when evaluating patients for clinical trial , intrauterine pregnancy is commonly considered an exclusion criteria , however guidelines do not exist to determine what to do should a pregnancy test result as positive .
the patient underwent standard - of - care therapy upfront with progression of disease and was referred to investigational therapeutics for phase i treatment .
pelvic ultrasound and -hcg heterophilic antibody testing were negative ruling out intrauterine and ectopic pregnancy or phantom hcg .
her elevated -hcg appeared consistent with paraneoplastic syndrome reflected in a decline in -hcg that correlated with a response to treatment .
a 34-year - old african american female with metastatic mucinous ovarian carcinoma presented with a pelvic mass discovered during her annual gynecological examination .
an ultrasound showed a 7.7    8.7  cm left ovarian mass with complex appearance .
laparoscopic left salpingo - oophorectomy showed a moderately differentiated mucinous ovarian carcinoma , stage ic1 , due to intraoperative rupture of the ovarian mass .
tumor cells were diffusely positive for keratin 7 and very focally positive for keratin 20 .
the patient was taken for diagnostic laparoscopy with appendectomy , omentectomy , and multiple peritoneal biopsies by a gynecologic oncologist ; all of which were negative for malignancy .
eight weeks later the patient started adjuvant chemotherapy with one cycle of capecitabine and oxaliplatin ( xelox ) , transitioned to four months of fluorouracil and oxaliplatin ( folfox ) due to insurance issues .
the ct abdomen and pelvis post folfox chemotherapy showed an enhancing 2.6  cm nodule in rectus abdominis muscle .
the patient underwent an exploratory laparotomy with excision of a 5    6  cm abdominal mass involving fascia and muscle , consistent with metastatic adenocarcinoma .
after recovery , the patient received chemotherapy with carboplatin and paclitaxel for 6  months .
the ct abdomen and pelvis performed following 6  months of carboplatin and paclitaxel showed progression of disease with new nodal and perihepatic implants .
the patient subsequently consulted with the md anderson cancer center department of investigational cancer therapeutics for phase i clinical trial options .
the patient was treated with a phosphatidylinositol-4,5-bisphosphate 3-kinase ( pi3k ) inhibitor plus a mitogen / extracellular signal - regulated kinase ( mek ) inhibitor with progression of disease after 5  months .
she then started on a second phase i trial with a polymeric micellar nanoparticle of the substance dach - pt ( 1,2-diaminocyclohexane platinum ) , an in vivo metabolite of oxaliplatin , with progression following 1  cycle of therapy .
the patient was then enrolled in a trial with paclitaxel , bevacizumab and temsirolimus ( pat ) . on the day of clearance to start treatment , she was found to have a positive urine and serum pregnancy test .
the left ovary was surgically absent however the right ovary was enlarged with complex cystic mass with solid components measuring 9.5    6.6  cm .
the work - up for false positive elevation of -hcg including serial dilutions , incorporation of animal serum and outside institutional validation testing for -hcg heterophile antibody , was negative .
therefore , the -hcg elevation was not thought to be related to a phantom hcg .
dilation and curettage to rule out trophoblastic disease was planned , but not completed due to discovery of a deep vein thrombosis and initiation of therapeutic anticoagulation .
as no intrauterine or extrauterine pregnancy could be identified , after several weeks , the patient returned to clinic and was cleared to start treatment . at that time , her -hcg was 210.3 .
three weeks post treatment with pat , the -hcg decreased to 27.5 and ct scans showed partial response ( fig .
, the patient was admitted to the intensive care unit for weakness due to guillain barre syndrome .
nearly all female patients undergoing enrollment on clinical trial are evaluated for pregnancy as part of standard exclusion criteria .
an elevated -hcg in the absence of viable pregnancy can occur for multiple reasons and has a broad differential diagnosis including miscarriage , ectopic pregnancy , pituitary hcg production , trophoblastic disease and phantom hcg .
ectopic pregnancy is frequently suspected when -hcg levels plateau or fail to double within 48  h without evidence of intrauterine pregnancy with ultrasound . when intrauterine and extrauterine pregnancy are ruled out ,
pituitary hcg may be produced in perimenopausal or postmenopausal women . as estrogen and progesterone production decreases , releasing gonadotropin releasing hormone ( gnrh ) from negative feedback , luteinizing hormone ( lh ) and follicular stimulating hormone ( fsh ) rise .
the  subunit gene of lh is found in a sequence of 7 hcg  subunit genes and therefore uncontrolled gnrh stimulation may lead to hcg production by pituitary gonadotrope cells ( cole , 2005 ) . using an fsh level of 45.0  miu
/ ml identified hcg of perimenopausal women , ages 4155  years , with mildly increased serum hcg concentrations ( 5.014.0  miu / ml ) , an fsh cutoff of 45.0  miu / ml identified hcg of placental origin with 100% sensitivity and 75% specificity .
fsh levels greater than 45  miu / ml were never observed when hcg was of placental origin . when hcg is less than 5.0  miu / ml , fsh testing is not performed as pregnancy is unlikely .
when hcg is greater than 14.0  miu / ml , fsh testing is not performed as this is consistent with pregnancy ( gronowski et al . , 2008 ) .
in one study , two weeks of estrogen - progesterone therapy suppressed pituitary hcg and may help confirm diagnosis ( cole et al . , 2007 ) .
gestational trophoblastic disease is a group of conditions that may be classified as either premalignant , in the case of a partial or complete hydatidiform mole , or malignant , including invasive mole , choriocarcinoma , placental - site trophoblastic tumor and epithelioid trophoblastic tumor .
although not always the case , -hcg is commonly found to be elevated in these conditions and these diseases are considered high on the differential diagnosis list when found .
phantom hcg is a phenomenon first described in 1998 by laurence cole , ph.d . , where patients have persistent mild elevations of -hcg , occasionally following miscarriage .
the elevated -hcg often falsely interpreted and misleads physicians to evaluate or incorrectly treat patients with cytotoxic agents for trophoblast disease ( cole , 1998 ) .
heterophilic antibodies against mouse , goat , rabbit , cow , horse , or sheep antigens can interfere with two - site immunoassays by creating complexes between the two anti--hcg antibodies without -hcg being present .
this leads to a false - positive result ( vladutiu et al . , 1982 ) .
people can develop heterophilic antibodies by exposure to the serum , tissue , or other antigens of nonhuman species .
heterophilic antibodies do not appear to be excreted in the urine and therefore urine assays can be used to identify false - positive serum results .
serial dilutions may also be performed to assess for interference . to avoid false positives ,
the excess of nonspecific antibodies saturates heterophilic antibodies in human serum and usually eliminates their interference with the assay ( johnson et al . , 2000 ) .
additionally , serum samples can be sent to outside laboratories with different assay systems to validate results . in our patient 's case ,
the patient continued to have normal menstrual cycles and was using two forms of contraception with her husband who had history of vasectomy .
the work up , including pelvic ultrasound and ct scans , was negative for pregnancy and trophoblastic disease .
it was therefore believed that the patient 's -hcg production was due to the patient 's tumor , consistent with a paraneoplastic syndrome .
paraneoplastic syndromes occur in about 8% of cancer patients and frequently develop with advanced disease .
they may appear earlier than symptoms of the primary tumor itself , leading to new diagnosis of cancer ( pelosof and gerber , 2010 ) .
it can also be found in the testis , liver , lung , colon , and stomach in small amounts .
malignancies in these organs may lead to an increased serum levels ( demirtas et al .
a gastric origin is the most frequent , ranging from 11% to 17% of this rare subset ( germann et al . , 2002 ) .
in our case , the patient had a primary ovarian neoplasm with metastases within the abdomen .
-hcg levels rose while the patient was on a treatment break , nearly impeding her from further treatment . with re - initiation of therapy
, the -hcg declined , corresponding to a partial response per response evaluation criteria in solid tumors ( recist ) on radiographic imaging .
urine hcg remained positive despite decline in serum hcg as the level was still over the detection threshold of 25 
interesting enough , other tumor markers ( ca 125 , ca 15 - 3 , ca 19.9 and cea ) all increased .
the decreased size of tumor within the pelvis corresponded with decreasing -hcg levels while increased hepatic metastasis corresponded to increases in other markers .
this lends evidence to the idea that the patient had tumoral heterogeneity with different markers produced by tumors in different areas of the body .
this is the first case of paraneoplastic -hcg production from an ovarian adenocarcinoma reported in the literature .
we provide a treatment algorithm to evaluate for paraneoplastic hcg production when assessing for clinical trial eligibility ( fig .
paraneoplastic syndrome should remain in the differential diagnosis in patients found to have elevated levels of -hcg without evidence of intra- or extra - uterine pregnancy .
informed consent to publish the information was granted from the patient . none of the authors have conflict of interest or competing interest .
jg participated in the design of the manuscript , analyzed the biomarker data and drafted the manuscript .
pp jg participated in the design of the manuscript , analyzed the biomarker data and drafted the manuscript .
sp conceived of the study , and participated in its design and coordination and helped to draft the manuscript .
 there is a broad range of possible diagnoses for an elevated beta human chorionic gonadotropin ( -hcg ) in the absence of intrauterine or ectopic pregnancy . when women of child bearing potential undergo evaluation for clinical trial , it is often unclear what course of evaluation to take when a pregnancy test is positive . 
 we describe the clinical course of a patient with widely metastatic mucinous ovarian carcinoma with metastasis to the peritoneum , lymph nodes and liver . the patient was found to have a mildly elevated -hcg during initial evaluation for clinical trial . 
 extensive work up for ectopic pregnancy , trophoblastic disease , and phantom -hcg were negative . 
 the patient 's -hcg levels continued to rise until initiation of therapy . 
 she was treated on a phase i protocol with restaging scans revealing a partial response . 
 the -hcg was retested and declined in conjunction with her response , consistent with paraneoplastic -hcg . here 
 , we propose a decision making algorithm to evaluate a patient with an elevated -hcg undergoing assessment for clinical trial . 