Mixed adenoneuroendocrine carcinomas (MANECs) are rare and aggressive tumors composed of both neuroendocrine and non-neuroendocrine epithelial components, with each component representing at least 30% of the tumor (1, 2). Although MANECs have been described throughout the gastrointestinal tract, involvement of jejunum is exceptionally uncommon, with very limited cases previously reported in the English literature (3, 4).

We report a unique case of jejunal MANEC that initially presented as a large ovarian mass and was diagnosed and treated as metastatic colorectal adenocarcinoma. The disease was not adequately controlled by chemotherapy directed toward the adenocarcinoma and progressed, resulting in small bowel perforation caused by jejunal MANEC. Histopathologic examination showed morphologic and immunophenotypic similarities between the jejunal MANEC and the ovarian metastatic tumor. Further molecular studies identified a novel protein tyrosine phosphatase receptor type K–R-spondin 3 (PTPRK-RSPO3) fusion. The rarity, diagnostic challenges, molecular pathogenesis, and prognosis of this entity are discussed.

A 51-year-old female presented with multiple episodes of abdominal pain. Non-contrast computed tomography (CT) demonstrated a 16.1×12.2×10.5 cm heterogeneous solid pelvic mass extending into the lower abdomen. The patient’s family history and serologic evaluation for ovarian tumor markers were unremarkable. The patient underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy, and intraoperative frozen sections of the right ovarian mass showed adenocarcinoma. More histopathologic evaluation of the ovarian tumor revealed an intestinal type of adenocarcinoma with solid components (Figure 1A and B). Immunohistochemical staining demonstrated positivity for CDX2 (Figure 1C) and SATB2 (Figure 1D), with negative staining for CK7 and PAX8. The immunophenotypic profile suggested metastatic adenocarcinoma of colorectal origin and argued against a primary ovarian neoplasm.

To look for the primary tumor site, colonoscopy was performed but no carcinoma or dysplasia identified. Upper endoscopy was subsequently conducted and did not reveal any upper gastrointestinal carcinoma. Positron emission tomography/computed tomography (PET/CT) later identified a lesion within the small bowel. The patient was treated with six months of FOLFOX (folinic acid, 5-fluorouracil, and oxaliplatin) chemotherapy. However, she developed symptoms of small bowel obstruction and perforation, necessitating emergency resection of the small bowel tumor and associated abdominal lymph nodes.

Gross examination demonstrated a jejunal perforation associated with a 3 cm mass involving jejunal mucosa and invading into the full thickness of the bowel wall to the serosa (Figure 2A). Histopathologic examination demonstrated MANEC composed of 55% intestinal type of adenocarcinoma with mucin-producing features mixed with 45% high-grade neuroendocrine carcinoma (NEC) components (Figure 2B-D). The neuroendocrine carcinoma component showed a large cell type with low nuclear-to-cytoplasmic ratio, round vesicular nuclei, prominent nucleoli, and increased mitotic activity. The NEC component showed diffuse positivity of synaptophysin (Figure 2C and D) and chromogranin, while the adenocarcinoma component was negative for neuroendocrine markers. The Ki-67 index was 70% in the NEC component and 40% in the adenocarcinoma component. Metastatic tumor was identified in two of the three regional lymph nodes examined. Given the morphologic similarity between the jejunal tumor and the previously resected ovarian tumor, synaptophysin and chromogranin immunostains were retrospectively performed on the section of the ovarian tumor shown in Figure 1. Both markers demonstrated diffuse positivity in a pattern comparable to that observed in the jejunal MANAC shown in the Figure 2, supporting that the ovarian mass represented metastatic disease from the jejunal primary. The final diagnosis of the jejunal tumor was MANEC, staged as pT4N1M1b.

Molecular profiling using the STRATA next generation sequencing (NGS) platform (Ann Arbor, MI, USA) identified genetic alterations previously reported in MANEC, including mutations in Kirsten rat sarcoma viral oncogene homolog(KRAS), SMAD family member 4 (SMAD4), and cyclin-dependent kinase inhibitor2A (CDKN2A) deep deletion. In addition, a novel PTPRK-RSPO3 fusion was identified. The tumor was microsatellite stable (MSS) with a low tumor mutational burden (TMB-L, 7 mutations/Mb).

Despite continued platinum-based chemotherapy targeting NEC, the patient developed ureteral obstruction with bilateral hydronephrosis and died 7 months after diagnosis of MANEC.

A 51-year-old female presented with multiple episodes of abdominal pain. Non-contrast computed tomography (CT) demonstrated a 16.1×12.2×10.5 cm heterogeneous solid pelvic mass extending into the lower abdomen. The patient’s family history and serologic evaluation for ovarian tumor markers were unremarkable. The patient underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy, and intraoperative frozen sections of the right ovarian mass showed adenocarcinoma. More histopathologic evaluation of the ovarian tumor revealed an intestinal type of adenocarcinoma with solid components (Figure 1A and B). Immunohistochemical staining demonstrated positivity for CDX2 (Figure 1C) and SATB2 (Figure 1D), with negative staining for CK7 and PAX8. The immunophenotypic profile suggested metastatic adenocarcinoma of colorectal origin and argued against a primary ovarian neoplasm.

To look for the primary tumor site, colonoscopy was performed but no carcinoma or dysplasia identified. Upper endoscopy was subsequently conducted and did not reveal any upper gastrointestinal carcinoma. Positron emission tomography/computed tomography (PET/CT) later identified a lesion within the small bowel. The patient was treated with six months of FOLFOX (folinic acid, 5-fluorouracil, and oxaliplatin) chemotherapy. However, she developed symptoms of small bowel obstruction and perforation, necessitating emergency resection of the small bowel tumor and associated abdominal lymph nodes.

Gross examination demonstrated a jejunal perforation associated with a 3 cm mass involving jejunal mucosa and invading into the full thickness of the bowel wall to the serosa (Figure 2A). Histopathologic examination demonstrated MANEC composed of 55% intestinal type of adenocarcinoma with mucin-producing features mixed with 45% high-grade neuroendocrine carcinoma (NEC) components (Figure 2B-D). The neuroendocrine carcinoma component showed a large cell type with low nuclear-to-cytoplasmic ratio, round vesicular nuclei, prominent nucleoli, and increased mitotic activity. The NEC component showed diffuse positivity of synaptophysin (Figure 2C and D) and chromogranin, while the adenocarcinoma component was negative for neuroendocrine markers. The Ki-67 index was 70% in the NEC component and 40% in the adenocarcinoma component. Metastatic tumor was identified in two of the three regional lymph nodes examined. Given the morphologic similarity between the jejunal tumor and the previously resected ovarian tumor, synaptophysin and chromogranin immunostains were retrospectively performed on the section of the ovarian tumor shown in Figure 1. Both markers demonstrated diffuse positivity in a pattern comparable to that observed in the jejunal MANAC shown in the Figure 2, supporting that the ovarian mass represented metastatic disease from the jejunal primary. The final diagnosis of the jejunal tumor was MANEC, staged as pT4N1M1b.

Molecular profiling using the STRATA next generation sequencing (NGS) platform (Ann Arbor, MI, USA) identified genetic alterations previously reported in MANEC, including mutations in Kirsten rat sarcoma viral oncogene homolog(KRAS), SMAD family member 4 (SMAD4), and cyclin-dependent kinase inhibitor2A (CDKN2A) deep deletion. In addition, a novel PTPRK-RSPO3 fusion was identified. The tumor was microsatellite stable (MSS) with a low tumor mutational burden (TMB-L, 7 mutations/Mb).

Despite continued platinum-based chemotherapy targeting NEC, the patient developed ureteral obstruction with bilateral hydronephrosis and died 7 months after diagnosis of MANEC.

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

RW contributed to literature review, interpretation of pathologic findings, and manuscript drafting. 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.