Case 2: Quarter 3, 2022

Case 2: Quarter 3, 2022

Clinical History

A 55-year-old female presented with right upper quadrant abdominal pain and fatigue. She reports a history of a pancreatic tail tumor status-post distal pancreatectomy and splenectomy approximately 25 years ago. The slides from her prior resection were no longer available for review, but per report demonstrated a large (8 cm), “centrally-necrotic” islet cell tumor with negative margins and no lymph node involvement. She had undergone 10 years of surveillance following the distal pancreatectomy with no evidence of recurrence or metastasis. The patient underwent an abdominal CT scan which demonstrated an 8.4 cm mass within the right lobe of the liver with occlusion of the right hepatic vein. The mass was described as mixed cystic and solid and radiologically the concern was for a mucinous cystic neoplasm with an associated invasive carcinoma. Per the radiologist, the findings were not typical of metastatic neuroendocrine tumor. A somatastatin receptor tracer Ga-68 Dotatate PET/CT scan showed no uptake in the liver lesion. As she had no evidence of other liver lesions or extra-hepatic disease, she was recommended to undergo an extended right hepatectomy.

Figure 1. Representative image of the tumor, H&E stain.
Figure 2. Representative image of the tumor/liver interface, H&E stain.
Figure 3. Areas with myxoid stroma in tumor, H&E stain.
Figure 4. Abundant eosinophilic hyaline globules in the tumor cells, H&E stain.

Macroscopic Description
The resection specimen showed a large, centrally necrotic, cystic, and solid mass in the superior aspect of the right hepatic lobe measuring 11.5 cm in greatest dimension. The mass abutted the liver parenchymal resection margin and was grossly suspicious for the involvement of vascular margins.

Histologic/Cytologic Features 

The H&E sections from the liver resection show a cellular neoplasm with poorly-cohesive cells adhering loosely to delicate branching blood vessels, imparting the appearance of papillary architecture without true fibrovascular cores (Figure 1). The tumor was clearly centered in liver parenchyma (Figure 2) and in areas there was myxoid stroma intermixed with solid nests of tumor cells (Figure 3). While the tumor is grossly cystic and solid, no true neoplastic lining was identified and the cystic areas were predominantly derived from the discohesive nature of the cells and central degeneration. Abundant brightly, eosinophilic hyaline globules were identified (Figure 4). Cytologically, the cells were polygonal with eosinophilic to focally clear cytoplasm with round to oval nuclei with scattered nuclear grooves (Figure 5). Mitoses were not easily identified. Immunohistochemical stains showed that the tumor cells labeled for synaptophysin (scattered, focal, Figure 6) and were negative for chromogranin (Figure 7). Cytokeratin AE1/3 was also focally positive in the tumor. The tumor cells were positive for PR and CD10. An immunohistochemical stain for beta-catenin showed an abnormal nuclear and cytoplasmic labeling pattern in the tumor cells.

Figure 5. High power view of tumor cytology, H&E stain.
Figure 6. Representative image of immunohistochemical stain for synaptophysin
Figure 7. Representative image of immunohistochemical stain for chromogranin
Figure 8. Representative image of immunohistochemical stain for beta-catenin

Please select your diagnosis in the poll, then see the answer and the discussion in the links below.


What is the correct diagnosis?

View Results

Loading ... Loading ...


Click Here To See The Answer

Answer: Metastatic solid-pseudopapillary neoplasm  of the pancreas

 


Click Here To See The Discussion

Final diagnosis:  

Metastatic solid-pseudopapillary neoplasm  of the pancreas after a 25 year interval

Discussion

This patient’s case is a rare example of metastatic solid pseudopapillary neoplasm of the pancreas to the liver after a long interval. While the presence of a primary solid-pseudopapillary neoplasm of the pancreas was not able to be definitively verified histologically in this case, multiple features of the patient’s history point to a potential misdiagnosis of her original tumor. The description of a “centrally necrotic” islet cell tumor is unusual. While necrosis can certainly be seen in well-differentiated neuroendocrine tumors, it is more commonly seem in higher grade tumors, which in turn, would be unlikely to show such indolent behavior over 25 years. The reported size of her original tumor, over 8 cm, is also somewhat unusual in terms of risk of progression over such a long time interval. Mostly likely, the original tumor represented a solid pseudopapillary neoplasm of the pancreas where large tumor size and necrosis are very common and the vast majority of tumors demonstrate very indolent behavior, as will be discussed in more detail below.

Solid-pseudopapillary neoplasms (SPN) of the pancreas are rare neoplasms, representing 1-2% of all pancreatic tumors. They are most commonly seen in younger women (90% female predominance) with a mean age at diagnosis of 29 years. For reference, our patient would have been 30 at the time of her original pancreatic surgery. Radiologically they are circumscribed to encapsulated heterogenous lesions, often with cystic degeneration. Grossly, SPN recapitulate this radiographic appearance and are variably mixed solid and cystic tumors with abundant necrosis/degenerative changes and hemorrhage (Figure 9, representative image). SPN can be located anywhere in the pancreas, but are most typically seen in the body/tail.

Figure 9. Gross and radiographic images of representative primary solid-pseudopapillary neoplasm of the pancreas

Histologically, tumors are comprised of loosely cohesive cells surrounding a delicate network of blood vessels, often with associated myxoid stromal change. Pseudopapillae form as the discohesive tumor cells fall apart around the blood vessels, creating the appearance of fibrovascular cores. Intracytoplasmic eosinophilic hyaline globules as well as cytoplasmic clearing and/or intracytoplasmic vacuoles can be seen. Degenerative changes with foamy macrophages, cholesterol clefts, hemorrhage and necrosis are very common in SPN. “Insidious invasion,” where the tumor extends into adjacent pancreas without generating significant stromal reaction is also common, despite an overall circumscribed appearance. Cytologically, the tumor cells of SPN are polygonal with eosinophilic cytoplasm and round to oval nuclei with nuclear grooves. Mitotic figures are rare, but degenerative atypia with pleomorphic nuclei and dark, “smudgy” chromatin and multinucleated atypical giant cells can be seen.

While the morphology of SPN is often very distinctive, there are overlapping features with other cellular neoplasms of the pancreas, most notably well-differentiated neuroendocrine tumors and acinar cell carcinomas.Immunohistochemistry can be very useful in sorting out these differentials. SPN are variably cytokeratin positive and characteristically label for CD56, CD10, and CD99 (perineuclear dot-like staining) as well as AR, PR, TFE3 and LEF1. Variable labeling with synaptophysin is typical, which can be misleading, particularly on a small biopsy, however, SPN should be negative for chromogranin, in contrast with well-differentiated neuroendocrine tumors of the pancreas, which are typically positive for chromogranin. Over 90% of SPN have a point mutation in exon 3 of CTNNB1, the gene encoding for beta catenin, leading to aberrant nuclear and cytoplasmic labeling with beta catenin antibodies. Immunohistochemical stains for E-cadherin and p120 catenin will also show the loss of membranous expression of these proteins in SPN.

While all SPN are considered to have low malignant potential, overall, the vast majority of cases are cured with surgical resection. Metastatic behavior is rare and can occur after a fairly long time interval from original diagnosis. Liver is the most common site of metastasis. Definitive evidence of clinical and histologic features predicting aggressive behavior and/or future metastases are lacking, although male sex, vascular invasion and perineural invasion, and the presence of metastasis among others, have been proposed. The degenerative atypia described above can be associated with increased Ki67 labeling but does not seem to track with metastatic behavior. Rare cases of SPN with diffuse growth, marked nuclear atypia with sarcomatoid features and markedly elevated mitotic rates have been described and were associated with highly aggressive clinical behavior.

Differential diagnosis:

The differential diagnosis of SPN primarily includes other cellular neoplasms of the pancreas: well-differentiated neuroendocrine tumors, acinar cell carcinoma and pancreatoblastoma. For the rare occurrence of metastatic SPN to the liver, primary liver tumors would also enter the differential, particularly if there was no known history of SPN or a previous pancreas resection.

Of the cellular neoplasms of the pancreas, the majority of morphologic and immunohistochemical overlap with SPN is seen with well-differentiated neuroendocrine tumors. More solid SPN with less cystic degeneration are also more likely to mimic neuroendocrine tumors morphologically. Neuroendocrine tumors can also form some pseudopapillae. Cytologically, the features of these two tumors is fairly distinct with neuroendocrine tumors having finely stippled “salt and pepper” chromatin and eosinophilic to amphophilic cytoplasm. As mentioned above, a major diagnostic pitfall is the combination of keratin, CD56, and synaptophysin reactivity in SPN. Despite these overlaps, SPN are almost uniformly chromogranin negative and neuroendocrine tumors should not show abnormal nuclear staining for beta-catenin. As long as one thinks of the diagnosis of SPN, Immunohistochemical studies can usually distinguish the two entities easily.

Cellular neoplasms with acinar differentiation including acinar cell carcinoma and pancreatoblastoma can be separated from SPN via distinct morphologic, cytologic and Immunohistochemical features. Acinar cell carcinomas have characteristically granular eosinophilic cytoplasm with a single, prominent nucleolus and label with antibodies against exocrine enzymes including trypsin and chymotrypsin. They also show strong granular, cytoplasmic labeling with BCL-10. Acinar cell carcinomas can show aberrant nuclear labeling with beta-catenin due to underlying molecular alterations, however SPN will not show reactivity with exocrine enzymes or BCL-10. Pancreatoblastoma has characteristic squamous morules in addition to acinar and variable neuroendocrine and ductal differentiation. These squamous morules will also show nuclear beta-catenin labeling, however their distinct morphology and areas of acinar differentiation on H&E and by immunohistochemistry will distinguish them from SPN.

While there is less morphologic overlap with primary liver tumors, this differential may arise when SPN metastasize to the liver. Hepatocellular carcinoma can be identified by labeling for Hep-Par1, arginase and glypican3. Intrahepatic cholangiocarcinoma can be identified by gland formation and strong, uniform keratin labeling. Both tumors will also show positivity for in situ hybridization for albumin.

References:

Hruban RH, Pitman MB, Klimstra DS. Tumors of the pancreas. Atlas of tumor pathology. Fourth Series, Fascicle 6 ed. Washington, DC: American Registry of Pathology and Armed Forces Institute of Pathology, 2007.

Abraham SC, Klimstra DS, Wilentz RE, Wu T-T, Cameron JL, Yeo CJ et al. Solid-pseudopapillary tumors of the pancreas are genetically distinct from pancreatic ductal adenocarcinomas and almost always harbor beta-catenin mutations. Am J Pathol. 2002; 160(4):1361-1369.

Klimstra DS, Wenig BM, Heffess CS. Solid-pseudopapillary tumor of the pancreas: a typically cystic carcinoma of low malignant potential. Semin Diagn Pathol. 2000; 17(1):66-80.

Tang LH, Aydin H, Brennan MF, Klimstra DS. Clinically aggressive solid pseudopapillary tumors of the pancreas: a report of two cases with components of undifferentiated carcinoma and a comparative clinicopathologic analysis of 34 conventional cases. Am J Surg Pathol. 2005;29 (4):512-9.

La Rosa S, Bongiovanni M. Pancreatic Solid-pseudpapillary Neoplasm: Key Pathologic and Genetic Features. 2020; 144(7):829-37.

Li L, Othman M, Rashid A, Wang H, Li Z, Katz MH, Lee JE, Pisters PW, Abbruzzese JL, Fleming JB, Wang H. Solid pseudopapillary neoplasm of the pancreas with prominent atypical multinucleated giant tumour cells. Histopathology 2013; 62(3):465-71

Estrella JS, Li L, Rashid A, Wang H, Katz MH, Fleming JB, Abbruzzese JL, Wang H. Solid Pseudopapillary neoplasm of the pancreas: clinicopathologic and survival analyses of 64 cases from a single institution. Am J Surg Pathol 2014; 38(2):147-57.

Case contributed by:

Elizabeth Thompson, MD, PhD, Assistant Professor of Pathology and Oncology

Main submitter’s email: ethomp36@jhmi.edu

Main submitter’s institution: The Johns Hopkins University School of Medicine

Second submitter’s name and title:

Huili Li, MD, Surgical Pathology Assistant

Second submitter’s institution: The Johns Hopkins University School of Medicine

Conflict of Interest: No

Message from the President

Dear Pancreatobiliary Pathology Society Members,

Despite all the challenges of the COVID19 pandemic, PBPath Society remained very productive last year, thanks to the members of the committees who worked extremely hard to strengthen the existing activities and to bring new initiatives to our organization. I’d like to share with you a few items:

PBPath Society participated in the annual CAP meeting in Chicago, IL in September 2021. Dr. Michelle Reid and I presented the society’s first official course titled “EUS-Guided and “SpyBite” Biopsies of Pancreatic and Biliary Tract Lesions (FNA versus Biopsy)”. This course is scheduled to be repeated at the next annual CAP meeting in October 2022.

The first joint virtual course organized by collaboration of PBPath Society and PathCast was a 2-day course held in January 2022. A total of eight international speakers presented a range of topics covering various aspects of pancreatobiliary pathology. The course was a huge success and was received more than 40,000 in multiple platforms including PBPath.org, YouTube, and Facebook. If you have not attended the course yet, it is still available on our website for virtual viewing (https://pbpath.org/pbps-pathcast-2022/).

Our annual Companion Society Meeting returned to the in-person format at the annual USCAP meeting in Los Angeles, CA in March, 2022. The featured theme “Clonal Evolution of Pancreatobiliary Neoplasms” was received extremely well. I want to thank our speakers, Drs. Yoh Zen, Elizabeth Thompson and David Klimstra for their excellent educational talks, our moderators Drs. Klimstra and Allende for hosting the Q&A session, and you, our members, for your record attendance.

At our annual business meeting, which followed the companion session, we welcomed many new members and presented the PBPath Society abstract award to Dr. Burcin Pehlivanoglu, for her research presentation entitled “TPPP-BRD9 Fusion-Related Gallbladder Carcinomas are Associated with Intracholecystic Neoplasia, Neuroendocrine Carcinoma and a Distinctive Small Tubular-Type Adenocarcinoma Commonly Accompanied with Syringomatous Pattern” (congratulations Dr. Pehlivanoglu!). The official minutes of the Business Meeting can be found on the PBPath Society website (https://pbpath.org/business-meeting-minutes/).

I am also excited to announce that Archives of Pathology and Laboratory Medicine recently published another special section based on the talks given in our previous Companion Society Meeting at USCAP in 2020. I would like to thank Drs. Michelle Reid, David Klimstra, Irene Esposito, and Jing-Young Jang, for their excellent review articles (Arch Pathol Lab Med March 2022 Volume 146 Issue 3; https://meridian.allenpress.com/aplm/issue/146/3)

The Working Groups have been productive as well and published 2 articles:
Dhall D, Shi J, Allende DS, Jang KT, Basturk O, Adsay V, Kim GE. Towards a More Standardized Approach to Pathologic Reporting of Pancreatoduodenectomy Specimens for Pancreatic Ductal Adenocarcinoma: Cross-continental and Cross-specialty Survey from the Pancreatobiliary Pathology Society Grossing Working Group. Am J Surg Pathol. 2021; 45(10):1364-1373.

Wang H, Chetty R, Hosseini M, Allende DS, Esposito I, Matsuda Y, Deshpande V, Shi J, Dhall D, Jang KT, Kim GE, Luchini C, Graham RP, Reid MD, Basturk O, Hruban RH, Krasinskas A, Klimstra DS, Adsay V; Pancreatobiliary Pathology Society. Pathologic Examination of Pancreatic Specimens Resected for Treated Pancreatic Ductal Adenocarcinoma: Recommendations from the Pancreatobiliary Pathology Society. Am J Surg Pathol. 2022; 46(6):754-764.

Finally, our Challenging Case Series, kindly edited by Dr. Rondell Graham, was created for the review of interesting and challenging pancreatobiliary cases in real time. The first case has already been published and can be found on our website (https://pbpath.org/welcome-to-pbps-challenging-cases/). Please keep an eye on our website for detailed discussion of this, and future cases.

I would like to thank the amazing members of the PBPath Society who are dedicated to the growth of our Society and have worked hard to make these accomplishments a reality! Several additional exciting opportunities for PBPath Society to increase our outreach and be impactful is already being explored; as these plans mature, we will share news about these events.

I am honored to have been elected President of the PBPS and I am proud to carry on the tradition of fostering excellence and collaboration in education, research, and the clinical practice of pancreatobiliary pathology around the world.

– Olca Basturk, MD

PBPS pathCast 2022

PBPS pathCast 2022

Dear members of the PBPS,

PBPS, together with PathCast, organized a free 2-day course which was streamed live on January 29-30, 2022 on FaceBook.com/PathCast as well as YouTube.com/pathCast. Here is link of the recorded course videos:

https://pathologycast.com/index.php?title=Pancreatobiliary_Pathology_Society_pathCast_Short_Course

January 29th 2022

8:00 – 9:20 AM (EST): Intraductal/cystic lesions of the pancreas (40 minute prerecorded didactic powerpoint – Dr Olca Basturk) followed by a 40 minute slide session on Intraductal/cystic lesions of pancreas – Dr David Klimstra); live Q and A at 9:20 AM (15 minutes) – Dr David Klimstra and Dr Olca Basturk

 

9:40 – 11:10 AM (EST): Neuroendocrine neoplasms of the pancreas and differential diagnosis: (40 minute prerecorded didactic powerpoint) followed by a 40 minute slide session); live Q and A at 11:10 AM (15 minutes) – Dr Stefano LaRosa and Dr Silvia Uccella

 

January 30th 2022

8:00 – 8:50 AM (EST): Gallbladder and bile duct: 50 minute didactic lecture followed by a 10 minute live Q and A at 8:50 AM – Dr Volkan Adsay

 

9:00 – 9:50 AM (EST): Cytology of the Bile Duct: 50 minute didactic lecture followed by a 10 minute live Q and A at 9:50 AM – Dr Michelle Reid

 

10:05 – 11:20 AM (EST):Pancreatic ductal adenocarcinoma and variants (40 minute pre-recorded didactic powerpoint – Dr Laura Wood); Approach to neoadjuvant treated pancreatic ductal adenocarcinoma (40 minute prerecorded didactic powerpoint – Dr Huamin Wang); Live Q and A at 11:20 AM – Dr Laura Wood and Dr Huamin Wang (15 minutes

 

 

 

The PBPS is seeking new Social Media Committee Members

The PBPS social media committee is seeking three new committee members (regular or associate) to join our team. This position has a 2-year term.

The integral members of this committee will actively disseminate and increase the visibility of Pancreatobiliary Pathology Society events and updates (via Twitter @pbpath).

Interested PBPS members should send their CV and Twitter account handle to info@pbpath.org by September 9, 2022. Successful committee members must be active members of the Pancreatobiliary Pathology Society.

Case 1: Quarter 3, 2022

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.

Figure 1. Low-power view of biopsy, H&E stain.
Figure 2. Additional low-power view of biopsy, H&E stain.
Figure 3. Higher-power view of biopsy, H&E stain.
Figure 4. Higher-power view of biopsy, H&E stain.

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).

Figure 5. Low-power view of intraductal proliferation, H&E stain.
Figure 6. Higher-power view of same field shown in Figure 5, H&E stain.
Figure 7. Complex, irregular nests with desmoplastic stroma, H&E stain.
Figure 8. Complex, irregular nests with desmoplastic stroma, H&E stain.
Figure 9. Complex, irregular nests with desmoplastic stroma, H&E stain.

Please select your diagnosis in the poll, then see the answer and the discussion in the links below.


What is the correct diagnosis?

View Results

Loading ... Loading ...


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.


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).

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.


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.

Figure 10. Gross image of ITPN showing mixed cystic and solid lesion.

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.


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).

References:

Tajiri T, Tate G, Inagaki T, et al. Intraductal tubular neoplasms of the pancreas: histogenesis and differentiation. Pancreas. 2005; 30:115-21.
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.

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

Welcome to PBPS Challenging Cases (Case 1)

 Instructions for participation:

  1. Review this digital case as though it arrived to you in consultation. 
  2. Provide your diagnosis, differential diagnoses and suggested ancillary tests at the bottom of this page within 2 weeks of the post date*.
  3. All responses will be collated and compiled along with the final diagnosis.
  4. Please return to this page in the coming weeks to view the final diagnosis as well as others’ responses. 

PBPS Challenging Case 1 – July 11, 2022

Clinical history:
A 32-year-old male with a history of Hodgkin’s lymphoma and biliary atresia. He had undergone transplant and was found to have distal pancreas mass during surveillance.

Pathologic findings:

Distal pancreatectomy revealed a 4.3 cm, well circumscribed, predominantly solid mass abutting the splenic vein. 

Representative scanned H&E slides (select link to open images)

H&E 1

https://pathpresenter.net/public/display?token=f8789272

H&E 2

https://pathpresenter.net/public/display?token=ca3927d4

Select scanned immunohistochemical (IHC) stains (select link to open images):

Cam 5.2 IHC

https://pathpresenter.net/public/display?token=6e1b407d

Calretinin IHC

https://pathpresenter.net/public/display?token=b4d3bde0

Beta-catenin IHC

https://pathpresenter.net/public/display?token=cb61d7fb

Summary of all IHC stains performed:

– Express: CAM 5.2 (scanned), CK19, CK5, Ber-EP4, claudin-4 (focal), calretinin (scanned), SATB2 (patchy), CD99 (patchy, membranous), inhibin (rare cells), CD10 (focal) and a Ki67 stain reveals a
proliferative rate of 15%.

– Do NOT express: CK7, CK20, CDX2, trypsin, chymotrypsin, carboxyl ester lipase, chromogranin, synaptophysin, INSM1, insulin, glucagon, somatostatin, pancreatic polypeptide, p40, p63, monoclonal CEA, EMA, TTF1, HepPar-1, Glypican-3, GATA3, PAX8, NKX3.1, SF-1, WT1, D2-40, SALL4, CD117, DOG1, CD34, SMA, calponin, ERG, CD45, S100, SOX10, melanoma cocktail

– Other: aberrant beta-catenin (nuclear and cytoplasmic, scanned), E-cadherin (membranous), p53 wild-type, RB1 retained, ATRX retained, MMR retained, mucicarmine negative

Next generation sequencing (NGS) result: No mutations, deletions or fusion detected

Case was submitted by: Dr. Klaudia Nowak from Toronto General Hospital, and Dr. Olca Basturk from Memorial Sloan Kettering Cancer Center.

*NOTE: The submission of case discussion has been closed.

*Thank you all for your feedback on the Pancreatobiliary Pathology Society’s first challenging case. A panel of experts (Drs. Volkan Adsay, Michelle Reid, and Huamin Wang) has also reviewed the case and rendered their diagnoses. Please see the discussion summary now posted HERE for details. 

The PBPS is seeking a new Journal Watch Committee Member

The PBPS journal watch (JW) is seeking a new committee member to join our team for a term of 3 years. The JW is posted every 2 months and includes articles to be highlighted from the most relevant journals in pancreatobiliary pathology. The JW is a valued educational tool among our community and a great way to network with others in the field.  

Interested PBPS members should send CV to info@pbpath.org by June 8, 2022.  Applicants must be paid members of the Pancreatobiliary Pathology Society. 

Daniela Allende, MD MBA, PBPS JW Editor 

USCAP 2022 Companion Society Program

Pancreatobiliary Pathology Society Companion Meeting USCAP 2022

Clonal Evolution of Pancreatobiliary Neoplasms

Despite advances in the field, our understanding of the clonal evolution of neuroendocrine neoplasms and macroscopic precursor lesions of the pancreatobiliary tract remains incomplete. Until recently the genetic alterations that contribute to these tumors’ development, progression and resistance to treatment were poorly understood. New and specific genetic alterations have now been identified in precursor lesions and specific cancer phenotypes have been shown to be associated with targetable genomic events. These advances offer pathologists a better understanding of the underlying pathogenesis of these diseases and allow more precise diagnosis and classification. This session will focus on recent advances in our understanding of mechanisms and clinical implications of the clonal evolution of neuroendocrine neoplasms and macroscopic precursors of the pancreatobiliary tract.  Updates in grading and classification and the use of novel diagnostic/prognostic markers for characterization will also be included. These are essential to practicing pathologists and pathology trainees, as they play an increasing and critical role as consultants on test selection and integrated diagnostic interpretation. Dr. Aldo Scarpa will describe molecular tumorigenesis of pancreatic neuroendocrine neoplasia and its implications on diagnosis, disease progression, treatment and prognosis. Dr. Elizabeth Thompson will provide an overview of the genomics of pancreatic cancer development from its macroscopic precursors, including intraductal neoplasms and mucinous cystic neoplasms, along with their impact on our understanding of pancreas cancer biology, diagnosis, and treatment. Dr. Yoh Zen, who has worked on defining and classifying macroscopic precursor biliary tract lesions (tumoral intraepithelial neoplasia), and their molecular associations, will summarize the current state in this rapidly evolving area.

Learning Objectives: Upon completion of this educational activity, learners will be able to:

  1. Describe the underlying molecular alterations in neuroendocrine neoplasms, and their involvement in diagnosis, association with tumor progression, newly updated WHO grading and tumor progression as well as prognosis.
  2. Describe the spectrum of molecular alterations involved in the development and progression of macroscopic precursor lesions of the pancreas (including intraductal neoplasms and mucinous cystic neoplasms) and their importance in diagnostic workup and therapeutic implications.
  3. Understand the classification system for macroscopic precursor lesions of the biliary tree, the genomic basis for invasive carcinoma development and prognostic implications of these molecular alterations.

Continuing Medical Education

The United States and Canadian Academy of Pathology is accredited by the ACCME to provide continuing medical education for physicians.

The United States and Canadian Academy of Pathology designates this live activity for a maximum of 2.0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.


Session Chairs

Moderator(s)
Daniela Allende, MD, Cleveland Clinic, Lerner College of Medicine of Case Western University School of Medicine
United States

David Klimstra, MD, Memorial Sloan Kettering Cancer Center
United States

 

[line]

Abstract Award in USCAP 2022

Pancreatobiliary Pathology Society Abstract Award

Dear members of the PBPS,

The PBPS is now accepting applications for this year’s PBPS Abstract Award. This award will go to a pathology trainee with an abstract (poster/platform) in pancreatobiliary pathology presented at the 2022 annual USCAP meeting. Submitted abstracts will be evaluated for originality, scientific merit and presentation, and the winner will receive a $500 prize. At least one author should be a PBPS member. Trainees are strongly encouraged to apply.

The deadline for submission of Award applications is February 15, 2022.

Please email your completed abstract in Word format along with the information below to the education committee chair Dr. Michelle Reid (michelle.reid@emory.edu).

Name:
Training Institution:
Position:
PGY Year:
Date/Time of Presentation:
Abstract Name:
Poster Number (if applicable):