Hormone profiling, WHO 2010 grading, and AJCC/UICC staging in pancreatic neuroendocrine tumor behavior

Abstract

Pancreatic neuroendocrine tumors (pNETs) are the second most common pancreatic neoplasms, exhibiting a complex spectrum of clinical behaviors. To examine the clinico-pathological characteristics associated with long-term prognosis we reviewed 119 patients with pNETs treated in a tertiary referral center using the WHO 2010 grading and the American Joint Committee on Cancer/International Union Against Cancer (AJCC/UICC) staging systems, with a median follow-up of 38 months. Tumor size, immunohistochemistry (IHC) profiling and patient characteristics-determining stage were analyzed. Primary clinical outcomes were disease progression or death. The mean age at presentation was 52 years; 55% were female patients, 11% were associated with MEN1 (multiple endocrine neoplasia 1) or VHL (Von Hippel-Lindau); mean tumor diameter was 3.3 cm (standard deviation, SD) (2.92). The clinical presentation was incidental in 39% with endocrine hypersecretion syndromes in only 24% of cases. Nevertheless, endocrine hormone tissue immunoreactivity was identified in 67 (56.3%) cases. According to WHO 2010 grading, 50 (42%), 38 (31.9%), and 3 (2.5%) of tumors were low grade (G1), intermediate grade (G2), and high grade (G3), respectively. Disease progression occurred more frequently in higher WHO grades (G1: 6%, G2: 10.5%, G3: 67%, P = 0.026) and in more advanced AJCC stages (I: 2%, IV: 63%, P = 0.033). Shorter progression free survival (PFS) was noted in higher grades (G3 vs. G2; 21 vs. 144 months; P = 0.015) and in more advanced AJCC stages (stage I: 218 months, IV: 24 months, P < 0.001). Liver involvement (20 vs. 173 months, P < 0.001) or histologically positive lymph nodes (33 vs. 208 months, P < 0.001) were independently associated with shorter PFS. Conversely, tissue endocrine hormone immunoreactivity, independent of circulating levels was significantly associated with less aggressive disease. Age, gender, number of primary tumors, and heredity were not significantly associated with prognosis. Although the AJCC staging and WHO 2010 grading systems are useful in predicting disease progression, tissue endocrine hormone profiling provides additional information of potentially important prognostic value.

Keywords: Carcinoid; gastrinoma; insulinoma; neuroendocrine tumors; pNET.

Figure 1

Relationship between primary pancreatic neuroendocrine tumor size and age with WHO grade and AJCC Stage. (A) Maximum tumor diameter in cm was stratified according to WHO grade. The median for G1 tumors was 1.8, for G2 2.6, for G3 8.7 (P = 0.023). (B) Maximum tumor diameter was stratified according to AJCC stage, resulting in a median for stage I of 1.4, 2.4 for stage IIA, 4.7 for stage IIB, 5.1 for stage IIIB, and 5.45 for stage IV (P < 0.001). (C) Age at diagnosis according to WHO grade with a G1 median of 54 years, 51 for G2, and 36 for G3 (NS). (D) Age diagnosis stratified by AJCC stage show a median of 52 years for stage I, 53.06 for IIA, 51.5 for IIB, 54.0 for IIIB, and 52 for stage IV (NS). (Low grade [G1], intermediate grade [G2], high grade [G3]).

Figure 2

Pancreatic NET disease stability by WHO grade and AJCC stage. (A) Comparison of disease stability according to WHO grade. Stable disease was noted in 42/49 G1, 22/38 G2, and 0/3 G3 (P < 0.001). (B) Progression of disease was stratified according to WHO grade. Disease progression was noted in 3/50 G1 tumors, 4/38 G2, and 2/3 G3 (P = 0.026). (C) Disease stability according to AJCC staging as present in 42/46 stage I patients, 22/26 stage IIA, 11/17 stage IIB, 6/10 stage IIIB, and 2/19 stage IV (P < 0.001). (D) Progression according to AJCC is shown. Accordingly, 1/46 stage I cases, 0/26 stage IIA, 2/18 stage IIB, 1/10 stage IIIB, and 12/19 stage IV (P = 0.033).

Figure 3

Progression free survival (PFS) analyses. (A) Kaplan–Meier survival analyses of PFS according to WHO grade. PFS estimates were 79.3 months for G1 (Ne = 39.5), 144.7 months for G2 (Ne = 29.5), and 20.6 months for G3 (Ne = 3) (P = 0.015). (B) Stratified by AJCC staging, PFS estimate was 218.3 months for stage I (Ne = 37), 114.0 months for stage IIA (Ne = 20.5), 60.8 months for stage IIB (Ne = 16.0), 45.0 months for stage IIIB (Ne = 7.5), and 24.6 months for stage IV (Ne = 17.5) (P < 0.001). (C) Extra-pancreatic extension (Ne = 23) results in a PFS estimate of 22.9 months versus 181.3 months for cases without it (Ne = 75.5) (P < 0.001). (D) The presence of lymph nodes shows a similar result with a PFS estimate of 33.8 months for positive (Ne = 20) versus 208.3 months for negative nodes (Ne = 78.5) (P < 0.001). (E) The presence of liver metastases (Ne = 15.5) was associated to a PFS of 20.5 months versus 173.0 months without metastases (Ne = 83.0) (P < 0.001). Ne, Number exposed to risk.

Figure 4

Protein tissue markers by IHC. Endocrine markers and NET markers are shown according to the following: (A) AJCC stage and clinical functioning status, showing significantly greater proportions of endocrine markers in earlier AJCC stages, but greater proportions of NET markers alone in more advanced stages (overall comparison: P < 0.001). (B) Clinical outcome, clinical functional status, and AJCC stage: lower stage, stable tumors showed a significantly higher proportion of endocrine markers (P < 0.001 and P = 0.019) whereas stage IV, progressing tumors showed a significantly higher proportion of NET markers alone (P = 0.001). (C) Death (intent-to-treat) and clinical functional status: endocrine markers showed a significantly higher proportion in functional tumors (41.0% vs. 2.6%, P < 0.001); in the demised group the proportion of endocrine markers in the nonfunctioning group is reduced (16.8% vs. 9.1%). (D) Death (intent-to-treat), clinical functional status and AJCC stage: Endocrine markers displayed significantly higher proportions in early stages (AJCC I: 62.5% vs. 27.5%, P = 0.040), whereas the proportion of NET markers alone was higher in more advanced stages (AJCC IV: 58.3% vs. 25%, P = 0.040); in the demised group, the proportions favored NET markers from early stages (AJCC IIA: 60% vs. 20%), but the small N precludes statistical interpretation.

Figure 5

Kaplan–Meier survival curves for time to progression according to AJCC stage and, (A) presence of NET marker, displaying a significant difference across stages (P < 0.001) or (B) presence of endocrine marker, also significantly different (P < 0.001). Kaplan–Meier survival curves for overall survival (intention-to-treat) according to AJCC stage and (C) presence of NET markers show significant difference between AJCC stages (P = 0.018) or (D) presence of endocrine markers, display a significant difference between AJCC stages (P = 0.021).