At a Glance
Although the most common cause of an elevated HCG level in females is pregnancy, occasionally, a HCG-secreting tumor is suspected and other conditions such as gestational trophoblastic disease (GTD), nontrophoblastic neoplasms, or a pituitary source of HCG, must be considered. The clinical description of the various trophoblastic and nontrophoblastic conditions is discussed only briefly, since ultrasound examination, along with histology is key to their diagnosis. The source of HCG in males is usually not a major confounding factor and is not considered in this discussion.
GTD comprises two benign forms (partial or complete hydatiform mole) and four malignant forms (invasive hydatiform mole, choriocarcinoma, placental site trophoblastic tumor, and its variant epitheliod trophoblastic tumor). Most women with benign GTD present with vaginal bleeding during pregnancy or suspected miscarriage in early pregnancy. These events usually lead to pelvic ultrasonography, histologic examination of the products of conception, and determination of serum HCG levels following which these conditions are suspected. Less frequently, patients present with uterine enlargement greater than expected for gestation, hyperemesis and pregnancy-induced hypertension.
Patients with invasive hydatiform mole or choriocarcinoma typically present with bleeding, following evacuation of the hydatiform mole, or with a metastatic lesion in the vagina.
Patients with choriocarcinoma have no characteristic signs and symptoms but may have symptoms related to invasion of the uterus by the tumor or because of distant metastasis. The lung is the most common site of distant metastasis and patients may present with dyspnea, chest pain and hemoptysis.
Patients with placental site trophoblastic tumor and its variant usually present with irregular bleeding and a past history of nonmolar gestation. In these patients, HCG levels are low, compared to the volume of disease present on imaging studies, and free BETA subunit levels are high.
In all of the mentioned conditions, the HCG levels can show a wide range from minimal elevation to massive elevation.
What tests should I request to confirm my clinical Dx? In addition, what follow-up tests might be useful?
HCG levels are elevated in all forms of GTD and are very important for diagnosis and post-treatment follow-up of these conditions.
Ultrasonography during pregnancy and histologic examination of any tissue obtained via curettage or following a miscarriage is a must. Ultrasonography can show the typical “snow storm” appearance in a complete hydatiform mole. Histologic findings are characteristic for the various morphologic subtypes (benign and malignant). Flow cytometry can be a useful adjunct modality to differentiate between hydatiform mole (diploid DNA content) and partial hydatiform mole (triploid by DNA content).
As follow-up testing, NLRP7 mutations have been found in some types of moles (androgenetic diploid complete moles and some triploid partial moles). Immunohistochemical staining for P57 is visible in placenta of all types of gestations, apart from androgenetic complete mole.
Are there any factors that might affect lab results?
The most important thing to appreciate about HCG testing is that not all HCG tests are the same and that different HCG assays detect the various HCG variants and degradation products with varying specificities.
HCG is comprised of α subunit shared with thyroid stimulating hormone (TSH), luteinizing hormone (LH), and follicular stimulating hormone (FSH), as well as a distinct b subunit that has significant similarity to the b subunit of LH. The term HCG encompasses three types of b HCG variants: regular HCG, hyperglycosylated HCG, and free b subunit. All three variants can be nicked by a protease to generate nicked HCG, nicked hyperglycosylated HCG, and a nicked free b subunit. Each “nicked” product can undergo further proteolytic degradation with loss of C-terminal peptide (CTP) to result in nicked HCG missing CTP, nicked hyperglycosylated HCG missing CTP, and a nicked free b-subunit missing CTP.
Trophoblastic tumors can make an excess of the secreted free a subunit. Thus, there are at least ten common degradation variants of HCG that could be detected in an ideal assay. During early pregnancy, most of the HCG is hyperglycosylated HCG. As the pregnancy advances, regular HCG increases, and, by the second or third trimester, hyperglycosylated HCG is only about 2% of total HCG. It can, thus, be appreciated that early pregnancy could be missed if the assay does not reliably detect hyperglycosylated HCG.
Regular HCG is made by syncytiotrophoblastic cells, and hyperglycosylated HCG is made by extravillous cytotrophoblast cells. Hyperglycosylated HCG is the principal form of HCG produced in a choriocarcinoma and is important for tumor invasion. The free b subunit is produced in many nontrophoblastic malignancies and is considered a poor prognostic marker for cancer. Its urine degradation product is the b-core fragment, which is a better marker for nontrophoblastic neoplasms.
Currently, HCG assays are only approved for the detection of pregnancy, and none are approved for the diagnosis of gestational trophoblastic disease or malignancy. It is important for the clinician to be aware of the specificity of the HCG assays used by their clinical laboratory. Thus, assays that detect only intact HCG dimer should be avoided in clinical practice. Most current assays are total HCG assays, also known as β HCG assays, which detect intact HCG dimer, as well as free b subunit, along with some of the nicked degradation products with varying sensitivity and specificity.
These problems arise, supposedly, because FDA regulations do not require that HCG assays detect hyperglycosylated HCG found in early pregnancy and the free b subunit that is produced in cancers. The Siemens Immulite assay for serum HCG is, perhaps, the best assay in detecting most of these variants. The Beckman Ikon 25 point of care assay is considered one the best for qualitative detection of urine HCG.
What lab results are absolutely confirmatory?
Histologic studies, along with appropriate ultrasound findings and HCG levels in the appropriate clinical background, are diagnostic.
Additional Issues of Clinical Importance
One must always be aware of the possibility of a HCG result being falsely positive or falsely negative. False positive results have led to patients being erroneously diagnosed with GTD, testicular cancer, or other malignancies, causing needless surgery or chemotherapy.
False positives can occur in individuals exposed to certain animals or animal byproducts. These individuals can form human antibodies against the animal antibodies (HAAAs) used in HCG assays, or sometimes humans naturally generate antibodies that cross react with animal antibodies (heterophilic antibodies). Since human antibodies are bivalent, these can bind to the capture and tracer antibodies used in the assay mix, with resultant false-positive results.
False positives due to HAAAs and heterophilic antibodies can be proven by showing the absence of HCG in urine (assuming that serum HCG is over 150 mIU/mL). Another method is to test the serum at two outside labs that use different antibody reagent kits. If the results vary greatly, or are otherwise discordant, a false positive may be presumed.
False negatives can occur with levels of HCG above 500,000 mIU/mL due to the “hook effect” because of the consumption of all antibody binding sites on both antibodies, permitting few or no sandwiches in the immunometric assay. In pregnancy, HCG rarely exceeds 200,000 mIU/mL, whereas, in a hydatiform, mole levels of up to 3 million mIU/mL have been described. When a false negative is suspected, the physician should request the laboratory to perform a 1 in 1000 serum dilution and then reassay. False negatives are significant, because they can lead to delayed diagnosis or even premature withdrawal of therapy.
Errors in Interpretation
Occasionally, a low level of HCG is detected in women around menopause, which raises questions regarding the possibility of a pregnancy, GTD, or even cancer. In these situations, the pituitary as the source of HCG should be a consideration. During perimenopause, estrogen levels decline. Estrogen normally inhibits GnRH production by feedback inhibition, but because of the lack of estrogen GnRH levels are not inhibited, which leads to detectably high LH and HCG levels of pituitary origin.
GTD can occasionally be complicated by hyperthyroidism. This occurs due to molecular mimicry between HCG and TSH in their mechanism of action. The HCG receptors share some similarity with the TSH receptor in thyroid tissue, as a result, very high levels of HCG can lead to increased secretion of FT3 and FT4, as well as a low TSH due to feedback inhibition. This hyperthyroidism due to increased HCG usually disappears following treatment of the GTD.
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