Prolonged response on olaparib maintenance in metastatic pancreatic acinar cell carcinoma associated with a germline BRCA 2 mutation, revealed by severe panniculitis

Abstract

This 38‐year‐old man has a familial BRCA2 mutation. He presented with skin erythema, polyarthritis, dactylitis, and febrile erythema nodosum; a biopsy of a liver metastase revealed acinar cell carcinoma of the pancreas. After FOLFIRINOX, olaparib was initiated, and 24 months after, the patient was PS 0 and asymptomatic.

Pancreas acinar cell carcinomas frequently present with skin lesions, dactylitis, and hyperlipasemia. In more than 20% of the cases, there exists a germline BRCA mutation allowing an efficient maintenance treatment by olaparib.

1. INTRODUCTION

Pancreatic cancer is a highly fatal disease with dismal 5‐year survival of less than 10%. Most cases are ductal adenocarcinomas. ¹ Pancreatic neoplasms with acinar differentiation, acinar cell carcinomas, and pancreatoblastomas are distinctive. Pancreatic acinar cell carcinoma (PACC) is rare, representing less than 2% of exocrine pancreatic adenocarcinomas; the prognosis for PACC is not as rapidly fatal as that of ductal adenocarcinoma. ² On histopathology, the differential diagnosis is primarily versus pancreatic neuroendocrine tumors. Clinically, approximately 15% of patients present with a unique clinical syndrome of subcutaneous fat necrosis, eosinophilia, and polyarthralgia (Weber–Christian paraneoplastic syndrome or Schmid's triad) due to high secretion of lipase by tumor cells. ³ Genomic alterations observed in PACC are different from those observed in ductal adenocarcinoma. Mutations of KRAS, SMAD4, CDKN2A, and TP53 are observed with lower frequency but BRCA2 mutations have higher frequency (20% vs. 7%–10%). ⁴ These mutations offer increased sensitivity of response to molecules such as selective inhibitors of poly(ADP‐ribose) polymerase (PARP) enzymes, notably olaparib, validated in maintenance treatment after stabilization during platinum‐based chemotherapy. ⁵

Here is the presentation of a case of PACC of the pancreatic tail with synchronous liver metastasis in a 38‐year‐old man with a germline BRCA 2 mutation, with Weber–Christian syndrome as the first sign, treated with FOLFIRINOX in first line for 6 months then olaparib in maintenance for now more than 24 months.

2. CASE REPORT

Written informed consent for publication of his clinical details and images was obtained from the patient.

This 38‐year‐old man has a familial history of proven BRCA2 mutation, with breast cancer in his mother and pancreatic cancer his maternal grandfather. In June 2019, he presented with skin erythema, followed by polyarthritis, dactylitis, and febrile erythema nodosum, and a biological inflammatory syndrome. Within 6 months, he had lost 12 kg (from 78 to 66 kg), and his albumin serum dropped to 31 g/L. However, the patient's general condition was preserved at diagnosis (Performance status 1).

The etiological work‐up CT scan revealed a 10‐cm mass in the pancreatic tail associated with secondary hepatic localizations, the largest of which (89 mm) was biopsied. The diagnosis was that of acinar cell carcinoma of the pancreas. On immunohistochemistry, the tumor cells were cytokeratin AE1/AE3+ and lipase+. They were chromogranin A‐, synaptophysin‐, and CD56‐.

Blood lipasemia was 2700 UI (normal: 60 UI/L); CA19‐9 was not expressed. On PET‐CT, in addition to visualization of the pancreatic mass and liver metastases, the skin lesions were clearly seen as FDG‐positive nodules (Figure 1). ⁶ US examination of the subcutaneous nodule confirmed panniculitis associated with synovitis (Figure 2).

FIGURE 1.

16FDG‐PET showing multiple FDG‐avid subcutaneous nodules on both lower limbs: panniculitis revealing metastatic pancreatic acinar cell carcinoma

FIGURE 2.

On the left, the US shows panniculitis (star) and synovitis (arrow head) on the dorsal side of the left foot

BRCA2 tumoral status was a heterozygous mutation c.37_44del (p[Glu13*]) in exon 2.

The final diagnosis was that of metastatic PACC associated with Weber–Christian paraneoplastic syndrome in a patient with a germline BRCA2 mutation.

Systemic chemotherapy with FOLFIRINOX was then initiated in September 2019 and was well tolerated. The paraneoplastic syndrome improved, then disappeared, and lipasemia (after an initial increase) decreased to 500 after 6 months of treatment. At this moment, after 12 cycles of FOLFIRINOX, the patient was PS 0, he went back to his normal weight (76 kg) and the CT scan demonstrated a partial response (metastasis: 50 mm in diameter).

Olaparib was initiated in March 2020. On CT scan, the tumor remained stable 2, 4, 6, 9, and 12 months after initiation of olaparib treatment, and the lipasemia went progressively down to normal values. The patient resumed his professional activity with initiation of olaparib.

In March 2022, 30 months after the first FOLFIRINOX cycle and 24 months after initiation of Olaparib, the patient was in perfect general status, asymptomatic and still on well‐tolerated olaparib.

3. DISCUSSION

This case is very special as this patient presented with most of the specificities of PACC: The first symptoms were related to a paraneoplastic syndrome due to tumor secretion of lipase, the lipase blood level evolved in parallel to a tumor, the genetic context was of germline BRCA2 mutation, platinum‐based systemic chemotherapy was efficient, as was olaparib, making long survival possible despite the initial metastatic context.

Acinar cells represent most pancreatic cells and ensure the exocrine function of the gland by producing enzymes (amylase, lipase, proteases). Most cases of usual pancreatic carcinogenesis start from metaplastic acinar cells which undergo ductal trans‐differentiation: acinar‐to‐ductal metaplasia. ⁷ , ⁸ Acinar cell carcinoma is very uncommon.

PACC may be seen before the age of 18, but peaks over the age of 60 years and is seen particularly in males. ² The clinical manifestations remain non‐specific (abdominal pain, weight loss, nausea, and vomiting), but in up to 15% of the patients, skin lesions caused by panniculitis associated with sterile polyarthritis may be the first signs of disease. This syndrome, caused by the peripheral lipolytic activity of circulating lipase, is usually due to pancreatic neoplasia but sometimes to other tumors or benign pancreatic disease. ⁹

Histologically, these cancers are usually highly cellular without prominent stroma; endocrine markers are often observed with frequent cases of mixed acinar‐endocrine carcinomas.

The molecular profile of PACC is different to that of pancreatic ductal adenocarcinoma. Common mutations detected in pancreatic ductal adenocarcinoma (KRAS, SMAD4, CDKN2A, TP53) are not found, while mutations of BRCA1, BRCA2, RB1, and mutations in the WNT‐b‐catenin pathway are frequent in PACC. ¹⁰

Deleterious germline mutations in the BRCA2 gene account for the largest fraction of known familial pancreatic cancer genes (found in 5%–10% of familial pancreatic cancer families), but is also frequently found in cases of sporadic pancreatic adenocarcinoma: In a series of 854 patients with apparently sporadic ductal pancreatic adenocarcinoma, 3.9% (33 cases) had deleterious germline mutations, the most frequent (1%; 12 / 33) on BRCA2. ¹¹

In PACC, BRCA2 mutations were found in 4%–43% of cases. ¹⁰ In a series of 44 cases of PACC, half had inactivating, genomic alterations in DNA repair genes (BRCA 1–2, ATM, MSH1‐2, RAD50, etc.), including DNA mutations in 20%. This can explain the improved efficacy of platinum derivatives, and particularly of oxaliplatin, in PACC, as observed in our case. ¹² PARP inhibitors are a novel therapeutic approach dedicated to BRCA mutation‐related cancers. Olaparib is a selective inhibitor of poly(ADP‐ribose) polymerase (PARP) enzymes, including PARP‐1, PARP‐2, and PARP‐3. Recently, the clinical activity of olaparib has been demonstrated in germline BRCA‐mutated metastatic pancreatic cancer that did not progress with first‐line platinum‐containing chemotherapy for at least 16 weeks (80% had had previous chemotherapy with FOLFIRINOX). It was compared to placebo as maintenance treatment. Olaparib improved progression‐free survival; quality of life was similar in both arms, but overall survival was not improved (cross‐over). ¹³ In our case, progression‐free survival was particularly long, as 24 months after initiation of olaparib the patient is still in partial response; moreover on olaparib, his lipase serum level is still decreasing. In the seminal trial, more than 20% of olaparib‐treated patients were still free of tumor progression and overall survival seemed to plateau around 35% after 24 months (25% in placebo patients). ⁵ It is unknown if PACC patients were included in this study, but taking into account their better prognosis, olaparib on BRCA‐mutated PACC may give excellent overall survival, eventually even providing a cure. In the literature, too few cases of metastatic PACC receiving olaparib have been reported to make it possible to draw conclusions. ¹⁴ , ¹⁵

4. CONCLUSIONS

To conclude, this case illustrates the specificities of PACC. Panniculitis, particularly if associated with polyarthritis, may be the first sign of the disease. This tumor occurs frequently in BRCA‐mutated patients and screening for this germline mutation is thus of great importance in PACC, particularly as that this mutation is associated with better prognosis with platinum derivative chemotherapy and will benefit from olaparib as maintenance.

AUTHOR CONTRIBUTIONS

Margaux Lelong, Jean‐Luc Raoul, and Hélène Senellart involved in writing of the manuscript. Hélène Senellart, Margaux Lelong, Yann Touchefeu, Jean‐Marie Berthelot, Paul Arnolfo, and Tamara Matysiak‐Budnik involved in cares of the patient. Margaux Lelong and Hélène Senellart involved in genomic analysis. All authors involved in corrections, modifications, and final acceptation.

FUNDING INFORMATION

No funding.

CONFLICT OF INTEREST

The authors have no conflict of interest to declare.

ETHICS STATEMENT

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. This clinical case does not require a study approval.

CONSENT

Written informed consent for publication of his clinical details and images was obtained from the patient.

Lelong M, Raoul J‐L, Touchefeu Y, et al. Prolonged response on olaparib maintenance in metastatic pancreatic acinar cell carcinoma associated with a germline BRCA 2 mutation, revealed by severe panniculitis. Clin Case Rep. 2022;10:e06718. doi: 10.1002/ccr3.6718

DATA AVAILABILITY STATEMENT

The original contributions presented in the study are included in the article. Further inquiries can be directed to the corresponding author.