A 64-year-old female with a past medical history of tobacco abuse (~24 pack-years) and fibroids and a past surgical history of total abdominal hysterectomy and bilateral salpingectomy presented to her primary care physician complaining of a 4-month history of progressive abdominal pain and distension. Magnetic resonance imaging revealed a 19.1-cm multiloculated cystic lesion filling the pelvis, most likely arising from one of the adnexal regions, and a 6.1-cm mass within the pancreatic tail, consistent with a locally advanced left-sided pancreatic cancer. The pancreatic mass was biopsied through endoscopic ultrasound-guided fine needle aspiration (FNA), and the patient was diagnosed with adenocarcinoma. She was then started on neoadjuvant chemotherapy for pancreatic adenocarcinoma.
Follow-up imaging revealed a minimal decrease in size of the invasive mass within the pancreatic body and tail to 5.9 cm (Fig. 1A). The pelvic mass, however, appeared to have enlarged, with extension into the abdomen, in keeping with malignancy (Fig. 1B).
Treatment response was additionally monitored with cancer antigen (CA) 19-9 levels, which ranged from a high of 114 U/mL on initial presentation to 35 U/mL after treatment with neoadjuvant chemotherapy. The patient's carcinoembryonic antigen (CEA) decreased from 12 ng/mL on initial presentation to 4.8 ng/mL, and her CA-125 decreased from 119 to 15.3 U/mL. The CA-125/CEA ratio was 9.9 on initial presentation, which was less than 25 and therefore consistent with possible gastrointestinal/hepatobiliary origin, not ovarian origin.
The patient was referred to our institution after initiation of neoadjuvant treatment, for discussion of surgical options in her treatment plan for her locally advanced adenocarcinoma of the body and tail of the pancreas and pelvic mass. Computed tomography of the abdomen/pelvis with contrast at her consultation visit revealed a pancreatic tumor with apparent encasement of adjacent vascular structures, including the celiac and superior mesenteric arteries and their branches. The differential for the pelvic mass was metastatic disease versus a primary ovarian process.
The patient then underwent additional chemotherapy, ultimately completing 10 cycles of combination chemotherapy with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX), followed by external beam radiation therapy with concurrent oral Xeloda. Her postradiation therapy CA 19-9 was 9 U/mL, and CEA was 1.6 ng/mL. Follow-up imaging showed that the mass lesion involving the body to tail of the pancreas was minimally decreased in size from prior. The pelvic mass had decreased in size, but with an increased number of small cystic foci. Based on clinical, biochemical, and radiologic findings, an Appleby procedure was planned for resection of the pancreatic mass, as well as resection of the pelvic mass and bilateral oophorectomy. The decision was made to move forward with the operation after discussion with the patient, given the opportunity for safe resection of the pancreatic and pelvic masses.
The patient underwent distal pancreatectomy and en bloc splenectomy with en bloc resection of a portion of the common hepatic artery, and resection of the left pelvic mass and bilateral oophorectomy. Intraoperatively, exploration of the duodenum and pancreas revealed a firm mass involving the pancreatic body and tail, with invasion into the retroperitoneum. The common hepatic artery at the superior margin of the pancreatic body appeared to be involved. The superior mesenteric artery vessels were easily dissected free intraoperatively and did not appear to be grossly encased by tumor. On exploration of the pelvis, a large 10+ cm left cystic adnexal mass was identified, which was adherent to the left pelvic sidewall and also to a portion of sigmoid colon. Both left and right ovaries were removed.
Gross examination of the distal pancreas revealed a 4.5-cm ill-defined mass in the pancreatic tail, located ~2.5 cm from the pancreatic neck margin. Permanent sections (Fig. 2A) showed only a few residual viable groups of poorly differentiated adenocarcinoma, morphologically consistent with pancreatic ductal carcinoma (1.0 cm in greatest dimension). There was evidence of extensive treatment effect with multiple pools of acellular mucin in the area of the pancreatic tumor.
The residual viable pancreatic neoplastic cells stained strongly for cytokeratin (CA) 7, CA 19-9, and showed very weak scattered nuclear positivity for CDX2. The residual viable pancreatic neoplastic cells were negative for CK20, PAX8, and SATB2. Although not a specific immunostaining pattern, this was considered consistent with a primary pancreatic neoplasm. Margins of surgical resection, including proximal pancreatic parenchymal margin and peripancreatic tissue, were microscopically free of viable malignant neoplasia. Ten regional lymph nodes were negative for metastatic disease and showed no evidence of intranodal therapeutic effect. The final pathologic stage was pT1cpN0 (American Joint Committee on Cancer, 8th edition).
Gross examination of the left ovary consisted of a 206 g, 11 x 8.5 x 4.5 cm multiloculated ovarian mass with both solid and cystic areas. Multicystic areas were composed of smooth-walled cysts containing both serous and mucoid material. Microscopic sections of the enlarged left ovary (Fig. 2B) showed multiple neoplastic cysts lined by intestinal type epithelial cells that showed stratification, including foci of cribriform architecture. The tumor showed a multinodular growth with some of the neoplastic cells being far away from other groups of neoplastic glands, which is not typically seen in primary ovarian carcinomas. There was a range of cytologic and architectural atypia associated with the tumor as one frequently sees with metastatic pancreaticobiliary carcinomas. There was additionally an associated desmoplastic reaction around some neoplastic glands, which is rarely seen in primary carcinomas of the ovary, but more common in metastases. There was also a focus suggestive of surface involvement in one section, another feature that would support the diagnosis of metastatic carcinoma. The right ovary showed no evidence of neoplasia.
The neoplastic epithelial cells marked strongly and diffusely positive for CK7, showed positivity for CA 19-9, MUC1, and were diffusely positive for the intestinal markers CK20 and CDX2. The neoplastic cells were negative for MUC2, SATB2, CA-125, estrogen receptor, and PAX8. Mucinous ovarian neoplasms of the intestinal type have previously been found to express intestinal type markers. The pathologic differential diagnosis included borderline mucinous tumor of the ovary, intestinal type, showing multiple scattered foci of intraepithelial carcinoma and focal microinvasion versus isolated metastasis from the patient's known pancreatic primary.
A pan-cancer molecular mutational panel was then performed separately on sections from the ovarian and the pancreatic tumor to aid in diagnosis. This panel is performed in-house at our institution, and provides comprehensive detection of somatic mutations in 30 important cancer-related genes (AKT1, ALK, BRAF, CTNNB1, DDR2, EGFR, EIF1AX, ERBB2, FGFR1, FGFR2, FGFR3, GNAS, HRAS, IDH1, IDH2, KIT, KRAS, MAP2K1, MET, NRAS, PDGFRA, PIK3CA, PTEN, RET, ROS, SMAD4, STK11, TERT, TP53, and TSHR). The test is performed on DNA extracted from formalin-fixed, paraffin-embedded tumor tissue or FNA biopsy specimens. The Archer VariantPlex Comprehensive Thyroid and Lung Panel is used to perform DNA sequencing, in conjunction with the SMAD4 gene, which uses anchored multiplex polymerase chain reaction to amplify regions of interest in the 30 genes listed. Amplicons are sequenced on an Illumina NextSeq next-generation sequencer. The ovarian tumor in this case showed exactly the same mutations, namely, KRAS G12R and TP53 G245S, as in the treated pancreatic cancer. This raised the high probability that these tumors originated from the same clonal event. The findings indicated that the ovarian tumor was an isolated metastasis of the pancreatic primary, despite the morphologic ambiguity between the two sites of neoplasia. Additional molecular testing by Perthera confirmed that the genomic profile in the left ovary was consistent with metastasis from a pancreatic primary. Outside testing further identified an inactivating mutation of CDKN2A and amplification of GATA6.
The patient is currently 15 months postoperation. Although she has improved significantly, her follow-up imaging and laboratory results are concerning for recurrent disease. Restaging imaging studies show an area of right upper quadrant omental infiltration (2.6 x 1.4 cm) and additional subtle abnormalities. Her CA 19-9 level has risen to 77 U/mL. There is no indication for surgery at this point. There was discussion of additional treatment with chemotherapy, but given the patient's difficult clinical course and a lack of data, the patient will instead follow up closely with medical oncology.
Informed patient consent was obtained by the authors before publication of this article.