Associations with Other Diseases

Klinefelter's syndrome (KS) is a genetic disorder of men that is characterized clinically by gynecomastia, testicular atrophy, and increased levels of follicle-stimulating hormone40 and is characterized genetically by the 47,XXY karyotype. An association between MNSGCT and KS exists. At Indiana University, 22 consecutive MNSGCT patients had chromosome studies performed on blood or a bone mar row aspirate; 18% (4 of 22) of the patients were diagnosed with KS by karyotype, and a fifth patient clinically appeared to have KS.11 This rate is much higher than expected when compared to the expected 0.2% incidence of KS in the general male population11 Although there are single case reports of KS

Figure 21-5. A 26-year-old patient presented with chest pain, weight loss, fatigue, and night sweats. Examination of a biopsy specimen revealed a pure mediastinal seminoma. A, Posterioranterior chest radiograph reveals a large anterior mediastinal mass projecting to the left, with loss of the left heart border. B, Computed tomography scan of the chest shows a complex solid and cystic mass with septations compressing the main pulmonary artery. (Courtesy of Dr. Kitt Shaffer, Dana-Farber Cancer Institute, Boston, MA.)

Figure 21-5. A 26-year-old patient presented with chest pain, weight loss, fatigue, and night sweats. Examination of a biopsy specimen revealed a pure mediastinal seminoma. A, Posterioranterior chest radiograph reveals a large anterior mediastinal mass projecting to the left, with loss of the left heart border. B, Computed tomography scan of the chest shows a complex solid and cystic mass with septations compressing the main pulmonary artery. (Courtesy of Dr. Kitt Shaffer, Dana-Farber Cancer Institute, Boston, MA.)

associated with retroperitoneal or intracranial EGGCTs, the vast majority of EGGCTs in KS patients are MNSGCTs.41 In a retrospective study of 455 GCT patients treated at M. D. Anderson Hospital from 1977 to 1985, 49 patients had EGGCTs, including 15 patients with MNSGCTs. Four (27%) of the fifteen MNSGCT patients were diagnosed with KS while none of the remaining 440 patients were found to have KS. The pathogenesis of this association remains unknown. Although the median age at diagnosis of MNSGCT in the KS patients was almost a decade younger than in the non-KS patients (16 years vs 27 years),41 survival and response to treatment did not differ between these two groups.

An association between MNSGCTs and hemato-logic disorders has been recognized for many years as well. Since the original recognition of this association in 1985,42 more than 70 cases have been identified.43 The most common hematologic diagnosis reported in this patient group is acute megakaryocytic leukemia.43 In addition, many other disorders of megakaryocyte lineage have been reported, including essential throm-bocytosis, myelodysplastic syndrome with abnormal megakaryocytes,12 and idiopathic thrombocytopenia.44,45 Although less commonly seen, there have also been recorded cases of acute lymphoblastic leukemia, acute myeloid leukemia, malignant mastocytosis, and malignant histiocytosis.43

Table 21-1. EVALUATION OF SUSPECTED MEDIASTINAL GERM CELL TUMOR

I. Suspect mediastinal GCT if

Presence of an isolated midline mass (especially in anterior mediastinum) Male gender Age of 20 to 35 years

II. Work-up for suspected mediastinal GCT

Testicular examination and ultrasonography Serum tumor markers (P-hCG, AFP, LDH) CT of thorax and abdomen Biopsy for definitive histologic diagnosis

III. Factors influencing treatment choice

Histology (seminoma vs nonseminoma) Extent of disease* IGCCCG prognostic classification* Good-risk vs intermediate-risk for seminoma All nonseminomas are poor-risk

AFP = a-fetoprotein; |P-hCG = human chorionic gonadotropin; CT = computed tomography; GCT = germ cell tumor; IGCCCG = International Germ Cell Cancer Collaborative Group; LDH = lactate dehydrogenase. 'Consideration of local treatment only for small seminomas. international Germ Cell Consensus Classification.15

This association is unique to MNSGCT. In a retrospective review of 635 patients with EGGCTs, 17 (6%) of 287 patients with MNSGCTs developed hematologic disorders whereas none of the remaining 348 patients with other types of EGGCTs did.43 The median time from diagnosis of the MNSGCT to the development of the hematologic disorder was 6 months, and two patients presented with both disorders simultaneously.43 Unfortunately, these hematologic malignancies tend to be extremely virulent and do not respond well to therapy. In the previous study, the median overall survival from the time of diagnosis of the hematologic disorder was 5 months, and all 17 patients died within 2 years of the diagnosis.43

There is considerable evidence that these rare hematologic disorders are not related to prior therapy but rather to the specific biology of MNSGCTs. Many of the MNSGCT patients developed the hema-tologic disorder prior to receiving any radiation or cytotoxic therapy.12 In addition, both the timing and type of the hematologic disorders seen are different than those of the typical treatment-related leukemias. Acute leukemia associated with alkylating agents typically presents at an average of 5 to 7 years after treatment and with a prodrome of myelodysplastic syndrome. Type II topoisomerase inhibitor-related leukemia occurs an average of 2 to 3 years after treatment and is typically an acute myeloid leukemia. Treatment-related leukemias have characteristic chromosomal alterations that are not commonly seen in the leukemias in the MNSGCT population.

In the above study, cytogenetic studies were performed on the leukemic cells of 13 patients; 38% demonstrated the i(12p) abnormality characteristic of GCTs.12 These findings lend support to the theory that the hematologic malignancies and the MNSGCTs arise from a common progenitor cell. It has been proposed that the leukemic cells develop from a population of neoplastic progenitor cells that are within the yolk sac tumor component of the MNSGCT and that undergo hematopoietic differentiation.46,47 Further research is needed to better understand the pathogen-esis behind this interesting disease association.

The presence of teratomatous elements within EGGCTs raises the possibility of an increased risk for these patients to develop nongerm cell malignancies. Theoretically, these teratomatous elements could undergo somatic differentiation into other types of solid tumors. In fact, the finding of sarcomatous elements (such as rhabdomyosarcoma and angiosarcoma) in MNSGCT specimens lends some credence to this theory.48 Recently, however, Hartmann and colleagues reviewed the records of 635 EGGCT patients, including 287 patients with MNS-GCTs, and found that the incidence of second solid malignancies in this group is not increased when compared with that of age-matched controls.49

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