Answer: Paraganglioma

Final diagnosis:  

Paraganglioma

Educational Objectives and Discussion:

Educational Objectives

1. Identify and describe a rare case of peripancreatic paraganglioma, a rare neoplastic disease that presents considerable diagnostic difficulty.
2. Review the clinicopathological characteristics of peripancreatic paragangliomas.
3. Discuss differential diagnosis of peripancreatic paragangliomas.

Discussion

Peripancreatic paragangliomas can be diagnostically challenging on small biopsies due to morphologic overlap with other primary pancreatic tumors (1, 2). In this case, an initial diagnosis of atypical epithelioid and spindle cell neoplasm was made on the biopsy and decision was made to proceed with surgery. Grossly, the resection specimen showed a 11.8 cm purple-red, ovoid, well-circumscribed peripancreatic mass surrounded by a thin fibrous capsule. Cut surface displayed a tan-pink to dark red, variegated focally nodular cut surface with multiple dilated vessels and focal areas of hemorrhage (Figure 4). Microscopic examination of the resection specimen showed neoplastic cells arranged in nests and trabeculae within a prominent vascular network (Figure 5-7). The cells were predominantly round to oval with some spindling and moderate to abundant eosinophilic granular cytoplasm. Additional IHC on the resection specimen showed that the tumor cells labeled with synaptophysin (strong), chromogranin (patchy) and S100 (patchy) and were negative for cytokeratin (Figures 8-10). In areas the S100 labeled in a sustentacular pattern (Figure 10). Succinate dehydrogenase (SDH) A and B were intact. A final diagnosis of paraganglioma was made. Subsequent blood work showed elevated plasma and urine catecholamines and molecular testing showed no targetable mutations. While the tumor was initially described radiographically as being located in the pancreatic head, subsequent imaging demonstrated a peri-pancreatic localization, much more typical of this entity. It can be critical to consider paraganglioma from both the radiographic and pathologic standpoint as repeated needle biopsies may trigger catecholamine surges and care must be taken during surgical interventions.

The classic microscopic features of paragangliomas are similar irrespective of location and include round-to-polygonal-shaped cells containing amphophilic-to-eosinophilic cytoplasm with stippled, often pleomorphic nuclei containing small inconspicuous nucleoli. In certain cases, cytoplasmic clear cell change, multinucleation, vesicular nuclei, and prominent nucleoli can also be observed (1). The tumor cells usually adopt a nested or organoid (“Zellballen”) pattern separated by highly vascularized fibrous septa. Cases with diffuse growth pattern with only focal areas of nested architecture have been reported (1). In areas of parenchymal invasion, the Zellballen growth pattern can be replaced by irregularly spaced nests of discohesive neoplastic cells. The tumor cells are synaptophysin and chromogranin positive while the surrounding sustentacular cells, label for S100. GATA3 and PHOX2B also show frequent immunoreactivity in extra-adrenal paragangliomas (3-5). Keratin is almost always negative, but rare cases have focal staining. In contrast, paragangliomas in the sacral region are typically keratin positive.

The genetic profile of paraganglioma is similar to that described for pheochromocytomas. Mutations in VHL, RET, NF1, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, and MAX have been reported (6). Knowledge of these mutations may have significant impact on clinical management and patient outcome. For instance, studies have reported germline mutations in SDHB in up to 30% of patients with metastatic disease arising from sporadic paragangliomas and an association with shorter survival (1, 7, 8). Complete surgical resection of primary and
metastatic disease, when possible provides the highest chance for symptom control. Currently, there are no reliable markers to predict malignancy, except the presence of metastases. Increasing tumor size (>5 cm), increasing Ki-67 proliferation rate, SDHB mutation, and MAX mutation have been reported as risk factors for metastatic behavior (9, 10). Various scoring systems (PASS, GAPP), have been developed to predict risk in pheochromocytomas and paragangliomas (11, 12). Patients with paragangliomas ultimately require follow-up as metastatic disease can appear years after diagnosis.

Differential diagnosis:

The differential diagnosis of peripancreatic paragangliomas includes pancreatic neuroendocrine tumor (PanNET), acinar cell carcinoma (ACC), spindle cell neoplasms, PEComas, and metastatic renal cell carcinoma (RCC).Peripancreatic paragangliomas and PanNET are both neuroendocrine neoplasms thus sharing many of the same characteristics. PanNETs often show distinctive plasmacytoid morphology, usually display round and uniform nuclei and are generally positive for AE1/AE3 and CAM 5.2 while peripancreatic paragangliomas are distinctly negative. Prominent nucleoli typically seen in ACC can be present in peripancreatic paragangliomas. However, the characteristic stippled chromatin of peripancreatic paraganglioma is absent in ACC. The presence of spindle cell morphology/nuclear pleomorphism in peripancreatic paragangliomas can mimic spindle cell neoplasms. These possibilities can usually be distinguished on the basis of immunohistochemistry. Further, the nuclear pleomorphism in paragangliomas typically has a degenerative appearance. Peripancreatic paragangliomas can show cytoplasmic clear cell change thus mimicking metastatic RCCs. However, metastatic RCCs will express PAX8 and are negative for S100 and neuroendocrine
markers.

References:

1. Singhi AD, Hruban RH, Fabre M, Imura J, Schulick R, Wolfgang C, Ali
   SZ. Peripancreatic paraganglioma: a potential diagnostic challenge in
   cytopathology and surgical pathology. Am J Surg Pathol. 2011
   Oct;35(10):1498-504. doi: 10.1097/PAS.0b013e3182281767.
   https://pubmed.ncbi.nlm.nih.gov/21921779/
2. Zeng J, Simsir A, Oweity T, Hajdu C, Cohen S, Shi Y. Peripancreatic paraganglioma mimics pancreatic/gastrointestinal neuroendocrine tumor on fine needle aspiration: Report of two cases and review of the literature. Diagn Cytopathol. 2017 Oct;45(10):947-952. doi: 10.1002/dc.23761. https://pubmed.ncbi.nlm.nih.gov/28560856/
3. Miettinen M, McCue PA, Sarlomo-Rikala M, Rys J, Czapiewski P, Wazny K, Langfort R, Waloszczyk P, Biernat W, Lasota J, Wang Z. GATA3: a multispecific but potentially useful marker in surgical pathology: a systematic analysis of 2500 epithelial and nonepithelial tumors. Am Surg Pathol. 2014 Jan;38(1):13-22. doi: 10.1097/PAS.0b013e3182a0218f. https://pubmed.ncbi.nlm.nih.gov/24145643/
4. Lee JP, Hung YP, O’Dorisio TM, Howe JR, Hornick JL, Bellizzi AM. Examination of PHOX2B in adult neuroendocrine neoplasms reveals relatively frequent expression in phaeochromocytomas and paragangliomas. Histopathology. 2017 Oct;71(4):503-510. doi: 10.1111/his.13243. https://pubmed.ncbi.nlm.nih.gov/28464318/
5. So JS, Epstein JI. GATA3 expression in paragangliomas: a pitfall potentially leading to misdiagnosis of urothelial carcinoma. Mod Pathol. 2013 Oct;26(10):1365-70. doi: 10.1038/modpathol.2013.76. https://pubmed.ncbi.nlm.nih.gov/23599157/
6. Gimenez-Roqueplo AP, Dahia PL, Robledo M. An update on the genetics of paraganglioma, pheochromocytoma, and associated hereditary syndromes. Horm Metab Res. 2012 May;44(5):328-33. doi: 10.1055/s-0031-1301302. https://pubmed.ncbi.nlm.nih.gov/22328163/
7. Brouwers FM, Eisenhofer G, Tao JJ, Kant JA, Adams KT, Linehan WM, Pacak K. High frequency of SDHB germline mutations in patients with malignant catecholamine-producing paragangliomas: implications for genetic testing. J Clin Endocrinol Metab. 2006 Nov;91(11):4505-9. doi: 10.1210/jc.2006-0423. https://pubmed.ncbi.nlm.nih.gov/16912137/
8. Amar L, Baudin E, Burnichon N, Peyrard S, Silvera S, Bertherat J, Bertagna X, Schlumberger M, Jeunemaitre X, Gimenez-Roqueplo AP, Plouin PF. Succinate dehydrogenase B gene mutations predict survival in patients with malignant pheochromocytomas or paragangliomas. J Clin Endocrinol Metab. 2007 Oct;92(10):3822-8. doi: 10.1210/jc.2007-0709. https://pubmed.ncbi.nlm.nih.gov/17652212/
9. Kimura N, Takayanagi R, Takizawa N, Itagaki E, Katabami T, Kakoi N, Rakugi H, Ikeda Y, Tanabe A, Nigawara T, Ito S, Kimura I, Naruse M; Phaeochromocytoma Study Group in Japan. Pathological grading for predicting metastasis in phaeochromocytoma and paraganglioma. Endocr Relat Cancer. 2014 May 6;21(3):405-14. doi: 10.1530/ERC-13-0494. https://pubmed.ncbi.nlm.nih.gov/24521857/
10. Assadipour Y, Sadowski SM, Alimchandani M, Quezado M, Steinberg SM, Nilubol N, Patel D, Prodanov T, Pacak K, Kebebew E. SDHB mutation status and tumor size but not tumor grade are important predictors of clinical outcome in pheochromocytoma and abdominal paraganglioma. Surgery. 2017 Jan;161(1):230-239. doi: 10.1016/j.surg.2016.05.050. https://pubmed.ncbi.nlm.nih.gov/27839933/
11. Kimura N, Takekoshi K, Naruse M. Risk Stratification on Pheochromocytoma and Paraganglioma from Laboratory and Clinical Medicine. J Clin Med. 2018. Sep; 7(9): 242. https://pubmed.ncbi.nlm.nih.gov/30150569/
12. Thompson LD. Pheochromocytoma of the Adrenal gland Scaled Score (PASS) to separate benign from malignant neoplasms: a clinicopathologic and immunophenotypic study of 100 cases. Am J Surg Pathol. 2002 May;26(5):551-66. doi: 10.1097/00000478-200205000-00002. https://pubmed.ncbi.nlm.nih.gov/11979086/

Case contributed by:

Oluwaseyi Olayinka, MD, MSc, Danbury Hospital

Ramapriya Vidhun, MD, Danbury Hospital

Conflict of Interest: NO

 

Answer: Intracholecystic papillary neoplasm

Final diagnosis:  

Intracholecystic papillary neoplasm

Educational Objectives and Discussion:

Educational Objectives

1. To understand the definition of intracholecystic papillary neoplasm
   (ICPN) of the gallbladder by 2019 WHO Digestive System Tumours.
2. To recognize the gallbladder lesions associated with metachromatic
   leukodystrophy (MLD), an unusual neurologic disease in pediatric patients.
3. To discuss the differential diagnosis of ICPN.

Discussion

Intracholecystic papillary neoplasm (ICPN) is a precancerous lesion of the gallbladder. Per the 2019 WHO Digestive System Tumours [1], ICPN encompasses/replaces the previous terminologies, including biliary
adenoma, tubulopapillary adenoma, intracystic papillary neoplasm, and papillomatosis. Grossly, these tumors form distinct polypoid/exophytic intraluminal masses that are grossly visible. Microscopically, these tumors show papillary and/or tubular configuration with varying degrees of epithelial dysplasia. There are four morphologic patterns recognized: biliary, intestinal, gastric, oncocytic, or combination of these. These morphologic patterns contrast with classifications of intraductal papillary mucinous neoplasms (IPMN) of the pancreas in which oncocytic lesions (intraductal oncocytic papillary neoplasms (IOPN)) have been separated from IPMN due to distinct molecular findings. Mucosa surrounding ICPN may demonstrate dysplasia as well. About 50% of ICPNs are associated with invasive adenocarcinoma, but they have a better clinical outcome than conventional gallbladder adenocarcinomas [1, 2].

Our case exhibited low-grade ICPN with combined biliary, gastric, and intestinal differentiation. Adjacent mucosa also showed diffuse low-grade dysplasia. No high-grade dysplasia or invasive carcinoma was identified in extensively submitted sections. The aforementioned unusual findings in the gallbladder from a 2-year-old baby triggered further work-up since there is a well-known association between ICPN (previously called gallbladder papillomatosis) and metachromatic leukodystrophy (MLD) [3-5]. Genetic analysis was performed and the results revealed homozygous deletion of pathogenic variant c.1283C>T (p.Pro428Leu) in ARSA gene, which is associated with MLD. Brain MRI findings were non-specific and she has no history of developmental delay, neurologic symptoms, or regression.

MLD is a lysosomal storage disease caused by a deficiency of arylsulfatase A (ASA) with autosomal recessive inheritance in most cases. The ASA deficiency leads to the accumulation of sulfatides in the central and peripheral nervous system, which results in the destruction of the myelin sheath and eventually leads to neurologic symptoms such as seizures, loss of motor functions, and peripheral neuropathy [6]. Sufatide accumulation is also detected in other organs, e.g., the gallbladder, kidney, lymph nodes, liver, and bone marrow. The gallbladder epithelial cells and macrophages contain cytoplasmic inclusions on electron microscopic examination, consistent with sulfatide accumulation [3, 7]. Almost all case reports described the presence of collections of the lamina propria macrophages in the gallbladder [3, 4, 7, 8], as seen in our case (Figure 4). This accumulation of macrophages could show histologic overlap with cholesterolosis, a more common finding in the gallbladder. In MLD, Giemsa and toluidine blue stains will show metachromasia of the cytoplasm of macrophages, consistent with the accumulation of sulfatide deposits. In contrast, the accumulation of cholesterol esters and triglycerides can be highlighted on frozen tissue with Oil red O or Sudan black stains.

According to the age of disease onset, there are three clinical subtypes of MLD, including late infantile-onset, juvenile-onset, and adult-onset. Our patient showed no neurologic symptoms but was homozygous for mutation of the ARSA gene, which encodes ASA. Numerous mutations in the ARSA gene have been identified, and c.1283C_T mutation in our case is usually seen in juvenile or adult-onset phenotype [6]. That may explain the neurologic symptom-free status of our patient. A possible treatment for MLD so far is hematopoietic stem cell transplantation for selected cases [4]. MLD-associated gallbladder abnormalities occasionally appear before the onset of neurologic symptoms or an MLD diagnosis [3]. One case series with 34 patients reported that 76% of MLD patients showed gallbladder involvement [4]. The gallbladder abnormalities consist of benign and malignant conditions, e.g., cholecystitis, cholelithiasis, mucosal hyperplasia, polypoid lesions (now most lesions are under the category of ICPN), and adenocarcinoma [3-5]. In conclusion, gallbladder abnormalities, in particular polypoid lesions, are rare during childhood. This condition can be seen in cases with MLD, Peutz-Jeghers’ syndrome, and pancreaticobiliary malunion [8]. Pathologists should pay close attention to unusual gallbladder abnormalities in pediatric and adolescent patients to consider the above-mentioned possibilities and associated risk of malignancy.

Differential diagnosis:

Pyloric gland adenoma is composed of lobules of small, tightly packed, bland-looking glands that are morphologically similar to pyloric or Brunner glands. The uninvolved gallbladder mucosa is mostly devoid of dysplasia or pyloric gland metaplasia. Of note, pyloric gland nodules <0.5 cm arising in a background of pyloric gland metaplasia should not be designated as pyloric gland adenoma [9].
Reactive epithelial hyperplasia, commonly due to secondary causes (e.g., cholelithiasis, chronic cholecystitis, inflammatory bowel disease, primary sclerosing cholangitis), shows focal or diffuse papillary-shaped and elongated mucosal folds lined by bland epithelial cells with or without metaplastic changes. The presence of significant inflammation and no discrete, grossly visible mass-forming lesion, may help distinguish reactive hyperplasia from ICPN [1,10].
Invasive adenocarcinoma is present in about 50% of the ICPN cases at the time of diagnosis [2]. Gallbladder adenocarcinoma arising in ICPN is more commonly associated with papillary growth patterns, biliary epithelial lineage, and high-grade dysplasia. The invasive component is often a tubular adenocarcinoma, although other types, such as mucinous, adenosquamous, or neuroendocrine carcinoma, have also been reported. Extensive sampling is warranted because approximately 60% of ICPN with carcinoma showed ≤ 5mm of invasive focus, and the carcinoma may also occur away from the main ICPN lesion. Some patients with non-invasive ICPN can also die of new primary carcinoma in the biliary tract, typically long after the diagnosis of ICPN, possibly due to the field cancerization phenomenon. This observation supports long-term surveillance of these patients with ICPN even after resection [1, 2].

References:

1. Basturk O, Aishima S, Esoposito I. World Health Organization Classification of Tumours. Intracholecystic papillary neoplasm. In: Digestive System Tumours. 2019, IARC, Lyon.
2. 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.
3. McFadden K, Ranganathan S. Pathology of the gallbladder in a child with metachromatic leukodystrophy. Pediatr Dev Pathol. 2015 May-Jun;18(3):228-30.
4. van Rappard DF, Bugiani M, Boelens JJ, van der Steeg AF, Daams F, de Meij TG, van Doorn MM, van Hasselt PM, Gouma DJ, Verbeke JI, Hollak CE, van Hecke W, Salomons GS, van der Knaap MS, Wolf NI. Gallbladder
   and the risk of polyps and carcinoma in metachromatic leukodystrophy. Neurology. 2016 Jul 5;87(1):103-11.
5. Kim J, Sun Z, Ezekian B, Schooler GR, Prasad VK, Kurtzberg J, Rice HE, Tracy ET. Gallbladder abnormalities in children with metachromatic leukodystrophy. J Surg Res. 2017 Feb;208:187-191.
6. Cesani M, Lorioli L, Grossi S, Amico G, Fumagalli F, Spiga I, Filocamo M, Biffi A. Mutation Update of ARSA and PSAP Genes Causing Metachromatic Leukodystrophy. Hum Mutat. 2016 Jan;37(1):16-27.
7. Rodriguez-Waitkus PM, Byrd R, Hicks J. Metachromatic leukodystrophy and its effects on the gallbladder: a case report. Ultrastruct Pathol. 2011 Dec;35(6):271-6.
8. Garavelli L, Rosato S, Mele A, Wischmeijer A, Rivieri F, Gelmini C, Sandonà F, Sassatelli R, Carlinfante G, Giovanardi F, Gemmi M, Della Giustina E, Amarri S, Banchini G, Bedogni G. Massive hemobilia and
   papillomatosis of the gallbladder in metachromatic leukodystrophy: a life-threatening condition. Neuropediatrics. 2009 Dec;40(6):284-6.
9.  Basturk O, Aishima S, Esoposito I. World Health Organization Classification of Tumours. Pyloric gland adenoma of the gallbladder. In: Digestive System Tumours. 2019, IARC, Lyon.
10. Umudum H, Gunbatili E, Sanal M, Ceyhan K. Primary diffuse papillary hyperplasia of the gallbladder. Pathology. 2006 Dec;38(6):591-2.

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Case contributed by:

Goo Lee, MD, PhD. University of Alabama at Birmingham

Rong Li, MD, PhD. Children’s of Alabama Benjamin Russell Hospital For Children

Conflict of Interest: NO

Answer: Mucinous cystic neoplasm

Final diagnosis:  

Mucinous cystic neoplasm

Educational Objectives and Discussion:

Educational Objectives

1. Discuss spindle cell lesions of the pancreas.
2. Review the clinicopathological characteristics of mucinous cystic neoplasms of the pancreas.
3. Identify an unusual presentation of mucinous cystic neoplasms with stromal overgrowth.

Discussion

Immunohistochemistry stains were performed, and the spindle cells were positive for estrogen and progesterone receptors (Figures 6-7) and focally positive for inhibin. The spindle cells were negative for CD117, DOG1, S100, pan-cytokeratin, and beta-catenin. The proliferation index assessed with Ki-67 was approximately 1%. Based on the lesion’s morphology and immunoprofile, the case was diagnosed as mucinous/non-mucinous cystic neoplasm with ovarian-type stroma.

After the diagnosis, distal pancreatectomy and splenectomy were performed. Grossly, there was a 2.2 x 1.6 x 1.6 cm partially cystic well-circumscribed mass in the pancreatic tail containing thick clear fluid (Figure 8). Serial sections showed a 60% cystic and a 40% solid component. The mass showed no communication with the pancreatic ductal system.

Microscopic pictures of the resection are shown in Figures 9 – 11. The histologic examination revealed multiple cysts lined by a single layer of cuboidal cells that lacked mucin and had abundant eosinophilic cytoplasm. A prominent densely packed spindle cell-rich stroma was identified. The spindle cells had elongated nuclei with fine chromatin and inconspicuous nucleoli. No malignant features were present.

Pancreatic mucinous/non-mucinous cystic neoplasm (MCN) is an epithelial tumor typically associated with ovarian-type stroma. The majority of these lesions are found in the body or tail of the pancreas, occur in women, and have a mean age at diagnosis of 48 years old (1). Clinically, patients with MCN present with abdominal discomfort or epigastric pain, while others may be asymptomatic, and the tumor is found incidentally (2).

The histogenesis of these lesions is still in debate. Some proposed hypotheses suggest that the mesenchymal component derives from ectopic ovarian stroma incorporated during embryogenesis in the pancreas or represents persistent fetal periductal mesenchyme under hormonal stimulation (1).

Grossly, MCN usually presents with large unilocular or multilocular cysts, filled with thick gelatinous material, and lacks communication between the cyst and the pancreatic ductal system (3). Microscopically, the cysts are lined by mucin-producing columnar cells with varying degrees of cytologic and architectural atypia. However, cuboidal cells with no mucin can also occur. Based on the level of atypia, MCNs are further categorized as MCN with low- or high-grade dysplasia. The stromal component, called “ovarian-type stroma,” forms bands of densely packed spindle cells amongst the cysts, and its presence is required for the diagnosis. Typically, the stroma represents a smaller constituent of the lesion, and in some cases, it is difficult to identify as it can become hypocellular and replaced by hyalinized tissue (3). The epithelial cells stain positive with CK7 and MUC5AC. The ovarian-type stroma expresses PR (60-90%), ER (30%), SMA, and desmin. Luteinized cells can stain for inhibin and calretinin (1).

Molecularly, most MCN epitheliums carry activating mutations in codon 12 of KRAS (50-66%), some can carry loss-of-function mutations in RNF43 (1).

The case reported here has a very unusual presentation, given the fact that the stroma represents the predominant component of the lesion. The subepithelial stroma in this lesion was cellular and composed of cytologically bland spindle cells mimicking ovarian-type stroma without any malignant features. To our knowledge, this rare presentation of MCN has only been reported twice in the literature (4-5).

Molecular studies have shown frequent mutations in ID3, ARID1A, APC, and CDKN2A tumor suppressor genes in ACC (5-7). TP53 mutation or deletion has been identified in 12-24% of ACC (5,6). About 23% of ACC harbor gene fusion involving BRAF and RAF1 with the most common fusions being SND1-BRAF and HERPUD1-BRAF (5). These tumors are more sensitive to MEK inhibitors. In addition, microsatellite instability has been found in 8-14% of ACC (8,9).

Differential diagnosis:

The specimen was composed predominantly of bland-looking stroma on the initial biopsy, lacking a prominent epithelial component. Hence the initial differential diagnosis of this case comprises MCNs with sarcomatous stroma, carcinosarcoma, and benign mesenchymal tumors.

MCNs with sarcomatous stroma are infrequent and have been reported more frequently in the tail of the pancreas (6). The sarcomatous component is hypercellular, contains mitotic figures, and shows atypia and pleomorphism, in contrast with the bland looking stroma of the typical MCN.

Carcinosarcoma of the pancreas is a neoplasm composed of malignant mixed epithelial and mesenchymal elements (7). The sarcomatous component is composed of highly cellular areas with pleomorphic spindle cells containing abundant cytoplasm, hyperchromatic nuclei, and prominent nucleoli. Occasional bizarre cells can be identified. The histogenesis of this tumor remains unclear.

Benign mesenchymal tumors of the pancreas are extremely rare; some examples include inflammatory myofibroblastic tumor, extra gastrointestinal stromal tumor (GIST), schwannoma, and solitary fibrous tumor (SFT). Very few cases of pancreatic SFT have been reported in the literature. In the present case, the stroma did not show prominent staghorn-like vascularization, or a short storiform arrangement of the spindle cells, characteristics of SFT (8). Inflammatory myofibroblastic tumors could also be excluded based on the absence of a significant chronic inflammatory cell component. Primary GIST of the pancreas has been reported, showing the typical morphologic characteristics of the uniform spindle or epithelioid cells arranged in short fascicles or whorls (9). Differential diagnosis between MCN stroma and these mesenchymal tumors is based on histology and immunohistochemistry findings. The immunoprofile of the ovarian-type stroma of MCNs, showing positivity for inhibin, calretinin, estrogen and progesterone receptors, is not shared by these benign mesenchymal lesions. GIST is positive for c-kit and DOG1, schwannoma for S100, and SFT for STAT6 and CD34.

Finally, in the resection specimen, intraductal papillary mucinous neoplasms (IPMNs) should be considered in the differential diagnosis. IPMNs are characterized by cystic dilatation of pancreatic ducts in which an intraductal proliferation of neoplastic mucin-producing cells is arranged in a papillary pattern. IPMNs do not contain the ovarian-type stroma that characterizes the MCN (10).

References:

1. Basturk O, Esposito I, Fukushima N et al. Pancreatic mucinous cystic neoplasm. In: Board WCoTE, ed. WHO Classification of Tumours: Digestive System Tumours. 5th ed. Lyon, France: IARC Press; 2019:319-321.
2. Fukushima N, Fukayama M. Mucinous cystic neoplasms of the pancreas: pathology and molecular genetics. J Hepatobiliary Pancreat Surg. 2007;14(3):238-42.
3. Jang KT, Park SM, Basturk O, Bagci P, Bandyopadhyay S, Stelow EB, Walters DM, Choi DW, Choi SH, Heo JS, Sarmiento JM, Reid MD, Adsay V. Clinicopathologic characteristics of 29 invasive carcinomas arising in 178 pancreatic mucinous cystic neoplasms with ovarian-type stroma: implications for management and prognosis. Am J Surg Pathol. 2015;39(2):179-87.
4. Handra-Luca A, Couvelard A, Sauvanet A, Fléjou JF, Degott C. Mucinous cystadenoma with mesenchymal over-growth: a new variant among pancreatic mucinous cystadenomas? Virchows Arch. 2004;445(2):203-
5. Lee WA. Mucinous cystadenoma of the pancreas with predominant stroma creating a solid tumor. World J Surg Oncol. 2005; 3:59.
6. Van den Berg W, Tascilar M, Offerhaus GJ, Albores-Saavedra J, Wenig BM, Hruban RH, Gabrielson E. Pancreatic mucinous cystic neoplasms with sarcomatous stroma: molecular evidence for monoclonal origin with subsequent divergence of the epithelial and sarcomatous components. Mod Pathol. 2000;13(1):86-91.
7. Farbod Darvishian, James Sullivan, Saul Teichberg, Kevin Basham; Carcinosarcoma of the Pancreas: A Case Report and Review of the Literature. Arch Pathol Lab Med. 2002; 126 (9):1114–1117.
8. Baxter AR, Newman E, Hajdu CH. Solitary fibrous tumor of the pancreas. J Surg Case Rep. 2015; (12): rjv144.
9. Trabelsi A, Yacoub-Abid LB, Mtimet A, et al. Gastrointestinal stromal tumor of the pancreas: A case report and review of the literature. N Am J Med Sci. 2009;1(6):324-326.
10. Basturk O, Esposito I, Fukushima N et al. Pancreatic intraductal papillary mucinous neoplasm. In: Board WCoTE, ed. WHO Classification of Tumours: Digestive System Tumours. Lyon, France: IARC Press; 2019:310-314.

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Case contributed by:

Julia A. Gallardo, M.D.

Sadhna Dhingra, M.D.

Department of Pathology and Immunology, Baylor College of Medicine

Conflict of Interest: NO

Answer: Acinar cell carcinoma

Final diagnosis:  

Acinar cell carcinoma

Educational Objectives and Discussion:

Educational Objectives

1.  Know the key histologic and immunohistochemical findings required for a diagnosis of acinar cell carcinoma.
2.  Recognize the most common gross findings and clinical presentation of acinar cell carcinoma.
3. Review the differential diagnosis and necessary workup to exclude histologically similar tumors.

Discussion

Acinar cell carcinoma (ACC) accounts for about 1-2 % of adult pancreatic neoplasms. The average age of adult patients is approximately 60 years. Some patients develop lipase hypersecretion and associated paraneoplastic syndrome. These tumors are generally well-circumscribed, at least partially encapsulated, solid, and large (average diameter 8-10 cm) with a homogenous pink to tan cut surface. They can arise in any part of the pancreas and are more common in the head region.

Microscopically, these tumors are typically denselycellular with minimal stroma. They may have different architectural patterns, solid and acinar patterns being the most prevalent. Less common patterns include a glandular and trabecular pattern. Individual tumor cells have striking eosinophilic cytoplasm, uniform nuclei, and a characteristic large central nucleolus. The mitotic rate is variable, ranging from 5 to 20 (mean 14) per 10 high power fields. Vascular invasion within the capsule of the neoplasm is common. The eosinophilic cytoplasm reflects the presence of cytoplasmic zymogen granules. However, in some cases, the cytoplasmic granularity is not well developed, and special stains are required to document their presence.

A cystic variant of ACC has been described as typically large, circumscribed tumors with cysts lined by single or multiple layers of neoplastic acinar cells. In these cystic lesions, there are areas of solid nests of acinar cells, areas of necrosis, and mitotic figures, which support a malignant process.

The finding of granular Periodic Acid-Schiff (PAS)/diastase positivity in the apical cytoplasm may be enough to confirm a diagnosis of acinar cell carcinoma (Figure 7). The butyrate esterase stain detects the presence of enzymatically active lipase in the neoplastic cells and is highly specific for acinar differentiation. Trypsin (Figure 8), chymotrypsin, and BCL10 (clone 331.1) (Figure 9) antibodies are the most sensitive, and simultaneous use of any two of them allows the detection of nearly 100% of acinar cell carcinomas. Of these, BCL10 is the most sensitive and specific. They have a favorable prognosis compared to the more common pancreatic ductal adenocarcinoma. (1-4)

Molecular studies have shown frequent mutations in ID3, ARID1A, APC, and CDKN2A tumor suppressor genes in ACC (5-7). TP53 mutation or deletion has been identified in 12-24% of ACC (5,6). About 23% of ACC harbor gene fusion involving BRAF and RAF1 with the most common fusions being SND1-BRAF and HERPUD1-BRAF (5). These tumors are more sensitive to MEK inhibitors. In addition, microsatellite instability has been found in 8-14% of ACC (8,9).

Differential diagnosis:

Well-differentiated pancreatic neuroendocrine tumor, previously called islet cell tumors/islet cell carcinomas, are the pancreatic counterparts of APUDomas (Amine Precursor Uptake and Decarboxylation tumors) or carcinoids. They can be functional or non-functional (more common), are composed of monotonous cells with typical coarse nuclear chromatin, and express general markers of neuroendocrine differentiation (diffuse/intense synaptophysin and usually also chromogranin staining). They are the most important differential diagnosis of acinar cell carcinoma. Similarities between the two include a solid, acinar, or glandular architecture, relatively minimal stroma, and nuclear uniformity. Features favoring the diagnosis of well-differentiated pancreatic neuroendocrine tumor include hyalinized or amyloid-like stroma between nests of neoplastic cells (indicative of insulinoma), trabecular or gyriform growth patterns (particularly when arranged in single cell-thick cords), central nuclear localization, a coarsely clumped “salt and pepper” chromatin pattern, paler cytoplasm with less granularity and diffuse rather than focal positivity for synaptophysin and chromogranin. (1,10)

Mixed acinar-neuroendocrine carcinomas are malignant epithelial neoplasms with both acinar and neuroendocrine differentiation. They are defined as having > 30% of each line of differentiation by immunohistochemistry. They are best regarded as a subtype of acinar cell carcinoma because they share its clinical behavior and genomic features. (1,10)

Mixed acinar-ductal carcinomas are malignant epithelial neoplasms with both acinar and ductal differentiation. They are defined as having > 30% of each line by immunohistochemistry. These tumors may present with extensive extracellular colloid-like pools of mucin or nests of columnar or signet ring cells with cytoplasmic mucin or individual gland pattern of infiltration with an associated desmoplastic stromal response. Ductal differentiation is based on immunohistochemical reactivity for glycoproteins such as CEA (using monoclonal antibodies), CA19-9, or B72.3. Treatment is like that of ACC. (1,11)

Pancreatoblastomas are malignant epithelial neoplasms of the pancreas, principally affecting children in the first decade of life. However, it can rarely occur in adults. These are very cellular tumors and typically have more prominent lobules separated by cellular stromal bands. They are predominantly composed of solid sheets and acini of uniform cells with characteristic squamoid nests or corpuscles. Lesser amounts of a neuroendocrine component, ductal component, and/or primitive round blue cell component may be seen. Though acinar differentiation is the most common and predominant pattern in most cases, careful microscopic examination and additional sampling may help reveal ductal and/or neuroendocrine components as well as squamoid nests and cellular stromal bands. The age of the patient helps suggest the right diagnosis as pancreatoblastoma. (1)

Solid pseudopapillary neoplasm (SPN) are low grade malignant pancreatic tumors composed of poorly cohesive epithelial cells forming solid and pseudopapillary structures that lack a specific line of pancreatic epithelial differentiation. SPN displaying a predominantly solid growth pattern without foamy cells or eosinophilic globules could be confused with ACC. However, SPN never exhibits true lumen formation, so the presence of an acinar or glandular pattern would
exclude this entity. In contrast to ACC, SPN does not label with specific acinar markers (trypsin and chymotrypsin) and consistently shows diffuse nuclear β-catenin staining. (1,12)

References:

1. International Agency for Research on Cancer. (2019). WHO Classification of Tumours of the Digestive System. Lyon: International Agency for Research on Cancer.
2. Klimstra DS, Heffess CS, Oertel JE, Rosai J. Acinar Cell Carcinoma of the Pancreas. Am J Surg Pathol. 1992;16(9):815-837.
3. Wood LD, Klimstra DS. Pathology and Genetics of Pancreatic Neoplasms with Acinar Differentiation. Semin Diagn Pathol. 2014;31(6):491-497.
4. Matos JM, Schmidt CM, Turrini O, Agaram NP, Niedergethmann M, Saeger HD, Merchant N, Johnson CS, Lillemoe KD, Grützmann R. Pancreatic Acinar Cell Carcinoma: A Multi-institutional Study. J Gastrointest Surg. 2009;13(8):1495-502.
5. Chmielecki J, Hutchinson KE, Frampton GM, Chalmers ZR, Johnson A, Shi C, Elvin J, Ali SM, Ross JS, Basturk O, Balasubramanian S, Lipson D, Yelensky R, Pao W, Miller VA, Klimstra DS, Stephens PJ. Comprehensive genomic profiling of pancreatic acinar cell carcinomas identifies recurrent RAF fusions and frequent inactivation of DNA repair genes. Cancer Discov. 2014;4(12):1398-405.
6. Jiao Y, Yonescu R, Offerhaus GJ, Klimstra DS, Maitra A, Eshleman JR, Herman JG, Poh W, Pelosof L, Wolfgang CL, Vogelstein B, Kinzler KW, Hruban RH, Papadopoulos N, Wood LD. Whole-exome sequencing of pancreatic neoplasms with acinar differentiation. J Pathol. 2014;232(4):428-35.
7. Jäkel C, Bergmann F, Toth R, Assenov Y, van der Duin D, Strobel O, Hank T, Klöppel G, Dorrell C, Grompe M, Moss J, Dor Y, Schirmacher P, Plass C, Popanda O, Schmezer P. Genome-wide genetic and epigenetic analyses of pancreatic acinar cell carcinomas reveal aberrations in genome stability. Nat Commun. 2017;8(1):1323.
8. Liu W, Shia J, Gönen M, Lowery MA, O’Reilly EM, Klimstra DS. DNA mismatch repair abnormalities in acinar cell carcinoma of the pancreas: frequency and clinical significance. Pancreas. 2014;43(8):1264-70.
9. La Rosa S, Sessa F, Capella C. Acinar Cell Carcinoma of the Pancreas: Overview of Clinicopathologic Features and Insights into the Molecular Pathology. Front Med (Lausanne). 2015;2:41.
10. Ulich T, Cheng L, Lewin KJ. Acinar-endocrine cell tumor of the pancreas. Report of a pancreatic tumor containing both zymogen and neuroendocrine granules. Cancer. 1982;50(10):2099-105.
11. Stelow EB, Shaco-Levy R, Bao F, Garcia J, Klimstra DS. Pancreatic Acinar Cell Carcinomas with Prominent Ductal Differentiation: Mixed Acinar Ductal Carcinoma and Mixed Acinar Endocrine Ductal Carcinoma. Am J Surg Pathol. 2010;34(4):510-8.
12. Notohara, Kenji, Hamazaki, Shuji, Tsukayama, Choutatsu, et al. Solid-Pseudopapillary Tumor of the Pancreas: Immunohistochemical Localization of Neuroendocrine Markers and CD10. Am J Surg Pathol. 2000;24(10):1361-1371.

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Case contributed by:

Pragya Jain, MD

Saryn Doucette, MD

Department of Pathology and Laboratory Medicine
Medical College of Wisconsin

Conflict of Interest: NO