Ectopic β-HCG production in a young patient with highly aggressive metastatic lung adenocarcinoma: A rare paraneoplastic manifestation

Abstract

We report an exceptionally rare case of β-hCG–producing lung adenocarcinoma in a 23-year-old patient, likely among the youngest described to date. The patient presented with progressive respiratory symptoms and was initially managed as cancer of unknown primary following non-diagnostic biopsies. Subsequent biopsies of metastatic lesions demonstrated strong β-hCG expression, leading to an initial misdiagnosis of a germ cell tumor and initiation of BEP chemotherapy. Comprehensive molecular analysis later revealed KRAS and TP53 mutations, with a methylation profile consistent with non-small cell lung cancer. Despite multiple lines of therapy, the disease exhibited an aggressive clinical course with rapid progression. This case underscores the importance of recognizing ectopic β-hCG secretion as a rare paraneoplastic phenomenon in lung cancer, particularly in young patients, and highlights the risk of diagnostic missclassifications. Furthermore, it suggests that deeper investigation into β-hCG–mediated signaling pathways may offer potential avenues for the development of novel therapeutic strategies.

1. Introduction

Lung cancer in young adults is exceptionally rare, accounting for only a small proportion of all cases worldwide. The underlying etiopathogenesis in this population remains largely unclear. Notably, disease in younger patients is frequently associated with an aggressive clinical course and poorer outcomes compared with older populations. [[1], [2], [3], [4], [5]]

Ectopic hormone production is a well-known phenomenon in oncology, with various neoplasms capable of secreting hormones such as antidiuretic hormone (ADH) and adrenocorticotropic hormone (ACTH), thereby giving rise to clinically significant paraneoplastic syndromes [[6], [7], [8]].

Beta-human chorionic gonadotropin (β-hCG) is a glycoprotein hormone that plays a pivotal role in the maintenance of pregnancy. It is secreted by syncytiotrophoblastic cells shortly after conception and exerts physiological effects, including stimulation of progesterone synthesis by the corpus luteum and modulation of the maternal immune system to support fetal tolerance. Accordingly, β-hCG is a well-established biomarker of pregnancy [9,10]. Elevated serum β-hCG levels may also result from ectopic production by malignancies, most notably germ cell tumors, in which it is widely used for diagnostic purposes as well as for monitoring treatment response [11,12].

Ectopic β-hCG production has been documented in several solid tumors and is associated with paraneoplastic syndromes ([11]). However, β-hCG-secreting non-germ cell primary lung tumors remain exceptionally rare, with only sporadic cases reported in the literature [[13], [14], [15], [16], [17], [18], [19], [20], [21], [22]].

Here, we report an exceptionally rare case of aggressive lung adenocarcinoma in a 23-year-old patient. The patient was initially managed as having cancer of unknown primary, as the site of origin could not be determined due to degradation of the initial biopsy specimens. Subsequent histopathological evaluation of metastatic lesions in the sigmoid colon and retroperitoneal lymph nodes demonstrated strong β-hCG expression, leading to a presumptive diagnosis of a germ cell tumor and initiation of appropriate therapy. Ultimately, comprehensive molecular genetic profiling of the tumor confirmed the diagnosis of primary lung adenocarcinoma.

The patient provided written informed consent for the use of clinical data and anonymized information for research and publication purposes. In accordance with local regulations and institutional policies, ethics committee approval was not required for the publication of this case report.

2. Case

A 23-year-old male patient was admitted to the Emergency Department of the Cantonal Hospital Baden in June 2019 with progressively worsening symptoms, including unintentional weight loss, cervical lymphadenopathy, thoracic pain, hemoptysis, and increasing dyspnea. His medical history was unremarkable. He was a current smoker with a cumulative exposure of 6 pack-years and reported no relevant occupational, environmental, or other substance-related exposures. Prior to admission, the patient had received outpatient antibiotic therapy for presumed pneumonia without clinical improvement. On presentation, the patient was hemodynamically stable and afebrile. Initial laboratory investigations revealed mildly elevated inflammatory markers without other significant abnormalities. A chest computed tomography (CT) scan demonstrated a 2.2 cm cavitary lesion in the right middle lobe, associated with compression of the right pulmonary artery and extensive mediastinal lymphadenopathy.

Given the initial suspicion of tuberculosis, the patient was hospitalized and placed in isolation for further diagnostic evaluation. However, repeated microbiological testing of sputum samples for Mycobacterium tuberculosis, as well as concomitant HIV serology, was negative. Additional autoimmune testing, including antinuclear antibodies (ANA) and antineutrophil cytoplasmic antibodies (ANCA), was negative. However, granulomatosis with polyangiitis could not be excluded on the basis of negative ANCA results alone. No clinical features suggested rheumatoid arthritis as an underlying cause of the solitary cavitary pulmonary lesion.

Cytopathological evaluation of cervical lymph node biopsies and bronchial secretions obtained during bronchoscopy revealed atypical necrotic cells but was non-diagnostic. Following clinical stabilization, the patient was discharged with plans for outpatient follow-up and subsequently readmitted for repeat bronchoscopy and surgical excision of a previously identified enlarged right cervical lymph node. Histopathology of the resected specimens demonstrated malignant cells consistent with a poorly differentiated carcinoma; however, definitive classification was precluded by extensive necrosis.

Subsequent positron emission tomography–computed tomography (PET-CT) demonstrated a rapidly progressive malignancy with extensive metastatic involvement, including the kidneys, adrenal glands, pancreas, bone, and soft tissues. Magnetic resonance imaging (MRI) confirmed cerebral metastasis. Imaging also showed subtotal compression of the right mainstem and lower lobe bronchi due to intensely metabolically active mediastinal lymphadenopathy, along with a right-sided pleural effusion.

Following these findings, the patient was urgently referred to the Department of Oncology for further diagnostic evaluation and treatment planning.

Subsequent Immunohistochemical evaluation of the excised right cervical lymph node at the initial institution and a second reference center demonstrated PD-L1 expression in 95% of tumor cells and negative staining for TTF-1, p40, CK20, CDX2, PLAP, and low- and high-molecular-weight cytokeratins and β-hCG. Next-generation sequencing (NGS) analysis excluded targetable oncogenic alterations (EGFR, ALK, ROS1, MET, or BRAF) but identified mutations in TP53 and KRAS.

In the absence of a definitive primary site, the patient was managed under the diagnosis of cancer of unknown primary. Given the rapidly progressive and invasive nature of the disease, palliative chemotherapy with carboplatin, paclitaxel, and etoposide was initiated. Due to compression of the superior vena cava, an endovascular stent was placed. A subsequent post-stenotic pneumonia was treated with empirical broad-spectrum antibiotics.

Following the second cycle of chemotherapy, the treatment regimen was modified to include carboplatin, paclitaxel, and the PD-L1 inhibitor atezolizumab. A follow-up PET-CT scan in August 2019 demonstrated a confirmed partial response, and therapy was subsequently transitioned to maintenance with atezolizumab. Therapy was discontinued in December 2019 due to disease progression with new brain and bone metastases, retroperitoneal lymphadenopathy, and a newly identified lesion in the sigmoid colon.

Palliative external beam radiotherapy to lesions in the acetabulum, sacroiliac joint, and knee provided substantial symptomatic relief. The patient declined stereotactic irradiation of the cerebral metastases.

Histopathological evaluation of biopsies from the sigmoid colon lesion and retroperitoneal lymph nodes revealed strong β-hCG expression in approximately 70% of tumor cells (Fig. 1a) with negative staining for TTF-1, CKL, CK20, and CDX2. Higher-power view (400x) demonstrating strong cytoplasmic β-hcG expression in tumor cells and few multinucleated giant tumor cells. Consistent with this finding, serum β-hCG was elevated to 653 mIU/mL (normal range <5 mIU/mL).

Fig. 1.

(A) β-hCG immunohistochemistry at 200× magnification showing immunoreactivity in approximately 70% of tumor cells. (B) Higher-power view (400×) demonstrating strong cytoplasmic β-hCG expression in tumor cells and a few multinucleated giant tumor cells.

Following multidisciplinary tumor board discussion, the findings were considered most consistent with a metastatic extragonadal germ cell tumor, and chemotherapy with bleomycin, etoposide, and cisplatin (BEP) was initiated. Given unexplained right-sided testicular discomfort, scrotal ultrasonography was performed to assess for a primary testicular tumor but revealed no abnormalities. Serum alpha-fetoprotein (AFP) levels were not measured as part of this evaluation. In view of rising β-hCG levels and a mixed radiographic response, treatment was subsequently intensified with the addition of paclitaxel and oxaliplatin (T-BEP-Ox regimen).

However, comprehensive molecular analysis from obtained tumor tissue (excised cervical lymph node) supported a diagnosis of lung adenocarcinoma. EPIC array–based DNA methylation profiling followed by UMAP-TCGA methylome analysis showed the closest correspondence to the lung adenocarcinoma methylation class (NSCLC AD). In light of these findings and the absence of a decline in serum β-hCG levels following one cycle each of BEP and T-BEP-Ox therapy, the elevated β-hCG was interpreted as a paraneoplastic phenomenon.

Based on the confirmed diagnosis of TP53/KRAS-mutated NSCLC, systemic therapy was changed to cisplatin and pemetrexed, which was administered from February to April 2020. During this period, the patient developed Staphylococcus lugdunensis endocarditis, which was treated with four weeks of intravenous flucloxacillin.

Despite initial clinical stabilization after two cycles of cisplatin and pemetrexed, the disease progressed rapidly, leading to severe complications including inferior vena cava compression, right renal artery occlusion, and grade III right-sided hydronephrosis. In the context of advanced disease, further systemic therapy was withheld, and best supportive care was initiated. The patient died on 29 April 2020, approximately 9.5 months after the diagnosis of malignancy. For clarity, Supplementary Fig. S2 provides a timeline summarizing the major diagnostic and therapeutic milestones.

3. Discussion

We report an extraordinary case of primary lung cancer in a young patient with an exceptionally atypical clinical course, marked by rapid progression, metastasis to an uncommon site (sigmoid colon), and paraneoplastic β-hCG secretion.

Paraneoplastic hormone secretion—most commonly involving adrenocorticotropic hormone (ACTH), parathyroid hormone, or antidiuretic hormone (ADH)—is a well-known phenomenon in oncology. In contrast, ectopic production of the pregnancy hormone β-hCG is exceedingly uncommon, with only sporadic cases described in the literature ([21]).

Peng et al. ([21]) reviewed 24 published cases of β-hCG–secreting non-germ cell primary lung tumors up to the time of their analysis, while Ganesh et al. [22] reported several additional cases in an updated review. We consolidated these reports into a single summary table and performed an updated PubMed literature search for cases published between 2021 and 2026 using combinations of the keywords "β-hCG", "human chorionic gonadotropin", "lung cancer", "lung carcinoma", "non-small cell lung cancer", "adenocarcinoma", and "ectopic hCG". After excluding primary pulmonary choriocarcinoma, germ cell tumors, and metastatic gestational trophoblastic disease, we identified six additional reports of β-hCG-producing primary lung carcinoma. A detailed summary of all published cases, including the present case, is provided in Supplementary Table S1. The principal findings are summarized in Table 1.

Table 1.

Summary of reported cases of β-hCG–producing primary lung carcinoma identified in the literature.

Characteristic	Summary of reported casesa
Total number of published case reports	34 (35 including the present case)
Individual patients (total number)	38 (39 including the present case)
Study period	1975–2026
Median age at diagnosis	50 years (range 23–84)b
Sex	Males (18/39, 46.1%)
	Females (21/39, 53.8%)
Most common histological subtype	Adenocarcinoma (17/39, 43.5%)
	Large cell carcinoma (10/39, 25.6%)
	Squamous cell carcinoma (5/39, 12.8%)
	NSCLC, non specified (3/39, 7.6%)
	Small cell lung cancer (1/39, 2.6%)
	Pleomorphic (3/39, 7.6%)
Common presenting manifestations	Gynecomastia, amenorrhea, dyspnea, cough, chest pain, weight loss, abdominal pain
Serum β-hCG/HCG level (mIU/mL)	6-16500
Treatment modalities	Surgery, platinum-based chemotherapy, radiotherapy, targeted therapy, or multimodal treatment

Abbreviations: β-hCG, beta-human chorionic gonadotropin; hcG human chorionic gonadotropin.

^aBased on the literature summarized in Supplementary Table S1.

^bAge was reported for 35 of 39 patients. Summary statistics were calculated using available data only and include the present case.

Based on our literature review, prior to the present report, 38 cases of primary lung carcinoma with paraneoplastic β-hCG secretion had been described in 34 published reports. Including the present case, a total of 39 cases have now been reported. The median age of the reported patients was 50 years (range, 23–84 years), with slight female predominance (21 females vs 18 males). The most common clinical manifestations at presentation were spontaneous gynecomastia, amenorrhea, dyspnea, cough, chest pain, and weight loss. Although rare, β-hCG/HCG production (serum level range 6-16500 mIU/mL) has been reported across a variety of histological subtypes, with adenocarcinoma and large-cell carcinoma representing the most common subtypes. To our knowledge, the present case represents the youngest patient reported to date. The case was further distinguished by the occurrence of a solitary sigmoid colon metastasis, an exceptionally rare site of metastatic spread from primary lung cancer. Parker et al. [23] identified only approximately 44 reported cases of colonic metastases from primary lung cancer worldwide, underscoring the rarity of this metastatic site.

In the present case, β-hCG expression led to an initial misdiagnosis of an extragonadal germ cell tumor and initiation of BEP chemotherapy in the context of rapidly progressive disease. Definitive diagnosis was only achieved through comprehensive molecular profiling, underscoring its pivotal role in avoiding diagnostic misclassification in atypical presentations.

It remains unclear whether ectopic β-hCG secretion was present at initial diagnosis or developed later during disease progression. The initial biopsy specimens obtained via bronchoscopy and cervical lymph node excision were insufficiently preserved for reliable immunohistochemical evaluation. It is plausible that autocrine β-hCG production evolved in parallel with tumor progression, reflecting the acquisition of a more aggressive phenotype with metastatic potential, as evidenced by involvement of the sigmoid colon and retroperitoneal lymph nodes.

Accumulative evidence suggests that β-hCG expression is associated with a more aggressive tumor phenotype. Uesato et al. [24] reported that β-hCG expression in pancreatic cancer correlated with higher recurrence rates, elevated tumor marker levels, and inferior survival outcomes. In their study, downregulation of β-hCG expression via shRNA in β-hCG–positive pancreatic cancer cell lines resulted in marked reduction in proliferative and migratory capacity.

Western blot analysis further revealed downregulation of epithelial markers and upregulation of mesenchymal markers, suggesting that β-hCG may play a crucial role in promoting epithelial-to-mesenchymal transition (EMT), a key mechanism underlying tumor invasion and metastasis. Similar observations have been reported in colorectal and ovarian cancer models [[25], [26], [27]].

Although the precise molecular mechanisms underlying autocrine β-hCG-mediated tumor progression are not fully defined, emerging evidence implicates β-hCG in the key oncogenic processes, including suppression of apoptosis, enhancement of cell survival signaling, promotion of angiogenesis, induction of EMT, and facilitation of immune evasion [[24], [25], [26], [27], [28]].

Elucidating these mechanisms may enable the development of targeted therapeutic strategies aimed at suppressing β-hCG signaling and thereby inhibiting tumor growth. Consistent with this, accumulating in vitro data indicate that inhibition of β-hCG promotes apoptosis and attenuates cancer cell proliferation.

Functional studies further support a role for β-hCG in tumor cell survival. Jankowska et al. [29] demonstrated that suppression of β-hCG expression in HeLa cells via anti-hCGβ U1 snRNAs resulted in a significant increase in apoptotic activity, with nearly 90% of cells exhibiting morphological features consistent with apoptosis. Similarly, in β-hCG-expressing bladder cancer cell lines, knockdown of β-hCG translation using shRNA lentiviral vectors reduced β-hCG expression by 60–80% and resulted in a greater than 40% decrease in cellular proliferation compared with controls [30].

Moreover, in vivo studies suggest that immunotherapeutic strategies targeting β-hCG may confer survival benefit and reduce tumor burden. Taken together, these data highlight β-hCG as a promising therapeutic target and support further investigation of β-hCG-directed strategies in the treatment of β-hCG-secreting malignancies [31,32].

To date, only a limited number of therapeutic strategies targeting β-hCG have been evaluated in clinical trials, with most efforts focusing on vaccine-based approaches designed to elicit anti-β-hCG immune responses. Moulton et al. ([33]) reported a clinical study of the CTP37/Avicine vaccine, a carboxy-terminal peptide of β-hCG conjugated to diphtheria toxoid, which induced measurable anti-β-hCG antibody responses. Notably, patients who developed higher antibody titers exhibited longer survival, suggesting an association between vaccine-induced immunity and clinical outcome. Despite these encouraging findings, further clinical development was not pursued. While the precise reasons remain unclear, several factors may have limited the therapeutic potential of β-hCG-directed vaccination, including modest clinical efficacy, the absence of biomarker-based patient selection, heterogeneity of β-hCG expression, and the immunosuppressive tumor microenvironment, which can impair the generation of durable antitumor T-cell responses.

In a separate Phase I study, Morse et al. ([34]) evaluated CDX-1307, a mannose receptor-targeted fusion protein comprising hCG-β linked to a human monoclonal antibody designed to deliver antigen directly to antigen-presenting cells. When administered in combination with immunostimulatory agents, including granulocyte-macrophage colony-stimulating factor (GM-CSF), resiquimod, and poly-ICLC, CDX-1307 induced both humoral and cellular hCG-β-specific immune responses and demonstrated an acceptable safety profile.

To date, clinical evaluation of β-hCG-targeted immunotherapy has remained limited. The principal clinical programs have involved the CTP37/Avicine vaccine and the antigen-presenting-cell-targeted vaccine CDX-1307. Although both vaccines demonstrated immunogenicity and acceptable safety profiles, neither advanced to late-stage clinical development or clinical adoption. To the best of our knowledge, no additional peer-reviewed clinical studies specifically targeting β-hCG as a therapeutic cancer antigen in patients have been reported since these clinical trials.

4. Conclusion

In conclusion, we describe a rare case of β-hCG–producing lung adenocarcinoma in a young patient, likely the youngest reported to date. Awareness of this entity is essential to prevent diagnostic confusion with germ-cell tumors and to guide appropriate management.

In addition, it highlights the need for further investigation into the role of β-hCG in tumor biology, as a deeper understanding of its signaling pathway may provide novel opportunities for targeted therapeutic approaches.

CRediT authorship contribution statement

André Warzecha: Writing – original draft, Visualization, Resources, Investigation, Formal analysis, Conceptualization. Sacha I. Rothschild: Writing – review & editing, Validation, Supervision.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Appendix A. Supplementary data

The following are the Supplementary data to this article: