Choriocarcinoma is an aggressive type of tumor made of cytotrophoblasts and syncytiotrophoblasts that metastasizes widely. Most cases are gestational choriocarcinoma, meaning that it develops after a molar pregnancy following gestational events such as ectopic pregnancies, abortions, or full-term pregnancies. Non-gestational choriocarcinoma originates from germ cells in the gonads and rarely in extragonadal sites unrelated to pregnancy such as the brain or stomach (1). Choriocarcinoma has an estimated annual incidence of 2 to 4 cases per 10 million males with primary choriocarcinoma in the gastrointestinal (GI) tract being even more rare since it often occurs in the testicles (2). Appendiceal primary choriocarcinoma in a male has only been documented one other time in English literature through PubMed search.

Diagnoses are made by recording high serum levels of beta-human chorionic gonadotropin (β-hCG) and specific histomorphological and immunohistochemical profiles. Histologically, choriocarcinoma features solid sheets of syncytiotrophoblasts as well as mononucleated cytotrophoblasts and intermediate trophoblasts in areas of necrosis and hemorrhage. Immunohistochemical profiles show characteristic positive staining patterns (3). Diagnosing an elderly male, as in our case, presenting with severe acute abdominal pain could be very challenging as adenocarcinoma arising from low-grade appendiceal mucinous neoplasm (LAMN) is quite common. We made this precise diagnosis based on the histologic features of the three carcinoma components, which were confirmed by the corresponding tumor markers. After our pathology diagnosis, the lab tests revealed an exceptionally high serum β-hCG titer of 289,308 mIU/ml. To the best of our knowledge, this is the first documented case of an elderly male with primary choriocarcinoma and background LAMN with poor prognosis. The rarity, diagnosis, treatment, and prognosis are discussed. Institutional Review Board approval and the requirement for informed consent were waived by the Institution.

A 75-year-old male presented with severe right lower abdominal pain at the emergency department. The physical exam revealed possible acute appendicitis suspicious for perforation. Others including a physical examination of the testicles were unremarkable. Emergency computed tomography (CT) scans revealed a 7.5 cm mass in the lower right quadrant as well as numerous liver hypoechoic nodules (Figure 1A). CT scans showed no lesions or nodules in his testicles and mediastinum. An emergency surgery with right hemicolectomy and a concurrent liver mass biopsy was performed and the specimens sent to pathology for assessment. Gross examination revealed a 7.5-cm mass occupying the distal third of the appendix, involving the full thickness of the appendiceal wall and extending into adjacent mesenteric adipose tissue, with associated perforation (Figure 1B). Sections of the 7.5 cm appendiceal mass and adjacent appendix were submitted for microscopic evaluation. In histology, the mass showed poorly differentiated carcinoma composed of three components of syncytiotrophoblasts, cytotrophoblasts and intermediate trophoblasts (Figure 1C). The carcinoma involved the appendiceal lumen, extended through the muscular wall into the mesoappendix, and was adherent to adjacent mesenteric adipose tissue. All margins were negative for carcinoma. The tumor was present in two of twenty-one regional lymph nodes examined with tumor extranodal extension (data not shown). The liver mass biopsy showed high-grade carcinoma with similar histology including syncytiotrophoblasts, cytotrophoblasts and intermediate trophoblasts and extensive tumor necrosis (Figure 1D). Immunohistochemistry was performed to confirm the choriocarcinoma and revealed the carcinoma was diffusely positive for cytokeratin 7 (CK7) (Figure 2A), positive for β-hCG (Figure 2B left), GATA-binding protein 3 (GATA 3) (Figure 2B right), and focally positive for Sal-like protein 4 (SALL4) (Figure 2C). Conversely, the tumor was negative for cytokeratin 20 (CK20), caudal type homeobox 2 (CDX2), and thyroid transcription factor-1 (TTF-1). This immunohistochemical profile, with the characteristic histomorphology and elevated serum biomarkers, is diagnostic of choriocarcinoma. The positivity for CK7, GATA3, and SALL4 establishes trophoblastic lineage, while β-hCG immunoreactivity confirms the presence of functional syncytiotrophoblasts. The negativity for CK20 and CDX2 definitively excludes appendiceal or colorectal adenocarcinoma, which would demonstrate the reverse immunophenotype of CK20 positivity and CDX2 positivity with CK7 negativity. The absence of TTF-1 staining rules out primary pulmonary adenocarcinoma, and the unremarkable testicular physical examination excludes a primary testicular germ cell tumor as the source. The final tumor stage was pT4, pN1b, pM1c as determined by the American Joint Committee on Cancer (AJCC) Cancer Staging Manual, 9th Edition. In addition, there was a background of low-grade appendiceal mucinous neoplasm (Figure 2D) arising from a sessile serrated adenoma with low-grade dysplasia (data not shown). Lab tests post-surgery revealed very high serum levels of β-hCG up to 289308 mIU/ml (normal <2-5 mlU/ml) and Lactate dehydrogenase (LDH) 702 U/l (normal 135-225 U/l). Other lab tests examined were unremarkable. After diagnosis, the patient was recommended hospice care due to sepsis and extensive liver metastasis. He expired one month after diagnosis.

Primary appendiceal choriocarcinoma in males is exceptionally rare with only one other documented case in English literature through PubMed search before this report. Primary choriocarcinoma of the gastrointestinal tract is uncommon, with the stomach being the most frequently involved site and colorectal involvement exceedingly rare, with only 35 cases of primary colorectal choriocarcinoma described over four decades (4). Choriocarcinoma arising from the appendix is even more uncommon, with the case reported by Khan et al. representing the first documented instance of primary appendiceal choriocarcinoma presenting in a 32-year-old male mimicking acute appendicitis (5). Therefore, the current case represents the second reported case of this diagnostic entity in a male patient, and the first documented case with background LAMN, adding to the limited literature on this subject.

The pathogenesis of extragonadal choriocarcinoma remains a subject of debate. In the gastrointestinal tract, these tumors frequently exhibit a biphasic growth pattern composed of both adenocarcinomatous and choriocarcinomatous components, with approximately 69.4% of reported colorectal choriocarcinomas showing associated adenocarcinoma (4). This observation supports the theory that primary gastrointestinal choriocarcinomas arise through a process of de differentiation or retro-differentiation of a conventional adenocarcinoma where carcinoma cells acquire trophoblastic features both functionally and morphologically (4). In the present case, no coexisting adenocarcinoma was identified by histologic or immunohistochemical evaluation. The presence of background low-grade appendiceal mucinous neoplasm in the current case provides a plausible precursor lesion, though the exact relationship between LAMN and choriocarcinoma requires further investigation with additional cases to establish a definitive pathogenetic link. In addition, in Khan’s case, a background of tubulovillous adenoma with high-grade dysplasia was also identified adjacent to the choriocarcinoma (5).

The diagnosis of primary appendiceal choriocarcinoma presents substantial challenges due to its nonspecific clinical presentation and the frequent presence of extensive tumor necrosis. As demonstrated in this case and the previously reported case by Khan et al., patients commonly present with acute right lower quadrant abdominal pain that mimics acute appendicitis, leading to emergency appendectomy without preoperative suspicion of a malignant process (5). The presence of appendiceal perforation and extensive necrosis further complicates histologic interpretation, as the characteristic features of syncytiotrophoblasts, cytotrophoblasts and intermediate trophoblasts may be obscured by ischemic changes and inflammatory infiltrate. This diagnostic difficulty is compounded by the fact that LAMN itself is often an incidental finding, and the associated conventional adenocarcinoma is quite common (6).

Although recognition of the three trophoblastic cell types is key to the morphologic diagnosis, immunohistochemical profiling is also essential for confirming the diagnosis and distinguishing primary appendiceal choriocarcinoma from other poorly differentiated carcinomas. The characteristic immunoprofile includes diffuse positivity for CK7 and GATA3, with strong expression of β-hCG in syncytiotrophoblasts (4). In the current case, the tumor cells demonstrated positivity for CK7, β-hCG, and GATA3, with focal positivity for SALL4, while being negative for CK20, CDX2, and TTF-1. This immunoprofile is consistent with choriocarcinomatous differentiation and helps exclude other primary malignancies, including appendiceal/colorectal adenocarcinoma, which typically shows CK20 and CDX2 positivity (6). The presence of an exceptionally elevated serum β-hCG titer of 289,308 mIU/ml and LDH 702 U/l in our case provides strong supportive evidence for the diagnosis with high tumor burden and poor prognosis, and these laboratory findings are key diagnostic features that should prompt consideration of choriocarcinoma when encountered in a patient with an appendiceal mass.

The co-occurrence of low-grade appendiceal mucinous neoplasm with primary appendiceal choriocarcinoma is notable. A narrative review by Colombo et al. on appendiceal tumors highlights the classification challenges and molecular distinctions of these rare neoplasms, noting that appendiceal tumors exhibit a different molecular profile compared to colorectal cancers, with significantly lower frequencies of TP53 and APC mutations (7). However, a study by Arshi et al. presented two rare cases of confined LAMN (pTis and pT3, respectively) with coexisting distant extraperitoneal metastasis at the time of diagnosis (8). This demonstrates that although the primary tumor is limited to the appendix, coexisting distant metastasis may occur on rare occasions. The present case, with its highly aggressive choriocarcinoma arising in the background of a LAMN, raises the possibility that LAMN may serve as a precursor lesion to choriocarcinomatous differentiation. LAMN is a rare neoplasm accounting for approximately 1% of gastrointestinal neoplasms and is characterized by bland mucinous epithelium with pushing margins, loss of muscularis mucosa, and submucosal fibrosis (6, 9). While LAMN is generally indolent, it carries the potential for progression to pseudomyxoma peritonei upon rupture, with prognosis dependent on the grade of peritoneal disease (10, 11). However, the transformation of LAMN into a highly aggressive choriocarcinoma has not been previously described, and this finding warrants further investigation. More such case reports are needed.

The prognosis for primary gastrointestinal choriocarcinoma is extremely poor, with most patients dying within the first year after diagnosis. A review of colorectal choriocarcinoma cases demonstrated a median survival of only 4 months, with 91.7% of patients presenting with metastasis at the time of diagnosis, the liver being the most common metastatic site (66.7% of cases) (4). The outcome of the case reported by Khan et al. is unknown as the patient failed to follow up post-acute appendicectomy (5). The current case exemplifies this aggressive natural history, with extensive liver metastasis, a pT4, pN1b, pM1c stage classification, and the patient expiring just one month after diagnosis. This rapid clinical deterioration is characteristic of choriocarcinoma and reflects its propensity for early lymphovascular spread and its high metabolic activity driven by the production of β-hCG.

The established treatment approach for gastrointestinal choriocarcinoma is not well-defined, given the rarity of the disease. Surgical resection is the primary intervention for localized disease, while chemotherapy regimens have been adapted from germ cell tumor protocols, including bleomycin, etoposide, and cisplatin (BEP), or from colorectal adenocarcinoma regimens such as modified 5-fluorouracil (5-FU), leucovorin, oxaliplatin, and irinotecan (mFOLFOXIRI) with bevacizumab (4). For mucinous appendiceal neoplasms, treatment approaches for peritoneal dissemination include cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC), with some patients receiving early postoperative intraperitoneal chemotherapy (EPIC). In a large retrospective study by Mercado et al. involving 545 patients undergoing CRS/HIPEC for mucinous appendiceal neoplasms, histology, peritoneal cancer index (PCI), and EPIC status were demonstrated to be independent factors that affected overall survival (OS) on multivariate analysis (12). Patients with CC-1 (complete cytoreduction with residual tumor <2.5 mm) who received EPIC had significantly improved OS (mean OS 14 years) than patients that did not receive EPIC (mean OS 6 years) (12). The benefit of EPIC was observed in both low-grade (p<0.001) and high-grade (p=0.012) disease (12). However, the effectiveness of these regimens is limited, and rapid regrowth with β-hCG escalation following treatment discontinuation is frequently observed. In the present case, the patient’s advanced age, extensive metastatic burden, and sepsis precluded the initiation of systemic chemotherapy, and hospice care was deemed the most appropriate management. This case highlights the critical need for early and accurate diagnosis and the development of more effective, standardized treatment protocols for this aggressive malignancy.

In summary, male primary appendiceal choriocarcinoma is an exceptionally rare and highly aggressive malignancy, with this case representing only the second reported instance in a male patient. The diagnosis is based on an elevated serum β-hCG titer, characteristic histomorphologic features including the presence of syncytiotrophoblasts, cytotrophoblasts and intermediate trophoblasts, and a supportive immunohistochemical profile demonstrating positivity for CK7, β-hCG, GATA3, and SALL4 and negativity for CK20, CDX2, and TTF-1. The presence of background low-grade appendiceal mucinous neoplasm raises the possibility of a precursor relationship, though further case accumulation and molecular studies are required to clarify the pathogenesis. The poor prognosis, with a median survival of only a few months, underscores the diagnostic and therapeutic challenges posed by this entity. Early recognition, complete surgical resection, and timely initiation of chemotherapy offer the best chance for prolonged survival, but the disease often presents at an advanced stage with metastatic disease, precluding curative intervention. Increased awareness of this rare diagnosis among pathologists and clinicians is essential to facilitate prompt diagnosis and appropriate management.

The Authors declare that they have no conflicts of interest regarding this article.

AF contributed to literature review, data analysis, and manuscript drafting; KYB, YG, RF and YL critically reviewed the article; JL made the diagnosis, collected the data, wrote and finalized the article.

No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.