) granular leukocyte.granulocyt´ic
band-form granulocyte band cell.
n. colony stimulating factor colony stimulating factor
A hormone produced in the cells lining the blood vessels that stimulates the bone marrow to synthesize white blood cells. (GCSF). He also developed grade 4 mucositis requiring naso-gastric feeding and diamorphine diamorphine
see heroin. for analgesia. The cycles of ACE were administered at 100% dose but for the subsequent cycles of POMB chemotherapy the dose of methotrexate was reduced to 25% and prolonged intravenous folinic acid rescue and GCSF support were given.
Serum tumour marker values fell satisfactorily and following the third cycle of POMB chemotherapy were: hCG 2 IU/l, AFP 176 ng/ml, LDH 491 IU/l. Repeat CT scan demonstrated a small left pleural effusion but the large mediastinal mass persisted; magnetic resonance imaging magnetic resonance imaging (MRI), noninvasive diagnostic technique that uses nuclear magnetic resonance to produce cross-sectional images of organs and other internal body structures. (MRI) showed cystic change corresponding to a necrotic tumour mass rather than residual active GCT.
He proceeded to excision of the mediastinal mass by the cardiothoracic team, which was complicated by bilateral pneumothoraces and ischaemic hepatitis secondary to an intra-operative hypotensive hypotensive /hy·po·ten·sive/ (-ten´siv) marked by low blood pressure or serving to reduce blood pressure.
1. Of or characterized by low blood pressure.
2. episode. The tumour was maximally debulked with a small paratracheal mass remaining for which a second thoracotomy thoracotomy /tho·ra·cot·o·my/ (-kot´ah-me) pleurotomy; incision of the chest wall.
Incision into the chest wall. Also called pleurotomy. was planned. Histology of the mediastinal tumour showed no somatic malignancy and no foci of residual viable germ cell tumour.
The patient made a full post-operative recovery including normalisation of liver function tests Liver Function Tests Definition
Liver function tests, or LFTs, include tests for bilirubin, a breakdown product of hemoglobin, and ammonia, a protein byproduct that is normally converted into urea by the liver before being excreted by the kidneys. apart from ALT 54 IU/l. A repeat CT scan 2 months after surgery showed that the remaining paratracheal mass was unchanged with no evidence of metastatic disease.
Two weeks later (10 weeks post sternotomy), apart from sternotomy pain and lethargy the patient felt well. His appetite had remained poor and weight was slow to recover. He was found to have a raised LDH (18,376 IU/l) with normal AFP (4 ng/ml) and hCG (2 IU/l). Routine full blood count showed him to be anaemic and thrombocytopenic (Hb 9.5g/dl, WCC 12.4x[10.sup.9]/l, platelets 16x[10.sup.9]/l) with a raised reticulocyte count (3.08%). Blood film showed a leucoerythroblastic picture consistent with malignant bone marrow infiltration. Clotting and liver function tests were deranged (bilirubin 20 [micro]mol/l, ALP 204 U/l, GGT 117 U/l). Bone marrow biopsy Bone marrow biopsy
A procedure in which cellular material is removed from the pelvis or breastbone and examined under a microscope to look for the presence of abnormal blood cells characteristic of specific forms of leukemia and lymphoma. showed an acute megakaryoblastic leukaemia on the background of myelodysplasia. He commenced allopurinol allopurinol /al·lo·pur·i·nol/ (al?o-pur´i-nol) an isomer of hypoxanthine, capable of inhibiting xanthine oxidase and thus of reducing serum and urinary levels of uric acid; used in prophylaxis and treatment of hyperuricemia and uric acid , steroids and intravenous fluid with the plan for chemotherapy for the leukaemia. However, the patient declined further chemotherapy and died peacefully from the leukaemia 3 days later.
Testicular germ cell tumours (GCT) carry a good prognosis with cure rates ranging from 80-96% even with disseminated disease. A case-control study of patients with HIV-related GCT concluded that the disease is not more aggressive than GCT in the general population .
Extragonadal germ cell tumours (EGCT) comprise 5-10% of all GCT , and although they are histopathologically and serologically similar to their testicular counterparts, they carry a poorer prognosis. Seminomatous M-GCT have a cure rate over 80% with radiotherapy or surgery alone as well as with cisplatin-based chemotherapy ; yet M-NSGCT are defined as poor risk with a 48% 5-year survival despite cisplatin-based chemotherapy . The poor outcome for the M-NSGCT has been attributed to difficulty in resecting the post-chemotherapy mass and to the associated risk of acute leukaemia reported in this patient group .
It is recognised that immunosuppression increases the risk of neoplasia. There are data to suggest that testicular GCT occur more frequently in HIV-disease [1,3-5,7]. Interestingly, it has been demonstrated in HIV-positive patients with metastatic testicular GCT treated with chemotherapy that similar disease-free survival may be expected as compared with HIV-negative controls .
Chemotherapy and radiotherapy are reported to produce immunosuppression and may result in a median fall in CD4 cell count of approximately 30% . However, patients with HIV and testicular GCT have not been reported to have developed opportunistic infections whilst receiving chemotherapy [7,16]. The patient described in this case received co-trimoxazole, aciclovir, itraconazole itraconazole /it·ra·co·na·zole/ (it?rah-kon´ah-zol) a triazoleantifungal used in a variety of infections.
n. and azithromycin as prophylaxis against opportunistic infections for the duration of chemotherapy; he also did not develop an opportunistic infection. The toxicities experienced by this patient were predictable, related to the intensive chemotherapy regimen administered, and did not appear to be worse than expected in the HIV-negative patient population. It is important that patient care includes HIV-physicians and oncologists to ensure maintenance of CD4 cell count and prophylaxis of opportunistic infections whilst receiving chemotherapy with curative intent.
This patient developed acute myeloid leukaemia (AML) of the French-American-British (FAB) classification megakaryoblastic subtype M7. There are three possible aetiologies for this: HIV-disease-related, primary M-NSGCT-related or resulting from chemotherapy.
HIV is thought to directly affect the survival and growth of haematopoietic Adj. 1. haematopoietic - pertaining to the formation of blood or blood cells; "hemopoietic stem cells in bone marrow"
haematogenic, haemopoietic, hematogenic, hematopoietic, hemopoietic progenitor cells (HPCs). The most consistent HIV-related haematopoietic abnormality is the failure of bone marrow regeneration in which on-demand haematopoiesis hematopoiesis, haematopoiesis
the formation of blood. — hematopoietic, haematopoietic, adj.
See also: Blood and Blood Vessels
Noun 1. is suppressed. HIV-myelopathy arises secondary to myelodysplastic changes seen in the bone marrow of HIV-positive individuals; these are non-specific in nature and diffuse in type . In this case the bone marrow had not been sampled prior to commencing chemotherapy for M-GCT, as this would not be part of standard management.
HIV-associated AML is rare and the prognosis poor. One study reported that HIV-positive individuals may have as much as a two-fold higher incidence of AML compared to the general population (standardised incidence ratio=2.05; 95% CI 1.17-3.34) . Case series have reported that HIV-associated AML is usually FAB [M.sup.2], M4 or M5 subtypes [19,20]. In the literature, as far as we are aware, there are no reports of an HIV-positive individual developing AML FAB M7 subtype, as described in this case history. Haematological neoplasia were first associated with EGCT in the 1980s with many reports since [15,21]. The incidence of haematological malignancies in patients with M-NSGCTs is 200-300-fold higher than in matched controls . Median time from the diagnosis of the GCT to development of leukaemia is 6 months (range 0-47 months)  and it often runs an aggressive course. The abnormality is usually of the megakaryocyte megakaryocyte /mega·karyo·cyte/ (-sit?) the giant cell of bone marrow containing a greatly lobulated nucleus, from which mature blood platelets originate.megakaryocyt´ic
n. lineage. No variable has been identified to explain why some patients with M-NSGCT develop leukaemias. A high incidence of isochromosome 12p in leukaemic blasts has been reported and this is a genetic abnormality found in EGCT and gonadal GCT . Embryologically, haematopoietic stem cells arise in the yolk sac and many M-NSGCTs contain yolk sac elements. Yolk sac tumours contain mesenchymal tissue with pluripotent components and, in mouse models, teratocarcinoma teratocarcinoma /ter·a·to·car·ci·no·ma/ (-kahr?si-no´mah) a malignant neoplasm consisting of elements of teratoma with those of embryonal carcinoma or choriocarcinoma, or both; occurring most often in the testis. cells differentiate along haematopoietic lineages. Histopathological, cytogenetic and molecular findings support this pluripotent model and the synchronous presentation of the two types of malignancy reinforce this idea [22,24,25].
A further concern was that the leukaemia was secondary to chemotherapy. This has been well documented in the treatment of GCTs [26,27]. Etoposide, a topoisomerase II inhibitor, is associated with development of AML ; they occur after 2-3 years and are of the FAB M4 or M5 subtypes . The incidence appears to be dose related: less than 0.5% patients who have received a total of dose <2g/[M.sup.2] develop therapy-related leukaemia [29,30] whereas this risk increases to 2% of patients who receive a total dose of >2g/[M.sup.2] [26,31]. In contrast, the haematological disorders associated with alkylating agents usually occur after a period of myelodysplasia with an interval of 5-7 years and develop AML of FAB subtype M1 or [M.sup.2] . This patient received a cumulative etoposide dose of <2g/[M.sup.2]. It is important to remember that, prior to the development of the cisplatin/etoposide regimens, overall 5-year survival for these patients was just 10%. Therefore, notwithstanding these data, the benefits of chemotherapy are felt to outweigh the risks in this patient group. Although, as with all patients receiving chemotherapy, the risks of developing a second malignancy should be discussed.
We believe this to be the first recorded case of secondary AML FAB M7 subtype in an HIV-positive individual. There has been one previous report of a primary AML FAB M7 subtype occurring in an HIV-positive patient receiving HAART . Our case is interesting because of multiple potential aetiologies for the development of AML. A review of the literature supports the view that the leukaemia was secondary to the primary M-NSGCT rather than secondary to HIV-infection or chemotherapy.
It is also an important case since, with intensive chemotherapy, this patient had been potentially cured of the M-GCT, with no viable tumour demonstrated post resection. The toxicities experienced by the patient were predictable and routinely managed--it was felt that they were not attributable to drug interactions between the chemotherapy and HAART. This case supports the view that standard chemotherapy should be administered with curative intent for patients with GCT, including EGCT, and that in order to prevent opportunistic infections and maintain control of HIV, patients with HIV-disease and cancer should be managed jointly with oncologists and HIV-physicians.
[1.] Hessol NA, Pipkin S, Schwarcz S et al. The impact of highly active antiretroviral therapy on non-AIDS-defining cancers among adults with AIDS. Am J Epidemiol, 2007, 165, 1143-1153.
[2.] Pantanowitz L, Schlecht HP, Dezube BJ. The growing problem of non-AIDS-defining malignancies in HIV. Curr Opin Oncol, 2006, 18, 469-478.
[3.] Logothetis C, Newell G, Samuels M. Testicular cancer in homosexual men with cellular immune deficiency: report of two cases. J Urol, 1985, 133, 484-486.
[4.] Gabutti G, Vercelli M, De Rosa M et al. AIDS related neoplasms in Genoa, Italy. Eur J Epidemiol, 1995, 11, 609-614.
[5.] Dal Maso L, Franceschi S, Polesel J et al. Cancer and AIDS Registry Linkage Study. Risk of cancer in persons with AIDS in Italy, 1985-1998. Br J Cancer, 2003, 89, 94-100.
[6.] Frisch M, Biggar R, Engels E et al. Association of cancer with AIDS related immunosuppression in adults. J Am Med Assoc, 2001, 285, 1736-1745.
[7.] Powles T, Bower M, Daugaard G et al. Multicenter study of human immunodeficiency virus-related germ cell tumors. J Clin Oncol, 2003, 21, 1922-1927.
[8.] International Germ Cell Collaborative Group. IGCCCG (1997) International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers. J Clin Oncol, 1997, 15, 594-603.
[9.] Powles T, Bower M, Shamash J et al. Outcome of patients with HIV-related germ cell tumours: a case-control study. Br J Cancer, 2004, 90, 1526-1530.
[10.] Ahmed M, Bhagan, B, Anibogu J. Primary mediastinal germ cell tumour in HIV infection. Am Fam Physician, 1998, 57, 946-947 (letter).
[11.] Fuentes Garcia MI, Mostaza Fernandez JL, Garcia Lopez N et al. Extragonadal germ cell tumour in HIV-positive female. Ann Med Internat, 2004, 21, 397-399.
[12.] Bower M, Brock C, Holden L et al. POMB/ACE chemotherapy for mediastinal germ cell tumours. Eur J Cancer, 1997, 33, 838-842.
[13.] Ganjoo KN, Rieger KM, Kesler KA et al. Results of modern therapy for patients with mediastinal nonseminomatous germ cell tumors. Cancer, 2000, 88, 1051-1056.
[14.] Goss PE, Schwertfeger L, Blackstein ME et al. Extragonadal germ cell tumors. A 14-year Toronto experience. Cancer, 1994, 73, 1971-1979.
[15.] Nichols CR, Hoffman R, Einhorn LH et al. Hematologic malignancies associated with primary mediastinal germ-cell tumors. Ann Intern Med, 1985, 102, 603-609.
[16.] Bernardi D, Salvioni R, Vaccher E et al. Testicular germ cell tumors and human immunodeficiency virus human immunodeficiency virus
Human immunodeficiency virus (HIV)
A transmissible retrovirus that causes AIDS in humans. infection: a report of 26 cases. Italian Cooperative Group on AIDS and Tumors. J Clin Oncol, 1995, 13, 2705-2711.
[17.] Ryu T, Ikeda M, Okazaki Y et al. Myelodysplasia associated with acquired immunodeficiency syndrome acquired immunodeficiency syndrome, see AIDS. . Intern Med, 2001, 40, 795-801.
[18.] Sutton L, Guenel P, Tanguy ML et al. French Study Group on acute myeloid leukaemia in HIV-infected patients. Br J Haematol, 2001, 112, 900-908.
[19.] Hemrich M, Rockstroh J, Sandner R et al. Acute myelogenous leukaemia and myelomonocytic blast crisis following polycythaemia vera in HIV-positive patients: report of cases and review of the literature. Ann Oncol, 2000, 11, 195-200.
[20.] Aboulafia DM, Meneses M, Ginsberg S et al. Acute myeloid leukaemia in patients infected with HIV-1. AIDS, 2002, 16, 865-876.
[21.] Nichols CR, Roth BJ, Heerema N et al. Hematologic neoplasia associated with primary mediastinal germ-cell tumours. N Engl J Med, 1990, 322, 1425-1429.
[22.] Hartmann JT, Nichols CR, Droz JP. Hematologic disorders associated with primary mediastinal nonseminomatous germ cell tumors. J Natl Cancer Inst, 2000, 92, 54-61.
[23.] Chaganti RS, Houldsworth J. Genetics and biology of adult human male germ cell tumors. Cancer Res, 2000, 60, 475-482.
[24.] Ladanyi M, Samaniegi F. Cytogenetic and immunohistochemical evidence for the germ cell origin of a subset of acute leukemias associated with mediastinal germ cell tumours. J Natl Cancer Inst, 1990, 82, 221-227.
[25.] Orazi A, Neiman RS, Ulbright TM et al. Hematopoietic hematopoietic /he·ma·to·poi·et·ic/ (-poi-et´ik)
1. pertaining to hematopoiesis.
2. an agent that promotes hematopoiesis.
1. pertaining to or affecting the formation of blood cells. precursor cells within the yolk sac tumour component are the source of secondary hematopoietic malignancies in patients with mediastinal germ cell tumours. Cancer, 1993, 71, 3873-3881.
[26.] Pedersen-Bjergaard J, Daugaard G, Hansen SW et al. Increased risk of myelodysplasia and leukaemia after etoposide, cisplatin,and bleomycin for germ-cell tumours. Lancet, 1991, 338, 359-363.
[27.] Fizazi K, Culine A, Droz JP et al. Primary mediastinal non seminomatous germ cell tumours: results of modern therapy including cisplatin-based chemotherapy. J Clin Oncol, 1998, 16, 725-732.
[28.] Ratain MJ, Rowley JD. Therapy-related acute myeloid leukaemia secondary to inhibitors of topoisomerase II: from the bedside to the target genes. Review Ann Oncol, 1992, 3, 107-111.
[29.] Bajorin DF, Motzer RJ, Rodriguez E et al. Acute nonlymphocytic leukemia acute non·lym·pho·cyt·ic leukemia
See acute myelogenous leukemia. in germ cell tumor patients treated with etoposide-containing chemotherapy. J Natl Cancer Inst, 1993, 85, 60-62.
[30.] Nichols CR, Breeden ES, Loehrer PJ et al. Secondary leukemia associated with a conventional dose of etoposide: review of serial germ cell tumor protocols. J Natl Cancer Inst, 1993, 85, 36-40.
[31.] Kollmannsberger C, Beyer J, Droz JP et al. Secondary leukemia following high cumulative doses of etoposide in patients treated for advanced germ cell tumors. J Clin Oncol, 1998, 16, 3386-3391.
[32.] Larussa D, Grisetti S, Pilozzi E et al. Acute megakaryoblastic leukemia in a patient receiving HAART. Am J Hematol, 2005, 80, 89.
Correspondence to: Dr CS Brock, Department of Oncology, Chelsea and Westminster Hospital, Fulham Road, London SW10 9NH. Email: email@example.com