Case Report

Primary intrapelvic seminoma in Klinefelter’s syndrome

Atsushi Kurabayashi,1 Mutsuo Furihata,1 Manabu Matsumoto,1 Hiroshi Sonobe,1 Yuji Ohtsuki,1

Masashi Aki2 and Morimasa Kuwahara2

1Department of Pathology II, Kochi Medical School, Nankoku, Kochi and 2Division of Urology, Fujisaki Hospital,Karatsu, Saga, Japan

but seminomas arising in Klinefelter’s syndrome are extre-mely rare.7–9 We report an unusual case of seminoma from the retrovesicular region, associated with Klinefelter’s syndrome.

CLINICAL SUMMARY

A 39-year-old man was admitted to the Division of Urology,Fujisaki Hospital, Karatsu, Saga, Japan, with the chief com-plaint of dysuria on 3 August 1998. Rectal examination dis-closed a large and hard mass of the prostate. Computedtomography (CT) and magnetic resonance imaging (MRI)revealed that the tumor originated from a retrovesicularregion, and invaded into the prostate (Fig. 1). No tumorlesions were detected in either testis by ultrasound and physical examinations. No mass was detected by diag-nostic imaging of other sites, including the mediastinum. Thetiter of serum lactic dehydrogenase (LDH) was elevated, at728 IU/L (normal range: 277–416. The b-subunit of humanchorionic gonadotrophin (b-hCG) was also slightly elevatedto 0.6 ng/mL (normal range: 0.09–0.41). Serum a-fetoprotein(AFP), g-seminoprotein (g-Sm), prostate-specific antigen(PSA) and carbohydrate antigen (CA) 19-9 were withinnormal limits.

The patient was 175.5 cm tall and weighed 62 kg, and hisarm span was 173.6 cm. He had bilateral atrophic testes,although his penis was normal. Serum luteinizing hormone(LH) and follicle-stimulating hormone (FSH) levels weremarkedly elevated, to 30 mL/L (normal range: 1.8–5.2) and49 mL/L (normal range: 2.9–8.2), respectively. In contrast,the serum testosterone level was decreased at 200 ng/mL,compared with the range in normal adult men which is250–1100). Chromosomal examination from his peripheralblood cells revealed a 47XXY karyotype. (Fig. 2). Based onthese findings, the patient was clinically diagnosed withKlinefelter’s syndrome.

Pathology International 2001; 51: 624–628

Seminoma arising in patients with Klinefelter’s syndrome isextremely rare; to our knowledge, only three cases havebeen reported in the English language literature. We report a case of intrapelvic seminoma in a 39-year-old man withKlinefelter’s syndrome. Gross examination revealed that thetumor was a solid and irregular mass measuring 90 mm indiameter. The cut surfaces of this ill-defined tumor wereyellow–white with necrotic foci. Histologically, the tumorcells were separated into lobules by branching, fibroussepta containing lymphocytes. In some parts of the tumor, acord-like arrangement of tumor cells was present. Immuno-histochemically, the tumor cells were strongly and diffuselypositive for antiplacental alkaline phosphatase antibodyalong their cytoplasmic membranes, but negative for bothchorionic gonadotrophin and a-fetoprotein. Based on thesefindings, we diagnosed this tumor as a seminoma. Thetestes when examined were found to be atrophic bilaterally,but with no tumor lesions. Chromosomal analysis yielded a47XXY karyotype, compatible with Klinefelter’s syndrome.These findings indicate a case of primary intrapelvic semi-noma in Klinefelter’s syndrome. The patient underwentintensive radiation therapy postoperatively, and he demon-strated no evidence of recurrence or metastasis during the13-month period following surgery.

Key words: Klinefelter’s syndrome, pelvis, placental alkalinephosphatase, seminoma

Several neoplasms arising in patients with Klinefelter’s syndrome have been reported, such as breast cancer,1,2 pro-static cancer,3 lymphoma,4 leukemia5 and malignant germcell tumor.6 In particular, the association of breast cancer with Klinefelter’s syndrome is well known, from a number of case reports.1,2 The association of malignant germ celltumor with Klinefelter’s syndrome has also been established,

Correspondence: Mutsuo Furihata, MD, Department of Pathology II,Nankoku, Kochi, 783-8505, Japan. Email: furihata@kochi-ms.ac.jp

Received 8 February 2001. Accepted for publication 6 April 2001.

Seminoma in Klinefelter’s syndrome 625

Pelvic exenteration, ileal conduit and colostomy were performed on 12 September 1998. Intensive postoperativeradiation therapy (intrapelvic 30 Gy; para-aortic 20 Gy) wasdone. After surgery and radiation therapy, the titers of serumLDH and b-hCG decreased to 250 IU/L and 0.4 ng/mL,respectively (within normal limits). The patient has demon-strated no evidence of recurrence or metastasis during the13-month period following surgery.

IMMUNOHISTOCHEMICAL STUDY

The surgically resected specimens were routinely fixed in10% phosphate-buffered formalin solution and embedded inparaffin. An immunohistochemical study with deparaffinizedsections was carried out using the streptavidin–biotin–peroxidase-complex method with a DAKO LSAB kit(Dakopatts, Kyoto, Japan), according to the manufacturer’sinstructions. The antibodies used are summarized in Table 1.For cytokeratin staining, the sections were predigested with0.1% pronase E (Sigma, St Louis, MO, USA) solution at 37°C for 20 min to enhance immunoreactivity.

PATHOLOGICAL FINDINGS

Gross examination revealed that the tumor was a solid andirregular mass measuring 90 mm in diameter. The cut sur-faces of this ill-defined tumor were yellow–white with necroticfoci (Fig. 3).

Figure 1 Sagittal T2-weighted magnetic resonance imaging of thepelvis in a patient with Klinefelter’s syndrome shows a heteroge-neously hyperintense large mass between the urinary bladder (U)and rectum (R). T, tumor.

Figure 2 Chromosome analysis ofperipheral blood showing a 47XXY kary-otype in the patient.

Histologically, the tumor cells were separated into lobulesby branching, fibrous septa (Fig. 4a) containing stromal lym-phocyte infiltration (Fig. 4b). The tumor cells invaded into theprostate and muscular coat of the urinary bladder, but not intothe rectum. The mucosa of the bladder was intact. Foci ofnecrosis were present in the tumor. In some parts of the

tumor, a cord-like arrangement of tumor cells was present.The tumor cells had centrally or slightly eccentrically located,hyperchromatic, large nuclei with one or two large prominentnucleoli, and a clear or granular cytoplasm. Cell borders wererelatively distinct. Some of the tumor cells contained glyco-gen granules (demonstrated by periodic acid–Schiff [PAS]staining). Immunohistochemically, antiplacental alkalinephosphatase (PLAP) antibody was detected to stain homo-geneously and strongly along the cytoplasmic membrane ofthe tumor cells (Fig. 4b). Tumor cells were negative whenstained with antibodies to neuron-specific enolase (NSE), S-100 protein, vimentin, leukocyte common antigen (LCA),hCG, AFP and cytokeratin. Based on our findings, we diag-nosed this tumor as a seminoma.

DISCUSSION

Klinefelter’s syndrome is a sex-chromosome anomaly occur-ring most frequently in patients with primary gonadal deficien-cies. Patients with Klinefelter’s syndrome tend to developmany kinds of neoplasms. Reports have revealed a high inci-dence of male breast cancer in patients with Klinefelter’s syn-drome.2 Indeed, the incidence of breast cancer in patientswith this syndrome has been estimated to be approximately20 times that in normal men.10 The hormonal changes associ-ated with Klinefelter’s syndrome were thought to be one ofthe risk factors of breast cancer.10,11 Reports also show a30–40 times higher incidence of Klinefelter’s syndrome inpatients with mediastinal extragonadal germ cell tumor(EGCT), compared to that in the general population.12 Gener-ally, EGCT develops due to the failure of migration of germcells from the primitive yolk sac to the gonadal ridge, inembryonic development. Sogge et al. suggested that thechromosomal abnormality associated with Klinefelter’s syn-drome may contribute to the development of germ celltumors.13 However, the reason for the higher incidence ofEGCT in patients with Klinefelter’s syndrome remainsunclear.

More than 70% of all EGCT arise in the mediastinum.6,14

The most common histological type of EGCT is seminoma.14

However, Gohji et al. reported that the most common histo-logical types of EGCT associated with Klinefelter’s syndromewere teratocarcinoma (32%) and choriocarcinoma (19%).6

Only three cases of seminomas in patients with Klinefelter’ssyndrome have been reported in the English language literature; two occurring in the testis and one in both the ret-roperitoneum and mediastinum.7–9 To our knowledge, onlyone case of extragonadal seminoma in Klinefelter’s syn-drome has been reported, out of more than 40 cases ofextragonadal germinal tumors associated with Klinefelter’ssyndrome.6,15–24 The rarity of seminoma in patients with Klinefelter’s syndrome has not yet been explained.

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Table 1 Antibodies used for immunohistochemistry

Antibody Dilution Source

MonoclonalCytokeratin (AE1/AE3) 1:400 Boehringer-Mannheim,

Indianapolis, IN, USACytokeratin (CAM5.2) 1:20 Becton-Dickinson,

San Jose, CA, USAEMA 1:50 Dakopatts, Kyoto, JapanLCA Neat DakopattsPSAP 1:200 DakopattsNSE 1:50 Dakopattsp53 1:30 Dakopatts

PolyclonalS-100 1:800 DakopattsPSA 1:200 DakopattsPLAP 1:200 DakopattshCG 1:400 DakopattsAFP 1:200 DakopattsVimentin 1:50 Dakopatts

AFP, a-fetoprotein; EMA, epithelial membrane antigen; hCG, humanchorionic gonadotrophin; LCA, leukocyte common antigen; NSE, neuron-specific enolase; PLAP, placental alkaline phosphatase; PSA, prostate-specific antigen; PSAP, prostate acid phosphatase.

Figure 3 Gross examination of the tumor, a solid and irregularmass. The cut surfaces of the ill-defined tumor are yellow–white, withnecrotic foci. U, urinary bladder; T, tumor.

Seminoma in Klinefelter’s syndrome 627

In the present case, the diagnosis of seminoma was basedon the characteristic histology of this type of this tumor. Thediagnosis was supported by the results from the immunohis-tochemical studies, in particular the lack of staining for epithe-lial markers and the presence of staining for PLAP in themajority of the tumor cells. Although the titer of b-hCG wasslightly elevated at 0.6 ng/mL (normal range: 0.09–0.41), thisis almost borderline to normal levels. In a previous report of apatient with Klinefelter’s syndrome and choriocarcinoma, theb-hCG titer was 42 000 ng/mL.25 In our case, no componentof choriocarcinoma was found histologically, and immunohis-tochemically, the tumor cells were negative for hCG andcytokeratin.

The problem was to determine whether the intrapelvicseminoma was primary or secondary. It has been demon-

Figure 4 The tumor cells are separated into lobulesby branching, fibrous septa. (a) The tumor cells havecentrally or slightly eccentrically located, hyperchro-matic, large nuclei with one or two large prominentnucleoli, and a clear or granular cytoplasm. Cell bordersare relatively distinct (HE). (b) Immunohistochemically,antiplacental alkaline phosphatase shows homoge-neous and strong staining along the cytoplasmic mem-brane of tumor cells, but not lymphocytes, in the fibroussepta.

strated that metastases from an occult testicular tumor maymasquerade as a primary extragonadal germ cell tumor, if theoriginal tumor site regresses.26 One report revealed evidenceof carcinoma in situ in testicular biopsy specimens in 53% of15 patients with EGCT.27 In our case, both testes of thepatient were atrophic, and testicular biopsy was unsuccess-ful. No tumor lesions were detected in the testes by ultra-sound and physical examination, and no mass was detectedby diagnostic imaging of other sites, including the medi-astinum. Based on these results, we diagnosed primaryintrapelvic seminoma.

In conclusion, this is a case report of primary extragonadalseminoma associated with Klinefelter’s syndrome. Thereason for the rare incidence of seminoma associated withKlinefelter’s syndrome is unclear, because the mechanism of

tumorigenesis of germ cells to seminoma in patients withKlinefelter’s syndrome remains unclear. However, systematicexamination including the intrapelvic region in patients withKlinefelter’s syndrome should be routinely carried out, andfurther studies of additional cases are needed to clarify themechanism of tumorigenesis of germ cells to seminoma.

ACKNOWLEDGMENT

The authors thank Mr Takuya Yamaguchi (Department ofPathology, Kochi Medical School, Nankoku, Kochi, Japan) forhis technical assistance.

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