Author: xuchen.zhang

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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Click Here To See The Discussion

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

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

Case 1: Quarter 1, 2021

Case 1: Quarter 1, 2021

Clinical History

A 73-year-old female with a history of monoclonal gammopathy of undetermined significance (MGUS) and small fiber peripheral neuropathy was found to have elevated transaminases and alkaline phosphatase (ALP) – ALT 54 U/L (normal range 15-41), AST 66 U/L (normal range 14-54), ALP 322 U/L (normal range 38-126) on routine laboratory testing. Total bilirubin was within normal limits (0.3 mg/dL), and gamma-glutamyl transferase was not performed. Abdominal CT showed diffuse thickening and enhancement of the extrahepatic and central intrahepatic biliary tree with associated areas of narrowing as well as mild intrahepatic biliary ductal dilation. During ERCP, mucus was seen extruding from a gaping papilla, thus clinically a pancreatic main duct intraductal papillary mucinous neoplasm (IPMN) was considered. Bile duct brushing cytology showed atypical cells, which were favored to represent a reactive process. Whipple resection was performed for the suspected IPMN. After the Whipple procedure, she experienced an initial improvement in laboratory values. A rheumatologic evaluation was negative, including autoimmune (ANA, ANCA, SSA, SSB, anti-dsDNA, and anti-mitochondrial antibodies), infectious (viral hepatitis, HIV), and immunoglobulin (SPEP, quantitative immunoglobulins, including repeated IgG4) testing. Since her initial improvement, follow-up MRI showed new and worsening areas of stricture and continued thickening and enhancement of her biliary tree. Since optimizing her immunosuppressive regimen, her disease has remained stable.

Macroscopic Description

No mass or cystic lesion was identified in the pancreas, bile duct, or gallbladder on gross examination.

Histologic/Cytologic Features 

Microscopic pictures of the gallbladder, cystic duct, common bile duct, ampulla, small bowel submucosa, and pancreas are shown in Figures 1-8. Sections showed that the small-sized veins of the gallbladder, cystic duct, common bile duct, ampulla, small bowel submucosa, and pancreas were involved by a predominantly lymphocytic infiltrate with rare poorly formed, non-necrotizing granulomas. Focal involvement of a medium-sized vein and artery with associated vessel wall fibrinoid necrosis was also seen. The gallbladder and cystic duct were thickened with marked chronic inflammation.

Figure-1. H&E stain of the gallbladder, 25X
Figure-2. H&E stain of the cystic duct, 50X
Figure-3. H&E stain of the common bile duct, 40X
Figure-4. H&E stain of the pancreas, 100X
Figure-5. H&E stain of the pancreas, 25X
Figure-6. H&E stain of the pancreas, 200X
Figure-7. H&E stain of the ampulla, 40X
Figure-8. H&E stain of the small bowel, 40X

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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: Vasculitis-related cholangiopathy

 

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Final diagnosis:  

Vasculitis-related cholangiopathy

Educational Objectives and Discussion:

Educational Objectives

  1. Recognize important histologic features in the assessment of vasculitis and other inflammatory disorders of the biliary tree.
  2. Understand the integration of histologic and laboratory evidence in generating a specific diagnosis.
  3. Review the differential diagnosis and necessary workup for benign mimickers and inflammatory lesions of the biliary tree.

Discussion

Vasculitis of the biliary system is rare and can present as a component of systemic disease or as single organ involvement, although progression from single organ to systemic disease can occur. Injury to the biliary tree via vasculitis can result in ischemic cholangiopathy. As an acute insult, ischemic cholangiopathy is characterized by edema, necrosis, and sloughing of the biliary epithelium. A chronic course, as may be seen with vasculitis, results in fibrosis of the bile duct with the risk of eventual obliteration [1, 2].

Immunohistochemical staining was performed for this case. CD3 and CD20 stains showed a lymphocytic inflammatory infiltrate composed of a mixed B and T cell population. CD138, IgG, and IgG4 staining showed no increase in IgG4-positive plasma cells (result not shown).

Classification criteria for more common vasculitides were developed by the American College of Rheumatology (ACR) in 1990. The ACR classification criteria integrate clinical characteristics and histopathologic findings, and efforts to systematically update these criteria are ongoing. The current nomenclature of vasculitis is described in the 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides, which also describes some classification features. Vasculitis can be categorized as infectious vs. noninfectious. Noninfectious vasculitis can then be further subdivided by the type of vessel predominantly affected – small, medium, or large. The presence of immune complexes or autoantibodies further contributes to classification in combination with clinical features (patient age, site of involvement, etc) [3].

Among specific rheumatologic entities, biliary involvement is most frequently seen in polyarteritis nodosa, which typically affects medium-sized arteries with a necrotizing inflammatory process and has no ANCA association [4]. The ANCA-associated vasculitides including microscopic polyangiitis (small vessel involvement without granulomas) and eosinophilic granulomatosis with polyangiitis (small to medium vessel involvement) can affect the biliary system as a component of systemic disease [5, 6]. Vasculitis of the extrahepatic biliary tree has also been reported in association with hepatitis B, cryoglobulinemia (including hepatitis C associated), IgA vasculitis, Takayasu vasculitis, and giant cell arteritis [7, 8].

Differential diagnosis:

While a cholestatic pattern of injury with bile duct thickening raises clinical concern for a neoplastic process, the differential diagnosis includes several benign entities. Choledocholithiasis generally can be detected through radiographic and/or endoscopic studies, but an obstructing stone can occasionally be missed. Infectious causes include bacterial, parasitic (Ascaris lumbricoides, Clonorchis sinensis, Opisthorchis viverrini), and opportunistic/AIDS-related (Cryptosporidium parvum, cytomegalovirus) entities.

IgG4-associated cholangiopathy often presents with diffuse involvement of the biliary tree on imaging studies but can mimic primary sclerosing cholangitis with segmental involvement [9]. Key histologic features in IgG4-related disease include a dense lymphoplasmacytic infiltrate that may preferentially affect peribiliary glands compared to the lamina propria, along with storiform fibrosis, and obliterative phlebitis. Immunohistochemical staining for CD138, IgG, and IgG4 with an IgG4+:IgG+ plasma cell ratio >0.4 supports the pathologic diagnosis when observed in combination with typical histologic features [10].

Primary biliary cholangitis (PBC) typically presents as chronic cholestasis, and an antimitochondrial antibody is identified in 95% of cases. Histologically, PBC is characterized by chronic, nonnecrotizing granulomatous lesions primarily affecting the small, intrahepatic bile ducts, although florid duct lesions with necrosis can be seen. Ductular reaction and ductal epithelial cell injury can be seen in early stage PBC. Ductopenia, septal fibrosis, and even cirrhosis can be seen in late stage PBC [11]. Primary sclerosing cholangitis (PSC), in contrast, frequently involves both the intra- and extrahepatic ducts, classically demonstrating a beaded appearance on imaging, which represents alternating segments of stricture and uninvolved duct. Affected bile ducts show a characteristic onion skin pattern of fibrosis that may be associated with mild chronic inflammation and can ultimately result in duct obliteration.

Sarcoidosis frequently involves the liver, and variable involvement of the extrahepatic biliary tree has been reported. The lesions can cause compressive cholestasis when arising along the biliary tree, thereby mimicking PSC [12]. Well-formed non-necrotizing granulomas comprised of epithelioid histiocytes with or without giant cells characterize this entity, typically with multi-organ involvement. While the granulomas of sarcoidosis are usually morphologically distinguishable from the poorly formed granulomas of PBC, the granulomas of PBC are typically a component of bile duct destruction, whereas granulomas of sarcoidosis generally appear as a “bystander” inflammatory process, providing an architectural aid in discerning these entities [13-16].

References:

  1. Deltenre P, Valla DC. Ischemic cholangiopathy. J Hepatol. 2006 Apr;44(4):806-17.
  2. Viola S, Meyer M, Fabre M, et al. Ischemic necrosis of bile ducts complicating Schonlein-Henoch purpura. Gastroenterology 1999;117:211-214.
  3. Jennette JC, Falk RJ, Bacon PA, et al. 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013 Jan;65(1):1-11.
  4. Barquist ES, Glodstein N, Zinner MJ. Polyarteritis nodosa presenting as a biliary stricture. Surgery 1991;109:16-19.
  5. Tinazzi I, Caramaschi P, Parisi A, et al. Pancreatic granulomatous necrotizing vasculitis: a case report and review of the literature. Rheumatol Int. 2007 Aug;27(10):989-91.
  6. Trabelsi ABS, Issaoui D, Ksiaa M, et al. Sclerosing cholangitis in Behçet’s disease. Case Rep Med. 2013;2013:692980.
  7. Hernández-Rodríguez J, Tan CD, Rodríguez ER, et al. Single-organ gallbladder vasculitis: Characterization and distinction from systemic vasculitis involving the gallbladder. An analysis of 61 patients. Medicine (Baltimore). 2014 Nov; 93(24):405-413.
  8. Zhang X, Furth EE, Tondon R. Vasculitis involving the gastrointestinal system is often incidental but critically important. Am J Clin Pathol. 2020 Sep 8;154(4):536-552.
  9. Deshpande V, Sainani NI, Chung RT, et al. IgG4-associated cholangitis: a comparative histological and immunophenotypic study with primary sclerosing cholangitis on liver biopsy material. Mod Pathol. 2009 Oct;22(10):1287-95.
  10. Deshpande V, Zen Y, Chan JKC, et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol 2012.
  11. Lindor KD, Bowlus CL, Boyer J, et al. Primary biliary cirrhosis: 2018 practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2019 Jan;69(1)394-419.
  12. Selvan O, Vij M, Narasiman G, et al. Sarcoidosis mimicking primary biliary cirrhosis – a clinic-pathological description. Trop Gastroenterol. Jul-Sep 2015;36(3):207-9.
  13. Farooq PD, Potosky DR. The Klatskin tumor that wasn’t: an unusual presentation of sarcoidosis. AGC Case Rep J. 2016 Oct 12;3(4):e141.
  14. Gaduputi V, Ippili R, Sakam S, et al. Extrahepatic biliary obstruction: an unusual presentation of hepatic sarcoidosis. Clin Med Insights Gastroenterol. 2015 Apr 19;8:19-22.
  15. Jebran AF, Schmidt WE, Kahraman A, et al. Sarcoidosis of the intra- and extrahepatic bile ducts with concomitant cholangitis in a patient with ulcerative colitis. Case Rep Gastroenterol. 2019 Mar 29;13(1):153-158.
  16. Lewis J. Histopathology of granulomatous liver disease. Clin Liver Dis (Hoboken). 2018 Apr 6;11(3)77-80.

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Case contributed by:

Christopher M Sande MD

Zhaohai Yang MD PhD

Department of Pathology and Laboratory Medicine
Perelman School of Medicine at the University of Pennsylvania

Conflict of Interest: NO