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Year : 2015  |  Volume : 11  |  Issue : 4  |  Page : 1034

Mediastinal mixed germ cell tumor in an infertile male with Klinefelter syndrome:A case report and literature review

1 Department of Pathology and Laboratory Medicine, Pushpanjali Crosslay Hospital, Delhi, India
2 Department of Surgery, Post Graduate Institute of Medical Education and Research, Chandigarh, India
3 Department of Pathology and Laboratory Medicine, Moffitt Cancer Center, Tampa, Florida, USA

Date of Web Publication15-Feb-2016

Correspondence Address:
Dinesh Pradhan
84D, Sukhdev Vihar, New Delhi - 110 025
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-1482.150697

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 > Abstract 

Klinefelter syndrome (KS) is a well-documented abnormality of the sex chromosome, with an incidence of 1 in 600 newborn males. It is characterized by a 47, XXY or a mosaic karyotype, hypergonadotrophic hypogonadism, infertility, reduced body hair, gynecomastia, and tall stature. Different neoplasms such as breast, testicular, and lymphoreticular malignancies may occur in 1% to2% of the cases with KS. Herein we describe a case of mediastinal mixed germ cell tumor (GCT) in a 40-year-old male with KS. Interestingly, this case also had mitral valve prolapse, and an incidental papillary microcarcinoma of the thyroid gland. In view of the presence of pulmonary nodules, antemortem differential diagnoses considered were mycobacterial infection, lymphoma, thymic carcinoma, and a primary/metastatic neoplasm of the lung. As GCT was not considered, the serum markers of a GCT were not performed. The diagnosis of this rare mediastinal mixed GCT with KS was made at autopsy.

Keywords: Germ cell tumor, Klinefelter syndrome, mediastinum, mitral valve prolapse, papillary thyroid carcinoma

How to cite this article:
Pradhan D, Kaman L, Dhillon J, Mohanty SK. Mediastinal mixed germ cell tumor in an infertile male with Klinefelter syndrome:A case report and literature review. J Can Res Ther 2015;11:1034

How to cite this URL:
Pradhan D, Kaman L, Dhillon J, Mohanty SK. Mediastinal mixed germ cell tumor in an infertile male with Klinefelter syndrome:A case report and literature review. J Can Res Ther [serial online] 2015 [cited 2019 Sep 21];11:1034. Available from: http://www.cancerjournal.net/text.asp?2015/11/4/1034/150697

 > Introduction Top

Klinefelter syndrome (KS) is the most common disorder that affects the sex chromosome.[1] It is characterized by one or more additional X chromosomes, which is usually acquired through a non-disjunction during parental gametogenesis of either paternal (53%) or maternal (44%) origin.[1] Various neoplasms including breast, testicular, and lymphoreticular malignancies may occur in individuals affected by KS.[2] Whether the risk of tumor occurrence is higher in KS or not, remains elusive and needs further research. However, the incidence of primary mediastinal germ cell tumors (GCT) is clearly increased.[3] In all, 8% of male patients with primary mediastinal GCT have KS.[4],[5] Herein we describe a case of mediastinal mixed GCT in a 40-year-old male with a 47, XXY karyotype. Massive pleural and pericardial effusion was the main hindrance for an antemortem needle core biopsy of the mediastinal mass. The diagnosis of mediastinal mixed GCT was made at autopsy.

 > Case Report Top

A 40-year-old male was admitted to the hospital with low-grade fever, persistent cough with expectoration, grade III dyspnea, and pleuritic type of chest pain for five months. He also had significant weight loss. He was a smoker for the last 20 years and used to smoke 6–8 cigarettes per day. On examination there was marked pallor and a localized non-tender bulge over the right side of the anterior chest wall.

The chest radiograph showed massive bilateral pleural effusion, pericardial effusion, and multiple cannon ball-like opacities on the bilateral lung fields with mediastinal widening. The differential diagnoses considered were metastatic tumor from unknown primary, pulmonary tuberculosis with disseminated infection, thymoma, or lymphoma. An image-guided needle core biopsy or fine needle aspiration was highly warranted at that stage but due to massive serous effusions that could not be done. Moreover, due to the rapidly deteriorating course of the patient and a very short survival of 12 hours after hospital admission, a computed tomography (CT) scan of the chest, CT abdomen or a positron emission tomography - CT (PET-CT) were not performed. Ultrasound of the abdomen showed a hypoechoic nodule in the upper part of the right lobe of the liver measuring 5.6 × 4.2 × 2.1 cm. The patient developed cardiopulmonary arrest and could not be revived.

A complete autopsy including the dissection of the brain was performed. A large anterior mediastinal tumor measuring 18 × 14 × 9 cm was seen extending into the bilateral pleura, lungs, parietal pericardium, and diaphragm forming subdiaphragmatic nodules. The tumor was lobulated and tan-grey. The cut surfaces were soft and variegated with solid, cystic, gelatinous, hemorrhagic, and necrotic areas [Figure 1]. Bilateral pulmonary tumor nodules, ranging from 0.9 cm to 9.6 cm were present. Direct extension of the tumor into the superior vena cava was also observed.
Figure 1: Heart lung complex showing a large anterior mediastinal tumor infiltrating bilateral pleura, lungs, parietal pericardium, and diaphragm. The tumor is lobulated, tan-grey, and has variegated appearance with solid, cystic, gelatinous, hemorrhagic, and necrotic areas

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Histology showed a mixed GCT with yolk sac tumor (YST) (70%) and immature and mature teratoma (IT) (30%) components [Figure 2]. Within the YST, various architectural patterns including endodermal sinus pattern with Schiller-Duval bodies [Figure 3], microcystic, myxomatous, macrocystic, papillary, alveolar-glandular, solid, and polyvesicular vitelline patterns were identified. Numerous periodic acid Schiff positive and diastase resistant intracytoplasmic and extracellular hyaline globules were present. The tumor cells were immunoreactive for alpha fetoprotein (AFP) [Figure 4]. Frequent mitosis, marked nuclear atypia, and extensive necrosis were noted. The IT component comprised of immature neuroepithelium admixed with mature cartilage, smooth muscle, and respiratory epithelium [Figure 5] and [Figure 6].
Figure 2: Low power photomicrograph showing mixed GCT with yolk sac tumor and immature and mature teratoma components (H and E, ×20)

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Figure 3: Higher power photomicrograph showing Schiller-Duval bodies indicating endodermal sinus pattern of Yolk Sac Tumor (H and E, ×20)

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Figure 4: Photomicrograph showing diffuse and strong cytoplasmic immunoreactivity for alpha feto protein within the yolk sac tumor areas (AFP, ×40)

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Figure 5: Photomicrograph showing the immature teratoma component comprising of immature neuroepithelium with rosettes (H and E, ×40)

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Figure 6: Photomicrograph showing the mature teratoma component in the form of cartilage within the tumor (H and E, ×40)

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Human chorionic gonadotropin, CD117, CD30, placental alkaline phosphatase, and epithelial membrane antigen were negative. Postmortem serum showed a very high AFP levels, whereas other tumor markers were not elevated.

The mitral valve showed interchordal hooding, elongation, and thickening of the posterior leaflets with attenuated and elongated chordae tendineae [Figure 7]. On microscopy there was myxoid degeneration of the mitral valve leaflet with significant thickening of the spongiosa and the fibrosa of the posterior leaflet, features consistent with a mitral valve prolapse (MVP) [Figure 8]. An incidental papillary microcarcinoma (0.8 cm in diameter) was detected in the right lobe of the thyroid gland [Figure 9] and [Figure 10]. Bilateral testes were of normal size. Microscopy of both testes showed diffuse leydig cell hyperplasia, mild atrophy of the seminiferous tubules, and peritubular fibrosis [Figure 11]. No tumor was present in the testes. Retroperitoneum, mesenteric, and periaortic lymph nodes were not involved by the tumor. A postmortem diagnosis of primary mediastinal mixed GCT (yolk sac and immature and mature teratoma components) was rendered. Chromosomal analysis done from postmortem blood sample revealed 47, XXY karyotype indicating KS in this patient.
Figure 7: The mitral valve with interchordal hooding, elongation, and thickened posterior leaflets and attenuation and elongation of chordae tendineae

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Figure 8: Myxoid degeneration of the mitral valve leaflet (Periodic acid Schiff- Alcian blue stain with significant thickening of the spongiosa and the fibrosa) (PAS-AB, ×20)

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Figure 9: Low power photomicrograph showing the incidental papillary microcarcinoma which was detected in the right lobe of the thyroid gland (H and E, ×20)

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Figure 10: High power photomicrograph of the papillary microcarcinoma showing papillary architecture, nuclear stratification and nuclear clearing (H and E, ×40)

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Figure 11: High power photomicrograph of the testis showing diffuse leydig cell hyperplasia, atrophy of the seminiferous tubules, and peritubular fibrosis (H and E, ×40)

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 > Discussion Top

KS remains undiagnosed in a significant number of males. KS has been shown to be associated with several malignancies including extragonadal GCTs mainly in the mediastinum. GCT are rare malignancies accounting for only 3.4% of all pediatric malignancies.[6] Schneider et al., analyzed tumor tissue of 20 children with nonseminomatous GCT, between age 1 week and 17 years. In younger patients (<8 years), a gain of chromosome 20 or 20p was frequent (70%), whereas in adolescents (>8 years) gains of 12p (60%) and X (50%) were the most frequent chromosomal abnormality.[7]

The pathogenesis of extragonadal GCTs has been postulated to be related to abnormal and/or incomplete migration of the primordial germ cells from the endoderm of the yolk sac to the gonads.[1] This abnormal localization may later result in malignant transformation of the midline germ cells along the urogenital ridge.[7],[8] The increased frequency of neoplastic transformation of germ cells in KS might be a result of the hormonal imbalance with persistently elevated gonadotropin levels.[7] Another explanation to carcinogenesis is by the role of genetic factors on the X chromosome. Genome sequencing have provided evidence for a testicular GCT susceptibility gene at Xq27.[9] However, it will require further studies to unfold why the increased risk of germ cell tumors associated with KS is apparently exclusively related to nonseminomatous neoplasms of mediastinal location.

Interestingly, our case had MVP with mid-systolic click. Fricke et al., have published a series on the association of MVP with KS that shows an increased incidence of MVP in KS patients.[10] The index case is also unique in the sense that no report of thyroid carcinomas in KS cases is available in the English literature.

In conclusion, association between KS and primary mediastinal GCT has been reported and hence it can be recommended that any male patient with KS and a mediastinal mass should undergo a thorough clinical examination, serum markers assay, and if possible, a needle core biopsy to arrive at a definitive diagnosis as the management and prognosis of a GCT is much favorable as compared to primary and secondary tumors of the lung, and is significantly different from a thymic neoplasm, lymphoma, and infective pathologies.

 > References Top

Volkl TM, Langer T, Aigner T, Greess H, Beck JD, Rauch AM, et al. Klinefelter syndrome and mediastinal germ cell tumors. Am J Med Genet A 2006;140:471-81.  Back to cited text no. 1
Aguirre D, Nieto K, Lazos M, Pena YR, Palma I, Kofman-Alfaro S, et al. Extragonadal germ cell tumors are often associated with Klinefelter syndrome. Hum Pathol 2006;37:477-80.  Back to cited text no. 2
Hasle H, Mellemgaard A, Nielsen J, Hansen J. Cancer incidence in men with Klinefelter syndrome. Br J Cancer 1995;71:416-20.  Back to cited text no. 3
Hasle H, Jacobson BB, Asschenfeldt P, Andersen K. Mediastinal germ cell tumor associated with Klinefelter syndrome. A report of case and review of the literature. Eur J Pediatr 1992;151:735-9.  Back to cited text no. 4
Matsuoka K, Orikasa H, Eyden B, Yamazaki K. Postmortem diagnosis of “occult” Klinefelter syndrome in a patient with chronic renal disease and liver cirrhosis. Arch Pathol Lab Med 2002;126:359-61.  Back to cited text no. 5
Miller RW, Young JL Jr, Novakovic B. Childhood cancer. Cancer 1995;75:395-405.  Back to cited text no. 6
Schneider DT, Calaminus G, Koch S, Teske C, Schmidt P, Haas RJ, et al. Epidemiologic analysis of 1,442 children and adolescents registered in the German germ cell tumor protocols. Pediatr Blood Cancer 2004;42:169-75.  Back to cited text no. 7
Carroll PR, Whitmore WF Jr, Richardson M, Bajorunas D, Herr HW, Williams RD, et al. Testicular failure in patients with extragonadal germ cell tumors. Cancer 1987;60:108-13.  Back to cited text no. 8
Lutke Holzik MF, Rapley EA, Hoekstra HJ, Sleijfer DT, Nolte IM, Sijmons RH. Genetic predisposition to testicular germ-cell tumors. Lancet Oncol 2004;5:363-71.  Back to cited text no. 9
Fricke GR, Mattern HJ, Schweikert HU, Schwanitz G. Klinefelter's syndrome and mitral valve prolapse. An echocardiographic study in twenty-two patients. Biomed Pharmacother 1984;38:88-97.  Back to cited text no. 10


  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11]


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