Pancreatic Acinar Cell Carcinoma with Germline BRCA2 Mutation and Severe Pancreatic Panniculitis: A Case Report

Pancreatic acinar cell carcinoma (ACC) is a rare condition accounting for up to 2% of all pancreatic neoplasms [1]. Most patients with ACC present with unspecific symptoms such as abdominal pain or weight loss [2]. In up to 15% of cases, patients develop symptoms that are related to the excessive release of lipases, such as pancreatic panniculitis (PP) or polyarthralgia [3]. On a genetic level, ACC displays mutations that are distinct from pancreatic ductal adenocarcinoma (PDAC) [1, 4]. Exome-sequencing studies showed that ACC harbors a higher number of nonsynonymous mutations, but not many recurrent alterations [5, 6]. Overall survival of patients with ACC is reported to be superior compared to PDAC, with 5-year survival rates ranging between 36–72%. Until now, no therapeutic standards have been established for ACC [3] and the efficiency of individual approaches is only described by case reports. In metastatic disease, chemotherapeutic regimens approved for PDAC are most commonly applied, but there is limited clinical data on their efficiency in ACC. In addition, a potential benefit of PARP inhibition in patients with breast cancer susceptibility gene (BRCA)-deficient ACC was previously described [7]. Here, we present the case of a patient with metastatic ACC and severe PP who was treated by a multimodal therapeutic concept, including surgery, systemic chemotherapy, and targeted therapy with the PARP inhibitor olaparib.

A 66-year-old male patient was admitted to our department with abdominal pain and vomiting in April 2016. The patient presented with an ECOG 1 performance status. His underlying health conditions included hypertension, atrial fibrillation, and chronic obstructive pulmonary disease. A computed tomography (CT) scan revealed a pancreatic mass of 5 × 3.8 cm in the pancreatic tail and endosonographic features were suspicious for local lymph node metastasis (Fig. 1A).

The patient underwent left-sided pancreatic resection with splenectomy in the same month. The postoperative tumor stage was: pT3, pN0, cM0, Pn0, V0 with R0 resection status, according to the 7th edition of the TNM Classification of Malignant Tumors. Immunohistochemistry demonstrated positive staining of tumor cells for NSE, EMA, CK7, chymotrypsin, weakly positive staining for synaptophysin and no expression of chromogranin, somatostatin, CEA, and p53. Based on the histopathology and immunohistochemistry findings, diagnosis of an ACC with additional neuroendocrine differentiation was established.

Six months after resection, the patient presented again with abdominal pain. A CT scan revealed multiple liver lesions in both lobes (Fig. 1A). Palliative chemotherapy with FOLFIRINOX regimen was initiated. A CT scan 3 months later showed partial regression of the hepatic lesions, and thus treatment was continued. Due to chemotherapy-induced neuropathic pain, therapy was deescalated to FOLFIRI. Following the initial response of the tumor and subsequent disease stabilization, atypical liver resections of metastases in segments VII and VIII were performed in March 2018. In November 2018, a new hepatic lesion in segment VII was detected by CT scan, and another atypical liver resection was performed. In February 2019, liver metastasis in segment V was observed, and chemotherapy (FOLFIRI regimen) was re-initiated. However, due to progressive disease, chemotherapy was switched to gemcitabine and nab-paclitaxel. Three months later, treatment was switched to nanoliposomal irinotecan, 5-fluorouracil and leucovorin after disease progression. However, due to progression of hepatic metastasis and new pulmonary lesions, therapy was finally changed to the OFF regimen with dose reduction of oxaliplatin in November 2019. Soon after, the patient developed painful nodules on both legs (Fig. 1B), with serum lipase levels increased to 23,635 U/L. Histopathological analysis of an excised nodule showed fat necrosis and pathognomonic “ghost” cells with calcifications, compatible with the diagnosis of PP (Fig. 1C). Therapy with NSAIDs did not alleviate symptoms. Wound management with several courses of debridement and extensive wound care was installed but did not improve wound healing. A CT scan in February 2020 revealed progressive pulmonary and hepatic lesions (Fig. 1A). The patient had a family history of BRCA2-associated cancers. Both the patients’ brother and sister died from breast cancer, and his daughter was diagnosed with bilateral breast cancer at the age of 36, with a confirmed germline BRCA2 mutation. BRCA testing was also performed in our patient and revealed a germline, heterozygous BRCA2 c.2808_2811de/ACAA (p.Ala938Profs*21) mutation. Therapy with olaparib at a dose of 300 mg twice daily was therefore initiated in February 2020. However, the patient was soon hospitalized due to renal failure and superinfected wounds in both legs and arms, leading to discontinuation of the treatment. Therapy with olaparib could not be re-initiated due to persistent renal failure and ECOG 3 performance status. Interdisciplinary palliative care was continued, and the patient died 47 months after first diagnosis of ACC. A timeline showing the course of the treatment is shown in Figure 1D.

ACC is a rare malignant disease with limited data on therapeutic management. In a case series, survival rates of 36 months were reported for patients with ACC who received tumor resection, compared to 14 months without surgical treatment [8]. Similarly, Zong et al. [9] described a 5-year survival rate of 65.6% for patients undergoing resection of ACC versus 16.9% without resection. In a retrospective analysis, adjuvant chemotherapy was associated with improved outcome in ACC [10], but no standard regimen of adjuvant therapy is established so far. Based on our case report, FOLFIRINOX and FOLFIRI are effective chemotherapy regimens for the treatment of metastatic ACC. Hence, we believe that patients with ACC will also benefit from adjuvant treatment with FOLFIRINOX, which is already an established option for the adjuvant therapy of PDAC [11]. Currently, there is a low level of evidence favoring tumor resection in metastatic ACC when the extent of metastasis is limited [12]. In our case, resection of the primary tumor and single liver metastases during the course of the disease allowed the patient to have treatment-free intervals. The use of chemotherapy in metastatic ACC is associated with improved survival [9], but no consensus on the choice of therapy regimen exists. In a retrospective analysis, the use of 22 different regimens in 18 cases of ACC was described, with reported disease control in patients who received irinotecan, fluorouracil and leucovorin as well as cytarabine and cisplatin [8]. Recently, a case report described FOLFIRINOX as an effective first-line treatment to control tumor growth and symptoms of lipase hypersecretion syndrome in ACC [13]. In our case report, partial response was also achieved with FOLFIRINOX and FOLFIRI, but treatment was discontinued due to chemotherapy-induced neuropathic pain. Novel treatment approaches for ACC include targeted therapy for BRCA-deficient cancers. ACC is known to harbor high frequencies of chromosomal instability and defective DNA repair [14]. Causal relationship between germline BRCA2 mutations and the development of ACC has been suggested, as up to 22% of patients with ACC harbor either somatic or germline mutations of BRCA2 [7]. It is known that patients with pancreatic cancers and BRCA2 mutations benefit from platinum-based therapies [15]. Furthermore, it was shown that PDAC with BRCA mutations that responded to platinum-based therapies benefit from treatment with olaparib, with an improved progression-free survival [16, 17]. In addition, Li et al. [18] recently described a case of ACC and germline BRCA2 mutation that responded to treatment with olaparib. In our case, the patient refused initial genetic testing, and thus treatment with olaparib was delayed. When therapy was initiated, the patient was already impaired by severe PP and renal failure, and olaparib was soon discontinued. Hence, insights from our case underline the importance of early genetic profiling of ACC. If BRCA mutations are detected, we believe that a therapeutic switch to maintenance therapy with a PARP inhibitor should be considered at an early time point after induction therapy with FOLFIRINOX. Subcutaneous fat necrosis due to excessive secretion of pancreatic enzymes, called PP, has been described in patients with ACC [7]. PP can occur in benign and malign pancreatic conditions, but up to 45.9% of cases are linked to neoplastic disease [19]. In ACC, PP occurs in up to 15% of patients, in both early [20, 21] and advanced disease stages [22]. In general, the occurrence of PP is associated with an advanced stage of ACC and considered to be a negative prognostic factor [22]. In our patient, serum lipase levels were initially not elevated, but increased dramatically to more than 23,000 U/L at the time PP was diagnosed. In parallel to the occurrence of PP, a massive tumor progression was radiologically diagnosed. Therefore, we believe that the trigger of PP was a significant disease progression. Treatment of PP should focus on the therapy of the underlying condition [19]. Case reports demonstrate that antineoplastic treatment can alleviate symptoms of PP, including resection or transarterial chemoembolization of hepatic lesions [22]. In contrast, the efficiency of octreotide, NSAIDs and steroids for treatment of PP remains elusive [19]. In summary, our case report highlights the importance of interdisciplinary treatment and early genetic profiling of ACC.

Written informed consent was obtained from the patient for publication of this case report and any accompanying images.

The authors have no conflicts of interest.

L.D. and T.Z. were supported by the Clinician Scientist programme “Interfaces and Interventions in Chronic Complex Conditions” funded by the DFG (EB 187/8-1).

T.Z.: concept and design. L.D., J.M., and T.Z.: data acquisition and interpretation. L.D. and T.Z.: drafting of the manuscript. All authors: critical revision of the manuscript.