Abdominal ultrasound displayed a solid cystic lesion at the pancreatic head measuring 4.2 x 3.9cms. Contrast enhanced computed tomography (CECT) revealed a heterogeneously enhancing mass accompanied by dilatation of the pancreatic ducts. No calcification or stricture was noted in the main pancreatic duct (MPD). The duodenal wall surrounding the pancreas was thickened (Figure 1A,B). A diagnosis of malignancy at the head of the pancreas with focal chronic pancreatitis was suggested.

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Figure 1: A,B) Axial section of shows a heterogeneous mass in head of pancreas (arrow) with a cystic component.

Endoscopic ultrasound (EUS) guided aspiration guided aspiration yielded fluid displaying a supranormal elevation of CA 19-9(12000 IU/ml). Carcinoembryonic antigen (CEA)(221ng/ml) and fluid amylase (5419 IU/ml) were also raised. The serum levels of CA 19-9 and CEA were also elevated (407.36 IU/ml and 70 ng/ml, respectively). Serum lipase and amylase, were within normal limits. A strong clinical suspicion of malignancy supported by imaging and biochemical findings culminated in a Whipple's pancreaticoduodenectomy. Per-operative findings showed a bulky pancreatic head with a palpable cystic lesion. The rest of the pancreas appeared firm and the MPD was dilated.

Gross examination of the specimen revealed a solid and cystic lesion in the head of the pancreas measuring 6.1 x 5.2 x 4.0 cm. The solid area was firm and yellow in colour (Figure 2A). Clear, non-viscous yellow fluid was noted in the cystic area. Microscopic examination showed dense inflammatory infiltrate composed of foamy histiocytes, hemosiderin laden macrophages and bile pigment largely replacing the normal pancreatic parenchyma and extending upto the duodenal mucosa with splaying of the muscularis mucosa (Figure 2B-D). Also seen were dilated pancreatic ducts with inspissated secretions (Figure 3A). Cholesterol clefts and foreign body giant cells were interspersed (Figure 3B,C). Extensive sectioning and complete exhaustion of the tissue showed no focus of malignancy. Pan-cytokeratin (CK) and epithelial membranous antigen (EMA) were employed in the sections to rule out any neoplastic epithelial cells. Both were negative. The sheets of macrophages were diffusely positive for anti macrophage markers CD 68 and HAM 56 (Figure 3D). Thus a final diagnosis of XGP was made. The patient is under follow up and shows no features of recurrence after seven months. C reactive protein is near normal (3.1 mg/dl). Follow up serum CA 19-9 & CEA have shown a reduction, though both have not touched the baseline reference values (CA 19-9:71.16, CEA: 9.86 ng/ ml).

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Figure 2: A) Gross photograph of the pancreas showing a solid area firm and yellow in color (arrow), red circle depicting preliminary sectioned pancreaticoduodenal groove. B) Dense inflammation replacing the normal pancreatic parenchyma. C) Inflammation extending upto the duodenal mucosa with splaying of the muscularis (H&E; x100). D) Higher magnification shows dense inflammatory infiltrate composed of foamy histiocytes, hemosiderin laden macrophages and bile pigment (H&E; x200). Arrows highlight residual pancreatic parenchyma in B,D.

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Figure 3: A) Dilated pancreatic ducts with inspissated secretions (H&E; x200). B,C) Cholesterol clefts with foreign body giant cells (H&E; x200). D) Immunostaining of HAM56 highlights the predominance of macrophages in the inflammatory infiltrate (HAM56; x200). Inset: Giant cells highlighted by HAM56 staining (x100).

To the best of our knowledge this is the only case with tumour marker elevation in the absence of any associated neoplastic process. One prior case with elevated tumour markers had an associated mucinous cystic neoplasm¹³. A review of the existing literature (Table I) revealed mean age at presentation of 59.4 years with a definite male predilection (76.4%). A distinct geographic predilection was noted with 13/14 (92.8%) reports published from the Asian -Eurasian belt including Turkey. The most common presenting symptom of such patients is abdominal pain (66.6%). On imaging, most cases presented as solid or cystic masses suggesting a pancreatic neoplasm. All patients underwent major surgical intervention highlighting the lacuna in picking up this form of pancreatitis preoperatively and hence the need to analyze this entity better.

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Table I: A review of reported cases of XGP in the literature

Histopathological study of resected specimens remains the gold standard of diagnosis with dense sheets of foamy macrophages and giant cells in the absence of neoplastic cells providing clues to nailing this lesion. In our case extensive sectioning at multiple levels was performed to exclude a neoplastic etiology. Florid xanthogranulomatous inflammation may mask rare malignant cells entrapped in the milieu. Hence, a meticulous approach must be employed by the pathologist. An immunostain panel employing cytokeratins, EMA and macrophage markers (CD 68, HAM 56) can prevent potential error in diagnosis. Well directed peroperative frozen sectioning may also help in giving the clinicians a timely diagnosis.

This case was unique as it was accompanied by tumour marker elevation in both serum and cyst fluid. Tumour marker analysis in pancreatic malignancy largely revolves around serum measurements of the widely available CA 19-9. Unfortunately, definite pitfalls exist in its diagnostic capabilities with elevated levels of CA 19-9 also being reported in benign conditions associated including pancreatitis¹⁵. The present case validates the American Society of Clinical Oncology (ASCO) guidelines which rule out the use of CA 19-9 for screening or diagnostic purpose¹⁶. Lewandrowski et al.¹⁵ in a detailed review pointed out that tumour marker elevation in cyst fluid is not pathognomic of malignancy. In fact, serous neoplasms may have perfectly normal values of tumour markers, similar to benign pancreatic pseudocysts. Imaging modalities like computerized tomography (CT), Magnetic resonance cholangiopancreaticography (MRCP) have also been unsatisfactory in picking up the xanthogranulomatous process rendering the diagnosis difficult at times¹⁰.

A close differential diagnosis to be considered in the present case is paraduodenal pancreatitis (PDP). Both PDP and XGP can mimic malignancy clinically and radiologically as seen in this case. Our patient did not have a history of chronic alcohol intake, a common predisposing factor for PDP. Gross examination is important to determine the site of pathology which in PDP centres at the pancreaticoduodenal groove and duodenal wall. Here, the pancreas was grossly the area of affliction and the duodenal mucosa appeared unremarkable. Histological features described in PDP¹⁷ such as Brunner gland hyperplasia, duodenal submucosal fibrosis, cysts in the duodenal wall, heterotopic pancreatic tissue and proliferation of myoid cells were all absent in this case. Interestingly prominent chronic inflammation as seen in this case is not a feature of PDP¹⁷. The singularly extensive presence of foamy histiocytes in areas grossly corresponding to the pancreas on the other hand rendered the diagnosis of XGP.

This case highlights that if unfavourable clinical and biochemical findings are juxtaposed, arriving at the correct diagnosis may be next to impossible before surgical resection. Frozen sections from the resected lesion used in tandem with rapid immunohistochemistry may be a useful modality in determining the extent of resection as has been suggested for the more frequently encountered XGC¹⁸.

In conclusion, we suggest that for solid cystic/cystic lesions of the pancreas- XGP, though rare must be kept as a possible differential diagnosis. Further studies would be needed to explore a valid biomarker for xanthogranulomatous inflammation and secondly to validate the efficacy of a frozen based approach in curtailing patient morbidity thus saving patients from unnecessary extensive surgical procedures.

Ethical Approval: Informed consent has been obtained from the patient for this report and due efforts have been made to uphold patient confidentiality in the writing of the manuscript.

Conflict of Interest: None

Funding/Grants/Sponsorship: None obtained

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