The Pancreatobiliary Pathology Society Journal Watch for the articles on the pancreatobiliary pathology will be released every other month.
We are reviewing the journals to select the articles about pancreas, gallbladder and biliary system pathologies. Original research articles, case series and reviews in the surgical pathology, cytopathology, and molecular pathology as well as related fields (i.e. novel methods, database studies) are included.
We have created several categories for convenience; however, articles in each category are in no particular order.
Below is the list of journals we search regularly:
Advances in Anatomic Pathology
American Journal of Clinical Pathology
The American Journal of Pathology
American Journal of Surgical Pathology
Annals of Diagnostic Pathology
Annals of Surgery
Annals of Surgical Oncology
Archives of Pathology & Laboratory Medicine
Cancer
Cancer Cytopathology
Cell
Clinical Cancer Research
Cytopathology
Diagnostic Pathology
Endocrine Pathology
Gastroenterology
Gut
Histology and Histopathology
Histopathology
Human Pathology
International Journal of Surgical Pathology
Journal of Clinical Pathology
Journal of Molecular Diagnostics
Journal of Pathology
Laboratory investigation
Lancet
Modern Pathology
Nature
Nature Reviews Gastroenterology & Hepatology
NEJM
Pancreas
Pancreatology
Pathology
Pathology International
Seminars in Diagnostic Pathology
Virchows Archiv
Pancreatobiliary Pathology Society Best Abstract Award of USCAP2020 goes to:
Julia R. Naso, MD/PhD University of British Columbia
Association of Inflammatory Cell Infiltrates with Signatures of Immunogenicity in Pancreatic Adenocarcinoma
See Poster at Tue, March 03 1:00 PM – 4:30 PM
LACC West Exhibit Hall A Poster Board Number: 164
The 2nd Pancreatobiliary Pathology Society companion society meeting at USCAP. From left to right: Michelle Reid, Irene Esposito, David Klimstra, Jin-Young Jang, Aatur Singhi
Jin-Young Jang lecturing on “Management Algorithms for Pancreatic Cysts and Intraductal Neoplasms: The Surgeon’s Perspective”
Michelle Reid educating us on the cytologic assessment of cystic/intraductal lesions
Aatur Singhi discussing preoperative molecular assessment of pancreatic cysts and intraductal lesions
David Klimstra gives an overview of mucinous cystic and intraductal neoplasms
Best Abstract Awardee Julia R. Naso (right) with Olca Basturk (left)
Speakers and moderators of the PBPS companion meeting, from left to right: Michele Reid, Aatur Singhi, Martha Bishop Pitman, David Klimstra, Irene Esposito, Deepti Dhall
2019 PBPS Executive Committee, from left to right: Olca Basturk, David Lewin, David Klimstra, Alyssa Krasinskas, Grace Kim
Dr. David Klimstra has been elected as the President of Pancreatobiliary Pathology Society. Congratulations Dr. Klimstra #PBPSpic.twitter.com/8lmqQYc7pg
We are pleased to announce that the Pancreatobiliary Pathology Society will be awarding a pathology trainee who is presenting an abstract (poster or platform) on the field of pancreatobiliary pathology at the annual meeting of the USCAP. Each abstract will be evaluated based on originality, scientific merit and presentation and the winner will receive a $250 prize. Please remind/encourage your trainees to apply. Applicants do not need to be society member in order to apply.
The deadline for the Abstract Awards is January 15, 2020.
To submit an application, please email your abstract and the following information to our chair of education committee Dr. Olca Basturk (basturko@mskcc.org)
Name:
Training Institute:
Position:
PGY Year:
Date/Time of Presentation:
Abstract Name:
Poster Number (if applicable):
Contact Email:
Comments:
PBPS Executive Committee
USCAP 2020: PANCREATOBILIARY PATHOLOGY COMPANION SOCIETY PROGRAM
Cystic and Intraductal Neoplasms of the Pancreatobiliary Tract When: February 29, 2020. 7-10PM Location: Los Angeles Convention Center
Moderators: Martha Bishop Pitman Deepti Dhall
Speakers: Jin-Young Jang: Management Algorithms for Pancreatic Cysts and Intraductal Neoplasms: The Surgeon’s Perspective Michelle D. Reid: Cytologic Assessment of Cystic/Intraductal Lesions of the Pancreatobiliary Tract Aatur D. Singhi: Preoperative Molecular Assessment of Pancreatic Cysts and Intraductal Lesions David S. Klimstra: Mucinous Cystic and Intraductal Neoplasms of the Pancreatobiliary Tract Irene Esposito: Non-mucinous Cystic Lesions of the Pancreas
Brief overview:
Despite numerous advances in the field, the diagnosis, classification, grading, and management of cystic and intraductal lesions of the pancreatobiliary tract remain controversial. Additionally, recently described entities such as intraductal tubulopapillary neoplasm (ITPN) and intraductal papillary neoplasm of the bile duct (IPNB) remain diagnostically challenging, and their prognostic implications are poorly understood. The mission of the Pancreatobiliary Pathology Society is to educate surgical and cytopathologists on the importance of the advances in this complex area and will hopefully transform the way we practice pancreatobiliary pathology. The Education Committee, in consultation with Society officers, determined the title, contents, and speakers of this companion meeting.
The chosen topics represent a 360-degree expert evaluation of cystic and intraductal pancreatobiliary lesions in the step-wise manner in which they are often encountered, from the surgeon’s perspective, to their cytomorphologic and molecular characteristics, as well as their histomorphology.
We are seeking enthusiastic volunteers to serve? We will have two open positions on the Education Committee and two open positions on the Membership/Website Committee. Applicants must be a member (regular, associate or emeritus) who has paid annual dues (only $50/year for regular members). The 2-year term will begin after USCAP 2020. If you are interested, please reply with the information (indicate with a “X”) below along with your CV to Vince Hoang (vincent.hoang@ucsf.edu) by February 14, 2020.
I am a member (regular, associate, emeritus) of Pancreatobiliary Pathology Society
I have paid 2020 membership dues (only applicable for regular members)
I would like to be considered for the Education Committee
I would like to be considered for the Membership/Website Committee
I know WordPress (blog tool/publishing platform) or am willing to learn
I have social media skills
Applications will be reviewed by Pancreatobiliary Pathology Society Executive Committee. The selected applicants will be informed via email.
Hot of the press! You can find the President’s letter on the website and learn what your Society does for you! Look forward to learning with you at our Pancreatobiliary Pathology Society Companion Meeting in Los Angeles on February 29, 2020.
Pancreatobiliary Pathology Society Executive Committee
Our society has been extremely productive over the past several months. The creation of an excellent program for the Companion Society by our Education Committee is only one of several accomplishments. I am excited to inform everyone that Archives of Pathology and Laboratory Medicine is going to publish review articles sponsored by the PBPath Society. These articles are based on the lectures that were given during our Companion Society Meeting at USCAP 2019. Please keep an eye out for these publications. Our Case of the Quarter Subcommittee remains active and has been providing educational cases for all members to tackle; this past fall, we welcomed 4 new members to the subcommittee: Deyali Chatterjee, Goo Lee, Yue Xue and Zhaohai Yang. Our bimonthly Journal Watch nicely highlights pertinent publications involving the pancreatobiliary tract.
And there is more good news. Because of Serdar Balci’s web-based knowledge and dedication to the society, the Membership/Website Committee, along with the Executive Committee, have appointed Serdar Balci as the official Webmaster for the society – congratulations Serdar on this well-deserved appointment! The PBPath Society is also now accepting ads for job and fellowship postings. The Working Groups have been productive as well: The Cytology group is wrapping-up a multi-institutional study assessing the minimal number of tumor cells required for Ki67 index calculation on pancreas FNA samples using corresponding resections as the gold standard for comparison, and the Neoadjuvant group presented their data at the 2019 USCAP Annual Meeting and is planning to write a consensus paper based on the group’s work. This past fall, PBPath Society members also participated in the ASCP, CAP and European Congress of Pathology annual meetings. Most recently, we’ve been asked to provide input on the ICCR’s draft dataset on carcinoma of the exocrine pancreas (please check your emails as the deadline is February 14th).
Our society continues to be a success because of you, its members! I would like to recognize the following members who continuously contribute time and effort to our society: Olca Basturk, for organizing another stellar USCAP Companion Society session; Serdar Balci for publishing the bimonthly journal watch; Mabel Ko for managing our website and the members of the Executive Committee, Grace Kim, David Klimstra, David Lewin, Volkan Adsay, and Olca Basturk, for keeping everything on track and in order.
The PBPath Society is an international organization that strives to improve the clinical practice of pancreatobiliary pathology by providing an environment of team work and cooperation. As my Presidency comes to an end, it amazes me how much we have accomplished over the past 2 years. None of what we now have would have been possible without such collegial, friendly, and motivated members. I am so happy and so proud that I had the chance to serve as the President of this great society.
A 58-year-old male with no past medical history presenting to the emergency department with 2-month history of increasingly severe generalized abdominal pain accompanied by intermittent “stabbing sensations” with or without eating. The patient states the pain is so severe he has been unable to sleep and over the past few weeks he has noted dark stools, intermittent fevers, nights sweats, and chills. He reports an approximately 43-pound weight loss over the past few months some of which he attributes to intentional weight loss. The patient reports vomiting after eating if he lays down and only able to eat or drink while standing. Social history includes a 10 pack-year smoking history with cessation 6 months ago. He denies heavy alcohol use or history of pancreatitis.
Computed tomography with contrast of the abdomen was significant for a 10.0 x 10.0 x 7.0 cm hypoattenuating pancreatic head mass with double duct sign and encasement of the surrounding vessels. Multiple, scattered hypodense lesions were noted throughout the right hepatic lobe concerning for metastatic disease. Endoscopic findings showed an ulcerated, infiltrating mass in the duodenal bulb. Images of the duodenal biopsies are shown below.
Figure 1. H&E stain
Figure 2. H&E stain
Figure 3. H&E stain
Figure 4. H&E stain
Figure 5. CK7
Figure 6. CK5/6
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Please Select Your Diagnosis in the Poll, Then See the Answer and the Discussion in the Links Below
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Answer: Undifferentiated carcinoma, anaplastic type
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Microscopic appearance: This is a high-grade malignancy revealing predominantly diffuse sheet-like growth pattern, without overt glandular differentiation, with hemorrhage and necrosis. It is composed of atypical epithelioid and spindle-shaped cells intermixed with pleomorphic, multinucleated cells with bizarre nuclei.
Immunohistochemistry: These cells are positive for pancytokeratin, CK7, Cam 5.2, EMA (focal), CK5/6, and p63 immunohistochemical stains.
Final diagnosis: Undifferentiated carcinoma, anaplastic type
Discussion: Undifferentiated carcinoma is one of the histologic subtypes of pancreatic ductal adenocarcinoma. Three morphological patterns of this subtype have been recognized by the current (5th edition) WHO.
Anaplastic type undifferentiated carcinoma is characterized by pleomorphic mononuclear cells admixed with bizarre-appearing giant cells with eosinophilic cytoplasm. At least 80% of the neoplasm consists of solid sheets of cells lacking gland formation and showing markedly pleomorphic nuclei. There is usually a neutrophilic inflammatory infiltrate. Keratin expression is typically present.
Sarcomatoid type undifferentiated carcinoma is characterized by spindle-shaped cells and may contain admixed heterologous elements of bone and cartilage. At least 80% of the neoplasm displays spindle cell features,with or without heterologous differentiation. A potential pitfall exists if only heterologous elements are sampled in a limited biopsy specimen, suggesting a soft tissue tumor, chondrosarcoma, or osteosarcoma. Sarcomatoid undifferentiated carcinomas with rhabdoid cells have also been described. Loss of nuclear expression of SMARC1 (INI1) is characteristic in these rare cases.
Carcinosarcoma reveals components with obvious epithelial morphology and sarcomatous elements, with or without heterologous differentiation, and requires each component to constitute 30% of the neoplasm.
Differential diagnosis:
Metastatic Melanoma to the small intestine is well documented and may histologically mimic undifferentiated carcinoma, anaplastic type. Morphologically, melanoma may show large pleomorphic cells with eosinophilic cytoplasm and macronuclei admixed with spindle or epithelioid cells. A panel of routine melanoma immunohistochemistry including Melan-A, HMB45, S100, and SOX10 is highly sensitive for metastatic melanoma.
Undifferentiated carcinoma with osteoclast-like giant cells, another histologic subtype of pancreatic ductal adenocarcinoma, is composed of neoplastic mononuclear cells, mononuclear histiocytic cells, and non-neoplastic osteoclast-like multinucleated giant cells. Heterologous elements such as bone and cartilage may be present.
Dedifferentiated GISTs are composed atypical spindle-shaped, epithelioid cells, and may contain large pleomorphic cells. These neoplasms are exceptionally rare and more frequently observed in patients with a history of GIST following long term tyrosine kinase inhibitor therapy. Notably, dedifferentiation typically includes a loss of KIT immunoreactivity.
Adenosquamous carcinoma of the pancreas comprises approximately 2% of pancreatic exocrine cancers. Squamous and glandular components may be intermixed or distinctly separate. The squamous component must comprise at least 30% of the tumor and will stain with p63, CK5/6, and high molecular weight cytokeratin.
References:
Gulati A, Kaushal V, Gupta N. Undifferentiated carcinoma of pancreas with osteoclast-like giant cells mimicking a pseudopancreatic cyst. J Cancer Res Ther. 2015;11(4):1046.
Hoorens A, Prenzel K, Lemoine NR, Klöppel G. Undifferentiated carcinoma of the pancreas: analysis of intermediate filament profile and Ki-ras mutations provides evidence of a ductal origin. J Pathol. 1998;185(1):53-60.
Manduch M, Dexter DF, Jalink DW, Vanner SJ, Hurlbut DJ. Undifferentiated pancreatic carcinoma with osteoclast-like giant cells: report of a case with osteochondroid differentiation. Pathol Res Pract. 2009;205(5):353-9.
Yonemasu H, Takashima M, Nishiyama KI et al. Phenotypical characteristics of undifferentiated carcinoma of the pancreas: a comparison with pancreatic ductal adenocarcinoma and relevance of E-cadherin, alpha catenin and beta catenin expression. Oncol Rep. 2001;8(4):745-52.
Patil DT, Rubin BP. Gastrointestinal stromal tumor: advances in diagnosis and management. Arch Pathol Lab Med. 2011;135(10):1298-310.
Odze RD, Goldblum JR. Odze and Goldblum surgical pathology of the GI tract, liver, biliary tract, and pancreas. Third edition. ed. Philadelphia, PA: Saunders/Elsevier; 2015:xix, 1612 pages.
WHO Classification of Tumours Editorial Board, World Health Organization., International Agency for Research on Cancer. Digestive system tumours. 5th ed. Lyon: IARC Press; 2019
Choi JJ, Sinada-Bottros L, Maker AV, Weisenberg E. Dedifferentiated gastrointestinal stromal tumor arising de novo from the small intestine. Pathol Res Pract. 2014;210(4):264-6.
Oka K, Inoue K, Sugino S et al. Anaplastic carcinoma of the pancreas diagnosed by endoscopic ultrasound-guided fine-needle aspiration: a case report and review of the literature. J Med Case Rep. 2018;12(1):152.
Sano M, Homma T, Hayashi E, Noda H, Amano Y, Tsujimura R, Yamada T, Quattrochi B, Nemoto N.Clinicopathological characteristics of anaplastic carcinoma of the pancreas with rhabdoid features. Virchows Arch. 2014;465(5):531-8.
Muraki T, ReidMD, Basturk O, Jang KT, Bedolla G, Bagci P, Mittal P, Memis B, Katabi N, Bandyopadhyay S, Sarmiento JM, Krasinskas A, Klimstra DS, Adsay Undifferentiated Carcinoma with Osteoclastic Giant Cells of the Pancreas: Clinicopathologic Analysis of 38 Cases Highlights a More Protracted Clinical Course Than Currently Appreciated. Am J Surg Pathol. 2016;40(9):1203-16.
Agaimy A, Haller F, Frohnauer J, Schaefer IM, Ströbel P, Hartmann A, Stoehr R, Klöppel G. Pancreatic undifferentiated rhabdoid carcinoma: KRAS alterations and SMARCB1 expression status define two subtypes.Mod Pathol. 2015;28(2):248-60.
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Case contributed by:
Adam L. Booth, MD Anatomic and Clinical Pathology Resident, PGY-4 University of Texas Medical Branch, Galveston, TX
Nicole D. Riddle, MD Assistant Professor, Associate Residency Program Director University of South Florida, Tampa, FL
74-year-old man was presented with jaundice, progressive anemia, dark urine, melena, and a reported weight loss of 10 kilograms in 2 weeks. His comorbidities included mild chronic renal failure, diverticulosis, and dyslipidemia. He was previously a smoker (20 cigs/day, stopped 35 years ago).
On examination, his BMI was 26.1, Hb: 8.7 g/dl, bilirubin total/fractionated (direct): 13.4/8.0 mg/dl, CEA 2.6 U/ml, CA 19-9: 2 U/ml. CT scan showed a 3 cm well-defined lesion in the pancreatic head/periampulla. There was no evidence of distant metastasis. The patient underwent a pancreaticoduodenectomy.
Gross examination:
The resection specimen was remarkable for a 3 cm well circumscribed, solid mass centered in the pancreatic head, with focal extension to the ampulla, distal bile duct, and peripancreatic adipose tissue. Cut surface was tan white and fleshy.
Figure 1: H&E section of tumor (original magnification 10X)
Figure 2: H&E section of tumor, in relation to duodenum (original magnification 4X)
Figure 3: H&E section of tumor, interface with adjacent pancreatic parenchyma (original magnification 40X)
Please Select Your Diagnosis in the Poll, Then See the Answer and the Discussion in the Links Below
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Answer: Medullary carcinoma
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Microscopic appearance:
Histopathological examination revealed a cellular neoplasm composed of relatively monomorphic cells with high N:C ratio and vesicular nuclei. The neoplasm had a syncytial growth pattern without obvious gland formation (Figure 1), scant stroma and overall pushing border (Figure 2) with focal microscopic infiltrative interface with the adjacent tissues (Figure 3). There was also a diffuse lymphocytic infiltration within the tumor (tumor-infiltrating lymphocytes, TILs). No confluent necrosis was identified. Lymphovascular invasion (involving both lymphatic spaces and large vessels) and lymph node metastases (in two lymph nodes, with extranodal extension) were present. No in-situ lesions, such as pancreatic intraepithelial neoplasia (PanIN) or adenomatous change in the duodenal or ampullary mucosa were identified.
Immunohistochemistry:
Performed immunohistochemical stains reveal that the tumor cells are positive for CK7 (Figure 4), MUC1/ EMA (Figure 5), and CK8/18, while negative for CK20, CDX2, MUC2, MUC5AC, Chromogranin, and Synaptophysin. CD3 highlighted intra- and peri-tumoral T lymphocytes, CD20 highlighted some peri-tumoral B lymphocytes, no intratumoral B lymphocytes were identified. Althoug expression of MLH1 and PMS2 proteins was retained, expression of MSH2 (Figure 6) and MSH6 proteins was absent in the cells. EBV-encoded RNA (EBER) in-situ hybridization was also negative in the tumor cells.
Molecular analysis:
Multiplex PCR for MSI, using HNPCC KIT 1-FL with 5 MSI markers (BAT-25, BAT-26, NR-21, NR-22, NR-24) reveled alterations in all 5 molecular markers, indicating microsatellite instable phenotype (MSI-H).
Final histological diagnosis: Medullary carcinoma of the pancreas.
Discussion:
Medullary carcinoma of the pancreas is a rare subtype of pancreatic neoplasms, pathogenetically and behaviorally distinct from pancreatic ductal adenocarcinoma (PDAC)1. Recognition of this subtype is important, not only for prognostic, but also for therapeutic purposes. Syncytial growth pattern composed of pleomorphic cells with no gland formation, pushing borders and the presence of intra- and peri-tumoral lymphocytes are helpful histological findings.
Medullary carcinoma of the pancreas has been recognized as a distinct but rare entity for only about two decades (first reported in 1998 by Goggins M et al2). Unlike conventional PDAC, the incidence of KRAS mutations is very low in this tumor type. Medullary carcinoma of the pancreas has a better prognosis than conventional PDAC3. Like other medullary carcinomas involving the tubular gastrointestinal tract, a significant proportion of medullary carcinomas of the pancreas reveal high microsatellite instability (MSI)4. A subset of these patients has been shown to carry germline mutations of mismatch repair genes (Lynch syndrome). Isolated cases with synchronous/metachronous colonic adenocarcinoma linked to Lynch syndrome have been reported5. In cases that are not linked to Lynch syndrome, there is an increased association with family history of other cancers. A case of medullary carcinoma of the pancreas was reported to be associated with EBV5.
With the current advances in oncology, promising treatment modalities have emerged, such as using immune checkpoint inhibitors in solid tumors with MSI-high phenotype, including pancreatic cancers6. Although MSI-high phenotype is very rare in conventional PDACs, overall accounting for <1% of all cases7; given its important therapeutic implications, MSI should at least be routinely investigated in the pancreatic cancer types in which an increased frequency of MSI-high phenotypes are encountered, such as medullary carcinoma or colloid carcinoma, and results should be integrated into the final pathology report.
Medullary carcinomas should be distinguished from
– Poorly differentiated pancreatic ductal adenocarcinomas, which almost always have some degree of gland formation, usually reveal an abundant desmoplastic stroma, an infiltrative growth pattern, and at least a focal intracytoplasmic mucin production.
– Poorly differentiated neuroendocrine carcinomas, which are composed of tumor cells arranged in nests and sheets, usually show an infiltrative growth pattern and abundant intratumoral necrosis. Granular chromatin and nuclear molding would also suggest neuroendocrine differentiation, and staining for neuroendocrine markers (chromogranin and synaptophysin) would confirm the diagnosis. There are also usually no intratumoral lymphocytes, unlike medullary carcinomas.
– High-grade lymphoma, such as diffuse large B-cell lymphoma, would also usually have a syncytial growth pattern, but intratumoral infiltration with mature lymphocytes are not a feature. Specific immunohistochemical stains to ascertain the cell lineage is necessary for the correct diagnosis.
– Metastatic melanoma is a consideration on H&E evaluation. Relevant history and immunohistochemical markers are necessary to exclude this diagnosis.
We are pleased to announce that the Pancreatobiliary Pathology Society will be awarding a pathology trainee who is presenting an abstract (poster or platform) on the field of pancreatobiliary pathology at the annual meeting of the USCAP. Each abstract will be evaluated based on originality, scientific merit and presentation and the winner will receive a $250 prize. Please remind/encourage your trainees to apply. Applicants do not need to be society member in order to apply.
The deadline for the Abstract Awards is January 15, 2020.
To submit an application, please email your abstract and the following information to our chair of education committee Dr. Olca Basturk (basturko@mskcc.org)
A female in mid-fifties underwent cholecystectomy due to cholelithiasis. No significant previous medical history was noted.
Macroscopy:
Grossly, gallbladder wall was mildly thickened, and serosal surface was ragged. Open sectioning, there were several yellowish calculi within the lumen but, no mass lesion was identified.
Microscopy:
The microscopic findings are shown below (Figures 1-4).
Figure 1. Low power image of gallbladder. Arrow: mucosal surface. (Click image to see full size)
Figure 2. Low power image of perimuscular soft tissue. Inset: medium power image of area with arrow. (Click image to see full size)
Figure 3. Low power image of perimuscular soft tissue. Inset: medium power image of area with arrow. (Click image to see full size)
Figure 4. High power image of small ducts within the subserosa. (Click image to see full size)
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Answer
Answer: Chronic cholecystitis with reactive proliferation of Luscka ducts.
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Discussion: Sections revealed acute/chronic cholecystitis with thickened wall and extensively denuded mucosa (Figure 1). There was also a florid glandular/ductular proliferation lined with bland-to-mildly atypical biliary-type epithelium within the perimuscular soft tissue (Figures 2- 4). These ductules were mostly uniform in size and were not connected to the lumen. Differential diagnoses included invasive adenocarcinoma despite the bland cytology as invasive adenocarcinoma of the gallbladder may reveal extremely bland cytology. However, based on the location of the lesion (within subserosa), and lack of mucosal dysplasia, a benign process, i.e., reactive/hyperplastic changes of Luschka ducts (also termed subvesical bile ducts[1]) was also considered.
As reported by Singhi et al[2], reactive proliferation of Luschka ducts is characterized with lobular aggregates of small ductules lined by bland epithelium, associated with centrally located, larger ductules surrounded by concentric fibrosis. On the other hand, irregular growth pattern, full thickness involvement, loss of concentric fibrosis, epithelial atypia with significant nuclear variation (4:1), and vascular/perineural invasion strongly suggest malignancy.
Upon reviewing the microscopic findings in this case, the architecture/arrangement of those atypical glands was somewhat irregular (Figure 3). However, there were some foci with classic lobular architecture (Figure 2: right lower corner) and ducts with concentric fibrosis (Figure 2: inset). More importantly, the lesion was within the perimuscular soft tissue, there was no connection between the mucosal surface and the ducts and there was no dysplasia within the mucosal surface (Figure 1). Also, the lining epithelial cells were predominantly bland (Figures 3: inset & 4). Although mild cytologic atypia with mitosis (Figure 4, Arrow) was seen in some areas, there was no significant nuclear variation (Figures 3 & 4). No lymph-vascular or perineural invasion was identified, either.
The case was shared with several experts, who did not find overt features of malignancy and specifically stated that, in the absence of other malignant features, mitotic activity alone would not argue against a benign diagnosis (i.e. Chronic cholecystitis with reactive proliferation of Luschka ducts).
Adenomyomatous hyperplasia is usually a grossly visible lesion characterized by a mural collection of cysts forming a small mass or a band of trabeculated thickening of the gallbladder wall, most often in the fundic region. “Adenomyomatosis” refers to the more diffuse form of this condition. Microscopic findings include cystically dilated and branched glands (Figure 5, thin arrows) surrounded by tunica muscularis (thick arrows). It should be noted that some glandular elements in benign adenomyomatous nodules may impinge on the nerves, mimicking perineurial invasion [3] .
Figure 5. Adenomyomatous hyperplasia of the gallbladder. (Click image to see full size)
Intracholecystic papillary neoplasm (ICPN) is a grossly visible (typically >1 cm) preinvasive epithelial neoplasms arising in the mucosa and projecting into the lumen of the gallbladder[4]. Grossly it is characterized by granular, friable excrescences or by a distinct polypoid/exophytic mass. Microscopically, it demonstrates papillary (Figure 6) and/or tubular configuration, different cell lineages (biliary, gastric, intestinal or oncocytic) and a spectrum of dysplastic change, which can be graded as low- or high-grade based on architectural and cytologic complexity. Adsay et al reported that about 50% of ICPNs are associated with invasive adenocarcinoma, particularly the ones with predominantly biliary morphology or extensive high-grade dysplasia. However, even when only ICPNs with an associated invasive carcinoma are considered, the overall outcome of ICPNs is incomparably better than that of conventional gallbladder adenocarcinomas [4].
Figure 6. Intracholecystic papillary neoplasm (ICPN) of the gallbladder. Broad-based, exophytic/polypoid intraluminal mass with predominantly papillary architecture. (Click image to see full size)
In conclusion, Luschka ducts are small bile ducts occasionally found at the gallbladder fossa and/or along the serosal surface. Rarely, prominent ductal proliferation with mild cytologic atypia might be seen and distinguishing this benign/reactive process from invasive adenocarcinoma could be difficult. Adequate sampling and meticulous microscopic examination may be required.
59 year-old man with a 5.0 cm mass in the head of the pancreas
Pancreaticoduodenectomy:
The patient underwent pancreaticoduodenectomy, which showed a 5.0 cm well circumscribed mass confined in the head of the pancreas. The cut surface of the tumor is tan, soft with mixed areas of necrosis and hemorrhage. The following images (Figure 1-4) are representative micrographs of the tumor.
Figure 1. Haematoxylin and eosin staining, 100x magnification. Figure 2. Haematoxylin and eosin staining, 100x magnification.Figure 3. Haematoxylin and eosin staining, 200x magnification.Figure 4. Haematoxylin and eosin staining, 400x magnification.
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Please Select Your Diagnosis in the Poll, Then See the Answer and the Discussion in the Links Below
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Answer
Solid papillary neoplasm with atypical multinucleated giant tumor cells
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Case Description:
Figures 1- 4 show representive images from the solid areas of tumor that are composed of uniform, non-cohesive polygonal cells intermixed with foamy histiocytes and many atypical multinucleated giant cells. The mononuclear tumor cells have eosinophilic cytoplasm with uniform, round to oval nuclei, finely stippled chromatin and low nuclei to cytoplasm (N/C) ratio. The atypical giant cells have multiple, markedly enlarged, hyperchromatic nuclei with smudged chromatin. Mitoses are rare. Nuclear grooves are present in some of the mononuclear cells. Area of pseudopapillae, intracytoplasmic vacuoles, eosinophilic globules and cholesterol crystals with foreign body giant cell reaction are present. Both mononuclear and atypical multinucleated giant cells are positive for β-catenin, progesterone receptor (PR) and vimentin, but are negative for pan-cytokeratin, synaptophysin, chromogranin, CD68, and trypsin. The tumor has a Ki-67 labeling index of less than 1%. The foamy histiocytes are positive for CD68.
Discussion
Solid pseudopapillary neoplasm (SPN) is a rare pancreatic tumor with low-grade malignant potential, accounting for approximately 1–3% of all pancreatic tumors (1-3). SPN occurs predominantly in young females in their 20s and 30s with a female to male ratio of 9:1 (2). The patients often presented with nonspecific, abdominal mass-related symptoms such as abdominal pain, early satiety etc. A recent study showed that up to 9% of asymptomatic pancreatic incidentalomas discovered by physical examination or abdominal imaging studies performed for other reasons are SPNs (4). Complete surgical resection is often curative and the prognosis for patients with SPN is very good with a 5-year survival rate of more than 90%. Hoewever, 10–15% of patients may develop recurrent SPN, liver or peritoneal metastases after surgical resection (5-8). Muscular vessel invasion and tumor stage have been shown to be important predictors of disease-specific survival in patients with SPN (9).
Grossly, SPNs are well circumscribed, often large masses with a average tumor size of 9 to 10 cm. The cut surface of SPN is soft and heterogeneous, consisting of tan to yellow solid areas, irregular areas of necrosis with cavities (cystic areas) and hemorrhagic areas. Histologically, the solid area of conventional SPN are characterized by the presence of numerous capillaries or delicate small blood vessels with variable amounts of hyalinized or myxiod stroma forming the vascular cores, which are surrounded by relatively uniform, non-cohesive polygonal cells to form the pseudopapillae. The nuclei of the tumor cells are located away from the vascular cores creating a zone of cytoplasm around the vescular cores. At the peripheries of the pseudopapillae, the tumor cells are often detached. The tumor cells have uniform, round to oval nuclei with finely stippled chromatin pattern, frequent nuclear grooves and low nuclei to cytoplasm (N/C) ratio. Mitoses are rare or absent. The cytoplasm is eosinophilic or clear. Intracytoplasmic vacuoles or periodic acid-Schiff (PAS)-positive diastase-resistant eosinophilic globules, foamy histiocytes and cholesterol crystals with foreign body giant cell reaction are commonly present in SPN.
SPNs are typically positive for β-catenin mutations, but negative for mutations in oncogenic Kras gene. Nuclear staining of β-catenin by immunohistochemistry has been widely used as one of the diagnostic markers for SPN (10, 11). SPNs are also positive for progesterone receptor (PR), SOX11, Transcription factor E3 (TFE3), alpha-1-antitrysin, vimentin, CD10, cyclin D1, neuron-specific enolase (NSE), CD56, and are negative for CK7, CK19, epithelial membrane antigen (EMA), carcinoembrynonic antigen (CEA), chromogranin, estrogen receptor (ER), BCL10, trypsin, and lipase. SPNs typically show either negative or weak/patch staining for cytokeratin AE1/AE3 and CAM5.2 and synaptophysin, and has a low Ki-67 labeling index (typically less than 2%).
Atypical multinucleated giant tumor cells have been reported in four (6.5%) SPN patients in a large cohort of 62 patients (12) and one (5%) of 20 patients (13), respectively. All four patients who have SPN with atypical multinucleated giant tumor cells in the study published by Li et al. were discovered incidentally by imaging studies for unrelated diseases and have a female to male ratio of 1:1 and a mean age of 51.3 years (range 36–59 years) at the time of diagnosis, which is significantly older than those with conventional SPN (mean age: 32.1 years, range: 9.4–62.2 years). The tumor is more likely located in the head of the pancreas (12). The atypical giant tumor cells present in the solid area of the tumor have multiple enlarged, hyperchromatic, irregular nuclei with smudged chromatin, ample eosinophilic or clear cytoplasm, which raise the concern of aggressive clinical behavior or high-grade malignancy. However these atypical multinucleated giant tumor cells have an immunohistochemical profile identical to the conventional SPN and are positive for vimentin, β-catenin, CD10 and progesterone receptor, but negative for pan-cytokeratin, chromogranin, synaptophysin, trypsin, Ki-67 and CD68 (12-14), which argue against a histiocytic origin of these giant cells. All four cases of SPN with atypical multinuclear giant tumor cells have a proliferation index (Ki-67) of <1%, which is typically seen in conventional SPNs. None of the three patients who had SPNs with atypical multinuclear giant tumor cells developed recurrence during follow-up of 2.7, 3.8 and 5.0 years. Therefore the presence of atypical multinuclear giant tumor cells in SPN most likely represents degenerative change of the tumor cells and does not seem to affect the prognosis based on the limited number of patients from this study (12). The similar degenerative nuclear atypia has also been reported in pleomorphic pancreatic neuroendocrine tumors,(15) symplastic leiomyomas,(16) symplastic glomus tumor,(17) symplastic haemangioma(18) and bizarre giant cells of mammary fibroadenomas (19).
The clear cell variant of SPN and two rare cases of clinically aggressive SPNs have also been reported in the literature. The clear cell variant of SPN has the similar clinical features, gross characteristics and immunohistochemical staining profile to those of conventional SPNs (20-22). The two cases of clinically aggressive SPNs, consisting of conventional SPN and an undifferentiated carcinoma component, which had a diffuse growth pattern, extensive tumor necrosis, significant nuclear atypia, and high mitotic count, have been reported. Both patients died of disease at 6 and 16 months after diagnosis, respectively (23).
The major differential diagnoses for SPN with atypical multinucleated giant tumor cells include pleomorphic pancreatic neuroendocrine tumor, undifferentiated carcinoma, and undifferentiated carcinoma with osteoclast-like giant cells, acinar cell carcinoma, pancreatoblastoma, and mixed acinar-neuroendocrine carcinoma. Pancreatic neuroendocrine tumor, acinar cell carcinoma, mixed acinar-neuroendocrine carcinoma, and pancreatoblastoma may have overlapping nuclear and cytologic features with SPN. However, the presence of pseudopapillae, foamy histiocytes, cholesterol crystals and intracytoplasmic eosinophilic globules favor the diagnosis of SPN. Squamoid nests, which are the diagnostic hallmark for pancreatoblastoma, is not present in SPN. Acinar cell carcinoma, undifferentiated carcinoma, and undifferentiated carcinoma with osteoclast-like giant cells are cohesive, pleomorphic high-grade carcinomas with frequent mitoses and may have focal lumen or glandular formation. On the other hand, the tumor cells in convertional SPN are discohesive and lack high-grade nuclear features, mitosis and lumen or glandular formation. The osteoclast-like giant cells in undifferentiated carcinoma are of histiocytic origin (positive for CD68) and lack the expression of PR and nuclear β-catenin. Given the above-mentioned unique immunohistochemical profile of SPN, a panel of immunohistochemical markers, including pan-cytokeratin, β-catenin, CD10, PR, chromogranin, synaptophysin, trypsin or chymotrypsin and BCL10 is rerecommended to establish the correct diagnosis. Since most SPNs express NSE, CD56, and alpha-1-antitrypsin, these markers are not useful in the differential diagnosis between SPN and pancreatic neuroendocrine tumor or acinar cell carcinoma.