Clinical History

A 50-year-old woman with no significant past medical history presented with abdominal pain and a syncopal episode. Abdominal MRI showed a multicystic mass with a significant solid component in the pancreatic tail, measuring 2.2 cm in the greatest dimension. A fine-needle biopsy of the lesion was performed.

Histologic/Cytologic Features 

Microscopic pictures of the biopsy are shown in Figures 1-5. The histologic examination revealed a spindle cell lesion. The cells had relatively uniform and elongated nuclei, and some had vesicular chromatin with conspicuous nucleoli; others appeared wavy and hyperchromatic. No significant nuclear atypia or mitotic activity was present. Background normal pancreatic parenchyma was also identified.

Figure. 1-3. 1. H&E stain of the tumor, 4X; 2. H&E stain of the tumor, 10X; 3. H&E stain of the tumor, 10X
Figure. 4-5. 4. H&E stain of the tumor, 20X; 5. H&E stain of the tumor, 20X


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What is the diagnosis of the lesion?

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Answer: Mucinous cystic neoplasm

 


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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.

Figure. 6-7. 6. Immunohistochemical stain for estrogen receptor, 20X; 7. Immunohistochemical stain for progesterone receptor, 20X

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.

Figure. 8. Gross photograph of the cystic lesion at the tail of the pancreas

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.

9-11. 9. H&E stain of the tumor in resection specimen, 10X; 10. H&E stain of the tumor in resection specimen, 10X; 11. H&E stain of the tumor in resection specimen,

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.


 

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

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