Intraductal Tubulopapillary Neoplasm of the Pancreas: An Overview

Intraductal tubulopapillary neoplasm is uncommon, accounting for less than 1% of all pancreatic exocrine tumors and 3% of pancreatic intraductal neoplasms.²  In previous studies, the age range was broad (35–83 years), with a mean age of 56 years at diagnosis.¹  Intraductal tubulopapillary neoplasm affects men and women equally (5:5).^2,5  Intraductal tubulopapillary neoplasms are most commonly located at the pancreatic head (15 of 29; 52%), followed by the body (5 of 29; 17%) and tail (2 of 29; 7%). Intraductal tubulopapillary neoplasms also involve the head and body (1 of 29; 3%), body and tail (2 of 29; 7%), or the entire pancreas (4 of 29; 14%).⁶  Patients with ITPNs present with nonspecific symptoms, such as abdominal pain or sense of fullness, fever, and weight loss, and at times the tumors are detected incidentally during evaluation for other conditions.^1,6,7  Radiologic studies, including endoscopic ultrasonography, computed tomography, and endoscopic retrograde cholangiopancreatography, can be used in identifying intraductal lesions. One study by Motosugi et al⁸  described a 2-tone duct sign and a cork-of-wine-bottle sign as helpful imaging findings of ITPN, but it also recognized the limitations of imaging to differentiate ITPN from IPMN. The 2-tone duct sign is composed of a higher-density tumor area, occluding the main pancreatic duct, and a lower-density luminal area representing dilated upstream lumen.⁹  The cork-of-wine-bottle sign is the tumor surrounded by pancreatic fluid in the dilated duct.⁹ 

All ITPNs have similar characteristic gross features, with solid nodular masses occupying the dilated duct without visible mucin secretion (Figure 1).¹⁰  The nodular masses are usually large (up to 9 cm; mean width, 4.7 cm), dense, and fleshy to rubbery.^1,10  The surrounding pancreatic tissue usually shows dense fibrosis.¹ 

Intraductal tubulopapillary neoplasms are characterized by tubulopapillary growth, uniform high-grade atypia, frequent necrotic foci, evident ductal differentiation, and absence of mucin.²  Intraductal tubulopapillary neoplasms usually form nodular masses with cribriform structures, which are composed of back-to-back tubular glands with occasional papillary growth components (Figure 2, A and B).¹  The nodules occasionally occupy the entire ductal lumen, creating well-circumscribed tumor nests surrounded by fibrotic stroma.¹  The neoplastic cells are cuboidal to columnar, with enlarged round to oval nuclei, and have eosinophilic to amphophilic cytoplasm (Figure 2, C). Typically high-grade atypia is observed throughout the tumor. In several cases, apocrine snoutlike appearance has been observed on the apical surface.¹  Mitoses are readily identifiable, varying from case to case with 0 to 10 mitoses per 10 high-power fields. Associated invasive carcinoma has been reported in 45.4% of cases.¹⁰  The invasive components commonly show a solid tubulopapillary pattern and cytologic appearance that is identical to that of noninvasive components.¹  The adjacent pancreatic parenchyma exhibits acinar atrophy with stromal fibrosis, common features of chronic obstructive pancreatitis.¹⁰ 

Immunohistochemical studies are useful to determine the ductal differentiation of pancreatic neoplasms.¹  The tumor cells show positive staining for cytokeratin 7 (CK7; 100%), CK19 (95%), MUC1 (strong apical stain; 88%; Figure 2, D), and MUC6 (diffuse cytoplasmic stain; 74%; Figure 2, E). However, trypsin, β-catenin, chromogranin, synaptophysin, fascin, MUC2, and MUC5AC (Figure 2, F) show negative staining.^6,10  Two reported cases of ITPN of the bile duct associated with peribiliary cysts suggest that ITPN may originate from peribiliary glands or cysts, and not from the surface epithelium.¹¹  Intraductal tubulopapillary neoplasms lack MUC5AC staining, and peribiliary glands are usually MUC5AC negative, which also supports the previous findings.¹¹  The Ki-67 labeling index shows variable expression (6%–43%).⁶ 

Somatic PIK3CA mutations have been reported in 18% (2 of 11) of patients with ITPN, KRAS in 10% (2 of 20), TP53 in 23% (5 of 22), and BRAF in 15% (2 of 13).⁶  Intraductal tubulopapillary neoplasms occasionally express KRAS mutations, which are exclusively observed in IPMN and PDAC.²  In contrast, PIK3CA mutation is more frequently found in ITPN than in IPMN and PDAC.²  However, there are limited studies regarding molecular profile of ITPN of pancreas; additional studies with larger numbers of cases are needed.

Although approximately 40% of reported pancreatic ITPNs are associated with invasive carcinoma and a high-grade cytologic atypia of the tumor cells, the invasive component is usually limited in extent.¹  This may explain the less aggressive clinical outcome of ITPN compared with IPMN and PDAC.¹²  Kolby et al⁶  described that 14 of 30 patients (46%) were alive and tumor-free at the last follow-up visit between 7 months and 6 years after surgery. Because of the limited follow-up data and the relatively few cases, further clinical studies with large numbers of cases are necessary to verify the actual prognosis of ITPN.²  A number of authors recommend radical surgery before the neoplasm evolves into an invasive carcinoma, to improve prognosis.⁶ 

Differences between ITPN and other intraductal neoplasms are summarized in the Table. It is important to distinguish ITPN from IPMN because ITPN has a favorable prognosis.⁶  Grossly, both may present with intraductal lesions with solid and cystic areas.¹  Intraductal tubulopapillary neoplasm shows solid and nodular masses occluding the pancreatic duct without mucin production, whereas IPMN shows polypoid tumors as mural nodules intruding into dilated duct with prominent cystic changes and visible mucin.⁵  Microscopically, formation of tubules and absence of mucin production are the main differences between ITPN and IPMN, although some IPMNs, including low-grade branch duct–type IPMNs, can exhibit tubule formation.¹³  Intraductal tubulopapillary neoplasms also often exhibit uniform high-grade dysplasia, which is less common in IPMNs, with the exception of the pancreatobiliary subtype of IPMN, and hence the main differential diagnosis of ITPN is the pancreatobiliary subtype of IPMN. Gastric and intestinal types of IPMNs can be distinguished from ITPNs by mucin profiles with MUC2 and MUC5AC positivity, whereas ITPNs are negative for these mucin stains and positive for MUC1 and MUC6.¹  In addition, ITPNs frequently show necrotic foci and negative fascin staining, and no KRAS mutation.¹⁰  Pancreatic ductal adenocarcinoma involving ducts should be differentiated from ITPN. Pancreatic ductal adenocarcinomas usually present as poorly circumscribed, invasive, and scirrhous neoplasms with irregular angulated glands or solid components, depending on the degree of differentiation.¹  Recently, a variant of acinar cell carcinoma with intraductal growth pattern, which can mimic ITPN, was reported.¹⁴  Intraductal and papillary variants of acinar cell carcinoma usually show parenchymal invasion, and the tumors are composed of eosinophilic or amphophilic granular cells with round nuclei and a single, prominent nucleolus forming acini. Intraluminal acidophilic secretions are usually present with no mucin, and tumor cells express trypsin or chymotrypsin.¹⁵  Rarely, neuroendocrine tumors can show intraductal growth pattern mimicking intraductal neoplasms; however, they usually show various organoid architectural patterns, characteristic coarsely clumped chromatin pattern (“salt and pepper”), and positivity for chromogranin and synaptophysin.¹⁶ 

Intraductal tubulopapillary neoplasm is a rare and distinct subtype of pancreatic intraductal neoplasm. Intraductal tubulopapillary neoplasm should be differentiated from other pancreatic tumors, including IPMN, PDAC, and intraductal variants of acinar cell carcinoma and neuroendocrine tumors, because ITPN has a favorable prognosis. Because a number of clinical, radiologic, and histopathologic features overlap among the previous tumors, characteristic immunohistochemical staining and molecular findings can be useful to distinguish them.