Paraganglia originate from the neural crest and include sympathetic ganglia (such as adrenal medulla) and parasympathetic ganglia (such as the carotid body) (1). Both pheochromocytoma and paraganglioma (PPGL) originate in the paraganglia, and the two are distinguished by the anatomical location of the tumor. Pheochromocytoma occurs in the adrenal medulla, and paraganglioma occurs in the paraganglia other than the adrenal gland. The incidence of PPGL is approximately 0.6 cases per 100,000 people (2). The peak incidence of PPGL is observed in 20–40-year-old individuals, the average age of onset of hereditary cases is 24.9 years, the average age of onset of sporadic cases is 43.9 years, and there are no differences among the incidences in terms of sex (3). In the 2017 WHO classification of endocrine tumors, PPGLs were classified as malignant tumors from previous benign, borderline, or biologically uncertain tumors. The WHO believes that all PPGLs have metastatic potential, so PPGL is classified as metastatic and non-metastatic types. The diagnosis was added to the 8th edition of the TNM staging system of the American Joint Committee on Cancer (1, 4). PPGL is mostly sporadic and partly hereditary, which is related to a variety of gene mutations. Current studies have reported a number of molecular changes related to poor prognosis of PPGL. Therefore, in addition to the application of conventional auxiliary diagnosis methods, this case also completes the molecular examination, in order to provide ideas and supplements for the patient's follow-up diagnosis and treatment.

The location of paraganglioma is basically the same as the normal distribution area of paraganglion in the human body. Paraganglioma is common in the carotid body, abdominal aorta, renal hilum, and inferior cavitary artery. Review of the domestic and foreign literature showed that paragangliomas that occur in the gastrointestinal tract are very rare and more common in the stomach, and there are a few literature reports of origination in the rectum (5). Colonic paragangliomas are extremely rare, with only 4 cases having been reported in the literature (6–9). The first case of colonic paraganglioma was reported by Yao et al. in 1997 (7). None of the four reported cases of colonic paraganglioma had metastases. In addition, owing to the earlier time, immature technology, or different professional focus, some cases of colonic paraganglioma that have been reported have limited clinical and pathological data. We reported our case of metastatic paraganglioma presenting as a primary colonic neoplasm with the goal of broadening the clinical and morphological spectrum and providing more complete and detailed clinical and pathological data, which will provide empirical support for any future study of paragangliomas in rare locations.

Analysis of five cases of colonic paraganglioma, including the present case, showed that the patients' male-to-female ratio was 2:3, and their respective ages were 12, 40, 49, 58, and 78 years (6–9). The average maximum diameter of the tumors was 3.16 cm. The main body of the tumor in the present case was located in the muscular layer and subserosal layer of the intestinal wall, and the tumors in the remaining most cases were mainly in the submucosa. These five cases of tumor cells were all arranged in nests with Zellballen pattern and abundant interstitial blood vessels. The immunohistochemical results were similar to those in our case; all cases were positive for neuroendocrine markers, and S-100 highlighted sustentacular cells. Furthermore, there are currently three reports of paraganglioma originating in the rectum, and we concluded that the microscopic morphological features and immunohistochemical results were similar to our case, with main organ-like nests (3, 5, 8). However, the cell proliferation activity in these three rectum-origin cases was high, and the index of Ki-67 was 20%, 41%, and 50%, respectively (3, 5, 8) Among the eight cases mentioned above, only three performed SDHB immunohistochemical staining and were diagnosed with SDHx-related paragangliomas. Only the case we reported performed next-generation sequencing.

Most PPGLs are sporadic, but studies have shown that approximately 40% are hereditary tumors and associated with germline and/or somatic mutations in ≥20 known susceptibility genes (10). Among these susceptibility genes, the most important and common ones are succinic dehydrogenase x (SDHx), receptor tyrosine kinase (RET), VHL (von Hippel-Lindau), and nerve neurofibromatosis type 1 (neurofibromatosis type 1, NF1), which come from a wide range of functional categories, and are related to the mechanism of tumorigenesis (10). Studies have found that the time to distant metastasis, local recurrence or regional lymph-node metastasis in patients with PPGL is significantly related to multiple molecular markers, including the MAML3 fusion gene, SDHB germline mutation, somatic mutation of SETD2 or ATRX gene, hypersomatic mutation, Wnt pathway changes, and hypermethylated subtypes. The above molecular changes will lead to a decrease in disease-free survival time; on the contrary, plasma and/or urine metanephrine or adrenaline positive, kinase signal expression, and hypomethylation are associated with longer disease-free survival time (11). Current studies have also found that changes in the TERT, RDBP, and FH genes are related to the poor prognosis of PPGL (12–14). In this case, NGS sequencing of tumor-related genes showed different degrees of variation in the SDHB gene and ATRX gene. Moreover, the lymph-node metastases in this case were relatively numerous, reaching 18/33, which also confirmed the results of the afore-mentioned study on the correlation between the SDHB gene and ATRX gene mutations and poor prognosis.

The definition of metastatic PPGL is the presence of metastatic lesions when recurrence or local tumor infiltration is excluded. The incidence of metastatic PPGL is <1 per 1,000,000. The metastasis of paraganglioma is more common than that of pheochromocytoma, and metastasis observed at the initial diagnosis is even rarer, occurring in approximately 10% of pheochromocytomas and approximately 34% of paragangliomas (15). The most common metastatic sites in patients with PPGL are lymph nodes, bone, liver, and lung (16). In this case, metastatic carcinoma was present in more than half of the lymph nodes. So far, recurrence or metastasis after surgery has not been observed in this patient, and he continues to take tegafur and temozolomide. The 5-year survival rate of patients with metastatic PPGL ranges from 12% to 84% (10). A meta-analysis of 1,338 patients with metastatic PPGL showed that the 5- and 10-year mortality rates were 24%–51% (seven studies, n = 738) and 17%–42% (two studies, n = 55) (17). A multi-center retrospective study of 169 patients with metastatic PPGL showed that a median survival time of 6.7 years, site of occurrence (neck and skull base), age <40 years, less than a five-fold increase in the level of catecholamines, and a low proliferation index (mitosis ≤3 per 10 high-power fields and/or Ki-67 ≤ 2%) were associated with better prognosis (18).

The current treatment options for metastatic PPGL include surgical resection, targeted radiolabeled carriers (such as 131I-MIBG or 90Y-DOTATE or 177LUTATE), thermal ablation, chemotherapy, and radiotherapy (2). So far, however, there is no standard chemotherapy regimen for the treatment of metastatic PPGL. Cyclophosphamide, vincristine, and dacarbazine (CVD) chemotherapy regimens are currently used to treat metastatic PPGL. A retrospective study showed that about one-third of patients experienced complete or partial remission after receiving CVD treatment, presenting tumor shrinkage and decreased secretion of catecholamines. This effect is maintained over time but not all patients with metastatic PPGL are suitable for CVD, and some patients have disease progression (10).

Colonic paraganglioma needs to be differentiated from the tumors described below. (1)

Clear-cell sarcoma of the gastrointestinal tract: This tumor is derived from the primitive melanocytes produced by the neural crest during the embryonic stage. Tumor cells are relatively uniform in size, mostly round, occasionally spindle shaped, and mostly arranged in nests or bundles separated by fibrous spacers. In this case, the expressions of S-100 and MelanA adversely affected differential diagnosis. In paraganglioma, S-100 is only found in the sustentacular cells around the cell nest. In clear-cell sarcoma, S-100 is more strongly expressed and may be accompanied by HMB-45 and MelanA positivity. Molecular testing can also help differential diagnosis of gastrointestinal clear-cell sarcoma; its characteristic EWSR1-ATF1/ t(12; 22) (q13; q12) chromosome translocation can be used as a basis for molecular pathological diagnosis.