Answer: Undifferentiated carcinoma, anaplastic type

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 (5^th 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

Answer: Medullary carcinoma

Microscopic appearance:

Histopathological examination revealed a cellular neoplasm composed of relatively monomorphic cells with high N:C ratio and vesicular nuclei. The neoplasm had a syncytial growth pattern without obvious gland formation (Figure 1), scant stroma and overall pushing border (Figure 2) with focal microscopic infiltrative interface with the adjacent tissues (Figure 3). There was also a diffuse lymphocytic infiltration within the tumor (tumor-infiltrating lymphocytes, TILs). No confluent necrosis was identified. Lymphovascular invasion (involving both lymphatic spaces and large vessels) and lymph node metastases (in two lymph nodes, with extranodal extension) were present. No in-situ lesions, such as pancreatic intraepithelial neoplasia (PanIN) or adenomatous change in the duodenal or ampullary mucosa were identified.  

Immunohistochemistry:

Performed immunohistochemical stains reveal that the tumor cells are positive for CK7 (Figure 4), MUC1/ EMA (Figure 5), and CK8/18, while negative for CK20, CDX2, MUC2, MUC5AC, Chromogranin, and Synaptophysin. CD3 highlighted intra- and peri-tumoral T lymphocytes, CD20 highlighted some peri-tumoral B lymphocytes, no intratumoral B lymphocytes were identified. Althoug expression of MLH1 and PMS2 proteins was retained, expression of MSH2 (Figure 6) and MSH6 proteins was absent in the cells. EBV-encoded RNA (EBER) in-situ hybridization was also negative in the tumor cells.

Molecular analysis:

Multiplex PCR for MSI, using HNPCC KIT 1-FL with 5 MSI markers (BAT-25, BAT-26, NR-21, NR-22, NR-24) reveled alterations in all 5 molecular markers, indicating microsatellite instable phenotype (MSI-H).

Final histological diagnosis: Medullary carcinoma of the pancreas.

Discussion:

Medullary carcinoma of the pancreas is a rare subtype of pancreatic neoplasms, pathogenetically and behaviorally distinct from pancreatic ductal adenocarcinoma (PDAC)¹. Recognition of this subtype is important, not only for prognostic, but also for therapeutic purposes. Syncytial growth pattern composed of pleomorphic cells with no gland formation, pushing borders and the presence of intra- and peri-tumoral lymphocytes are helpful histological findings.

Medullary carcinoma of the pancreas has been recognized as a distinct but rare entity for only about two decades (first reported in 1998 by Goggins M et al²). Unlike conventional PDAC, the incidence of KRAS mutations is very low in this tumor type. Medullary carcinoma of the pancreas has a better prognosis than conventional PDAC³. Like other medullary carcinomas involving the tubular gastrointestinal tract, a significant proportion of medullary carcinomas of the pancreas reveal high microsatellite instability (MSI)⁴. A subset of these patients has been shown to carry germline mutations of mismatch repair genes (Lynch syndrome). Isolated cases with synchronous/metachronous colonic adenocarcinoma linked to Lynch syndrome have been reported⁵. In cases that are not linked to Lynch syndrome, there is an increased association with family history of other cancers. A case of medullary carcinoma of the pancreas was reported to be associated with EBV⁵.

With the current advances in oncology, promising treatment modalities have emerged, such as using immune checkpoint inhibitors in solid tumors with MSI-high phenotype, including pancreatic cancers⁶. Although MSI-high phenotype is very rare in conventional PDACs, overall accounting for <1% of all cases⁷; given its important therapeutic implications, MSI should at least be routinely investigated in the pancreatic cancer types in which an increased frequency of MSI-high phenotypes are encountered, such as medullary carcinoma or colloid carcinoma, and results should be integrated into the final pathology report.

Medullary carcinomas should be distinguished from

– Poorly differentiated pancreatic ductal adenocarcinomas, which almost always have some degree of gland formation, usually reveal an abundant desmoplastic stroma, an infiltrative growth pattern, and at least a focal intracytoplasmic mucin production.

– Poorly differentiated neuroendocrine carcinomas, which are composed of tumor cells arranged in nests and sheets, usually show an infiltrative growth pattern and abundant intratumoral necrosis. Granular chromatin and nuclear molding would also suggest neuroendocrine differentiation, and staining for neuroendocrine markers (chromogranin and synaptophysin) would confirm the diagnosis. There are also usually no intratumoral lymphocytes, unlike medullary carcinomas.

– High-grade lymphoma, such as diffuse large B-cell lymphoma, would also usually have a syncytial growth pattern, but intratumoral infiltration with mature lymphocytes are not a feature. Specific immunohistochemical stains to ascertain the cell lineage is necessary for the correct diagnosis.

– Metastatic melanoma is a consideration on H&E evaluation. Relevant history and immunohistochemical markers are necessary to exclude this diagnosis.

References:

1. WHO Classification of Tumours Editorial Board. Digestive system tumours. Lyon (France): International Agency for Research on Cancer; 2019.
2. Goggins M, Offerhaus GJ, Hilgers W, Griffin CA, Shekher M, Tang D, Sohn TA, Yeo CJ, Kern SE, Hruban RH. Pancreatic adenocarcinomas with DNA replication errors (RER+) are associated with wild-type K-ras and characteristic histopathology. Poor differentiation, a syncytial growth pattern, and pushing borders suggest RER+. Am J Pathol. 1998 Jun;152(6):1501-7. Am J Pathol. 1998 Jun;152(6):1501-7.
3. Mostafa ME, Erbarut-Seven I, Pehlivanoglu B, Adsay V. Pathologic classification of “pancreatic cancers”: current concepts and challenges. Chin Clin Oncol. 2017 Dec;6(6):59.
4. Yamamoto H, Itoh F, Nakamura H, et al. Genetic and clinical features of human pancreatic ductal adenocarcinomas with widespread microsatellite instability. Cancer Res 2001;61:3139-44.
5. Wilentz RE, Goggins M, Redston M, Marcus VA, Adsay NV, Sohn TA, Kadkol SS, Yeo CJ, Choti M, Zahurak M, Johnson K, Tascilar M, Offerhaus GJ, Hruban RH, Kern SE. Genetic, immunohistochemical, and clinical features of medullary carcinoma of the pancreas: A newly described and characterized entity. Am J Pathol. 2000 May;156(5):1641-51.
6. Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, Lu S, Kemberling H, Wilt C, Luber BS, Wong F, Azad NS, Rucki AA, Laheru D, Donehower R, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Greten TF, Duffy AG, Ciombor KK, Eyring AD, Lam BH, Joe A, Kang SP, Holdhoff M, Danilova L, Cope L, Meyer C, Zhou S, Goldberg RM, Armstrong DK, Bever KM, Fader AN, Taube J, Housseau F, Spetzler D, Xiao N, Pardoll DM, Papadopoulos N, Kinzler KW, Eshleman JR, Vogelstein B, Anders RA, Diaz LA Jr. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017 Jul 28;357(6349):409-413.
7. Luchini C, Bibeau F, Ligtenberg MJL, Singh N, Nottegar A, Bosse T, Miller R, Riaz N, Douillard JY, Andre F, Scarpa A. ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: a systematic review-based approach. Ann Oncol. 2019 May 6 [Epub ahead of print].

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Case contributed by:

Claudio Luchini, MD, PhD

Associate Professor of Pathology

Department of Diagnostics and Public Health

Section of Pathology

University and Hospital Trust of Verona

37134 Verona, Italy

Email: claudio.luchini@univr.it

Deyali Chatterjee, MD

Assistant Professor

Department of Pathology and Immunology

Washington University School of Medicine

425 S Euclid Ave

St. Louis, MO 63110

Email: deyali@wustl.edu

Answer

Answer: Chronic cholecystitis with reactive proliferation of Luscka ducts.

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] .

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].

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

Answer

Solid papillary neoplasm with atypical multinucleated giant tumor cells

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.
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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