Clear cell carcinoma of the pancreas: a case report of a not so clear disease

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is the 10^th most common cancer yet the 4^th leading cause of cancer-related deaths in the United States (1,2). Diagnosis is rare before 45 years of age, and most disease is found at an advanced stage with only 15–20% of patients eligible as surgical candidates (2). Five-year survival is known to be poor at 12.5% and only marginally improves with surgical resection. In those who undergo surgery associated with an R0 resection (defined as no evidence of macroscopic or microscopic disease), 5-year survival is 30% for node negative and 10% for node positive disease (1). PDAC be can subdivided into subcategories based on histomorphological features and molecular profiles (3). One rare type is known as clear cell carcinoma of the pancreas (CCCP) and is defined by the World Health Organization (WHO) as a “miscellaneous” carcinoma (4). CCCP was first described in 1980 at Memorial Hospital in New York City when pancreas tumors at autopsy were found to exhibit clear cells resembling those seen in the kidney and adrenal glands (5). Prior to 2008, little data has described the pathogenesis of this disease and aspects that guide prognosis and therapeutics (3). To date, there are only 14 cases documented in the literature and research is sparse. Treatment of CCCP follows the same algorithm of PDAC despite having more aggressive behavior with most patients succumbing to this disease over a short time (5). Here, we present the following case of CCCP in a healthy 47-year-old female discovered when she developed abdominal pain and subcutaneous nodules after a recent hysterectomy. We present this case in accordance with the CARE reporting checklist (available at https://apc.amegroups.com/article/view/10.21037/apc-24-20/rc).

Case presentation

A 47-year-old female (body mass index 22 kg/m²) who was six weeks post robotic-assisted laparoscopic hysterectomy for heavy menstrual bleeding presented to the Emergency Department (ED) with severe epigastric abdominal pain and a recent unexpected 10-pound weight loss that developed since her surgery. Her initial labs revealed a mild leukopenia, thrombocytopenia, and a normal lipase. On exam, her abdomen was tender to palpation in the epigastric region. Imaging included a computed tomography (CT) scan of the abdomen/pelvis and magnetic resonance imaging (MRI) of the abdomen (Figure 1). This revealed pancreatitis with likely walled off necrosis, a possible hemangioma in the right liver, and a nonvisualized splenic vein suggesting chronic thrombus. She was diagnosed with acute pancreatitis, treated conservatively with pain control and hydration, and ultimately discharged home. She then re-presented to the ED less than two weeks later with persistent abdominal pain. Repeat CT abdomen/pelvis at this time (twelve days since her prior scan; Figure 2) showed stable pancreatitis, now with new hepatic lesions concerning for metastatic disease. Given the concern for malignancy, she was referred to hepatopancreatobiliary surgery. In clinic, she reported waxing and waning abdominal pain for the past year with a recent increase in severity. Furthermore, she reported two subcutaneous nodules that formed at the previous port site incisions from her recent hysterectomy. A core needle biopsy was obtained, and pathology resulted as metastatic adenocarcinoma with clear cell features. Figure 3 represents low power (10×) hematoxylin and eosin (H&E)-stained slides representing an infiltrative, gland-forming epithelioid cell neoplasm, consistent with adenocarcinoma with focal intraluminal mucin production. Figure 4 shows high power (40×) H&E stained slide showing prominent cytoplasmic clearing and vacuolation. Immunohistochemical stains revealed diffuse positivity for CK7 (Figure 5), focal positivity for CK20, CDX2, and GATA3, but were largely negative for TTF1 and PAX8. Given all these pathologic findings and her clinical symptoms, a pancreatobiliary neoplasm was deemed the primary malignancy. Of note, the hysterectomy pathology revealed changes of chronic cervicitis with squamous metaplasia, benign endometrial polyps and an intramural leiomyoma. Further tumor markers were obtained and carcinoembryonic antigen (CEA) was within normal limits, cancer antigen-125 (CA-125) was elevated at 90.3 U/mL and cancer antigen 19-9 (CA 19-9) was significantly elevated at 2,046 U/mL. Other etiologies of pancreatitis were excluded including a normal immunoglobulin G4 (IgG4) and triglycerides. Repeat CT abdomen/pelvis (Figure 6) at this time, 24 days later, revealed a 4.6 cm × 7 cm infiltrative pancreatic mass (previously thought to be walled-off necrosis) encasing the celiac axis and superior mesenteric artery, increased hepatic metastases, and ascites. Given her young age, she was referred to genetics for germline and somatic testing. She was found to carry variants of KRAS, TP53 and a single pathogenic variant of undetermined significant in the gene FANCL, but there was no genetic mutation identified for hereditary pancreatic cancer. She denied any family history of pancreatic cancer or pancreatitis. She denied tobacco use and admitted to occasional alcohol use. Given the disease was metastatic, she was not a surgical candidate and thus was referred to medical oncology. She was initially started on FOLFIRINOX [folinic acid (leucovorin), fluorouracil, irinotecan, oxaliplatin] but was unable to tolerate this regimen and developed a malignant bowel obstruction requiring temporary venting gastrostomy tube and subsequent loop ileostomy. Her chemotherapy treatment was then changed to gemcitabine and paclitaxel, which she received for 9 months. Most recent surveillance imaging showed progressive disease with new liver metastasis. Her chemotherapy regimen was changed to infusional 5-fluorouracil (5-FU) with liposomal irinotecan. The plan is to continue treatment with palliative chemotherapy.

Figure 1 CT (A) and MRI (B) showing pancreatitis with area of walled off necrosis and suspected liver hemangioma (arrow). CT, computed tomography; MRI, magnetic resonance imaging.

Figure 2 Twelve days later. One of the new metastatic hepatic lesions (left, arrow) and one of the subcutaneous nodules (right, arrow).

Figure 3 Low power (10×) H&E stained slide showing an infiltrative, gland-forming epithelioid cell neoplasm, consistent with adenocarcinoma with focal intraluminal mucin production. H&E, hematoxylin and eosin.

Figure 4 High power (40×) H&E stained slide showing prominent cytoplasmic clearing and vacuolation. H&E, hematoxylin and eosin.

Figure 5 Immunohistochemistry staining showing diffuse positivity for CK7 and focal positivity for CK20, CDX2, and GATA3 (magnification, ×20).

Figure 6 Twenty-four days later. (A) Pancreas mass; (B) worsened hepatic metastatic burden and ascites.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

Annually, 66,000 patients are diagnosed with exocrine pancreatic cancer (2). The median age of diagnosis is 70 years of age, peaking between 65–69 years in males and 75–79 years in females (1,2). Risk factors include age, smoking, diet, obesity, and genetic mutations (2). Specifically, the KRAS oncogene is present in >90% of pancreatic cancers (5). Both histomorphological features and genetic mutations contribute to the tumor biology and treatment response in PDAC (3). The clear cell variant of pancreatic cancer is known to be a very aggressive subtype with most cases metastatic at the time of diagnosis (5). This disease has been associated with syndromes such as Von Hippel Lindau but can also be sporadic (5). Diagnosis relies largely on the pathologic presence of clear cells, which are defined as “cells with abundant clear cytoplasm and centrally or peripherally located round nuclei without prominent nucleoli (4)”. Although the exact percentage of clear cell dominance needed for diagnosis is unclear, most authors site at least 75% involvement (4). Clear cells are thought to contribute to the spread of disease with one study finding a dominance of these cells in metastatic lesions (4). Regarding our patient, the differential diagnosis of the primary source of clear cells included gynecologic origin. However, this was ruled out with the benign pathology of her recent hysterectomy. Additionally, the H&E stained characteristics and immunohistochemical results along with the patient’s clinical symptoms and findings of the pancreatic mass on imaging directed the diagnosis as a primary pancreas neoplasm. Regarding our case, clear cells were evident at the trocar sites which supports the tendency of the disease to metastasize. This also suggests that this tumor may seed tracks and allow for faster spread. Another important feature of this case is how quickly the liver lesions progressed. Significant change was seen over a short period of 24 days between interval imaging, owing to the aggressiveness of this disease. Since there is a lack of data outlining the behavior of this disease, treatments are limited and further studies are needed to fill this gap.

Conclusions

CCCP is a rare malignancy with rapidly progressive behavior. Little is known about the biology of this cancer and thus, providers do not have sufficient information to guide treatment strategies. Further research must be done to guide clinical management of this disease as well as to develop potential treatment strategies.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://apc.amegroups.com/article/view/10.21037/apc-24-20/rc

Peer Review File: Available at https://apc.amegroups.com/article/view/10.21037/apc-24-20/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://apc.amegroups.com/article/view/10.21037/apc-24-20/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

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