Tag: case of the quarter

Case 3: Quarter 3, 2019

Case 3: Quarter 3, 2019

History:

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 1. Low power image of gallbladder. Arrow: mucosal surface. (Click image to see full size)
 

 

Figure 2. Low power image of gallbladder, focused on perimuscular soft tissue. Inset: medium power image of area with arrow. (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 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. (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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Please Select Your Diagnosis in the Poll, Then See the Answer and the Discussion in the Links Below

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Which of the following conditions does this patient most likely have?

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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.
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.
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.

 

References:

1. Schnelldorfer T, Sarr MG, Adams DB. What is the duct of Luschka?–A systematic review. J Gastrointest Surg. 2012 Mar;16(3):656-62.

2. Singhi AD, Adsay NV, Swierczynski SL, Torbenson M, Anders RA, Hruban RH, Argani P. Hyperplastic Luschka ducts: a mimic of adenocarcinoma in the gallbladder fossa. Am J Surg Pathol. 2011 Jun;35(6):883-90

3. Albores-Saavedra J, Keenportz B, Bejarano PA, Alexander AA, Henson DE. Adenomyomatous hyperplasia of the gallbladder with perineural invasion: revisited. Am J Surg Pathol. 2007 Oct;31(10):1598-604.

4. Adsay V, Jang KT, Roa JC, Dursun N, Ohike N, Bagci P, Basturk O, Bandyopadhyay S, Cheng JD, Sarmiento JM, Escalona OT, Goodman M, Kong SY, Terry P. Intracholecystic papillary-tubular neoplasms (ICPN) of the gallbladder (neoplastic polyps, adenomas, and papillary neoplasms  that are ≥1.0 cm): clinicopathologic and immunohistochemical analysis of 123 cases. Am J Surg Pathol. 2012 Sep;36(9):1279-301.

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Case contributed by:

Cherif Ibrahim, MD, FRCPC
Department of Laboratory Medicine
Queensway Carton Hospital
Ottawa, ON, Canada
E-mail: cibrahim@qch.on.ca

Goo Lee, MD, PhD
Department of Pathology
University of Alabama at Birmingham
Birmingham, AL, USA
E-mail: glee@uabmc.edu

Case 2: Quarter 2, 2019

Case 2: Quarter 2, 2019

History:

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. Representative low power image of the tumor (Haematoxylin and eosin 
staining, 100x magnification).
Figure 1. Haematoxylin and eosin staining, 100x magnification.

Figure 2. Representative low power image from different different area of the tumor (Haematoxylin and eosin staining, 100x magnification).
Figure 2. Haematoxylin and eosin staining, 100x magnification.

Figure 3. Representative higher power view of the tumor (Haematoxylin and eosin staining, 200x magnification).
Figure 3. Haematoxylin and eosin staining, 200x magnification.

Figure 4. Representative high power view of the tumor (Haematoxylin and eosin staining, 400x 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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What is the most likely diagnosis of this patient?

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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.

 

References

  1. Adsay NV. Cystic neoplasia of the pancreas: pathology and biology. J Gastrointest Surg 2008; 12, 401-404.
  2. Hruban RH, Pitman MB, Klimstra DS, eds. Tumors of the Pancreas. Washington DC: American Registry of Pathology, 2007.
  3. Klimstra DS, Wenig BM, Heffess CS. Solid-pseudopapillary tumor of the pancreas: a typically cystic carcinoma of low malignant potential. Semin Diagn Pathol 2000; 17, 66-80.
  4. Lahat G, Ben Haim M, Nachmany I, Sever R, Blachar A, Nakache R, Klausner JM. Pancreatic incidentalomas: high rate of potentially malignant tumors. J Am Coll Surg 2009; 209, 313-319.
  5. Horisawa M, Niinomi N, Sato T, Yokoi S, Oda K, Ichikawa M, Hayakawa S. Frantz’s tumor (solid and cystic tumor of the pancreas) with liver metastasis: successful treatment and long-term follow-up. J Pediatr Surg 1995; 30, 724-726.
  6. Saiura A, Umekita N, Matsui Y, Maeshiro T, Miyamoto S, Kitamura M, Wakikawa A. Successful surgical resection of solid cystic tumor of the pancreas with multiple liver metastases and a tumor thrombus in the portal vein. Hepatogastroenterology 2000; 47, 887-889.
  7. Rebhandl W, Felberbauer FX, Puig S, Paya K, Hochschorner S, Barlan M, Horcher E. Solid-pseudopapillary tumor of the pancreas (Frantz tumor) in children: report of four cases and review of the literature. J Surg Oncol 2001; 76, 289-296.
  8. Seo HE, Lee MK, Lee YD, Jeon SW, Cho CM, Tak WY, Kweon YO, Kim SK, Choi YH, Bae HI, Kim SG, Yoon YK. Solid-pseudopapillary tumor of the pancreas. J Clin Gastroenterol 2006; 40, 919-922.
  9. Estrella JS, Li L, Rashid A, Wang H, Katz MH, Fleming JB, Abbruzzese JL, Wang H. Solid pseudopapillary neoplasm of the pancreas: clinicopathologic and survival analyses of 64 cases from a single institution. Am J Surg Pathol 2014; 38, 147-157.
  10. Tanaka Y, Kato K, Notohara K, Hojo H, Ijiri R, Miyake T, Nagahara N, Sasaki F, Kitagawa N, Nakatani Y, Kobayashi Y. Frequent beta-catenin mutation and cytoplasmic/nuclear accumulation in pancreatic solid-pseudopapillary neoplasm. Cancer Res 2001; 61, 8401-8404.
  11. Abraham SC, Klimstra DS, Wilentz RE, Yeo CJ, Conlon K, Brennan M, Cameron JL, Wu TT, Hruban RH. Solid-pseudopapillary tumors of the pancreas are genetically distinct from pancreatic ductal adenocarcinomas and almost always harbor beta-catenin mutations. The American journal of pathology 2002; 160, 1361-1369.
  12. Li L, Othman M, Rashid A, Wang H, Li Z, Katz MH, Lee JE, Pisters PW, Abbruzzese JL, Fleming JB, Wang H. Solid pseudopapillary neoplasm of the pancreas with prominent atypical multinucleated giant tumor cells. Histopathology 2013; 62, 465-471.
  13. Ersen A, Agalar AA, Ozer E, Agalar C, Unek T, Egeli T, Ozbilgin M, Astarcioglu I, Olguner M, Obuz F, Sagol O. Solid-Pseudopapillary neoplasm of the pancreas: A clinicopathological review of 20 cases including rare examples. Pathology, research and practice 2016; 212, 1052-1058.
  14. Policarpio-Nicolas MLC, McHugh KE, Sae-Ow W, Brainard JA. Pleomorphic and atypical multinucleated giant cells in solid pseudopapillary neoplasm of pancreas: A diagnostic pitfall in cytology and a review of the literature. Diagn Cytopathol 2019; 47, 488-493.
  15. Zee SY, Hochwald SN, Conlon KC, Brennan MF, Klimstra DS. Pleomorphic pancreatic endocrine neoplasms: a variant commonly confused with adenocarcinoma. Am J Surg Pathol 2005; 29, 1194-1200.
  16. Downes KA, Hart WR. Bizarre leiomyomas of the uterus: a comprehensive pathologic study of 24 cases with long-term follow-up. Am J Surg Pathol 1997; 21, 1261-1270.
  17. Falleti J, Vita G, De Cecio R, Schonauer F, Insabato L, Natella V, Mascolo M. Symplastic glomus tumor: report of a challenging lesion with literature review. Pathology, research and practice; 208, 372-375.
  18. Goh SG, Dayrit JF, Calonje E. Symplastic hemangioma: report of two cases. Journal of cutaneous pathology 2006; 33, 735-740.
  19. Berean K, Tron VA, Churg A, Clement PB. Mammary fibroadenoma with multinucleated stromal giant cells. Am J Surg Pathol 1986; 10, 823-827.
  20. Albores-Saavedra J, Simpson KW, Bilello SJ. The clear cell variant of solid pseudopapillary tumor of the pancreas: a previously unrecognized pancreatic neoplasm. Am J Surg Pathol 2006; 30, 1237-1242.
  21. Hav M, Lem D, Chhut SV, Kong R, Pauwels P, Cuvelier C, Piet P. Clear-cell variant of solid-pseudopapillary neoplasm of the pancreas: a case report and review of the literature. The Malaysian journal of pathology 2009; 31, 137-141.
  22. Tanino M, Kohsaka S, Kimura T, Tabu K, Nishihara H, Sawa H, Kawami H, Kamada H, Shimizu M, Tanaka S. A case of clear cell variant of solid-pseudopapillary tumor of the pancreas in an adult male patient. Annals of diagnostic pathology; 16, 134-140.
  23. Tang LH, Aydin H, Brennan MF, Klimstra DS. Clinically aggressive solid pseudopapillary tumors of the pancreas: a report of two cases with components of undifferentiated carcinoma and a comparative clinicopathologic analysis of 34 conventional cases. Am J Surg Pathol 2005; 29, 512-519.

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Case contributed by:

Huamin Wang, M.D., Ph.D.

Department of Anatomical Pathology

Department of Translation Molecular Pathology

MD Anderson UTHealth Graduate School of Biomedical Sciences

University of Texas M.D. Anderson Cancer Center

1515 Holcombe Blvd

Houston, TX 77030

Email: hmwang@mdanderson.org

Case 1: Quarter 1, 2019

Case 1: Quarter 1, 2019

History: A 69-year-old African American female had chronic epigastric and back pain post hiatal hernia repair.

Radiology: Abdominal computed tomography scan was performed and revealed a 2.5 cm, solid pancreatic tail mass with associated pancreatic duct dilation. Radiologically this was suspicious for either pancreatic ductal adenocarcinoma or a neuroendocrine tumor.

FNA: Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) was performed after which the patient elected to have a distal pancreatectomy and splenectomy. The following images (Figures 1 – 6) are from the EUS-FNA and subsequent pancreatectomy specimens.

Figure 1. Smear from fine needle aspiration of pancreatic mass (Papanicolaou stain, 400x magnification).
Figure 1. Smear from fine needle aspiration of pancreatic mass (Papanicolaou stain, 400x magnification).

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Figure 2. Bi-valved distal pancreatectomy specimen.
Figure 2. Bi-valved distal pancreatectomy specimen.

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Figure 3. Low power image of pancreatic mass (H&E stain, 100x magnification).
Figure 3. Low power image of pancreatic mass (H&E stain, 100x magnification).

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Figure 4. Intermediate power image of pancreatic mass (H&E stain, 200x magnification).
Figure 4. Intermediate power image of pancreatic mass (H&E stain, 200x magnification).

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Figure 5. High power image of pancreatic mass (H&E stain, 400x magnification).

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Figure 6. High power image of pancreatic mass (H&E (left) and Elastin stain (right), 400x magnification).
Figure 6. High power image of pancreatic mass (H&E (left) and Elastin stain (right), 400x magnification).

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Based on the microscopic findings which of the following conditions does this patient most likely have?

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Answer e. Sinus histiocytosis with massive lymphadenopathy

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Images

The smear (Figure 1) shows a large histiocyte with abundant granular cytoplasm, large eccentric nucleus with prominent nucleoli and emperipolesis of neutrophils, lymphocytes, and debris. On cell block these cells were positive for S100, CD68 and CD163 (not shown), and negative for CD1a, IgG4, AFB and GMS. The cytomorphology and immunoprofile were compatible with sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman Disease [RDD]). After diagnosis the patient refused steroid and radiation therapy and opted for distal pancreatectomy which confirmed the diagnosis. Gross examination revealed a 2.3 cm firm circumscribed and lobulated yellow mass (Figure 2). Histologic sections showed storiform pattern fibrosis and a lymphoplasmacytic infiltrate (Figure 3). In areas there were sheets of plump histiocytes with eccentric nuclei, prominent nucleoli and abundant pale pink granular cytoplasm containing intracytoplasmic red blood cells and chronic inflammatory cells (emperipolesis) (Figure 4 -5). The latter were strongly positive for S100 and CD163. Focal obliterative phlebitis was also noted within the mass (Figure 6) and 2 of 14 peri-pancreatic lymph nodes were also involved by RDD.

Discussion

Sinus histiocytosis with massive lymphadenopathy or Rosai-Dorfman disease (RDD) is a rare benign histiocytic disorder characterized by proliferating S100-positive histiocytes. It was first described by Rosai in 1972 and is diagnosed by identification of proliferation of distinctive histiocytes on histopathologic review.1 Although originally described in lymph nodes, it can also involve extra-nodal sites including skin, lung, breast and other organs. GI involvement however is rare and pancreatic involvement is even less common, with fewer than 10 reported cases in the literature.2-6  RDD in the pancreas may present as a distinct mass and on imaging may be mistaken for ductal adenocarcinoma. Its’ morphology however is distinctive and the identification of the hallmark atypical histiocytes with emperipolesis of inflammatory cells should prompt performance of the appropriate discerning immunostains (S100 and histiocyte markers). The atypical histiocytes are characterized by large nuclei with pale or vesicular chromatin and nucleolar prominence, features not otherwise seen in typical histiocytes. Most cases of pancreatic RDD described in the literature were diagnosed on resection and there is only one report of a case that was diagnosed on fine needle aspiration, a procedure with significantly lower morbidity and mortality than pancreatectomy which is not indicated for the treatment of RDD.6 The case presented herein was also diagnosed on fine needle aspiration. However, because of the patient’s wishes a distal pancreatectomy was performed.

Based on morphology and location the main differentials include other fibro-inflammatory conditions particularly IgG4 related disease (autoimmune pancreatitis [AIP]). Recent studies have demonstrated overlapping features between RDD and IgG4 related disease, which may complicate pathologic diagnosis and distinction.7-10 These features include dense IgG4-positive lymphoplasmacytic infiltrates, increased fibrosis, including storiform fibrosis, and/or the presence of obliterative phlebitis/vasculitis. Marked fibrosis is a known manifestation of extra-nodal RDD that sometimes results in such significant histiocyte distortion that it may obscure their presence as well as the entity-defining emperipolesis. Although this patient showed major criteria for type 1 AIP the IgG4 immunostain showed no increase in IgG4-positive plasma cells nor were there ductal granulocytic epithelial lesions characteristic of type 2 AIP. Her serum IgG4 level was also not elevated. Chronic pancreatitis particularly that secondary to alcohol is also characterized by a chronic fibro-inflammatory process that results in loss of acini and ductal cells. However it does not show the proliferating atypical histiocytes seen in RDD.

Other differentials include granulomatous pancreatitis secondary to infection or sarcoidosis. The proliferating sheets of plump histiocytes that are seen in RDD may mimic necrotizing/non-necrotizing infection-related granulomas. However negative stains for acid-fast bacilli and fungi and as well as histiocyte positivity for S100 should allow accurate distinction between these two differentials. Additionally, conventional histiocytes of granulomatous disease are much smaller than those of RDD and have small oval or bean-shaped nuclei with small nucleoli, and are not of the markedly atypical type seen in RDD. Granular cell tumor (GCT), a rare benign neoplasm of Schwann cells, may occasionally involve the pancreas.11 Cytomorphologically GCT may show strong resemblance to the proliferating histiocytes in RDD. Additionally, both are positive for S100, which further compounds distinction. The identification of emperipolesis and the positive staining of the granular cells with histiocyte markers should facilitate the diagnosis of RDD and distinction from GCT.

When evaluating a mass-forming lesion in the pancreas, even in the presence of major histologic criteria of IgG4-related disease (AIP) and IgG4 positive plasma cells, RDD should be considered in the differential diagnosis and excluded with the appropriate stains.

References

  1. Rosai J, Dorfman RF: Sinus histiocytosis with massive lymphadenopathy: A pseudolymphomatous benign disorder. Analysis of 34 cases. 1972;30:1174-1188.
  2. Esquivel J, Krishnan J, Jundi M, Sugarbaker PH. Rosai-Dorfman disease (sinus histiocytosis with massive lymphadenopathy) of the pancreas: first case report. Hepatogastroenterology. 1999;46:1202-1205.
  3. Lauwers GY, Perez-Atayde A, Dorfman RF, Rosai J. The digestive system manifestations of Rosai-Dorfman disease (sinus histiocytosis with massive lymphadenopathy): review of 11 cases. Hum Pathol. 2000;31:380-385.
  4. Zivin SP, Atieh M, Mosier M, Paner GP, Aranha GV. Rosai-Dorfman disease (sinus histiocytosis with massive lymphadenopathy) of the pancreas: second case report. J Gastrointest Surg. 2009;13:806-809.
  5. Romero Arenas MA, Singhi AD, Hruban RH, Cameron AM. Rosai-dorfman disease (sinus histiocytosis with massive lymphadenopathy) of the pancreas: third reported occurrence. J Gastrointest Cancer. 2012;43:626-629.
  6. Smith DJ, Sekhar A, Memis B, AdsayVN, Alese OB. Rosai-Dorfman Disease Menifesting as a Pancretaic Head Mass Diagnosed Nonoperatively. J Oncol Pract. 2017 Jan;13(1):61-62.
  7. Liu L, Perry AM, Cao W, et al. Relationship between Rosai-Dorfman disease and IgG4-related disease: study of 32 cases. Am J Clin Pathol. 2013;140:395-402.
  8. Zhang X, Hyjek E, Vardiman J. A subset of Rosai-Dorfman disease exhibits features of IgG4-related disease. Am J Clin Pathol. 2013;139:622-632.
  9. Kuo TT, Chen TC, Lee LY, Lu PH. IgG4-positive plasma cells in cutaneous Rosai-Dorfman disease: an additional immunohistochemical feature and possible relationship to IgG4-related sclerosing disease. J Cutan Pathol. 2009;36:1069-1073.
  10. Liu M, Li X, Li Y, et al. Rosai-Dorfman disease with features of IgG4-related disease in the breast: Cases report and literature review. Asian Pac J Allergy Immunol. 2018 Mar;36(1):51-57.
  11. Kanno A, Satoh K, Hirota M, Hamada S, Umino J, et al. Granular cell tumor of the pancreas: A case report and review of literature. World J Gastrointest Oncol. 2010 Feb 15; 2(2): 121–124.

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Case contributed by:

Michelle D Reid, MD, MS

Professor Department of Pathology

Emory University Hospital

1364 Clifton Rd NE Room G179B

Atlanta GA 30322

Pancreatobiliary Pathology Society is seeking volunteers for Case of the Quarter Subcommittee positions

Dear Pancreatobiliary Pathology Society (PBPS) members and other interested parties in the pancreatobiliary pathology community,

PBPS is seeking enthusiastic volunteers for Case of the Quarter Subcommittee positions.

Applicants need to be active members in (or they can join) the PBPS. The subcommittee will have 4 members. Term for all members is 2 years. Each member will generate a case report to be published on the website once a year.

If you are interested in, please send an email, along with your CV, to Dr. Olca Basturk (basturko@mskcc.org) by April 12, 2019. Applications will be reviewed by PBPS Executive Committee and chosen applicants will be informed via e-mail and will be posted in our website (http://www.pbpath.org/) no later than April 30, 2019.

Olca Basturk, M.D.

(on behalf of PBPS Executive committee)

 

Olca Basturk, M.D.

Associate Attending Pathologist

Memorial Sloan Kettering Cancer Center

Department of Pathology

1275 York Ave. New York, NY 10065

Phone: (212) 639-6078

Email: basturko@mskcc.org

Case 1: Quarter 4, 2018

Case 1: Quarter 4, 2018

CASE # 1: QUARTER 4, 2018

A 57-year-old male, with a history of bladder and prostate cancer, and pancreatitis, presents with dark urine and clay-colored floating stools. Labs were notable for white blood cell count 5900, lipase 449, alkaline phosphatase 731, total bilirubin 6.3, AST 381, and ALT 991. CA 19-9 was elevated at 184 and CEA was less than 1. Serum IgG4 level was within normal limit. MRI showed worsening left lateral intrahepatic biliary ductal dilatation with abrupt cutoff at a stellate focus of enhancement, raising concern for cholangiocarcinoma. He underwent endoscopic retrograde cholangio-pancreatography (ERCP), which showed localized stricture of the left main hepatic duct. A bile duct brushing revealed atypical ductal epithelial cells. The patient elected for a left lateral liver segmentectomy. The following sections resulted from the liver segmentectomy (Figures 1-4).

Case1 Figure1 4x
Figure 1. Section from area of biliary stricture. H&E, 4X

Case1 Figure2 10x
Figure 2. Closer view of the bile duct shown in Figure 1, demonstrating dense periductal lymphoplasmacytic inflammation. H&E, 10X

Case1 Figure3 40x
Figure 3. High magnification of the periductal inflammatory cells shown in Figure 1 & 2. H&E, 40X

Case1 Figure4 10x fibrosis
Figure 4. Periductal stromal changes. H&E, 10X

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Please Select Your Diagnosis in the Poll, Then See the Answer and the Discussion in the Links Below

What is the most likely diagnosis of this patient?

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Click Here To See The Answer

Answer: D. IgG4-related sclerosing cholangitis

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Click Here To See The Discussion

Discussion:

The histopathologic features of IgG4-related disease (IgG4-RD) were first described in 2001 by Hamano et al (1) for sclerosing pancreatitis (type I autoimmune pancreatitis). Later discoveries of similar diseases in other organs, including the biliary system, led to the recognition of IgG4-related disease as a systemic immune-mediated disease (2). The consensus criteria for histopathologic diagnosis of IgG4-RD requires two or more of the following characteristic features (3):

  1. a dense lymphoplasmacytic infiltrate,
  2. storiform fibrosis,
  3. obliterative phlebitis (Figure 5),
  4. increased IgG4+ plasma cells/HPF (Figure 6), and
  5. IgG4+/IgG+ plasma cell ratio of >40%.

However, definitive diagnosis of IgG4-RD requires correlation with clinical features. Therefore, it is recommended to classify cases into one of three categories (3):

  1. histologically highly suggestive of IgG4-RD,
  2. probable histologic features of IgG4-RD, and
  3. insufficient histopathologic evidence of IgG4-RD.

The first category (highly suggestive of IgG4-RD) requires the presence of either storiform fibrosis or obliterative phlebitis, together with an elevated absolute and relative IgG4+ plasma cell count.

The second category (probable histologic features of IgG4-RD) typically lacks some of the histopathologic features of IgG4-RD but shows an elevated IgG4+ plasma cell count. These cases require correlation with clinical and radiologic findings, including serum IgG4 levels, and investigation for other organ involvement. A caveat is that up to half of the patients with IgG4-RD have normal serum IgG44, as in this case.

The third category of ‘insufficient histopathologic evidence of IgG4-RD’ includes cases not meeting criteria for the above first two categories. However, this category does not exclude the possibility of IgG4-RD.

IgG4-related sclerosing cholangitis (IgG4-RSC) often presents with obstructive jaundice, elevated liver enzymes, and imaging findings of biliary stricture or mass (5-6). IgG4-RSC is often associated with autoimmune pancreatitis, as in this patient. Intrahepatic bile duct involvement is characterized by a portal mixed inflammatory infiltrate with lymphocytes, increased IgG4+ plasma cells (Figure 6 and 1-3), eosinophils, and a variable amount of fibrosis (Figure 4). Obliterative phlebitis is also present in this patient (Figure 5).

The exact pathophysiology of IgG4-RD is not clear. However, aberrant T- cell regulation was suggested to be the underlying mechanism. Follicular helper T cells and regulatory T cells are thought to play an essential role in IgG4-RD, specifically in the class switching of B cells (7). Interestingly, it is hypothesized that the increased IgG4+ plasma cells may be secondary to cytokine production rather than being pathogenic. A recent study identified Annexin A11 as a potential auto-antigen involved in the pathogenesis of autoimmune pancreatitis (8).

Treatment decisions are based on clinical presentation, organ involvement, and risk of recurrence, but treatment is not always necessary, especially in asymptomatic patients. However, treatment is recommended in patients with vital organ involvement, such as pancreatobiliary organs, kidneys, and the central nervous system. Most patients respond to steroid therapy regardless of organ involvement and clinical presentation. In relapsed IgG4-RD patients, other immunosuppressive medications have been used to maintain disease remission and decrease the side effects of steroids. Of note, this patient responded well to steroid and CellCept therapy and is currently in clinical remission.

Other answer choices:

  1. Inflammatory myofibroblastic tumor (IMT) also has an intense lymphoplasmacytic infiltration, sometimes storiform fibrosis and obliterative phlebitis. However, the stromal cells in IMT are often very prominent with cytologic atypia, which is not seen in this case. Most IMTs are positive for ALK1 and ROS1 expression, while IgG4-RSC is negative for both markers.
  2. Infectious cholangitis, including bacterial, mycobacterial, viral, and spirochetal, can also mimic IgG4-RSC. However, infectious cholangitis usually does not present with significantly increased IgG4+ plasma cells or other histologic features of IgG4-RSC, and serum IgG4 is often not elevated. Suggestive histologic features, such as granulomas seen in mycobacterial infection, IHC or special stains may be helpful to point to a specific infectious pathogen.
  3. Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease that involves small intrahepatic bile ducts and most commonly seen in middle aged women. Histologically, the characteristic features are portal granulomatous inflammation with bile duct damage and cholestatic reaction. Most patients have a positive anti-mitochondrial antibody. Portal tracts infiltrated by plasma cells are rare, and there is no significant increase in IgG4+ plasma cells.
  4. IgG4-related sclerosing cholangitis (Correct Answer)
  5. Primary sclerosing cholangitis (PSC) is another entity that can closely mimic IgG4-RSC both clinically and histologically. The distinction between the two can be very difficult at times. However, PSC has a strong association with ulcerative colitis. ERCP is the gold standard for diagnosis of sclerosing cholangitic diseases. The cholangiogram for PSC often shows beading, whereas IgG4-RSC often has long strictures involving hilar structures, including extrahepatic bile ducts and the lower common bile duct, which was seen in this case. Cholangiography for IgG4-RSC has specificity of 88% but sensitivity of 45% (9). Histologically, PSC often has patchy lymphocytic injury of bile ducts with concentric fibrosis around bile ducts- so called “onion-skin” like fibrosis. The bile duct caliber is often out of proportion to accompanying vasculature and there is degeneration of duct epithelium, also known as fibro-obliterative lesions. In contrast, expansile and circumscribed portal fibroinflammatory nodules favor IgG4-RSC, in addition to significantly increased IgG4+ plasma cells and elevated serum IgG4 level. In addition, more often than not, IgG4-RSC is associated with autoimmune pancreatitis and responds to steroid therapy.

Case1 Figure5 MOVAT obliterative phlebitis 20x
Figure 5. Obliterative phlebitis. MOVAT stain, 40X

Case1 Figure6 IgG4 10x
Figure 6. Many plasma cells are positive for IgG4. IHC, 10X

References:

  1. Hamano H, Kawa S, Horiuchi A, Unno H, Furuya N, Akamatsu T, et al. High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med 2001;344: 732–738.
  2. Kamisawa T, Egawa N, Nakajima H. Autoimmune pancreatitis is a systemic autoimmune disease. Am J Gastroenterol. 2003;98: 2811–2812.
  3. Deshpande V, Zen Y, Chan JK, Yi EE, Sato Y, Yoshino T, et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol. 2012;25: 1181–1192.
  4. Wallace ZS, Deshpande V, Mattoo H, Mahajan VS, Kulikova M, Pillai S, et al. IgG4-related disease: clinical and laboratory features in one hundred twenty-five patients. Arthritis Rheumatol. 2015;67: 2466–2475.
  5. Deshpande V, Sainani NI, Chung RT, Pratt DS, Mentha G, Rubbia-Brandt L, et al. IgG4-associated cholangitis: a comparative histological and immunophenotypic study with primary sclerosing cholangitis on liver biopsy material. Mod Pathol. 2009;22: 1287–1295
  6. Ghazale A, Chari ST, Zhang L, Smyrk TC, Takahashi N, Levy MJ, et al. Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy. Gastroenterology. 2008;134: 706–715.
  7. Akiyama M, Yasuoka H, Yamaoka K, Suzuki K, Kaneko Y, Kondo H, et al. Enhanced IgG4 production by follicular helper 2 T cells and the involvement of follicular helper 1 T cells in the pathogenesis of IgG4-related disease. Arthritis Res Ther. 2016;18: 167.
  8. Hubers LM, Vos H, Schuurman AR, Erken R, Oude Elferink RP, Burgering B, et al. Annexin A11 is targeted by IgG4 and IgG1 autoantibodies in IgG4- related disease. Gut. 2018;67: 728–735.
  9. Kalaitzakis E, Levy M, Kamisawa et al. Endoscopic retrograde cholangiography does not reliably distinguish IgG4-associated cholangitis from primary sclerosing cholangitis or cholangiocarcinoma. Clinical Gastroenterology and Hepatology. 2011;9: 800-803.

Case contributed by:

Jonathan Mowers, MD, PhD
Gastrointestinal and Hepatobiliary Pathology Fellow
Jiaqi Shi, MD, PhD
Assistant Professor of Pathology
Department of Pathology Clinical Labs
University of Michigan
2800 Plymouth Rd, Bldg 35
Ann Arbor, MI 48109