Case 3: Quarter 4, 2022

Case 3: Quarter 4, 2022

Clinical History

A 41 y/o male initially presented with nausea, vomiting, epigastric pain and severe diarrhea. Imaging (CT scan and MRI) revealed a 3.9 cm hypervascular mass centered on the pancreatic uncinate process with no evidence of metastatic disease. The imaging findings were concerning for lymphoma or a neuroendocrine tumor. Laboratory studies including amylase, lipase, and CA 19-9 were within normal limits. Endoscopy with fine needle biopsy of the lesion was performed.

Histologic/Cytologic Features 

The biopsy showed infiltrating neoplastic cells characterized by cytologically bland nuclei and abundant finely vacuolated, clear cytoplasm embedded in a collagenized/fibrotic stroma [Figure 1A/B]. No necrosis or mitotic figures were identified. The remainder of the biopsy material showed unremarkable pancreatic parenchyma and reactive lymphoid tissue.

Figure 1. Representative images of the mass , H&E stain.

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What is the most likely diagnosis based on the information provided?

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Answer: Well-differentiated pancreatic neuroendocrine tumor (Pan-NET), lipid rich variant.


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Final diagnosis:  

Well-differentiated pancreatic neuroendocrine tumor (Pan-NET), lipid rich variant.

Educational Objectives and Discussion

Educational Objectives

  1. Identify and describe the histologic features of lipid rich variant of PanNET
  2. Review the clinical implications of a diagnosis of lipid rich variant of PanNET
  3. Discuss the differential diagnosis for lipid rich variant of PanNET

Immunohistochemical stains were performed on the biopsy material. The neoplastic cells were positive for pan-CK (strong and diffuse), synaptophysin (strong and diffuse) [Figure 2], chromogranin (strong but focal) and inhibin (strong and diffuse) while negative for CK7, RCC, PAX-8, S-100, Melan-A (MART-1), and beta catenin. A MIB-1 (Ki-67) stain showed a low proliferation index (<3%). A diagnosis of well-differentiated pancreatic neuroendocrine tumor, Grade 1, lipid rich variant was rendered.

Figure 2. The neoplastic cells: Positive for synaptophysin

The patient subsequently underwent surgical resection (pancreaticoduodenectomy). Sectioning of the pancreas revealed a tan-white to tan-yellow, stellate, firm, fibrous mass measuring 4.0 cm in greatest dimension. The microscopic and immunophenotypic features of the tumor in the resection specimen mirrored those of the biopsy material. Sections showed neoplastic cells arranged in nests/clusters and cords, surrounded by marked collagenized/fibrotic stroma [Figure 3]. The tumor cells demonstrated clear/foamy vacuolated cytoplasm and small uniform nuclei with finely dispersed chromatin [Figure 4]. Mitotic figures were virtually absent. The MIB-1 (Ki-67) stain was repeated on the resection specimen and showed a proliferation index of 5-7% in hot spots. A final diagnosis of well-differentiated pancreatic neuroendocrine tumor, Grade 2, lipid rich variant was rendered

Figure 3. Neoplastic cells arranged in nests/clusters and cords, surrounded by marked collagenized/fibrotic stroma
Figure 4. The tumor cells demonstrated clear/foamy vacuolated cytoplasm and small uniform nuclei with finely dispersed chromatin

PanNET with vacuolated, lipid rich cytoplasm was first described in 1997 by Ordonez and Silva [1]. Singh et al and Xue et al’s series on PaNET variant cases both offered additional valuable contributions to the literature [2,3]. The lipid rich variant affects both men and women and can occur in the head or tail of the pancreas, ranging in size from 2-11 cm. Microscopically, this variant represents a diagnostic challenge (see differential diagnosis section). The prototypical neuroendocrine growth pattern may be absent. The cytologic features are deceptively bland; tumor cells are characterized by round to pyknotic nuclei with fine chromatin and inconspicuous nucleoli. The classic stippled “salt and pepper” chromatin may not be evident. Nuclear “endocrine” atypia is also not identified. The cytoplasm is not only clear but also finely vacuolated; lipid droplets and neuroendocrine secretory granules can be identified ultrastructurally with electron microscopy. Mitotic activity is absent to low and MIB-1 (Ki-67) staining usually does not exceed 5% based on published data [2,3]. Given how unusual these histologic features are compared to a typical low grade neuroendocrine tumor, immunohistochemical stains are an essential adjunct aid. The neoplastic cells routinely express pan-cytokeratin and neuroendocrine markers chromogranin and synaptophysin (focal to diffuse staining). Inhibin and HIF-1α staining can be seen in a subset of tumors, while Melan-A (MART-1) and MUC6 expression is absent [2].
Xue et al. include the lipid rich variant in the “aggressive variant group” alongside hepatoid, oncocytic, plasmacytoid, and discohesive variants due to propensity for greater tumor size, T-stage, metastases, and progression rates [3]. Furthermore, patients with lipid rich PanNET fall into one of two categories: younger patients with familial/functional/syndromic tumors (rare) and older patients with non-functioning/sporadic tumors (common). While inhibin, HIF-1α, and Melan-A (MART-1) expression by immunohistochemistry in clear cell PanNET has a strong association with von Hippel Lindau (VHL) disease, this correlation is less robust in lipid rich PaNET [2,4]. Regardless, it may still be prudent for clinicians to exclude VHL disease or MEN1 (multiple endocrine neoplasia type 1) syndrome as lipid rich PaNETs have rarely been reported in these patients [2].

Differential diagnosis:

The pathologist should keep a broad differential diagnosis in mind when approaching a low-grade pancreatic lesion with clear/vacuolated cytoplasm:
Clear cell PanNET:
PanNET with clear cell change are not uncommon and have a strong association with VHL disease, particularly when HIF-1α, inhibin, and/or Melan-A (MART-1) expression by immunohistochemistry is seen in addition to traditional neuroendocrine markers. VHL-associated clear cell PanNETs usually occur in younger women and are non-functioning tumors [4-7]. While the cytoplasm is clear, it lacks the vacuolated/microvesicular appearance of lipid rich PanNET.
Solid pseudopapillary neoplasm (SPN):
SPNs are uniquely characterized by pseudopapilla, nuclear grooves, and hyaline globules. SPNs can exhibit clear cytoplasm and frequently contain foamy macrophages, and therefore could appear similar to lipid rich PanNET in small biopsy specimens. While SPNs can express synaptophysin, chromogranin is usually negative. More importantly, nuclear staining of the neoplastic cells with beta catenin is a key diagnostic clue for the diagnosis of SPN, reflecting underlying mutations in CTNNB1 [8]. Additionally, these tumors most commonly occur in adolescent girls/young women under the age of 35 and arise most frequently in the body or tail of the pancreas.
Perivascular epithelioid cell tumor (PEComa or so called “sugar tumor”):
PEComas are rare mesenchymal neoplasms with myomelanocytic differentiation. The tumors grow in sheets or nests and are characterized by epithelioid cells with clear to eosinophilic, granular cytoplasm, which has a moth-eaten appearance (“spider cells”) with a spindle cell component present in a minority of cases. Co-expression of smooth muscle markers (SMA, desmin, h-caldesmon) and melanoma markers (e.g. Melan-A/MART-1, HMB45) is characteristic. Neuroendocrine labeling and strong and diffuse keratin expression is notably absent [8].
Morphologic patterns of pancreatic ductal adenocarcinoma:
While pancreatic ductal carcinoma typically shows significant cytologic atypia and has a uniquely infiltrating gland-forming growth pattern accompanied by a desmoplastic stromal response, certain morphologic patterns can appear deceptively bland and lack gland formation. The foamy gland and clear cell patterns of invasive ductal adenocarcinoma of the pancreas both are included in this category. Helpful distinguishing characteristics from lipid rich PanNET include gland formation, possible presence of mucin and the lack of neuroendocrine marker expression. Additionally, PanNETs most often present as well-circumscribed lesion on imaging/EUS/gross examination, as opposed to the poorly-defined, infiltrative growth pattern seen with ductal adenocarcinomas [8].
Adrenal cortical tissue/neoplasm:
Adrenal cortical tissue/neoplasms share many overlapping histopathologic features with lipid rich PanNET and immunohistochemistry can be a helpful aid. Adrenal cortical lesions mark with antibodies to SF-1, calretinin, inhibin, Melan-A (MART-1), and CD68 [9]. Adrenal cortical lesions however lack keratin and neuroendocrine marker positivity. Please note, that inhibin expression (as in our case) can be seen in a subset of lipid rich PanNET; therefore, a broad panel of stains is essential.
Clear cell renal cell carcinoma (ccRCC):
ccRCC should always be considered when encountering pancreatic lesions with “clear” cytoplasm. Renal cell carcinoma is in fact the most common reason for a metastasis to the pancreas. While PAX-8 is a helpful ancillary screening marker used for renal cell carcinoma, it is important to note that PanNET can also express PAX-8 [10]. Therefore, additional antibodies such as RCC and CD10 (for renal cell carcinoma) and synaptophysin and chromogranin (for PaNET) should be included as part of the larger panel of stains.


[1] Ordonez NG, Silva EG. “Islet cell tumor with vacuolated, lipid rich cytoplasm: a new histologic variant of islet cell tumor.” Histopathology 1997; 31:157-160.
[2] Singh R, Reid MD et al. “Lipid-rich variant of pancreatic endocrine neoplasms.” Am J Surg Pathol 2006; 30:194-200.
[3] Xue Y. et al “Morphologic variants of pancreatic neuroendocrine tumors: clinicopathologic analysis and prognodtic stratification.” Endocr Pathol 2020 31:3, 239-253.
[4] Hoang MP, Hruban RH et al. “Clear cell endocrine pancreatic tumor mimicking renal cell carcinoma: a distinctive neoplasm of von Hippel Lindau disease.” Am J Surg Pathol 2001; 25:602-609.
[5] Guarda LA, Silva EG et al. “Clear cell islet cell tumor.” Am J Surg Pathol 1983; 79:512-517.
[6] Mount SL, Weaver DL et al. “Von Hippel Lindau disease presenting as a pancreatic neuroendocrine tumor.” Virchows Arch 1995; 426:523-528
[7] Musso C, Paraf F. et al. “Pancreatic neuroendocrine tumors and von Hippel Lindau disease” Ann Pathol. 2000; 20:130-133.
[8] Nagtegaal ID, Odze RD, Klimstra D, Paradis V, Rugge M, Schirmacher P, Washington KM, Carneiro F, Cree IA; WHO Classification of Tumours Editorial Board. The 2019 WHO classification of tumours of the digestive system. Histopathology. 2020 Jan; 76(2):182-188. doi: 10.1111/his.13975. Epub 2019 Nov 13. PMID: 31433515; PMCID: PMC7003895.
[9] Sangoi A., Fujiwara M et al. “Immunohistochemical Distinction of Primary Adrenal Cortical Lesions from Metastatic Clear Cell Renal Cell Carcinoma: A Study of 248 Cases.” Am J Surg Pathol 2011; 35(5): 678-686.
[10] Bellizi AM “Immunohistochemistry in the diagnosis and classification of neuroendocrine neoplasms: wat can brown do for you?” Hum Pathol 2020; 96:8-33.

Case contributed by:

Susanne K. Jeffus, MD – University of Arkansas for Medical Sciences
Camila Simoes, MD – University of Arkansas for Medical Sciences
Felicia D. Allard, MD – University of Arkansas for Medical Sciences


Special thanks to David Klimstra, MD, of Memorial Sloan Kettering Cancer Center for his consultative expertise.

Conflict of Interest: No