Rectal Paraganglioma.

A 57-year-old woman was admitted with lower abdominal pain and bloody bowel discharge. She was diagnosed with rectal tumor by colonoscopy, and a biopsy was performed. Surgery was performed, resulting in a diagnosis of rectal paraganglioma. Since recurrence was confirmed three years later, reoperation was done, and chemotherapy with cyclophosphamide, vincristine and dacarbazine (CVD) was subsequently carried out for further recurrence. After the administration of up to 15 courses of CVD, we delivered best supportive care due to disease progression. She died a year and a half after starting chemotherapy. We herein report this rare disease with a review of the relevant literature.

Introdution

Although pheochromocytoma is a well-known tumor occurring in the adrenal medulla, about 10% of cases occur in the adrenal gland sympathetic ganglia and are called paraganglioma. Paraganglioma often occur near the carotid artery or along the nerve pathway of the head and neck, and it is rare to find a primary tumor in the gastrointestinal tract, especially the rectal primary is rare. We herein report this rare disease with a review of the relevant literature.

Case Report

A 57-year-old woman visited a local doctor with a chief complaint of lower abdominal pain and bloody bowel discharge without headache, palpitation or excess sweating. She was diagnosed with rectal tumor by colonoscopy and referred to our hospital for a further examination and treatment．

At our hospital, she underwent colonoscopy again, which revealed an elevated lesion in the rectum. It was a non-epithelial, soft tumor that easily bled (Fig. 1). A biopsy was performed for the rectal tumor. The pathological findings were as follows: vesicular nesting of cells with pale eosinophilic vacuoles and blood vessel proliferation. Chromogranin A, synatopophysin and tyrosine hydroxylase were positive, supporting a diagnosis of paraganglioma. There was a clear increase in the blood catecholamine levels, which also supported the diagnosis of paraganglioma．

Figure 1.

Colonoscopy revealed an elevated lesion in the rectum that was a non-epithelial, soft tumor that easily bled.

Lower anterior resection was performed, and the pathological findings showed a Zellballen pattern, pseudorosette formation, positivity for vascular invasion, lymph node metastasis and more than 50% of the cells were Ki-67 positive in a 200-fold high-power field. The tumor cells were chromogranin A-, tyrosine hydroxylase- and dopamine β-hydroxylase-positive and phenylethanolamine-N-methyltransferase (PNMT)-negative, findings that were consistent with norepinephrine-producing paraganglioma (Fig. 2).

Figure 2.

It shows macro specimen (A), low-power field (B), and high-power field (C-F). The pathological findings showed a Zellballen pattern (C), pseudorosette formation (D), positivity for vascular invasion, lymph node metastasis and more than 50% of the cells were Ki-67 positive at a 200-fold high-power field. The tumor cells were chromogranin A- (E), tyrosine hydroxylase- (F) and dopamine β-hydroxylase-positive (G) and PNMT-negative (H), findings that were consistent with norepinephrine-producing paraganglioma.

She did not require any preoperative drug treatment, and there were no issues with the changes in the blood pressure during the operation. The postoperative course was good, and she was followed up at our hospital, but three years later, left-side abdominal aortic lymph node and right common iliac artery lymph node enlargement was observed, which was suspected of being invasion of the inferior vena cava. Para-aortic lymph node dissection and inferior vena cava excision were therefore performed. The postoperative pathology revealed metastasis of paraganglioma.

The following year, para-aortic lymphadenopathy was observed, so surgical para-aortic lymph node dissection was performed. The postoperative pathology revealed metastasis of paraganglioma. The abdominal para-aortic lymphadenopathy spread from the para-aortic to the posterior part of the diaphragmatic legs and was judged to be unresectable; we therefore introduced chemotherapy.

The next month, chemotherapy with cyclophosphamide (CPA), vincristine (VCR) and dacarbazine (DTIC) (together, CVD) was started. CVD consisted of CPA at a dose of 750 mg/m2 on day 1, VCR at a dose of 1.4 mg/m2 on day 1 and DTIC at a dose of 600 mg/m2 on days 1-2, every 3 weeks.

Although hypertensive crisis due to tumor collapse is a known risk with chemotherapy for paraganglioma, no evidence of hypertensive crisis was observed with the prophylactic administration of doxazosin mesilate. Grade 3 leukopenia and Grade 4 neutropenia were observed as hematotoxicities, but pegfilgrastim was administered from the third course as primary prevention, and pyrogenic neutropenia was not observed, so the treatment was well tolerated.

CT at the initial evaluation revealed stable disease per the Response Evaluation Criteria in Solid Tumors version 1.1, but disease progression was gradually recognized (1).

After the administration of up to 15 courses of CVD, we adopted best supportive care. She ultimately died a year and a half after starting chemotherapy.

Discussion

Although pheochromocytoma is a well-known tumor occurring in the adrenal medulla, about 10% of cases occur in the adrenal gland sympathetic ganglia and are called paraganglioma (2). The incidence is 2-8 people per million per year (3). The peak occurrence is in the 20s to 40s, and the average age at the diagnosis is 24.9 years for hereditary cases and 43.9 years for sporadic cases (4). There is no gender difference in the incidence (5). It is found in 0.1-1% of patients with high blood pressure, and adrenal masses are found by chance in about 5% of patients (4, 6-8). Approximately 25% of cases occur in families with hereditary syndrome, and genes such as the RET gene are known to be causative genes (5, 9).

The term “metastatic pheochromocytoma/paraganglioma” is used to replace “malignant pheochromocytoma/paraganglioma” in the Update on Adrenal Tumours in 2017 World Health Organization (WHO) of Endocrine Tumours (10). Paraganglioma often occur near the carotid artery or along the nerve pathway of the head and neck, and it is rare to find a primary tumor in the gastrointestinal tract, especially the rectal primary is rare (11).

Among the published reports of rare primary sites, cases of pancreas (12) and primary cases of the mesenterium (13) are found. We found only one case of rectal primary disease (11). For cases with distant metastasis, there is no established drug therapy at present. However, in Japan, CVD is administered (14, 15). The combined use of CVD and anthracyclines; the combined use of cisplatin and 5-fluorouracil; the combined use of vepeside, carboplatin, vincristine, cyclophosphamide, adriamycine; and the combined use of temozolomide and thalidomide have been reported (16-19). Although cases of combined use with metaidodobenzylguanidine (MIBG) therapy have also been reported, the effectiveness of such a combination has not been clearly shown (20). Since cisplatin and doxorubicin enhance the uptake of MIBG in the neuroblastoma cell line, there have been reports in which MIBG therapy combined with cisplatin and doxorubicin therapy was performed, but these cases were few in number, and the effect was not obvious (21, 22). 131 I-MIBG therapy has been reported as part of a phase II trial, with a response rate of 35% and a survival rate of 5 years of 64%, but insurance approval for this regimen has not yet been granted in Japan (23).

In the present case, we observed a reduction in complications, such as diabetes and blood pressure fluctuation, with the improvement of catecholamine values due to CVD. Although the effect of prolonging overall survival is unknown by CVD, in some cases it is expected to improve symptoms due to tumor shrinkage (3). Although short-term effectiveness has been recognized in many case reports, the duration of the effect is assumed to be one to two years, and the long-term effect is unknown (24-26). In the present case as well, chemotherapy was able to be continued for over one year, and disease progression was reported to be somewhat ameliorated by Gonias et al. (23). Nomura et al. also described cases receiving and not receiving CVD and reported that there was no marked difference in the survival rate between the two groups (27). Thus, there is no evidence that chemotherapy contributes to the improvement of the survival rate.

The classification of pheochromocytoma and paraganglioma is described in “Grading of Adrenal Pheochromocytoma and Paraganglioma (GAPP)”(Table) (28). The pathological findings of this case were moderate cellularity, vascular invasion, a Ki-67 labeling index ＞3%, and norepinephrine type. The histological pattern was characterized by large and irregular cell nests and pseudorosettes. The total score was 7 points, and 7-10 points were classified as poorly differentiated type. This case therefore corresponds to a poorly differentiated type according to the histological grading, and a severe prognosis was presumed (29).

Table.

Pathological Findings.

Grading of Adrenal Pheochromocytoma and Paraganglioma (GAPP)
Parameters	Points scored
Histological pattern
Large and irregular cell nest	1
Pseudorosette (even focal)	1
Cellularity
Moderate (150-250 cells/U)	1
Comedo necrosis
Absence	0
Vascular or capsular invasion	1
Presence
Ki67 labelling index (%)
>3	2
Catecholamine type
Norepinephrine type (NE or NECDA)	1
Total score	7
Poorly diffenetiated type

The pathological findings of this case were moderate cellularity, vascular invasion, a Ki-67 labeling index >3% and a norepinephrine type. The histological pattern was characterized by a large and irregular cell nests and pseudorosettes. The total score was 7 points, and 7-10 points were classified as poorly differentiated type. This case therefore corresponds to the poorly differentiated type according to the histological grading.

Although whether or not chemotherapy had a life-prolonging effect in this case is unclear, it is possible that the side effects of chemotherapy were tolerable. There is therefore the possibility that this regimen could be useful for maintaining the quality of life without the appearance of symptoms caused by paraganglioma. This is a rare cancer, making large-scale clinical trials difficult to perform. The development of genetic testing protocols and further treatments, such as personalized medicine, is desired.

The authors state that they have no Conflict of Interest (COI).