Clinical History
A 50-year-old female presented with left upper quadrant pain, difficulty eating, and weight loss. An ultrasound showed a 3.0 cm mass in the head of the pancreas with a markedly dilated pancreatic duct. A subsequent CT scan demonstrated a solid mass involving the pancreatic head/neck and body. Laboratory studies showed a serum CA 19-9 of 13.4 U/ml. Endoscopic ultrasound with biopsy was performed and showed a 3.8 cm mass in the body of the pancreas with extension to the neck and associated dilatation of the main pancreatic duct. Core biopsies showed a predominantly tubular proliferation with small, anastomosing papillary fronds and significant nuclear atypia (Figures 1-4). Intracellular mucin was not apparent. Focal areas of necrosis were present. The proliferation was predominantly seen in detached tissue fragments and there was no clear evidence of stromal invasion. Immunohistochemical stains were performed and the lesional cells labeled for cytokeratin AE1/3, CK7 and MUC1 with no labeling seen for CDX2, GATA3, MUC2, synaptophysin, chromogranin, INSM1, BCL10 and trypsin. The lesional cells showed a normal, membranous labeling pattern for β-catenin. DPC4/SMAD4 expression was retained. The patient was referred for surgical resection.
Macroscopic Description
A Whipple resection was attempted, however, an intraoperative frozen section of the pancreatic neck margin showed extensive tumor involving the main pancreatic duct with expansion into multiple side-branch ducts and a decision was made to proceed with a completion total pancreatectomy. Grossly, both the Whipple resection and distal pancreatectomy were involved by a multi-nodular, intraductal mass spanning 4.0 cm in total with multiple adjacent ill-defined solid lesions.
Histologic/Cytologic Features
Sections from the resection specimens showed marked expansion of the native ducts by a complex proliferation of tubular glands lined with cuboidal cells with minimal cytoplasm and significant atypia forming a tubular and cribriform growth pattern with anastomosing papillae and areas of central necrosis (Figures 5,6). There was no obvious intracellular mucin. In multiple areas, often expansile in nature, there are irregular, infiltrative nests with associated desmoplastic stroma (Figures 7,8,9).
Please select your diagnosis in the poll, then see the answer and the discussion in the links below.
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Click Here To See The Answer Answer: Intraductal tubulopapillary neoplasm with associated invasive carcinoma.
Click Here To See The Discussion Final diagnosis: Intraductal tubulopapillary neoplasm with associated invasive carcinoma. Discussion Intraductal tubulopapillary neoplasms (ITPN) are rare intraductal neoplasms of the pancreas, comprising about 3% of all intraductal lesions. Originally described in 2004 and termed “intraductal tubular carcinomas,” the term “intraductal tubulopapillary neoplasm was proposed in 2009 and incorporated into the last two editions of the WHO Classification. Associated invasive carcinomas are very common, seen in approximately 70% of cases. Given the expansile, nodular growth pattern of ITPN, it can be difficult to ascertain exactly how much of the tumor is invasive, but the presence of small, angulated glands and nests with an infiltrative pattern and desmoplastic stroma are useful in the identification of invasive carcinoma. Interestingly, ITPN with an associated invasive carcinoma still display fairly indolent behavior, with a 70% 5-year survival, dramatically improved relative to IPMN-associated carcinomas and ductal adenocarcinomas. Differential diagnosis: The main differential diagnosis is with other intraductal neoplasms of the pancreas and with solid cellular neoplasms of the pancreas that sometimes show intraductal growth within native pancreatic ducts, such as acinar cell carcinoma (ACC) and neuroendocrine neoplasms, predominantly well-differentiated neuroendocrine tumors (NET). Both ACC and NET may show morphologic features (acini and small tubules/pseudoglandular structures) that may mimic the growth patterns of ITPNs. References: Tajiri T, Tate G, Inagaki T, et al. Intraductal tubular neoplasms of the pancreas: histogenesis and differentiation. Pancreas. 2005; 30:115-21. Case contributed by: Elizabeth Thompson, MD, PhD. The Johns Hopkins University School of Medicine Zahra Maleki, MD. The Johns Hopkins University School of Medicine Conflict of Interest: No
The mean patient age is 55 years, fairly evenly split between male and female patients. About half of ITPN are located in the head of the pancreas with a much smaller percentage (about 15%) in the tail and about 30% are more diffuse, as seen in our case, involving both head and body/tail and sometimes the entire gland. Radiologically, ITPN can mimic more common intraductal lesions such as intraductal papillary mucinous neoplasms. However, their often solid appearance, as was seen in the current case, can also mimic ductal adenocarcinomas and other solid neoplasms of the pancreas. It can be challenging on cross-sectional imaging to determine the extent of intraductal versus invasive components in an ITPN.
Grossly, ITPN manifest as multinodular mixed cystic and solid masses (Figure 10) (Image is a representative ITPN, but not the specific tumor from this case), although the confluent intraductal growth often yields an overall solid, fleshy appearance of the tumors with a polypoid growth pattern to the intraductal component. Microscopically, ITPN show confluent growth of back-to-back tubules and anastomosing papillae often markedly expanding native ducts. Cytologically, the tubules and papillae are lined by cuboidal cells with a moderate amount of eosinophilic cytoplasm without appreciable mucin and moderate to marked nuclear atypia. Intracytoplasmic vacuoles and/or clear cell changes can be seen. Luminal secretions and central necrosis are common, often imparting a similar appearance to ductal carcinoma in situ of the breast. There is no specific immunohistochemical staining profile, however certain patterns are supportive. ITPN characteristically label with antibodies for cytokeratins 7 and 19 as well as MUC1 and MUC6. Overall, however, the diagnosis is based predominantly on morphology with immunohistochemistry mainly serving to rule out other possibilities (see Differential Diagnosis, below).
Molecular analysis demonstrates that ITPN harbor distinct alterations from other intraductal neoplasms of the pancreas. Notably, ITPN lack mutations in KRAS and GNAS commonly seen in IPMNs. Mutations in chromatin remodeling genes and in the phosphatidylinositol (PI3K) pathway have been reported as well as a subset of tumors with FGFR2 fusions. Work is ongoing in further unraveling the molecular underpinnings of ITPN and may ultimately contribute both to pre-operative diagnoses via molecular analysis of cyst fluid or fine needle aspiration specimens and to our understanding of the relatively indolent behavior of ITPN-associated invasive carcinomas.
Among the intraductal neoplasms, ITPN most resemble pancreatobiliary-type IPMN. Intestinal- and gastric-type IPMN are easily distinguished by their distinct and abundant apical mucinous cytoplasm, which is lacking in ITPN. Pancreatobiliary-type IPMNs do have cuboidal cells with less abundant mucin, similar to ITPN, however, in general all IPMN have longer, more well-developed papillary fronds than ITPN, which are often more dominated by a tubular pattern, with papillae being more blunted and/or anastomosing. Glycoprotein expression varies in IPMN depending on histologic differentiation. While pancreatobiliary-type IPMNs may share MUC1 and MUC6 expression with ITPN, they may also label for MUC5AC, which should be absent in ITPN. MUC2 and MUC5AC expression in intestinal-type IPMNs and MUC5AC expression in gastric-type IPMNs can also help distinguish them from ITPN.
ITPN can usually be distinguished from intraductal oncocytic papillary neoplasms (IOPN) by the unique cytologic features of the latter: abundant pink, granular cytoplasm and a single prominent nucleolus. IOPN also have characteristic delicate, arborizing papillae and typically do not show tubular morphology. Approximately 60% of IOPN will show diffuse labling for HepPar1, which is typically rare and focal in ITPN.
Acinar cell carcinomas with an intraductal component can be separated from ITPNs based on their classic cytologic features: granular eosinophilic cytoplasm and single prominent central nucleolus as well as characteristic labeling for exocrine enzymes (trypsin, chymotrypsin) and BCL10. Similarly, the differential between ITPN and a neuroendocrine neoplasm showing intraductal growth can be resolved based on the cytologic features of neuroendocrine tumors (salt and pepper chromatin, eosinophilic to amphophilic cytoplasm) and labeling with neuroendocrine makers (synaptophysin, chromogranin).
Yamaguchi H, Shimizu M, Ban S, et al. Intraductal tubulopapillary neoplasms of the pancreas distinct from pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms. Am J Surg Pathol. 2009; 33:1164-72.
Yamaguchi H, Kuboki Y, Hatori T, at al. Somatic mutations in PIK3CA and activation of AKT in intraductal tubulopapillary neoplasms of the pancreas. Am J Surg Pathol. 2011; 35:1812-7.
Basturk O, Adsay V, Askan G, et al. Intraductal tubulopapillary neoplasm of the pancreas: a clinicopathologic and Immunohistochemical analysis of 33 cases. Am J Surg Pathol. 2017; 41:313-25.
Basturk O, Berger MF, Yamaguchi H, et al. Pancreatic intraductal tubulopapillary neoplasm is genetically distinct from intraductal papillary mucinous neoplasm and ductal adenocarcinoma. Mod Path. 2017; 30:1760-772.