hCG: Utility as a biomarker in different tumours
Gestational trophoblastic diseases
The utility of the hCG as a biomarker has been widely validated in gestational trophoblastic diseases (GTD) . GTD is a group of pregnancy related disorders that originate from trophoblast cells. The group consists of benign and malignant diseases, the malignant ones are known as gestational trophoblastic neoplasia (GTN), such as invasive mole, choriocarcinoma, placental site trophoblastic tumour, and epithelioid trophoblastic tumour .
hCG is considered the ideal tumour marker for every gestational trophoblastic disease. In fact, women with hydatidiform mole are normally monitored via hCG to detect possible persistent trophoblastic disease. According to multiple studies, sensitivity and specificity for trophoblast malignant tissue is close to 100% . By measuring the circulating concentration of total hCG, it is possible to determine the amount of hydatidiform mole or tumour tissue as the relationship is proportional. This hormone is also used for diagnosis and follow-up of the effectiveness of GTN therapy. During the follow-up of these malignancies, assay of hCG alone is sufficient but the determination of βhCG can reveal a relapse earlier than hCG. The half-life of subunit free βhCG is longer, so the ratio between βhCG/hCG will increase when the levels of hCG decrease after successful therapy.
Germ cell tumours
Moreover, we can find serum hCG in germ cell tumours. Testicular cancer is the most common solid tumour malignance in males between 15–35 years of age . Testicular cancers are classified as seminomas and non-seminomatous germ cell tumours (NSCGTs), the expression of hCG is different between them. Despite its lower sensitivity in testicle cancer than in trophoblastic tumours, hCG is still used in practice, as shown below. It is possible to observe the serum expression of hCG in both groups, but high serum concentrations (300–1000 IU/l) only occur in NSCGTs. Elevated serum levels of hCG occur in 40–50% of patients with NSCGT and only 15–20% in those with seminomas. The evaluation of hCG and βhCG may help to detect a relapse of the disease . About the symptoms, serum hCG elevation in adult men results in gynecomastia and hyperthyroidism, whereas rising levels in children leads to early puberty.
Among female germ cell tumours, the most prevalent group is dysgerminomas . These germ cell tumours of the ovary often express hCG and it can be used for daily clinical management of the tumour. As in testicular cancer, the levels of the biomarker decline after surgery or treatment, reflecting the efficacy of the treatment or operation. In addition to this, hCG levels depend on the histological type and burden of isease. When we have a histologically undifferentiated tumour, biomarkers such as hCG α-fetoprotein are a valuable clue about what type of cells form the tumour . In our opinion, it’s worth mentioning that this serum marker could be useful in staging and evaluating the disease.
In recent years, the importance of this hormone as a biomarker of trophoblastic and non-trophoblastic tumours has increased. In fact, elevated expression of hCG in serum, urine or tumour tissue is a strong indicator of an adverse prognosis in many non-trophoblastic tumours. In particular, carcinomas of the bladder, urinary tract, lung and breast may have increased hormone levels. The immunoreactivity is mainly for βhCG (30–60%
of non-trophoblastic tumours produce βhCG but not hCG).
As mentioned before, high concentrations of hCG have been observed in human tumours that do not derive from the trophoblastic tissue. Usually, laboratories evaluate both hCG and βhCG to measure total βhCG increase. Among non-trophoblastic tumours, hCG has been described more widely in bladder and urinary tract tumours, showing a strong relationship with poor prognosis, resistance to radiotherapy and metastatic behavior. The interpretation should be cautious elevated because expression has been observed in healthy urothelial cells also . In lung cancer, hCG levels in serum above 5 IU/L were observed in 12–14% of small cell lung cancers, and these were associated with short survival. Expression on serum βhCG is not associated with any specific histological subtypes, although some authors have found that is more common in adenocarcinoma . With regard
to breast cancer, between 10 and 50% of patients have been found to have increased hCG in serum – this relationship has been studied but the results are not clear-cut. This finding could be related to menopausal status and cross reaction with LH: clearly elevated status is rare. However, changes in βhCG levels did not reflect properly the effectiveness of the chemotherapy.
Finally, to give a comprehensive overview of the topics discussed thus far, we are sharing our experience of a very fascinating case. A 50-year-old female non-smoker was admitted to the emergency service with stomach pain and abnormal menstrual bleeding. She had no relevant medical antecedents. The initial analysis revealed that hCG levels were elevated 3487 IU/L. Subsequent ultrasound examinations by the medical team appeared to be normal. Ultimately, she was diagnosed with extrauterine gestation versus incipient gestation. After this, treatment with methotrexate was started. A week later, the patient returned to the hospital for a routine follow-up. hCG serum levels were still elevated, so the patient was admitted to hospital. During the following days, our team discussed the case with the tumour committee, and, given her hCG levels, the decision was to do a CT scan. The imaging revealed a multi-cystic lesion in the right upper lobe of the lung, supporting the diagnosis of a malignant tumour. Our colleagues from pathological anatomy confirmed a squamous cell carcinoma of the lung (P40+ TTF1˗). The patient underwent a bilobectomy and chemotherapy. Right after these procedures her hCG levels fell (Fig. 1a). In the following year, she experienced multiple relapses, each coinciding with an elevation in hCG levels. In 2022, her last relapse, was detected initially through hCG analysis, and subsequently confirmed with the reappearance of a hypermetabolic component (Fig. 1b).