High level of beta-hCG simulating pregnancy in recurrent osteosarcoma: case report and review of literature

Abstract

Purpose

A high serum level of beta human chorionic gonadotropin (hCG) normally indicates pregnancy in healthy women. We were confused by this finding in one of our patients. This 18-year-old girl presented with amenorrhoea of 1-month duration, a positive pregnancy test and a high beta-hCG serum level although taking contraceptives. Pregnancy was excluded by ultrasound. Three years previously, she had had an osteosarcoma of the humerus. The tumour initially had been wide resected and had shown a good response to neoadjuvant chemotherapy with COSS-96-protocol.

Methods

We reviewed the original histological result and the literature about possible similar findings. We analysed therapeutic options and the value of beta-hCG levels as a therapy monitor.

Results

During examination we detected a recurrent osteosarcoma of the left humerus. The local relapse evidently expressed beta-hCG which, retrospectively, could only sparsely be shown in the primary resectate. After intralesional surgery, chemotherapy and radiotherapy levels of beta-hCG normalised.

Conclusion

Osteosarcoma very rarely is able to produce a paraneoplastic syndrome by high levels of beta-hCG. This may well be of diagnostic value and offer an additional monitoring tool. It can indicate tumour recurrrence and dedifferentiation.

Introduction

The ectopic production of hormones is recognised to be of diagnostic and therapeutic value. Human chorionic gonadotropin (hCG) is a glycoproteine hormone synthesised by syncytiotrophoblasts of the placenta in healthy pregnant women from the sixth day after conception. The HCG can also be produced in gonadal and nongonadal tumours as a paraneoplastic syndrome (Braunstein et al. 1973; Tormey et al. 1975; McManus et al. 1976), but routine measurement of hCG has proved to be of limited use as a diagnostic test (Gailani et al. 1976). The HCG consists of two different noncovalently linked subunits: alpha and beta. The alpha subunit is similar to FSH and LH, and is therefore non-specific and not of use as a tumour marker (Marcillac et al. 1992). The beta subunit is 80% homologous and has 28 amino acid residues at its carboxyl terminal, thus causing beta-hCG’s biological and immunochemical specificity (Hussa 1980). In gynaecology, beta-hCG plays an important role in the diagnosis of pregnancy and pregnancy-related disorders (Fiala et al. 2003). It can also be produced by gestational and germ cell tumours, mainly carcinomas, as a paraneoplastic syndrome (Goldstein et al. 1974). Production of beta-hCG by sarcomas is an uncommon phenomenon that has rarely been documented. We only found a few cases in the literature: one chondrosarcoma (Mack et al. 1977), four leiomyosarcomas (Meredith et al. 1986; Gohji et al. 1993; Seidl et al. 1998; Mansi et al. 2002) and five osteosarcomas (Goldstein et al. 1974; Gailani et al. 1976; Kalra et al. 1984; Ordonez et al. 1989) with high levels of beta-hCG.

The diagnostic and therapeutic value has been matter of debate. We document a case of a recurrent osteosarcoma of the humerus associated with high levels of serum beta-hCG which normalised after intralesional tumour resection and combined chemo- and radiation therapy. Immunohistochemical staining for beta-hCG established the tumour to be the source of this paraneoplastic syndrome. We re-examined the initial tumour retrospectively and found only sparsely expression of beta-hCG. Initial serum level of beta-hCG was also in normal limits (3.4 mU/ml). Although it was wide resected and the initial therapy had a good response, the tumour recurred.

Case report

A 16-year-old girl was referred to us with a permeatic lytic lesion of the proximal humerus on the X-ray (Fig. 1). An incision biopsy was performed and the diagnosis of chondroblastic-osteoblastic osteosarcoma was rendered (Fig. 2a). The girl was treated with neoadjuvant chemotherapy according to protocol COSS-96 of the Cooperative Osteosarcoma Study Group (Bielack et al. 2002). After induction chemotherapy, tumour resection with endoprosthetic reconstruction of the proximal humerus was performed. The resection margin was wide, and a response grade 3 according to the Salzer-Kuntschik classification was achieved (<10% viable tumour). After that, chemotherapy protocol was continued.

Fig. 1.

X-ray of initial tumour. Permeatic lytic lesion of the proximal humerus with severe sclerotic parts, Codmans triangle and a sun burst sign demonstrate a high aggressive periostal reaction. A soft tissue mass surrounds the bone

Fig. 2a,b.

Histology of primary tumour. a Hematoxylin–eosin staining demonstrates a mixed chondroblastic-osteoblastic osteosarcoma (bar=200 mm). b retrospective analysis of beta-hCG expression shows only sparsely positive reaction (arrow; bar=100 mm)

Two years later, the now 18-year-old girl was again admitted to our hospital for pain in the left upper arm of 3-week duration. The girl already had had amenorrhoea for 1 month, although use of contraceptives and a pregnancy test was positive. Serum hCG-level was <0.3 mU/ml, but beta-hCG subunit antibody test was 717.4 mU/ml. We suspected pregnancy, but this could be excluded by ultrasound. The MRI showed a lump in the axillary region at the dorsal aspect of the endoprosthesis of 6–9 cm diameter (Fig. 3a,b). A biopsy was taken and a recurrent chondroblastic osteosarcoma was diagnosed. The patient then received a forequarter amputation because tumour extension next to vital structures did not enable us to perform limb salvage. The histological result showed an intralesional resection margin with a combined lymph node and local relapse. It revealed a poorly differentiated sarcoma with severe proliferative activity (MIB1 50–60%) and massive expression of beta-hCG (Fig. 4a,b). Compared with the primary tumour the tissue showed further dedifferentiation but proved to be a relapse of the previously diagnosed osteosarcoma. We re-examined the initial tumour for beta-hCG expression. Only a few tumour cells were found with a positive staining (Fig. 2b). Reanalysis of the patient’s frozen plasma from the date of initial diagnose demonstrated a serum level of beta-hCG in normal limits (3.4 mU/ml). One week after resection, chemotherapy after COSS-96 relapse protocol with carboplatin and etoposide as well as a radiation therapy were initiated. Serum level of beta-hCG decreased significantly (Fig. 5).

Fig. 3a,b.

Magnetic resonance imaging of recurrent tumour. T1 axial and coronal sequence shows a low intense soft tissue mass in the axillary region (arrows) surrounding the prosthesis (dark with artefacts)

Fig. 4a,b.

Histology of recurrent tumour. a Hematoxylin–eosin staining demonstrates a highly dedifferentiated sarcoma as a relapse of the previously diagnosed osteosarcoma (bar=200 mm). b Immunohistochemical staining shows massive expression of beta-hCG by the tumour cells (bar=100 mm)

Fig. 5.

Patient’s chronological beta-hCG level. The normal value of beta-hCG level in serum is 0–5 mU/ml (red line). Our patient initially had 717.4, after amputation beta-hCG decreased to 59.0. After week 2, combined chemo- and radiation therapy was initiated. In week 6, serum level reached normal value and remained under 0.3 mU/ml. The black line shows the trend

Discussion

To the best of our knowledge, a paraneoplastic expression of beta-hCG has never been involved with pregnancy and has never indicated tumour recurrence. In our patient, a positive urinary test and high serum levels of beta-hCG simulated pregnancy, but the tumour was revealed to be the source of the hormone production.

A high paraneoplastic serum beta-hCG has been well described by several authors, above all, in carcinomas: in 50% of patients with testicular cancers; in 47% of bladder; 32% of pancreatic; and 30% of cervical carcinomas (Marcillac et al. 1992) and subtypes of small cell lung cancer patients (Szurmowicz et al. 1995). In sarcomas, a paraneoplastic syndrome with beta-hCG is rare: Meredith et al. (1986), Gohji et al. (1993), Seidl et al. (1998) and Mansi et al. (2002) found high levels of beta-hCG in four leiomyosarcomas of the small bowel, paratesticular, the spermatic cord and retroperitoneal.

The production of beta-hCG by a primary malignant bone tumour is extremely rare (Table 1). Braunstein et al. (1973) in their study included 12 patients with an osteosarcoma without measurable serum levels of hCG. Gailani et al. (1976) demonstrated one case of five patients with an osteogenic sarcoma and a hCG positive serum level of 3.2 ng/ml. Mack et al. (1977) reported a case of a chondrosarcoma of the pelvis associated with the production of beta-hCG to a level of 5250 mU/ml. Immunoperoxidase staining demonstrated positive evidence of beta-hCG in the cytoplasm of the cartilaginous matrix. Kalra et al. (1984) described a case of a 21-year-old woman with an osteosarcoma of the femur and a high beta-hCG serum level of 5000 mU/ml. A week after palliative hip disarticulation, serum levels decreased to 500 mU/ml. She was treated with a combined chemotherapy but finally died of disease a few weeks later. Immunohistochemistry of the tumour for beta-hCG stained intensely positive. Thereby, they were the first to prove expression of beta-hCG by the tumour cells of an osteosarcoma itself. Ordonez et al. (1989) had also one case of high beta-hCG levels and positive staining in a 26-year-old woman with an osteosarcoma of the fibula. They studied ten additional osteosarcomas and found another case in which some cells were positive for beta-hCG. They concluded that beta-hCG can be used as a marker of persistent or recurrent disease in some uncommon cases of osteosarcoma.

Table 1.

Osteosarcomas with high serum human chorionic gonadotropin (hCG) levels

Reference	No. of patients	Positive for hCG	Expression of tumour cells proven?
Braunstein et al. (1973)	12	0	Not applicable
Goldstein et al. (1974)	2	1	No
Gailani et al. (1976)	5	1	No
Kalra et al. (1984)	1	1	Yes
Ordonez et al. (1989)	11	2	Yes
Total	31	5 (16%)

Other paraneoplastic syndromes and abnormal endocrinological functions with primary osteosarcoma were studied by Goodman et al. (1978). They found abnormal glucose, insulin or growth hormone response curves to oral glucose tolerance tests in 78% of the study population. Elevated somatomedin values were noted in 72% of the patients tested, but changes showed no statistical correlation with any known factor. He therefore constituted a new paraneoplastic syndrome in primary osteosarcoma patients.

In carcinomas, some authors state that a paraneoplastic syndrome with beta-hCG in carcinomas displays an additional prognostic value for more resistant tumours and poor prognosis (Gailani et al. 1976; Szurmowicz et al. 1995). Yoshimura et al. (1994) found a higher incidence of hCG beta-core fragment dependant of the stage of disease from 35.7% in stage 1 to 72.7% in stage 4.

It is concluded that a probable dedifferentiation within malignant cells causes depression of beta-hCG producing genes (Kalra et al. 1984).

Little is reported about the diagnostic and therapeutic value of beta-hCG in osteosarcomas . Kalra’s (1984) patient died of disease. Ordonez et al. (1989) discussed the meaning of beta-hCG as a sign of persistent or recurrent disease. An osteosarcoma after initial wide resection and a good response to chemotherapy very unlikely tends to recur (Picci et al. 1994; Bielack et al. 1996). With a good response to chemotherapy, 73.4% patients stayed relapse free and after wide resection, 64.8% were disease free (Bielack et al. 2002). Although our patient had good prognostic factors, she suffered a relapse. At the moment she is doing well, but follow-up is still short.

Ectopic production of beta-hCG in osteosarcoma is a very rare incident but can be a sign of tumour dedifferentiation. This leads possibly to a more resistant tumour with poor prognosis. In cases of intralesional resection, a combined relapse protocol of COSS-96 and radiation therapy should be used (Ozaki et al. 2003). Our analysis shows that beta-hCG serum level is not only a sign for pregnancy but can be helpful in patients with various malignancies, also osteosarcoma. In such rare cases, beta-hCG serum levels can be used to monitor therapy.