Intraductal Tubulopapillary Neoplasm of the Pancreas: A Clinicopathologic and Immunohistochemical Analysis of 33 Cases

Abstract

Intraductal tubulopapillary neoplasm (ITPN) is a relatively recently described member of the pancreatic intraductal neoplasm family. Thus, the literature on its histologic and immunohistochemical features, clinical behavior, and its similarities and differences from other pancreatic neoplasms is limited. Thirty-three cases of ITPN, the largest series to date, were identified. Immunohistochemical labeling for cytokeratins, glycoproteins, pancreatic enzymes, markers for intestinal and neuroendocrine differentiation, and antibodies associated with genetic alterations previously described in pancreatic neoplasms was performed. Clinicopathologic features and survival was assessed. Seventeen patients were female and 14 were male. Mean age was 55 years (range, 25 to 79 y). Median overall tumor size was 4.5 cm (range, 0.5 to 15 cm). Forty-five percent of the tumors occurred in the head, 32% in the body/tail, and 23% showed diffuse involvement. Microscopically, the tumors were characterized by intraductal nodules composed of tightly packed small tubular glands lined by cuboidal cells lacking apparent mucin. Although it was often challenging to determine its extent, invasion was present in 71%. Almost all tumors labeled for CAM5.2, CK7, and CK19; most expressed CA19.9, MUC1, and MUC6. CDX2, MUC2, trypsin, chymotrypsin, chromogranin, and synaptophysin were not expressed. SMAD4 expression was retained in 100%; p16 expression and p53 overexpression was seen in 33% and 27%, respectively. Follow-up information was available for 22 patients (median follow-up, 45 mo; range, 11 to 173 mo). Two patients with invasive carcinoma died of disease at 23 and 41 months, respectively. One patient died of unrelated causes at 49 months. Twelve patients were alive with disease. Seven patients were alive with no evidence of disease. The overall 1-, 3-, and 5-year survival rates were 100% in patients without an invasive component and 100%, 91%, and 71%, respectively, in patients with an invasive component (P=0.7). ITPN is a distinct clinicopathologic entity in the pancreas. Despite the difficulties of determining the extent of invasive carcinoma in many cases, the overall outcome seems to be relatively favorable and substantially better than that of conventional pancreatic ductal adenocarcinoma, even when only the cases with invasive carcinoma are considered.

Figure 1

Intraductal tubulopapillary neoplasm, gross appearance. Note the polypoid component (A) within the main pancreatic duct (B)

Figure 2

Microscopically, intraductal tubulopapillary neoplasm is characterized by nodules of back to back tubular glands, resulting in large cribriform structures within dilated pancreatic ducts (A). Solid areas with scattered abortive glandular arrangements may also be seen (B).

Figure 3

Continuity of the neoplastic epithelium with histologically normal-appearing ductal epithelium may be identified in some tumor nodules.

Figure 4

Tumor cells are cuboidal with modest amount of eosinophilic to amphophilic cytoplasm and round to oval atypical nucleus. Mitotic figures are easily identified.

Figure 5

Rare cases may reveal focal or extensive clear cell morphology.

Figure 6

Intraluminal eosinophilic secretions may be seen but intracellular mucin is minimal/non-existent in intraductal tubulopapillary neoplasms.

Figure 7

Necrosis within the tumor nodules, some with comedo-like pattern, is common.

Figure 8

Invasion, either in the form of individual/thin strands of cells extending away from the periphery of the involved ducts (A) or individual malignant glands clearly infiltrating (B) into the surrounding desmoplastic stroma, were identified in two third of the tumors.

Figure 9

The MUC family of proteins shows a fairly consistent pattern of labeling, with most cases staining for MUC1 and MUC6 but no cases expressing neither MUC2 nor MUC5AC.

Figure 10

The Kaplan-Meier analysis comparing the overall disease-specific survivals of patients without an invasive component and patients with an invasive component.