Eighty-two cases fulfilled the criteria described for IAPN (Textbox 1). The prevalence among ampullary glandular neoplasms was 33% and 5.5% among pancreatoduodenal/ampullary resection specimens. The mean age was 64 years (range: 27 to 85 y). Fifty-seven patients were male and 24 were female (ratio: 2.4). Main presentation symptoms were available in 19 cases and included jaundice (19), weight loss (4), abdominal pain (4), nausea/vomiting (3), pruritis (2), and dark urine/light stool (2), and tarry stool (1). Imaging studies (5 endoscopic retrograde cholangiopancreatography, 9 computed tomography, and 1 magnetic resonance imaging) generally described dilated CBD and intra/extrahepatic ducts, ampullary, duodenal or pancreatic mass, and enlarged and/or irregular papillae. The preoperative diagnosis was available for 49 cases and was “ampullary mass” in 18 cases, “ampullary carcinoma” in 20, “duodenal carcinoma” in 4, “distal CBD carcinoma” in 3, “pancreatic carcinoma” in 1, and “pancreatic mass” in 3 cases ().
General Characteristics of the Cases With and Without Invasive Component
These tumors were characterized by prominent exophytic growth within dilated intra-ampullary ducts and formation of obstructive papillary/polypoid masses, often with dilatation of the upstream biliary or pancreatic ducts (). The macroscopic pattern mostly corresponded to what has been referred to as an “intramural protruding form,”57,63
although in rare cases there was minimal involvement of the duodenal surface of the papilla of Vater, thus representing the “exposed protruding form” or “ulcerating form.” By definition, those cases with more prominent involvement of the papilla were excluded. Mucin hypersecretion was recognized in 7 cases (8.5%). The mean overall tumor size was 2.7 cm (range: 0.8 to 6.7 cm). Although 2 preinvasive tumors were less than 1 cm (0.8 and 0.9 cm), they were included in this study because they were easily distinguished from the flat lesions by their compact exophytic growth () and their clear-cut delineation from the surrounding tissue.
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 (more ...)
These lesions were characterized by well-organized, back to back epithelial units, either in tubular () or papillary () architecture or both, with minimal or no intervening stroma between the units, similar to other preinvasive neoplasms. The base of the lesions was sharply demarcated; however, the dysplastic process often showed complexity because of the involvement of the tributary glands comprising the ampullary ductules. This created an architectural complexity and a pseudoinvasive pattern, which, at times, was difficult to distinguish from true invasion. In 38 cases (46%), the exophytic (preinvasive) lesion extended by pagetoid spread to the duodenal surface of the papilla of Vater, but by definition this duodenal lumen-facing component comprised less than 25% of the tumor.
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 (more ...)
Histologic Growth Pattern
Forty-seven cases (57%) had a tubulopapillary configuration (each component was >25% of the lesion), (Tables , ), whereas 19 (23%) were predominantly (>75%) papillary (or villous), and 16 (20%) were predominantly tubular. The mean tumor size did not seem to differ between these groups: 2.4 cm in the papillary and tubular groups and 2.9 cm in the tubulopapillary group ().
Papillary examples had a higher tendency for HGD than the tubular and tubulopapillary groups (P<0.05). The extent of HGD in the papillary group was focal in 11%, substantial in 37%, and extensive in 47% of cases; these figures were 49%, 26%, and 19% for tubulopapillary, and 44%, 25%, and 25% for tubular examples. However, the prevalence of an associated invasive carcinoma was lower in the papillary group (68%) than in tubulopapillary (81%) or tubular (81%) groups. There were no significant differences in prognostic factors such as tumor stage, lymph node involvement, or 3 and 5-year survival rates between these groups.
Five cases (6%) had no HGD, 32 (39%) had focal, 23 (28%) had substantial, and 22 cases (27%) had extensive HGD (). The prevalence of an associated invasive carcinoma for these groups was 0%, 76%, 87%, and 86%. In addition, the 3 and 5-year survival rates of the former 2 groups (focal or no HGD) seemed to be higher than those of the latter 2 groups (substantial or extensive HGD), but the difference was not statistically significant (P = 0.09) ().
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 (more ...)
Histomorphologic Subtyping Based on Cell Lineage
Using an approach that acknowledged any existing pattern of cell-lineage morphology, almost half of the cases (37 cases; 45%) were found to have mixed patterns (at least some foci of a secondary pattern, ), whereas 35 (43%) were pure INT () and 10 cases were (12%) pure GPB (). When evaluated with the forcedbinary classification approach, the predominant pattern was INT () in 61 cases (74%) and GPB () in 21 cases (26%) ().
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 (more ...)
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 (more ...)
Predominate Cell Lineages in Preinvasive Component
On the basis of the combination of predominate cell-lineage morphology and growth pattern, the cases were classified into the following categories:
INT-type (61 Cases)
The majority of INT-type cases were similar to conventional colonic/duodenal tubular adenomas consisting of relatively simple villous or tubular glandular units, lined by tall columnar INT-type cells with pseudostratified cigar-shaped nuclei (). Occasionally, cribriform architecture was observed. The apical cytoplasm was usually densely chromophilic, but was pale or clear with abundant apical mucin in 3 cases. Goblet, brush border, and/or Paneth cells were prominent in some cases (). Mucin hyperproduction into the lumen, akin to that seen in pancreatic IPMNs, was seen in only 3 cases.
Forty (66%) of the INT-type cases were tubulopapillary, 14 (23%) were tubular, and 7 (11%) were papillary (or villous). Importantly, 43% had secondary GPB cells (), which is unusual in conventional colonic/duodenal adenomas. Prevalence and proportion of HGD in the INT group was significantly lower than that of the GPB group presented below. Seven percent of cases had no HGD and 52% had focal, whereas 30% had substantial, and only 11% of cases had extensive HGD. An associated invasive carcinoma was identified in 77% of INT cases. The type of invasive carcinoma was INT in 79% and GPB in 21% of these cases; the size of invasion was less than 0.5 cm in 13%, 0.5 to 1 cm in 30%, and greater than 1 cm in 57% of cases.
GPB-type (21 Cases)
Two distinct subtypes of GPB could be discerned based on cytoarchitectural characteristics. The first was characterized by a papillary (75%) or tubulopapillary (25%) growth pattern and cytomorphology similar to that of PB-type IPMNs (). The second GPB subtype was characterized by a striking tubular growth pattern and an overall appearance of a pyloric gland adenoma ().
PB-papillary subtype (16 cases): Almost all PB-papillary-type cases had complex arborizing papillae. The cytologic features often showed transition to a more gastric phenotype (), which further supported their kinship with the gastric type and also justified their combined classification. However, all had HGD/carcinoma in situ in the papillary areas. In addition, HGD was extensive in 75% and substantial in the remaining 25%; none of the cases were classified as focal. An associated invasive carcinoma was identified in 81% of PB-papillary-type cases all of which were GPB-type, and tended to be larger (0% were <0.5 cm, 38% were 0.5 to 1 cm, and 62% >1 cm) than invasions seen in INT-type or the gastric-tubular type discussed below.
Gastric-tubular subtype (5 cases): The gastric-tubular-type lesion was recognized as a separate variant because of its highly distinctive morphology among lesions with GPB lineage. The lesions were characterized by a closely packed, uniform, tubular growth pattern reminiscent of pyloric or Brunner glands. The glands were arranged back-to-back and lined by a single layer of cuboidal to columnar GPB-type cells with basally oriented nuclei and abundant apical mucinous cytoplasm (). Two gastric-tubular-type cases formed polypoid masses resembling the pyloric gland type of adenoma in that one was devoid of HGD and the other exhibited transformation into arborized papillary areas with HGD. The remaining 3 cases showed monotonous, small tubular proliferation with extensive HGD and formation of expansile masses which resembled intraductal tubular/tubulopapillary carcinoma of the pancreas, although some with a more mucinous-appearing cytoplasm. Expansile proliferation replaced most of the residual ductal epithelium and made recognition of the intraductal (duct-confined) nature of the process challenging. An associated invasive carcinoma was present in 4 cases (80%) and all were of PB-type. Invasion, however, seemed to be relatively small at the time of diagnosis, compared with INT-type or PB-papillary subtype, in that 3 (75%) were 0.5 to 1.0 cm, and only 1 (25%) was larger than 1 cm.
No significant difference in prognostic factors such as pathologic tumor (pT) stage, lymph node involvement, or 3 and 5-year survival rates were identified among these subtypes.
Cases With an Associated Invasive Carcinoma (64 Cases)
Sixty-four of 82 cases (78%) had an associated invasive carcinoma (64 of 230, 28%, of all invasive carcinomas within the ampulla arose in association with IAPNs). The average age and sex ratio of the patients was similar in the invasive and noninvasive groups (64 vs. 63 y; the male/female ratio was 2.2 vs. 3.5, P = 0.91 and P = 0.44, respectively). The overall size of the tumor tended to be larger in the invasive group than in the noninvasive (2.8 vs. 2.1 cm, respectively; P = 0.04). The size of invasion was less than 0.5 cm in 6 cases (9%), 0.5 to 1 cm in 22 (34%), and greater than 1 cm in 36 cases (56%).
The histologic type of invasive carcinoma included 60 ordinary adenocarcinomas and 4 mixed adenocarcinomas (2 with mucinous, 1 squamous, and 1 with neuroendocrine components).
As for the cell-lineage morphology, associated invasive carcinomas were classified as pure INT-type in 5 cases (8%), mixed in 46 (72%), and pure PB-type in 13 cases (20%). On the basis of the forced-binary approach (which eliminated the mixed category), however, the cases were finally divided into INT-type (37 cases; 58%) and PB-type (27 cases; 42%). The representative histology of each type is shown in .
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 (more ...)
In terms of preinvasive components, among the 61 preinvasive lesions of INT cell lineage, 47 (77%) had an associated invasive carcinoma including 37 invasive lesions of INT cell lineage and 10 invasive lesions of PB cell lineage. On the other hand, among the 21 preinvasive lesions of GPB cell lineage, 17 (81%) had an associated invasive carcinoma all of which were of PB cell lineage ().
Among the 64 cases with an associated invasive carcinoma, the preinvasive component was INT-type in 47 (73%) and GPB-type in 17 cases (27%). There was lineagetype concordance between preinvasive and invasive components in 54 cases, whereas 10 were discordant; all 10 discordant cases had INT-type preinvasive neoplasms but PB-type invasion. All cases with a GPB-type preinvasive component also had a PB-type invasive component.
Fifty-nine cases were available for immunohistochemical staining. The preinvasive components of INT cell-lineage morphology (41 cases) showed immunolabeling (diffuse+focal) for MUC2 (31%+54%) in 85% of the cases, 94% (78%+16%) for CDX2, 93% (83%+10%) for CK20, 21% (8%+13%) for MUC1, 31% (5%+26%) for MUC5AC, 24% (3%+21%) for MUC6, and 63% of cases (53%+10%) for CK7 (Figs. , ).
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 (more ...)
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.
Those with GPB cell-lineage morphology (18 cases) showed immunolabeling (diffuse+focal) for MUC2 in 22% (0%+22%) of the cases, 39% (11%+28%) for CDX2, 39% (28%+11%) for CK20, 89% (67%+22%) for MUC1, 95% (56%+39%) for MUC5AC, 83% (39%+44%) for MUC6, and 89% (89%+0%) of cases showed immunolabeling for CK7 (Figs. , ).
The sensitivity and specificity for INT cell-lineage markers were as follows: MUC2, 85% and 78%; CDX2, 94% and 61%; and CK20, 93% and 61%. The sensitivity and specificity for GPB cell-lineage markers were as follows: MUC1, 89% and 79%; MUC5AC, 95% and 69%; and MUC6, 83% and 76%. CKs 7 and 20 were coexpressed in 53% of all cases available for immunohistochemical staining.
When the subsets of GPB type were analyzed separately, it was noted that all PB-papillary cases had at least focal MUC5AC, and all gastric-tubular subtype had at least focal expression of MUC1.
Tissue from 24 invasive INT-type carcinomas was available for evaluation. Immunolabeling (diffuse+focal) was positive for the following percentage of cases: MUC2 67% (25%+42%); CDX2 78% (52%+26%); CK20 83% (75%+8%); MUC1 46% (4%+42%); MUC5AC 59% (13%+46%); MUC6 17% (4%+13%); and CK7 67% (54%+13%).
Twenty-three PB-type invasive carcinomas were available for evaluation. Immunolabeling (diffuse+focal) was positive for the following percentage of cases: MUC2 17% (4%+13%); CDX2 34% (17%+17%); CK20 48% (35%+13%); MUC1 96% (83%+13%); MUC5AC 61% (26%+35%); MUC6 39% (22%+17%); and CK7 83% (83%+0%).
For invasive carcinoma of the INT cell lineage, sensitivity and specificity results were as follows: MUC2 67% and 83%; CDX2 78% and 66%; and CK20 83% and 52%. Sensitivity and specificity for invasive carcinoma of the PB cell lineage were as follows: MUC1 96% and 54%; MUC5AC 61% and 41%; MUC6 39%and 83%; and CK7 83% and 33%.
Prognosis (Clinical Outcome)
Cases without invasion had a very good prognosis, as evidenced by 3 and 5-year survival rates (100% and 100%) significantly better than those cases with an associated invasive carcinoma (69% and 45%, respectively) (). There were significant differences between these 2 groups in terms of tumor size (2.1 vs. 2.8 cm), and HGD proportion (no or focal HGD/substantial or extensive HGD 67%/33%, P = 0.04 vs. 39%/61%, P = 0.04). Only 1 patient with noninvasive carcinoma died; he had substantial HGD/carcinoma in situ and died 85 months after undergoing a Whipple resection.
Univariate and multivariate analyses were performed on 53 cases with an associated invasive carcinoma for which all the parameters tested were available (eg, cases with incomplete lymph node dissection because of local excision, like ampullectomies, were excluded). In univariate analysis, pT stage (P<0.01), lymph node involvement (P = 0.01), and tumor budding (P = 0.03) were found to be the significant prognostic factors, whereas venous invasion (P = 0.06) and pattern of invasion (infiltrative vs. expansile) also approached statistical significance (P = 0.08) (). In a stepwise, multivariable Cox regression analysis which incorporated these 5 factors, pT stage (P = 0.01) was the only significant independent factor related to prognosis, although tumor budding did approach statistical significance (P = 0.09) ().
Univariate Analysis of Prognostic Factors on Patients With an Associated Invasive Carcinoma
Multivariate Analysis of Prognostic Factors on Patients With an Associated Invasive Carcinoma
Comparison With Other Ampullary Carcinomas
When IAPNs with an associated invasive carcinoma were compared with conventional invasive carcinomas of the ampulla, the mean tumor size was not significantly different (2.8 cm vs. 2.5 cm), but there was a significant difference in the size of invasion (mean size of invasion 1.4 cm vs. 1.9 cm, P<0.001). Minimal invasion (<5 mm) was more common in the former (9% vs. 2%). IAPNs with an associated invasive carcinoma also had significantly better tumor differentiation (P<0.001), were more frequently of INT cell lineage (P<0.001), had a lower tumor stage (P<0.001), and had less lymph node involvement (P = 0.05). More importantly, cases of invasion associated with IAPNs had a significantly better prognosis than conventional invasive carcinomas of the ampulla. The mean survival time was 51 versus 31 months (P<0.001) and the 3-year survival rate was 69% versus 44% (P<0.01); although, the difference in 5-year survival rate (45% vs. 28%) did not reach statistical significance (P = 0.06) (, ).
Comparison of IAPNs With an Associated Invasive Carcinoma and Conventional Invasive Carcinomas of the Ampulla
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 (more ...)