Case 4: Quarter 4, 2020

Case 4: Quarter 4, 2020

Clinical History

A 58-year-old woman with no significant past medical history developed left abdominal pain. An abdominal MRI showed an irregular enhancing 4.5 x 4.0 cm pancreatic tail mass that was inseparable from vessels in the splenic hilum. Endoscopic ultrasound-guided fine-needle aspiration showed rare malignant cells, favoring adenocarcinoma. The patient subsequently underwent neoadjuvant therapy with Gemcitabine/Abraxane followed by a distal pancreatectomy, splenectomy, partial omentectomy and removal of surrounding lymph nodes.

Histologic/Cytologic Features 

Figures 1-4 are representative photomicrographs of the tumor. The histologic examination revealed a small component of invasive ductal adenocarcinoma involving pancreatic parenchyma. Malignant glands were admixed with prominent nests of cells with cribriform/microcystic architecture containing intermingled epidermoid cells, mucin secreting cells, and intermediate/clear cells (the latter features resemble mucoepidermoid carcinoma of the salivary gland). The proportion of different cell types and microcystic architecture varied in different areas. Focal high grade pancreatic intraepithelial neoplasia (formerly PanIN-3) and pancreatic atrophy were also noted.

Figure-1. H&E stain of the tumor, 2X
Figure-2. H&E stain of the tumor, 4X
Figure-3. H&E stain of the tumor, 20X
Figure-4. H&E stain of the tumor, 20X

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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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What is the diagnosis of the lesion?

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Answer: Pancreatic adenosquamous carcinoma with mucoepidermoid carcinoma-like features

 

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Final diagnosis:  

Pancreatic adenosquamous carcinoma with mucoepidermoid carcinoma-like features

Educational Objectives and Discussion:

Educational Objectives

1. Review the clinicopathologic features of pancreatic adenosquamous carcinoma with mucoepidermoid carcinoma-like features
2. Understand the molecular alterations of pancreatic adenosquamous carcinoma with mucoepidermoid carcinoma-like features
3. Discuss pertinent differential diagnosis for pancreatic adenosquamous carcinoma with mucoepidermoid carcinoma-like features

Discussion

The current tumor demonstrated that tumor cells were positive for pan-cytokeratin. p40, p63, and CK5 highlighted epidermoid tumor cells. CDX2 and CK20 highlighted luminal cells and mucin-producing cells. Synaptophysin, chromogranin, and CD56 stains were negative. Intracytoplasmic and luminal mucinous secretions were highlighted by mucicarmine stain (Figures 5-7). Molecular study showed mutations in KRAS, CDKN2A, SF3B1, and TP53 genes.

Figure-5. P40 immunohistochemical stain, 40X
Figure-6. CDX2 immunohistochemical stain, 40X
Figure-7. Mucicarmine stain, 40X

Pancreatic mucoepidermoid carcinoma (PAN-MEC, more appropriately termed as pancreatic adenosquamous carcinoma with mucoepidermoid carcinoma-like features) has been proposed as one of the histologic subtypes of pancreatic adenosquamous carcinoma because of their
clinicopathologic and molecular similarities (1). To date, approximately 20 PAN-MEC cases have been documented (1-6). This tumor is more frequently located at the pancreatic body/tail and is significantly larger in size and more aggressive than those of the conventional pancreatic ductal adenocarcinomas (1). 

Similar to salivary gland MECs, three intermingled cell types, including mucin-producing cells, epidermoid cells, and intermediate cells, are usually present in varying proportions in PAN-MEC. Mucin-producing cells (mucocytes) produce mucin (and are positive for mucin stains such as mucicarmine). These cells may have a vacuolated, columnar, or goblet cell-like appearance (Figure 8). Mucocytes often form the lining of microcysts or duct-like structures.

Figure-8. H&E stain of the tumor, 20X

Epidermoid cells are polygonal and squamoid in appearance with dense eosinophilic cytoplasm, which can be highlighted by immunohistochemical stains such as p40, p63, or CK5/6. Epidermoid cells commonly have nested, or sheet-like growth pattern and are often located at the periphery of the nests or cribriform/microcystic structures. While intercellular bridges may be found, keratin pearl formation, overt keratinization, or dyskeratosis is not typically seen. Intermediate cells are less differentiated, and are morphologically not mucous or fully epidermoid cells. Their appearance may vary from small clear cells to small basaloid cells with scant basophilic cytoplasm or intermediate oval cells with pale eosinophilic cytoplasm. The intermediate cells are often admixed with epidermoid cells or mucocytes (Figure 9).

Figure-9. H&E stain of the tumor, 40X

Despite morphologic similarity, PAN-MEC appears not to be a counterpart of MEC of the salivary gland. In the salivary gland, a high proportion of MECs have been reported to harbor an oncogenic CRTC1/3MAML2 gene fusion; whereas in the pancreas, these gene fusions were not detected by PCR in a study involving 16 PAN-MEC cases (all cases were classified as high-grade based on the salivary gland MEC grading system) (1). In addition, PAN-MEC has been reported to harbor KRAS and TP53 mutation, which is similar to the most common molecular signature found in pancreatic ductal adenocarcinomas (4)

Differential diagnosis:

Due to morphologic similarity, metastatic mucoepidermoid carcinoma or clear cell carcinoma of the salivary gland should be one of the first differentials to consider. However, the lack of clinical history of a salivary gland tumor, the presence of a pancreatic precursor lesion (high grade pancreatic intraepithelial neoplasia), and a component of conventional  invasive ductal adenocarcinoma would support this tumor being a primary pancreatic carcinoma with MEC features as opposed to a metastasis from salivary gland. Goblet cells and microcystic structures are generally not seen in clear cell carcinoma of the salivary gland, although squamous differentiation and mucinproduction are not uncommon (7).

Conventional pancreatic adenosquamous carcinoma is also in the differential diagnosis. By definition, this tumor has at least a 30% squamous cell carcinoma component with coexisting ductal adenocarcinoma. Apparent keratinization and squamous pearl formation, as well as focal nuclear anaplasia, are often noted. Low-grade mucoepidermoid carcinoma-like features are generally absent.

Neoadjuvant therapy has been reported to induce squamous metaplasia of ductal columnar cells. However, there was no squamous metaplasia identified in the background pancreatic tissue of the present case. Although focal squamous transdifferentiation from the small ductal adenocarcinoma component induced by neoadjuvant therapy (8) cannot be completely excluded, the diffuse squamoid cells intermingled with other cell types and predominant cribriform/microcystic architecture are difficult to be explained by focal squamous transdifferentiation changes.

Pancreatoblastoma is an uncommon malignant epithelial neoplasm characterized by multilineage differentiation including at least prominent acinar differentiation and focal squamoid morules that exhibit nuclear beta-catenin immunopositivity. Tumors are commonly seen in children but can occur in adults. Ductal/glandular or neuroendocrine differentiation can also be seen but are generally focal (9-10).

References:

  1. Saeki K, Ohishi Y, Matsuda R, et al. “Pancreatic Mucoepidermoid Carcinoma” Is not a Pancreatic Counterpart of CRTC1/3-MAML2 Fusion Gene-related Mucoepidermoid Carcinoma of the Salivary Gland, and May More Appropriately be Termed Pancreatic Adenosquamous Carcinoma With Mucoepidermoid Carcinoma-like Features. Am J Surg Pathol. 2018;42:1419-1428.
  2. Onoda N, Kang SM, Sugano S, Yamashita Y, Chung YS, Sowa M. Mucoepidermoid carcinoma of the pancreas: report of a case. Surgery. 1995;25:843-847.
  3. Ma R, Yu YQ, Li JT, Peng SY. Mucoepidermoid carcinoma of the pancreas: a case report and a review of literature. Journal of research in medical sciences: the official journal of Isfahan University of Medical Sciences. 2012;17:886-889.
  4. Kardon DE, Thompson LD, Przygodzki RM, Heffess CS. Adenosquamous carcinoma of the pancreas: a clinicopathologic series of 25 cases. Mod Pathol. 2001;14:443-451.
  5. Hu HJ, Zhou RX, Liu F, Wang JK, Li FY. You cannot miss it: Pancreatic mucoepidermoid carcinoma: A case report and literature. Medicine. 2018;97:e9990.
  6. Boecker J, Feyerabend B, Tiemann K, et al. Adenosquamous Carcinoma of the Pancreas Comprise a Heterogeneous Group of Tumors With the Worst Outcome: A Clinicopathological Analysis of 25 Cases Identified in 562 Pancreatic Carcinomas Resected With Curative Intent. Pancreas. 2020;49:683-691.
  7. Hsieh MS, Wang H, Lee YH, Ko JY, Chang YL. Reevaluation of MAML2 fusion-negative mucoepidermoid carcinoma: a subgroup being actually hyalinizing clear cell carcinoma of the salivary gland with EWSR1. Hum Pathol. 2017;61:9-18.
  8. Marcus R, Maitra A, Roszik J. Recent advances in genomic profiling of adenosquamous carcinoma of the pancreas. The Journal of pathology. 2017;243:271-272.
  9. Klimstra DS, Wenig BM, Adair CF, Heffess CS. Pancreatoblastoma. A clinicopathologic study and review of the literature. Am J Surg. 1995;19:1371-1389.
  10. Tanaka Y, Kato K, Notohara K, et al. Significance of aberrant (cytoplasmic/nuclear) expression of beta-catenin in pancreatoblastoma. The Journal of pathology. 2003;199:185-190.

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Case contributed by:

Wei Zheng, Assistant Professor

Alyssa M. Krasinskas, Professor

Department of Pathology and Laboratory Medicine

Emory School of Medicine

Conflict of Interest: NO

Case 3: Quarter 3, 2020

Case 3: Quarter 3, 2020

Clinical History

A 38-year-old female with a history of hypertension presented to the emergency department with complaints of nausea, vomiting, and back pain. MRI showed a T1 hypointense, T2 hyperintense, nonenchancing cystic lesion at the tail of the pancreas, which caused mass effect upon the spleen and stomach. A distal pancreatectomy was subsequently performed. The patient is currently being followed with no evidence of recurrence or malignant transformation.

Macroscopic Description
Grossly, there was a well-circumscribed 11.5 x 10 x 3.7 cm cyst at the tail of the pancreas containing cloudy, milky fluid (Figure 1). The lining of the cyst was smooth, without papillary projections or solid areas. There was no communication between the cyst and the main pancreatic duct.

Figure-1. Gross photograph of the cystic lesion at the tail of the pancreas

 Histologic/Cytologic Features 
Microscopic pictures of the cyst wall are shown in Figures 2 – 4. Sections show a unilocular cyst lined by 1-2 cell layers of bland cuboidal epithelium with abundant eosinophilic granular apical cytoplasm and basally oriented nuclei consistent with acinar differentiation. There was  little intervening ductal differentiation (mucin-containing ductal epithelium). No substantial nuclear atypia or mitotic activity was present. The cyst was surrounded by a thick fibrous pseudocapsule, which was composed of dense collagen with scattered fibroblasts. No ovarian type stroma was identified.

Figure-2. H&E stain low power view of the cyst wall
Figure-3. H&E stain median power view of the cyst wall
Figure-4. H&E stain high power view of the cyst wall
 

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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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What is the diagnosis of the lesion?

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Answer: Acinar cystic transformation of the pancreas

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Final diagnosis:  

Acinar cystic transformation of the pancreas

Educational Objectives and Discussion:

Educational Objectives

  1. To understand the clinicopathologic features of the acinar cystic transformation of the pancreas.
  2. To understand the molecular alterations of the acinar cystic transformation of the pancreas.
  3. To discuss the differential diagnoses of the acinar cystic transformation of the pancreas.

Discussion

Acinar cystic transformation of the pancreas, also called acinar cell cystadenoma, is currently considered a non-neoplastic cystic pancreatic lesion that is lined by benign-appearing acinar and ductal epithelium. These lesions can occur throughout the pancreas, but they are more common in the pancreatic head. Some examples may diffusely involve the entire organ. Acinar cystic transformation commonly occurs in adults (mean age 43 years old) and shows female predominance (F:M=3:1) (1-9). Clinically it can present as recognized macroscopic lesions or incidental microscopic lesions. Patients can present with abdominal pain, dyspepsia or palpable mass. Some cases are completely asymptomatic. The etiology is unknown, but some cases may be related to obstruction. The size of these lesions can range from 1.5 cm – 19.7 cm (mean 5.8 cm) and cysts may be unilocular or multilocular with a smooth cyst lining and rare communication with the main pancreatic duct.

Microscopically, acinar cystic transformation is characterized by cysts of variable sizes lined by bland cuboidal eosinophilic epithelium with both acinar and ductal differentiation, cytoplasmic zymogen rich granules and without significant nuclear atypia, mitotic figures, necrosis, or infiltrative growth pattern.

The apical zymogen granules stain positively for the periodic acid-Schiff (PAS) stain and are resistant to diastase (Figures 5 & 6). Immunohistochemical labeling for the pancreatic enzymes trypsin (Figure 7), chymotrypsin, and lipase is seen in the lining epithelial cells, and cytokeratins (such as cytokeratin 7) are also detectable in the lining epithelium.

Molecular studies have been done on a few cases with one showing chromosomal gains of 1p, 3p, 5q, 6p, 7q, 8, 10q, 11, 14, 20, and X by array comparative genomic hybridization (10). However, another study performed X-chromosome inactivation analysis on 5 cases and showed that these lesions have a random X-chromosome inactivation pattern (11), supporting a non-neoplastic process.

Figure-5. PAS stain of the cyst wall
Figure-6. PAS-D stain of the cyst wall
Figure-7. Immunohistochemical stain for trypsin

Differential diagnosis:

Serous cystadenoma of the pancreas is a benign epithelial cystic neoplasm that is composed of uniform cuboidal, glycogen-rich pale pink to clear cells that often form cysts containing serous fluid. Immediately underlying the clear epithelium is an interweaving network of capillaries that is challenging to see on H&E but can be highlighted by CD31 stain. A central scar can be present, which consists of hyalinized stroma. Owing to the presence of abundant intracytoplasmic glycogen, PAS staining is positive in tumor cells but PAS-D staining is negative. Serous epithelium is immunoreactive for inhibin and Glut-1.

Mucinous cystic neoplasm (MCN) is another differential that is also characterized by pancreatic cysts of the body/tail that do not communicate with pancreatic duct. Cysts are characteristically lined by mucinous/non-mucinous epithelium with underlying entity defining ovarian-type stroma. Acinar epithelial lining is not a feature of MCN.

Squamoid cysts of the pancreatic duct are not neoplastic and are lined by epithelium with squamous or transitional differentiation instead of acinar and ductal differentiation.

Acinar cell cystadenocarcinoma is exceedingly rare. The epithelium of acinar cell cystadenocarcinoma is more complex than that of acinar cystic transformation and the acinar cells are less well polarized, and show significant nuclear atypia, including pleomorphism and prominent nucleoli. Areas of necrosis, solid nests of neoplastic cells, easily identifiable mitoses, and infiltration into the surrounding stroma support a malignant diagnosis.


References:

1. Zamboni G, Terris B, Scarpa A, et al. Acinar Cell Cystadenoma of
the Pancreas: A New Entity? Am J Surg Pathol. 2002, 26(6): 698-704.
2. Albores-Saavedra J. Acinar Cystadenoma of the Pancreas: A
Previously Undescribed Tumor. Ann Diagn Pathol. 2002, 6(2): 113-5.
3. Chatelain D, Paye F, Mourra N, et al. Unilocular Acinar Cell
Cystadenoma of the Pancreas an Unusual Acinar Cell Tumor. Am J Clin
Pathol. 2002, 118(2): 211-4.
4. G Klöppel. Pseudocysts and Other Non-Neoplastic Cysts of the
Pancreas. Semin Diagn Pathol. 2000 Feb; 17(1); 7-15.
5. McEvoy MP, Rich B, Klimstra D, et al. Acinar Cell Cystadenoma of
the Pancreas in a 9-year-old Boy. J Pediatr Surg. 2010, 45(5): e7-9.
6. Wolf AM , Shirley LA, Winter JM, et al. Acinar Cell Cystadenoma of
the Pancreas: Report of Three Cases and Literature Review. J
Gastrointest Surg. 2013l,17(7): 1322-6.
7. Singhi AD, Norwood S, Liu TC, et al. Acinar Cell Cystadenoma of the
Pancreas: A Benign Neoplasm or Non-Neoplastic Ballooning of Acinar and
Ductal Epithelium. Am J Surg Pathol. 2013, 37(9): 1329-35.
8. Wang G, Ji L, Qu FZ, et al. Acinar Cell Cystadenoma of the
Pancreas: A Retrospective Analysis of Ten-Year Experience From a
Single Academic Institution. Pancreatology, 2016, 16(4): 625-31.
9. Zhang X, Zhu H, Yang X, et al. Post-obstructive Cyst Formation in
Pancreas and Cystic Acinar Transformation: Are They Same? Pathol Res
Pract 2017, 213(8): 997-1001.
10. Khor TS, Badizadegan K, Ferrone C, et al. Acinar cystadenoma of
the pancreas: a clinicopathologic study of 10 cases including
multilocular lesions with mural nodules. Am J Surg Pathol.
2012;36(11):1579‐1591.
11. Singhi AD, Norwood S, Liu TC, et al. Acinar cell cystadenoma of
the pancreas: a benign neoplasm or non-neoplastic ballooning of acinar
and ductal epithelium? Am J Surg Pathol. 2013;37(9):1329‐1335.

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Case contributed by:

Yue Xue, MD, PhD

Rebecca C. Obeng, MD, PhD

Department of Pathology and Laboratory Medicine

Northwestern University, Chicago, IL 60611, USA

Conflict of Interest: NO

PBPath Journal Watch

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.

See the Current Issue here, and the draft of the Upcoming Issue here.

Older Issues will be collected under the archive.

Please let us know your comments and suggestions. Please fill the feedback form.

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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

Message from the President

Message from the President

Dear Colleagues, 

I am sad to share news of the death on July 7 in Milan, Italy of Dr. Juan Rosai. 

Dr. Rosai was clearly one of the most influential figures in surgical pathology in the last 50 years, whose broad diagnostic expertise was recognized worldwide.  For much of his career, he served as a consultant to the international pathology community, providing expert second opinions and making enormous contributions to direct patient care.  As a researcher, Dr. Rosai was best known for his work on neoplasms of the thyroid, thymus, and vascular system, but essentially there is no subspecialty area that did not receive his investigative attention.  In fact, he wrote many papers on pancreatic neoplasms, and it was his encouragement of me to pursue a case of pancreatic acinar cell carcinoma that led me to the field of pancreatic pathology.  Dr. Rosai was among the first to embrace technologies like electron microscopy, immunohistochemistry, and molecular biology to enhance pathologic diagnosis. He was also one of the first pathology leaders to promote digital pathology and predicted the field’s evolution from microscopic to digital pathology many years before it occurred, and he pushed for subspecialization of academic pathology years before it became commonplace – ironic, given that he himself was the quintessential generalist.  But perhaps his most lasting contributions were made as a mentor and teacher, roles he took on with great enthusiasm. He fostered the careers of countless trainees, many of whom are now in leadership positions around the world.   Recitation of his numerous achievements, awards, and honors can await more formal tributes that will appear in time, but no one can doubt that Juan Rosai achieved as much as any individual can in our field, and his influence has been felt across all subspecialties.  A world-renowned surgical pathologist, as well as a treasured friend to many, Dr. Rosai’s generous spirit and ability to build consensus are as much a part of his legacy as his unparalleled expertise. Our thoughts are with his wife, Dr. Maria Luisa Carcangiu, and his children.

David Klimstra

President, Pancreatobiliary Pathology Society

 

Pancreatobiliary Pathology Society’s Special Section in Archives of Pathology and Laboratory Medicine

Pancreatobiliary Pathology Society’s Special Section in Archives of Pathology and Laboratory Medicine

Dear Pancreatobiliary Pathology Society Members

I am writing to draw your attention to the newly released Archives of Pathology and Laboratory Medicine (https://archivesofpathology.org/toc/arpa/144/7) which includes a Special Section containing review articles on the topics we presented at our 2019 USCAP Companion Meeting session.

You will find comprehensive and authoritative reviews written by our speakers, Drs. Laura Wood, Laura Tang, Stefano La Rosa, and Huamin Wang, along with selected collaborators.  We are particularly pleased and grateful to the Editors of Archives, Drs. Philip Cagle and Donna Hansel, for agreeing to publish a Special Section based on our meeting, and to Managing Editor Katie Giesen, whose assistance was tremendously helpful during the process.

I am also happy to report that we will be publishing a second installment based on the presentations at the 2020 USCAP Companion Meeting, so stayed tuned.  Thanks to all who participated in authoring, reviewing, and publishing these reviews, and I hope you all enjoy reading them.

Best wishes, and Stay Safe!

David Klimstra

On behalf of the Executive and Education Committees

Pancreatobiliary Pathology Society

 

Case 2: Quarter 2, 2020

Case 2: Quarter 2, 2020

Clinical History

A 24-year-old female presented to the emergency department with severe left-sided abdominal pain. CT abdomen/pelvis showed a heterogeneous mass in the tail of the pancreas with multiple metastatic liver lesions and lymphadenopathy. Liver lesion biopsies were attempted and yielded necrotic debris with outlines of atypical cells that were positive for pancytokeratin (AE1/AE3). The patient next underwent a distal pancreatectomy.

Fig. 2
Figure-2.-HE-stain-of-tumor-20X
Figure-3.-HE-stain-of-tumor-40X
Figure-4.-PAS-Diastase-stain-40X
Figure-5.-CK-AE1AE3-immunohistochemical-stain-20X
 

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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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What is the diagnosis of the lesion?

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Answer: Undifferentiated carcinoma, sarcomatoid type with rhabdoid features

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Microscopic description:
The tumor had a predominantly solid architecture and was primarily composed of loosely cohesive sheets of large ovoid-to-polygonal tumor cells. Focal glandular architecture was also seen. The tumor cells had large atypical vesicular nuclei, prominent nucleoli, and
eosinophilic to amphophilic cytoplasm with abundant intracytoplasmic eosinophilic globules, which displaced the tumor nuclei peripherally, creating a rhabdoid appearance. Multifocal lymphovascular and perineural invasion, abnormal mitoses, and areas of necrosis were also present.

Immunohistochemistry and special stains:
The tumor cells were positive for pancytokeratin (AE1/AE3), vimentin, and EMA. Ki-67 immunostain was positive in 60% of tumor cells. Intracytoplasmic eosinophilic globules were positive for PAS and were resistant to diastase digestion. Tumor cells showed diffuse loss of INI1 immunostain not only in solid areas, but also in areas of glandular differentiation. The tumor cells were negative for CK7, CD10, synaptophysin, chromogranin, and CD34.

Molecular analysis:
SMARCB1 gene mutation was detected.

Final diagnosis:  

Undifferentiated carcinoma, sarcomatoid type with rhabdoid features

Educational Objectives and Discussion:

Educational Objectives
1. Review undifferentiated carcinoma of pancreas and its subtypes

2. Discuss the clinicopathologic features of a recently described entity, pancreatic undifferentiated rhabdoid carcinoma

3. Understand pertinent differential diagnosis for undifferentiated carcinoma, sarcomatoid type with rhabdoid features

Discussion

Undifferentiated carcinoma is one of the histologic subtypes of pancreatic ductal adenocarcinoma. Tumors are usually hypercellular and composed of poorly cohesive tumor cells which often coexpress cytokeratin and vimentin. Osteoclast-like giant cells are typically lacking. Perineural and vascular invasion are also frequent findings. The current (5th) edition of WHO Classification of Tumors (Digestive System Tumors) recognizes three subtypes of undifferentiated carcinoma based on the tumor’s morphological patterns. These include anaplastic, sarcomatoid, and carcinosarcoma (1).

Sarcomatoid type undifferentiated carcinoma is composed of poorly cohesive atypical spindle-shaped tumor cells resembling a sarcoma. Tumors may contain admixed heterologous elements including bone and cartilage. At least 80% of the tumor typically shows spindle cells, with or without heterologous differentiation (1). A more specific morphologic type of sarcomatoid undifferentiated carcinomas with rhabdoid features has also been described, as with the case illustrated here (2). These are composed of sheets of dishesive rhabdoid cells with myxoid stroma. Pleomorphic giant cells, spindling and tubular components may also be seen and loss of nuclear positivity for SMARCB1 (INI1) is characteristic. SMARCB1/INI1 is known to encode for a tumor suppressor gene located on chromosomal band 22q11.2 (3, 4), and is a core subunit of a group of chromatin-modeling complexes, the SWI/SNF family. Biallelic inactivation of this gene is associated with highly malignant tumors with prominent rhabdoid morphology, including malignant rhabdoid tumor (both renal and “pure” extrarenal), atypical teratoid/rhabdoid tumor, epithelioid sarcoma and renal medullary carcinoma, among others. (3, 5, 6, 7).

Agaimy et al. recently described a group of pancreatic undifferentiated carcinomas with prominent rhabdoid morphology, which they named pancreatic undifferentiated rhabdoid carcinoma (PURC) (8). The authors described 14 such cases from their home institution as well as an additional 46 cases discovered on review of the literature. There were 44 males and 16 females (male-to-female ratio=2.8:1) of mean age 65 years (range 30 -96 years). Patients had an extremely poor prognosis with 45 of 49 (92%) with available follow-up information reportedly dying of disease within 1-19 months.

Agaimy et al also described two distinct subtypes of pancreatic undifferentiated rhabdoid carcinoma based both on the histomorphologic features and molecular profiles. One subtype is the pleomorphic giant cell subtype which shows highly pleomorphic neoplastic cells with abundant eosinophilic cytoplasm frequently containing rhabdoid inclusions. Molecular studies have shown this particular subtype to have a strong association with KRAS alteration and intact SMARCB1 gene. The second subtype, which is similar to the current case, is the monomorphic anaplastic subtype. This subtype shows uniformly atypical rhabdoid cytological features without significant pleomorphism. The tumor cells in the monomorphic anaplastic subtype have medium to large vesicular nuclei, prominent nucleoli, and eosinophilic cytoplasm which frequently contains rhabdoid cytoplasmic inclusions. This subtype shows diffuse loss of SMARCB1 nuclear immunostain as well as SMARCB1 gene mutation. However, no KRAS alterations are detected in these tumors (8).

Figure-6.-INI1-immunohistochemical-stain-20X

Differential diagnosis:

The morphologic features of undifferentiated carcinoma, sarcomatoid type with rhabdoid features raises several differential diagnoses one of which is poorly differentiated neuroendocrine carcinoma, particularly the large cell variant. The large cell variant of neuroendocrine carcinoma is often composed of round to polygonal cells which can have vesicular nuclei and prominent nucleoli. Glandular differentiation can rarely be present. However, unlike pancreatic undifferentiated carcinomas with rhabdoid morphology neuroendocrine carcinoma almost always expresses at least one neuroendocrine marker (synaptophysin and chromogranin) and shows intact INI1 (9).

Solid pseudopapillary neoplasm (SPN) is another differential to consider. The presence of a pancreatic neoplasm in a female in her 20’s should always raise the possibility of SPN as a
differential diagnosis. The presence of PAS-positive and diastase resistant intracytoplasmic globules is also characteristic of SPN. However, SPN often has a “pseudo-papillary” morphology, with nuclear beta-catenin labeling and is negative or focally positive for cytokeratin (1,10).

Melanomas can also display rhabdoid morphology, and can lose HMB45 and Melan-A expression. However, melanoma with rhabdoid morphology is often is positive for S100, shows intact INI1 staining and is cytokeratin negative (11).

Proximal-type epithelioid sarcoma is another neoplasm that can have predominant rhabdoid features with negative INI1 staining/INI1 loss. Differentiating undifferentiated carcinoma with rhabdoid features and SMARCB1 (INI1) loss from proximal-type epithelioid sarcoma can be very difficult. However, the presence of glandular architecture in this case makes this entity less likely. CD34 immunostain is positive in approximately 50% of epithelioid sarcoma (8,12).


References:

1.WHO Classification of Tumours Editorial Board, World Health Organization., International Agency for Research on Cancer. Digestive system tumours. 5th ed. Lyon: IARC Press; 2019.
2. Alguacil-Garcia A, Weiland LH. The histologic spectrum, prognosis, and histogenesis of the sarcomatoid carcinoma of the pancreas. Cancer 1977;39:1181-1189.
3. Kohashi K, Oda Y. Oncogenic roles of SMARCB1/INI1 and its deficient tumors. Cancer Sci. 2017;108(4):547-552.
4. Cho YM, Choi J, Lee OJ, et al. SMARCB1/INI1 missense mutation in mucinous carcinoma with rhabdoid features. Pathol Int 2006;56:702-706.
5.Fuller CE. All things rhabdoid and SMARC: An enigmatic exploration with Dr. Louis P. Dehner. Semin Diagn Pathol. 2016;33(6):427‐440.
6. Donner LR, Wainwright LM, Zhang F, et al. mutation of the INI1 gene in composite rhabdoid tumor of the endometrium. Hum Pathol 2007;38:935–939.
7. Fuller CE, Pfeifer J, Humphrey P, et al. Chromosome 22q dosage in composite extrarenal rhabdoid tumors:clonal evolution or a phenotypic mimic? HumPathol 2001;32:1102–8.
8. Agaimy A, Haller F, Frohnauer J, et al. Pancreatic undifferentiated rhabdoid carcinoma: KRAS alterations and SMARCB1 expression status define two subtypes. Mod Pathol. 2015;28(2):248‐260.
9. Basturk O, Tang L, Hruban RH, et al. Poorly differentiated neuroendocrine carcinomas of the pancreas: a clinicopathologic analysis of 44 cases. Am J Surg Pathol. 2014;38(4):437‐447.
10. 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.
11. Abbott JJ, Amirkhan RH, Hoang MP. Malignant Melanoma With a Rhabdoid Phenotype: Histologic, Immunohistochemical, and Ultrastructural Study of a Case and Review of the Literature. Arch Pathol Lab Med. 2004;128(6):686-8
12. Sullivan LM, Folpe AL, Pawel BR, et al. Epithelioid sarcoma is associated with a high percentage of SMARCB1 deletions. Mod Pathol 2013;26:385-392.

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Case contributed by:

Aaron Sohn, M.D.
Anatomic and Clinical Pathology Resident, PGY-4
Baylor University Medical Center, Dallas, TX

Atin Agarwal, M.D.
Staff Pathologist
Baylor University Medical Center, Dallas, TX

Conflict of Interest: NO

USCAP 2020 Highlights

USCAP 2020 Highlights

COMPANION SOCIETY HANDOUTS

Cystic and Intraductal Neoplasms of the Pancreatobiliary Tract

Moderators:
Martha Bishop Pitman, Deepti Dhall

Speakers:
Jin-Young Jang: Management Algorithms for Pancreatic Cysts and Intraductal Neoplasms: The Surgeon’s Perspective
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Michelle D. Reid: Cytologic Assessment of Cystic/Intraductal Lesions of the Pancreatobiliary Tract
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Aatur D. Singhi: Preoperative Molecular Assessment of Pancreatic Cysts and Intraductal Lesions
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David S. Klimstra: Mucinous Cystic and Intraductal Neoplasms of the Pancreatobiliary Tract
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Irene Esposito: Non-mucinous Cystic Lesions of the Pancreas
Click to Download

 


BEST ABSTRACT AWARD

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




USCAP 2020 Abstract Award

Dear Colleagues,
 
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.

Openings and Happenings

Pancreatobiliary Pathology Society Members,

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

Message from the President

Message from the President

Dear Pancreatobiliary Pathology Society Members,

Happy Winter!

We are gearing up for the annual USCAP meeting! Our Companion Society session will be held on Saturday, February 29th from 7-10 pm in room LACC 502-A. Our annual Business Meeting will immediately follow. This year is the end of the two-year terms for the Executive Committee so we will be presenting the slate for President, Vice President and Secretary Treasurer. Please attend and cast your votes!  Also, nominations have been submitted for the PBPath Society Abstract Award and the winner will be announced at the Business Meeting.

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.

Alyssa M. Krasinskas, MD

 

Case 1: Quarter 1, 2020

Case 1: Quarter 1, 2020

Clinical History

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 1. H&E stain

 

Figure 2. H&E stain
Figure 2. H&E stain

 

Figure 3. H&E stain
Figure 3. H&E stain

 

Figure 4. H&E stain
Figure 4. H&E stain

 

Figure 5. CK7
Figure 5. CK7

 

Figure 6. CK5/6
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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What is the diagnosis of the lesion?

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Click Here To See The Answer

Answer: Undifferentiated carcinoma, anaplastic type

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Click Here To See The Discussion

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:

  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. Patil DT, Rubin BP. Gastrointestinal stromal tumor: advances in diagnosis and management. Arch Pathol Lab Med. 2011;135(10):1298-310.
  6. 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.
  7. WHO Classification of Tumours Editorial Board, World Health Organization., International Agency for Research on Cancer. Digestive system tumours. 5th ed. Lyon: IARC Press; 2019
  8. 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.
  9. 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.
  10. 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.
  11. 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. 
  12. 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