Intra-ampullary papillary-tubular neoplasm (IAPN): characterization of tumoral intraepithelial neoplasia occurring within the ampulla: a clinicopathologic analysis of 82 cases

Abstract

Background: There has been no uniform terminology for systematic analysis of mass-forming preinvasive neoplasms (which we term tumoral intraepithelial neoplasia) that occur specifically within the ampulla. Here, we provide a detailed analysis of these neoplasms, which we propose to refer to as intra-ampullary papillary-tubular neoplasm (IAPN).

Materials and methods: Three hundred and seventeen glandular neoplasms involving the ampulla were identified through a review of 1469 pancreatoduodenectomies and 11 ampullectomies. Eighty-two neoplasms characterized by substantial preinvasive exophytic component that grew almost exclusively (>75%) within the ampulla (in the ampullary channel or intra-ampullary portions of the very distal segments of the common bile duct or pancreatic duct) were analyzed.

Results: (1) Clinical: The mean age was 64 years, male/female ratio was 2.4, and mean tumor size was 2.7 cm. (2) Pathology: The tumors had a mixture of both papillary and tubular growth (each constituting at least 25% of the lesion) in 57%; predominantly (>75%) papillary in 23%, and predominantly (>75%) tubular in 20%. High-grade dysplasia was present in 94% of cases, of which 39% showed focal (<25% of the lesion), 28% showed substantial (25% to 75%), and 27% showed extensive (>75%) high-grade dysplasia. In terms of cell-lineage morphology, 45% had a mixture of patterns. However, when evaluated with a forced-binary approach as intestinal (INT) versus gastric/pancreatobiliary (GPB) based on the predominant pattern, 74% were classified as INT and 26% as GPB. (3) Immunohistochemistry: Percent sensitivity/specificity of cell-lineage markers were, for INT phenotype: MUC2 85/78 and CDX2 94/61; and for GBP: MUC1 89/79, MUC5AC 95/69, and MUC6 83/76, respectively. Cytokeratin 7 and 20 were coexpressed in more than half. (4) Invasive carcinoma: In 64 cases (78%), there was an associated invasive carcinoma. Size of the tumor and amount of dysplasia correlated with the incidence of invasion. Invasive carcinoma was of INT-type in 58% and of pancreatobiliary-type in 42%. Cell lineage in the invasive component was the same as that of the preinvasive component in 84%. All discrepant cases were pancreatobiliary-type invasions, which occurred in INT-type preinvasive lesions. (5) OUTCOME: The overall survival of invasive cases were significantly worse than that of noninvasive ones (57% vs. 93%; P=0.01); and 3 years, 69% versus 100% (P=0.08); and 5 years, 45% versus 100% (P=0.07), respectively. When compared with 166 conventional invasive carcinomas of the ampullary region, invasive IAPNs had significantly better prognosis with a mean survival of 51 versus 31 months (P<0.001) and the 3-year survival of 69% versus 44% (P<0.01).

Conclusions: Tumoral intraepithelial neoplasia occurring within the ampulla are highly analogous to pancreatic or biliary intraductal papillary and tubular neoplasms as evidenced by their papillary and/or tubular growth, variable cell lineage, and spectrum of dysplastic change (adenoma-carcinoma sequence), and thus we propose to refer to these as IAPN. IAPNs are biologically indolent; noninvasive examples show an excellent prognosis, whereas those with invasion exhibit a malignant but nevertheless significantly better prognosis than typical invasive ampullary carcinomas unaccompanied by IAPNs. Twenty eight percent (64 of 230) of invasive carcinomas within the ampulla arise in association with IAPNs.

FIGURE 1

A, Prominent exophytic growth dilating and filling the intra-ampullary ducts and forming obstructive papillary/ polypoid mass. B, By definition, there is only minimal (<25%) tumor at the duodenal surface of the papilla. CBD indicates common bile duct.

FIGURE 2

A, Predominant (>75%) tubular growth was observed in 20% of the cases. Typically these were composed of compact, back-to-back tubular elements with minimal or no intervening stroma between the units. In this case, the duct is filled with a neoplastic lesion whereas the duodenal mucosa is spared by the process. Note that the overall picture is quite similar to intraductal tubulopapillary neoplasms of the pancreas. B, Predominant (>75%) papillary pattern was observed in 23% of the lesions. These were characterized with well-formed papillae projecting into the intra-ampullary ducts.

FIGURE 3

Variable grades of dysplasia could be seen in intra-ampullary papillary-tubular neoplasms, both within the group but also in a given case. Picture on the left illustrates a focus of low-grade dysplasia whereas those in the middle and the right exhibit transition to high-grade dysplasia, which was noted, at least focally, in 96% of the cases. These were characterized with significant architectural atypia with disorganization of cells and loss of polarity, as well as nuclear atypia, including pleomorphism, nuclear irregularities, and hyperchromatism.

FIGURE 4

Almost half of the cases (45%) were found to have mixed cell-lineage morphology, depicted in this photomicrograph as intestinal (INT; on the left) and gastric/pancreatobiliary (GPB; on the right), both from the same case.

FIGURE 5

A, Intestinal-type intra-ampullary papillary-tubular neoplasms were similar to conventional colonic/duodenal tubular adenomas consisting of relatively simple villous or tubular glandular units, lined by tall columnar cells with pseudostratified cigar-shaped nuclei. B, Goblet cells were prominent in some cases, and endocrine-type cells with distinctive granules could also be seen.

FIGURE 6

A, Most gastro-pancreatobiliary-subtype intra-ampullary papillary-tubular neoplasms, similar to pancreatobiliary-type intraductal papillary-mucinous neoplasm in the pancreas, revealed papillary pattern, although some had tubulopapillary growth. B, Gastric-tubular subtype of gastric/pancreatobiliary phenotype was characterized by an exclusive tubular growth pattern. More importantly, the glands were arranged back-to-back and lined by a single layer of cuboidal-to-columnar cells with basally oriented nuclei and abundant apical cytoplasm with mucin, exhibiting cytologic features very similar to gastric pyloric glands or Brunner glands. Despite the relatively bland appearance of the overall lesion, this case was associated with invasive carcinoma.

FIGURE 7

Invasive carcinomas were generally of tubular-type and were subclassified as pure intestinal (8%; left), pure pancreatobiliary type (20%; right), or mixed (72%; middle). Most cases with “mixed” features were classifiable as intestinal when a forced-binary (favored) approach was used.

FIGURE 8

Most of intestinal type papillae revealed CDX2 (92%) and MUC2 (85%) expression; however, the specificity of these markers for this phenotype was fairly low (61% and 78%, respectively). In contrast, all pancreatobiliary subtype papillae (100%) were, at least focally, positive for MUC5AC and all gastric-tubular subtype papillae (100%) were, at least focally, positive for MUC1.

FIGURE 9

A, Immunoprofile of intestinal (INT)-type IAPN, preinvasive component. B, Immunoprofile of gastric/pancreatobiliary (GPB)-type IAPN, preinvasive component. CK, cytokeratin; IAPN, intra-ampullary papillary-tubular neoplasm.

FIGURE 10

Comparison of invasive IAPNs with conventional invasive carcinomas of the ampulla (unaccompanied with IAPN): Although, the mean survival time was 51 vs. 31 months (P < 0.001) and the 3-year survival rate was 69% vs. 44% (P < 0.01), the difference in 5-year survival rate (45% vs. 28%) did not reach statistical significance (P = 0.06).