Pancreatobiliary Pathology Society Abstract Award at USCAP 2023

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 to be presented at the 2023 USCAP Annual Meeting. Submitted abstracts will be evaluated by the members of Education Committee for originality, scientific merit, and presentation. The selected winner will be notified by email from the Chair of Education Committee and the winner will receive a $500 prize. The qualifications for this award are listed below:

  • Only abstracts that were accepted for presentation at this year’s annual USCAP meeting are qualified for the PBPS Best Abstract Award.
  • Only trainees (medical students, residents, or fellows) are qualified for this award.
    The submitting trainee must be a member of the PBPS. Please note that associate membership in the PBPS is free for trainees. Trainees are strongly encouraged to apply.
  • The submitting trainee must be first author (except in rare instances in which the trainee may be listed as the senior author).
  • Trainees will not receive an award if they have won in the prior year. If you are the winner of the PBPS award for last year, then you do not qualify for consideration for the current year.
  • The deadline for submission of Award applications is 12:00 pm (US Central time) on February 6, 2023.

Please submit your abstract online (https://pbpath.org/abstract-submission/).

We look forward to receiving your submission.

Education Committee

The Pancreatobiliary Pathology Society

Case 3: Quarter 4, 2022

Case 3: Quarter 4, 2022

Clinical History

A 41 y/o male initially presented with nausea, vomiting, epigastric pain and severe diarrhea. Imaging (CT scan and MRI) revealed a 3.9 cm hypervascular mass centered on the pancreatic uncinate process with no evidence of metastatic disease. The imaging findings were concerning for lymphoma or a neuroendocrine tumor. Laboratory studies including amylase, lipase, and CA 19-9 were within normal limits. Endoscopy with fine needle biopsy of the lesion was performed.

Histologic/Cytologic Features 

The biopsy showed infiltrating neoplastic cells characterized by cytologically bland nuclei and abundant finely vacuolated, clear cytoplasm embedded in a collagenized/fibrotic stroma [Figure 1A/B]. No necrosis or mitotic figures were identified. The remainder of the biopsy material showed unremarkable pancreatic parenchyma and reactive lymphoid tissue.

Figure 1. Representative images of the mass , H&E stain.

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


What is the most likely diagnosis based on the information provided?

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Click Here To See The Answer

Answer: Well-differentiated pancreatic neuroendocrine tumor (Pan-NET), lipid rich variant.

 


Click Here To See The Discussion

Final diagnosis:  

Well-differentiated pancreatic neuroendocrine tumor (Pan-NET), lipid rich variant.

Educational Objectives and Discussion

Educational Objectives

  1. Identify and describe the histologic features of lipid rich variant of PanNET
  2. Review the clinical implications of a diagnosis of lipid rich variant of PanNET
  3. Discuss the differential diagnosis for lipid rich variant of PanNET

Discussion
Immunohistochemical stains were performed on the biopsy material. The neoplastic cells were positive for pan-CK (strong and diffuse), synaptophysin (strong and diffuse) [Figure 2], chromogranin (strong but focal) and inhibin (strong and diffuse) while negative for CK7, RCC, PAX-8, S-100, Melan-A (MART-1), and beta catenin. A MIB-1 (Ki-67) stain showed a low proliferation index (<3%). A diagnosis of well-differentiated pancreatic neuroendocrine tumor, Grade 1, lipid rich variant was rendered.

Figure 2. The neoplastic cells: Positive for synaptophysin

The patient subsequently underwent surgical resection (pancreaticoduodenectomy). Sectioning of the pancreas revealed a tan-white to tan-yellow, stellate, firm, fibrous mass measuring 4.0 cm in greatest dimension. The microscopic and immunophenotypic features of the tumor in the resection specimen mirrored those of the biopsy material. Sections showed neoplastic cells arranged in nests/clusters and cords, surrounded by marked collagenized/fibrotic stroma [Figure 3]. The tumor cells demonstrated clear/foamy vacuolated cytoplasm and small uniform nuclei with finely dispersed chromatin [Figure 4]. Mitotic figures were virtually absent. The MIB-1 (Ki-67) stain was repeated on the resection specimen and showed a proliferation index of 5-7% in hot spots. A final diagnosis of well-differentiated pancreatic neuroendocrine tumor, Grade 2, lipid rich variant was rendered

Figure 3. Neoplastic cells arranged in nests/clusters and cords, surrounded by marked collagenized/fibrotic stroma
Figure 4. The tumor cells demonstrated clear/foamy vacuolated cytoplasm and small uniform nuclei with finely dispersed chromatin

PanNET with vacuolated, lipid rich cytoplasm was first described in 1997 by Ordonez and Silva [1]. Singh et al and Xue et al’s series on PaNET variant cases both offered additional valuable contributions to the literature [2,3]. The lipid rich variant affects both men and women and can occur in the head or tail of the pancreas, ranging in size from 2-11 cm. Microscopically, this variant represents a diagnostic challenge (see differential diagnosis section). The prototypical neuroendocrine growth pattern may be absent. The cytologic features are deceptively bland; tumor cells are characterized by round to pyknotic nuclei with fine chromatin and inconspicuous nucleoli. The classic stippled “salt and pepper” chromatin may not be evident. Nuclear “endocrine” atypia is also not identified. The cytoplasm is not only clear but also finely vacuolated; lipid droplets and neuroendocrine secretory granules can be identified ultrastructurally with electron microscopy. Mitotic activity is absent to low and MIB-1 (Ki-67) staining usually does not exceed 5% based on published data [2,3]. Given how unusual these histologic features are compared to a typical low grade neuroendocrine tumor, immunohistochemical stains are an essential adjunct aid. The neoplastic cells routinely express pan-cytokeratin and neuroendocrine markers chromogranin and synaptophysin (focal to diffuse staining). Inhibin and HIF-1α staining can be seen in a subset of tumors, while Melan-A (MART-1) and MUC6 expression is absent [2].
Xue et al. include the lipid rich variant in the “aggressive variant group” alongside hepatoid, oncocytic, plasmacytoid, and discohesive variants due to propensity for greater tumor size, T-stage, metastases, and progression rates [3]. Furthermore, patients with lipid rich PanNET fall into one of two categories: younger patients with familial/functional/syndromic tumors (rare) and older patients with non-functioning/sporadic tumors (common). While inhibin, HIF-1α, and Melan-A (MART-1) expression by immunohistochemistry in clear cell PanNET has a strong association with von Hippel Lindau (VHL) disease, this correlation is less robust in lipid rich PaNET [2,4]. Regardless, it may still be prudent for clinicians to exclude VHL disease or MEN1 (multiple endocrine neoplasia type 1) syndrome as lipid rich PaNETs have rarely been reported in these patients [2].

Differential diagnosis:

The pathologist should keep a broad differential diagnosis in mind when approaching a low-grade pancreatic lesion with clear/vacuolated cytoplasm:
Clear cell PanNET:
PanNET with clear cell change are not uncommon and have a strong association with VHL disease, particularly when HIF-1α, inhibin, and/or Melan-A (MART-1) expression by immunohistochemistry is seen in addition to traditional neuroendocrine markers. VHL-associated clear cell PanNETs usually occur in younger women and are non-functioning tumors [4-7]. While the cytoplasm is clear, it lacks the vacuolated/microvesicular appearance of lipid rich PanNET.
Solid pseudopapillary neoplasm (SPN):
SPNs are uniquely characterized by pseudopapilla, nuclear grooves, and hyaline globules. SPNs can exhibit clear cytoplasm and frequently contain foamy macrophages, and therefore could appear similar to lipid rich PanNET in small biopsy specimens. While SPNs can express synaptophysin, chromogranin is usually negative. More importantly, nuclear staining of the neoplastic cells with beta catenin is a key diagnostic clue for the diagnosis of SPN, reflecting underlying mutations in CTNNB1 [8]. Additionally, these tumors most commonly occur in adolescent girls/young women under the age of 35 and arise most frequently in the body or tail of the pancreas.
Perivascular epithelioid cell tumor (PEComa or so called “sugar tumor”):
PEComas are rare mesenchymal neoplasms with myomelanocytic differentiation. The tumors grow in sheets or nests and are characterized by epithelioid cells with clear to eosinophilic, granular cytoplasm, which has a moth-eaten appearance (“spider cells”) with a spindle cell component present in a minority of cases. Co-expression of smooth muscle markers (SMA, desmin, h-caldesmon) and melanoma markers (e.g. Melan-A/MART-1, HMB45) is characteristic. Neuroendocrine labeling and strong and diffuse keratin expression is notably absent [8].
Morphologic patterns of pancreatic ductal adenocarcinoma:
While pancreatic ductal carcinoma typically shows significant cytologic atypia and has a uniquely infiltrating gland-forming growth pattern accompanied by a desmoplastic stromal response, certain morphologic patterns can appear deceptively bland and lack gland formation. The foamy gland and clear cell patterns of invasive ductal adenocarcinoma of the pancreas both are included in this category. Helpful distinguishing characteristics from lipid rich PanNET include gland formation, possible presence of mucin and the lack of neuroendocrine marker expression. Additionally, PanNETs most often present as well-circumscribed lesion on imaging/EUS/gross examination, as opposed to the poorly-defined, infiltrative growth pattern seen with ductal adenocarcinomas [8].
Adrenal cortical tissue/neoplasm:
Adrenal cortical tissue/neoplasms share many overlapping histopathologic features with lipid rich PanNET and immunohistochemistry can be a helpful aid. Adrenal cortical lesions mark with antibodies to SF-1, calretinin, inhibin, Melan-A (MART-1), and CD68 [9]. Adrenal cortical lesions however lack keratin and neuroendocrine marker positivity. Please note, that inhibin expression (as in our case) can be seen in a subset of lipid rich PanNET; therefore, a broad panel of stains is essential.
Clear cell renal cell carcinoma (ccRCC):
ccRCC should always be considered when encountering pancreatic lesions with “clear” cytoplasm. Renal cell carcinoma is in fact the most common reason for a metastasis to the pancreas. While PAX-8 is a helpful ancillary screening marker used for renal cell carcinoma, it is important to note that PanNET can also express PAX-8 [10]. Therefore, additional antibodies such as RCC and CD10 (for renal cell carcinoma) and synaptophysin and chromogranin (for PaNET) should be included as part of the larger panel of stains.

References:

[1] Ordonez NG, Silva EG. “Islet cell tumor with vacuolated, lipid rich cytoplasm: a new histologic variant of islet cell tumor.” Histopathology 1997; 31:157-160.
[2] Singh R, Reid MD et al. “Lipid-rich variant of pancreatic endocrine neoplasms.” Am J Surg Pathol 2006; 30:194-200.
[3] Xue Y. et al “Morphologic variants of pancreatic neuroendocrine tumors: clinicopathologic analysis and prognodtic stratification.” Endocr Pathol 2020 31:3, 239-253.
[4] Hoang MP, Hruban RH et al. “Clear cell endocrine pancreatic tumor mimicking renal cell carcinoma: a distinctive neoplasm of von Hippel Lindau disease.” Am J Surg Pathol 2001; 25:602-609.
[5] Guarda LA, Silva EG et al. “Clear cell islet cell tumor.” Am J Surg Pathol 1983; 79:512-517.
[6] Mount SL, Weaver DL et al. “Von Hippel Lindau disease presenting as a pancreatic neuroendocrine tumor.” Virchows Arch 1995; 426:523-528
[7] Musso C, Paraf F. et al. “Pancreatic neuroendocrine tumors and von Hippel Lindau disease” Ann Pathol. 2000; 20:130-133.
[8] Nagtegaal ID, Odze RD, Klimstra D, Paradis V, Rugge M, Schirmacher P, Washington KM, Carneiro F, Cree IA; WHO Classification of Tumours Editorial Board. The 2019 WHO classification of tumours of the digestive system. Histopathology. 2020 Jan; 76(2):182-188. doi: 10.1111/his.13975. Epub 2019 Nov 13. PMID: 31433515; PMCID: PMC7003895.
[9] Sangoi A., Fujiwara M et al. “Immunohistochemical Distinction of Primary Adrenal Cortical Lesions from Metastatic Clear Cell Renal Cell Carcinoma: A Study of 248 Cases.” Am J Surg Pathol 2011; 35(5): 678-686.
[10] Bellizi AM “Immunohistochemistry in the diagnosis and classification of neuroendocrine neoplasms: wat can brown do for you?” Hum Pathol 2020; 96:8-33.

Case contributed by:

Susanne K. Jeffus, MD – University of Arkansas for Medical Sciences
Camila Simoes, MD – University of Arkansas for Medical Sciences
Felicia D. Allard, MD – University of Arkansas for Medical Sciences

Acknowledgment:

Special thanks to David Klimstra, MD, of Memorial Sloan Kettering Cancer Center for his consultative expertise.

Conflict of Interest: No

Pancreatic Cancer Awareness Month

Dear All,

November is the Pancreatic Cancer Awareness Month. Recognition of the growing prevalence of pancreatic cancer, with the help of foundations and organizations like the Pancreatobiliary Pathology Society, can help direct resources towards research and clinical care efforts. Thursday, November 17 is World Pancreatic Cancer Day – an even more focused opportunity to recognize this disease and the numerous efforts to improve the care of those affected. Please remember to “wear purple” and spread the word.

We, the Pancreatobiliary Pathology Society, send our support to the survivors, their families and to everyone who has lost a loved one to this deadly disease. This is also an opportunity to thank our membership for their dedication to improve the clinical practice and management of pancreatic cancer and to foster tissue-based research. 

Olca Basturk, President 

Pancreatobiliary Pathology Society

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?

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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?

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Answer: Intraductal tubulopapillary neoplasm with associated invasive carcinoma.

 


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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

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Beta-catenin IHC

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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.