Multicenter Analysis of Presacral Neuroendocrine Neoplasms-Clinicopathological Characterization and Treatment Outcomes of a Rare Disease

Abstract

Background and aims: Neuroendocrine neoplasms (NENs) of the presacral space are an extremely rare disease entity with largely unknown outcome and no established standard of care treatment. Therefore, we wanted to analyze clinical presentation, histopathological findings, treatment outcomes, and prognosis in a multicentric patient cohort.

Methods: We searched local databases of six German NEN centers for patients with presacral NEN. Retrospective descriptive analyses of age, sex, stage at diagnosis, symptoms, grade, immunohistochemical investigations, biomarkers, treatment, and treatment outcome were performed. Kaplan-Meier analysis was used to determine median overall survival.

Results: We identified 17 patients (11 female, 6 male) with a median age of 50 years (range, 35-66) at diagnosis. Twelve cases presented initially with distant metastases including bone metastases in nine cases. On pathological review the majority of patients had well-differentiated G2 tumors. Immunohistochemical profile resembled rectal NENs. All but one patient had non-functioning tumors. Somatostatin receptor imaging was positive in 14 of 15 investigated cases. Eight patients were treated surgically including palliative resections; 14 patients received somatostatin analogs with limited efficacy. With 14 PRRTs completed, 79% showed clinical benefit, whereas only one patient with neuroendocrine carcinoma (NEC) responded to chemotherapy. Treatment with everolimus in three patients was not successful, whereas cabozantinib resulted in a disease stabilization in a heavily pretreated patient. During a median observation period of 44.5 months, 6 patients died. Median overall survival was not reached.

Conclusion: Presacral NEN are histopathologically similar to rectal NENs. Presacral NEN should be considered as possible primary in NEN of unknown primary. The majority of tumors is non-functioning and somatostatin receptor positive. PRRT demonstrated promising activity; tyrosine kinase inhibitors warrant further investigations. Further molecular characterization and prospective evaluation of this rare tumor entity are needed.

Keywords: CUP-NET; PRRT; carcinoid; neuroendocrine carcinoma; neuroendocrine tumor; presacral; prognosis; retrorectal.

Figure 1

(A) Magnetic resonance imaging. Coronal view demonstrating primary presacral neuroendocrine neoplasm (yellow arrow) and liver metastases. (B) Coronal view of a 68Ga-DOTATOC-PET/CT scan showing SSTR expression of the whole body. While the liver metastases showed a homogeneous SSTR expression, only a part of the presacral lesion showed a homogeneous SSTR expression (yellow arrow), suggesting a SSTR-negative/cystic portion besides the SSTR-positive solid presacral NEN. MRI and 68-DOTATOC-PET/CT are from the same patient (study-ID III) at different time points.

Figure 2

(A) Primary presacral neuroendocrine neoplasm stained using H&E (100×). Immunohistochemical staining (100×) shows a well-differentiated neuroendocrine neoplasm with a (B) Ki67 index of 7% and positivity for (C) synaptophysin, (D) chromogranin a, and (E) PSAP. Scale bars represent 50 µm.

Figure 3

Representative imaging and genomic rearrangements of molecularly characterized patients IX (LCNEC G3) and XII (NET G2). (A) CT and (D) DOTATOC-PET/CT of presacral primary (white arrowheads) and metastases (white arrows). (B) CT-guided biopsy of retroperitoneal lymph node metastasis and (E) ultrasound-guided biopsy of liver metastasis for fresh tissue for genomic analysis. (C, F) Circle plots of genomic rearrangements. Despite slightly lower tumor mutational burden, case XII shows a much higher number of rearrangements as a sign of homologous DNA repair deficiency possibly due to a pathogenic frameshift SETD2 mutation.

Figure 4

Kaplan–Meier curve analysis of (A) duration of observation and (B) overall survival of patients with primary presacral NEN (n = 17).