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Acinar cell carcinoma (ACC) of the pancreas is a rare neoplasm, accounting for 1% of all pancreatic neoplasms. There remains a lack of data regarding the use of systemic therapy in this disease. We present a series of 40 consecutive cases of ACC of the pancreas treated at Memorial Sloan-Kettering Cancer Center, with an emphasis on evaluation of activity of new therapeutic agents.
Patients reviewed at our institution from January 2000 through January 2011 were identified from an institutional database with prior institutional review board approval. Pathology was confirmed in all cases as ACC or a closely related entity.
Forty patients were identified; 29 were male (73%). The median age at diagnosis was 65 years (range, 16–87 years). The median overall survival (OS) time for patients with localized, resectable disease was 56.9 months and the OS time for patients with metastatic ACC (n = 18) was 19.6 months. Six patients with metastatic or recurrent ACC had a partial response to chemotherapy and five patients had stable disease for ≥6 months on systemic chemotherapy. Clinical observation was made of a patient with ACC and hereditary nonpolyposis colorectal cancer and a patient with ACC and a BRCA1 germline mutation.
ACC is moderately chemoresponsive to agents that have activity in pancreatic adenocarcinoma and colorectal carcinoma. A potential association between germline mutations in DNA mismatch repair genes and ACC warrants further evaluation.
Acinar cell carcinoma (ACC) is a rare pancreatic exocrine malignancy, accounting for ~1% of all pancreatic cancer diagnoses. ACC differs significantly from the more common pancreatic ductal adenocarcinoma (PDA); the histologic and immunohistochemical (IHC) findings are distinctive and the molecular alterations share little with PDA. Lacking mutations in genes associated with PDA, such as V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), tumor protein 53 (TP53), deleted in pancreatic cancer 4 (DPC4), and p16, ACCs may have abnormalities in the adenomatosis polyposis coli–β-catenin pathway, similar to colorectal carcinomas (CRCs) . Limited data are available regarding the efficacy of systemic therapy in the management of advanced ACC, with the published experience to date limited to small case series and case reports. The largest single-institution study was published from the Memorial Sloan-Kettering Cancer Center (MSKCC) in 2002; at that time, the reported experience with systemic chemotherapy for ACC was not promising . Over the last decade, the U.S. Food and Drug Administration has approved irinotecan and oxaliplatin for the management of CRC and erlotinib has been approved for use in patients with PDA. In the absence of prospective data to guide therapy, treatment strategies for ACC patients frequently incorporate chemotherapy agents known to have activity in patients with PDA or CRC, an approach with a plausible biologic rationale based on our current knowledge of the molecular pathways involved in the pathogenesis and maintenance of ACC. We reviewed our institutional experience with ACC over the last 10 years to evaluate the activity of current systemic therapy regimens in the management of this rare malignancy. We also report potential associations of ACC with hereditary nonpolyposis colon cancer (HNPCC) and BRCA1 mutation.
Adult patients reviewed at our institution for treatment of ACC of the pancreas or a closely related entity from January 2000 to January 2011 were identified from the prospectively maintained pathology database at MSKCC. Prior approval for the project was obtained from the institutional review/privacy board. Pathology results were reviewed by the reference pathologist (D.K.) in all cases to confirm acinar differentiation; patients with mixed acinar–neuroendocrine carcinoma  or mixed acinar–ductal carcinoma  were included if the tumor had a predominantly acinar differentiation. One adult patient with pancreatoblastoma (PB) was included because these tumors have been shown to have similar biologic features to those of ACC when diagnosed in adulthood .
Clinical and pathological data were obtained from chart review, including age at diagnosis, sex, epidemiologic information, personal and family history of malignancy, presenting symptoms, tumor site, pathology and cytology results, date and type of operation, systemic therapy, radiation therapy, and status at last follow-up. Records were reviewed to determine treatment regimens and radiology reports were reviewed to determine response to therapy. Overall survival was calculated from the date of cytological or pathological confirmation of diagnosis to the date of death or last follow-up, and was calculated using the Kaplan–Meier method.
Forty patients were identified over an 11-year period at MSKCC. Thirty patients had pure ACC and one adult patient had PB of the pancreas. Seven patients were included in a previously reported series from our institution . Four patients had mixed acinar–ductal carcinoma and five patients had mixed acinar–neuroendocrine carcinoma, although the tumor was predominantly of acinar histology in all cases. The clinicopathologic features of patients with ACC are summarized in Table 1.
Twenty-five percent of patients had a prior personal history of malignancy. One patient with adult PB had a known history of familial adenomatous polyposis (FAP) and was diagnosed with ACC at the time of presentation with synchronous locally advanced rectal cancer. One female patient had ACC arising on a background of HNPCC, Muir-Torre variant, and one male patient with ACC had a known germline BRCA1 mutation.
The primary tumor was located in the head of the pancreas in 22 patients (55%). The median tumor size was 4 cm (range, 1.2–27 cm). In two patients with metastatic disease, no primary tumor could be located in the pancreas although biopsy from the metastatic site had a characteristic appearance of ACC on light microscopy and the tumor demonstrated positive IHC staining for trypsin and chymotrypsin. Pathologic characteristics are summarized in Table 2.
Abdominal pain was the most common presenting symptom (n = 18, 45%), followed by weight loss (n = 14, 35%) and jaundice (n = 8, 20%). Serum lipase was elevated in seven of 16 patients (44%) who had a lipase level at diagnosis available, two of whom presented with the characteristic panniculitis and skin rash typical of lipase hypersecretion syndrome.
One patient with a strong family history of colon cancer and breast cancer was diagnosed with metastatic ACC on a background of previous invasive breast cancer, resected sebaceous carcinoma, and basal cell carcinoma (BCC) of the skin. IHC analysis for mismatch repair proteins was performed on liver biopsy material and demonstrated intact expression of mutL homolog 1, mutS homolog 2 (MSH2), and postmeiotic segregation increased 2 (PMS 2); MSH6 staining was equivocal. IHC was then repeated on the sebaceous carcinoma tissue and demonstrated absent expression of MSH6, with normal expression of MLH1, MSH2, and PMS2. Direct gene sequencing of the MSH6 gene was performed, which identified the mutation 1312insA, consistent with a diagnosis of HNPCC, Muir-Torre variant. One case of ACC arising in a known BRCA1 mutation carrier was identified; that patient also had a prior personal history of papillary renal cancer and colon cancer and had a history of acromegaly.
Nineteen patients (47.5%) had localized disease at presentation and underwent surgical resection. Eight of those patients (42%) developed recurrent disease at a median time to recurrence of 7.8 months (range, 3–28.5 months). One patient had a local recurrence and the remainder relapsed with distant metastases. The median overall survival duration for patients with localized, resectable disease was 56.9 months. Twelve patients (63%) received adjuvant therapy (chemotherapy alone, n = 9; chemoradiation, n = 3), of whom five patients relapsed (42%), whereas three patients of seven (42%) who did not receive adjuvant therapy relapsed, all with distant metastases. Of note, seven of eight patients (88%) who relapsed had node-positive disease (N1), whereas just two of the 11 resected patients (18%) who remained without evidence of disease at last follow-up had N1 disease at the time of surgery.
One patient underwent a palliative R1 surgical resection in the setting of known liver metastases. Three patients had inoperable locally advanced (LA) disease at presentation, one of whom declined all therapy and lived for 18 months. The second patient underwent R1 surgical resection following neoadjuvant chemoradiation and remained free of disease after 16 months of follow-up. The third patient with LA disease received radiation and systemic therapy and survived almost 5 years from diagnosis.
Eighteen patients had metastatic disease at diagnosis; the liver was the most common site of metastasis (14 patients, 78%). The median overall survival duration of patients with metastatic disease at presentation was 19.6 months. Of 27 patients with metastatic disease at diagnosis or recurrence, two declined systemic therapy. Treatment records for 20 of the remaining 25 patients were available. In total, 17 different combination regimens were administered. Six patients had a partial response (PR) to chemotherapy (35%): two patients treated with gemcitabine and oxaliplatin, one patient each treated with gemcitabine, docetaxel, and capecitabine (GTX), cisplatin plus irinotecan, cisplatin plus gemcitabine, and gemcitabine plus erlotinib (Fig. 1). One patient had a PR to gemcitabine plus oxaliplatin following a period of prolonged stable disease (SD) on gemcitabine plus irinotecan. Two of the six patients were responsive to more than one line of chemotherapy. A further five patients had SD for ≥6 months on systemic chemotherapy without a radiographic PR, giving a clinical benefit rate (PR plus SD) of 55% (Table 3).
The characteristic pathologic findings of ACC differ from those of PDA, reflecting its differentiation toward the enzyme-producing cells of the pancreatic acini rather than the epithelial cells lining the pancreatic ducts. Typical findings at microscopy include a highly cellular tumor that lacks the prominent stromal component seen in PDA, whereas cells typically demonstrate a uniform appearance on microscopy with large, centrally located nucleoli (Fig. 2). The cytoplasm is typically eosinophilic and granular as a result of the presence of zymogen granules. IHC staining for the enzymes trypsin and chymotrypsin can detect acinar differentiation with 95% sensitivity . These findings were previously well described; more recently, however, it was also identified that the molecular signature of ACC is distinct from that of PDA. KRAS, TP53, and DPC4 gene alterations are not typically found in ACC, whereas mutations in the APC–β-catenin pathway similar to those found in CRC occur in ~25% of ACCs but not in PDA .
The association of ACC with other malignancies or inherited cancer predisposition syndromes remains unclear. In this series, 10 patients (25%) with ACC had a prior personal history of malignancy, with prior diagnoses including neuroblastoma, BCC, melanoma, lung cancer, urothelial cancer, Hodgkin's lymphoma, and prostate cancer. We also identified one patient with ACC arising on a known background of HNPCC. A previous study that evaluated 21 ACC tumor samples for microsatellite instability (MSI) also identified one high MSI case . One patient with pancreatoblastoma also had a diagnosis of FAP. That case was previously described as demonstrating a possible extracolonic manifestation of FAP resulting from germline mutation of APC . Notably, frequent alterations in the Wnt signaling pathway have been demonstrated in colorectal adenocarcinomas with MSI . The Wnt pathway is involved in tumorigenesis via mutations in regulatory genes including APC, whereas mutations in the APC pathway are sometimes found in ACC. Although there is a plausible scientific basis for an association between HNPCC and FAP and ACC, further study is needed to investigate these clinical observations.
We also report a case of ACC arising in a known BRCA1 germline mutation carrier. Although patients with germline mutations in BRCA1 and BRCA2 are known to have a higher risk for PDA, an association with ACC has not been well-elucidated to date. A recent study of a transgenic mouse model of BRCA mutation–associated PDA showed that mice with biallelic inactivation of BRCA2 within the pancreatic tissue predominantly developed ACC . Evaluation of seven human pancreatic tumor samples (three ACC, four PDA) from patients with a known BRCA2 mutation from an Icelandic registry found that three of four tumor samples with typical ductal histology did not exhibit loss of heterozygosity (LOH) at the mutation site, whereas all three ACCs demonstrated LOH for BRCA2. Evaluation of a larger number of human tumor samples is required to further explore the hypothesis that monoallelic loss of BRCA2 in pancreatic tissue in germline BRCA2 mutation carriers leads to PDA whereas biallelic loss favors differentiation into ACC.
ACC has classically been associated, in up to 10% of cases, with Schmidt's triad of s.c. nodules from fat necrosis (panniculitis) with eosinophilia and polyarthragias . Although serum lipase was elevated at diagnosis in ~50% of patients, just two patients presented with the classic panniculitis associated with hypersecretion of lipase by ACC. In one patient the skin manifestations preceded the diagnosis of pancreatic malignancy by several months, and in both cases the serum lipase level was elevated >1,000 u/dL. We identified this syndrome in just two patients (5%), which may reflect the relatively large number of patients with operable disease included in our series.
In two patients, no primary tumor within the pancreas could be identified, despite biopsy of the metastatic site clearly demonstrating typical histologic and IHC features of pancreatic ACC. Tumors with acinar cell differentiation arising from the stomach and the colon have been reported previously [11–13]; however, endoscopic evaluation did not demonstrate tumor elsewhere in the gastrointestinal tract in either of our patients. Because neither patient underwent surgical exploration, one potential explanation for this may be the presence of a small, radiographically occult primary pancreatic lesion.
The median survival time of 33.9 months in this cohort of patients is consistent with previously published smaller institutional series and large database reviews of ACC, which have shown a better prognosis for ACC patients than for PDA patients (Table 4) [2, 14–22]. We report a median survival time of 56.9 months for patients presenting with localized disease amenable to surgical resection (Fig. 3). The impact of adjuvant chemotherapy or radiation on survival following surgical resection is difficult to determine in the absence of prospective data, and limited conclusions may be drawn from this retrospective series. We did observe a higher frequency of disease recurrence in patients who underwent resection of node-positive disease than in those with node-negative pathology. This suggests that patients who undergo resection of node-positive ACC are at significant risk for systemic relapse and should be considered for adjuvant therapy.
The median survival time of 19 months for patients with advanced disease may reflect the less aggressive biology and greater chemosensitivity of ACC than PDA. Of 20 patients with metastatic disease who received chemotherapy, a PR to treatment was demonstrated in six patients (30%). A further five patients had prolonged SD on combination chemotherapy (Table 3). The greater clinical benefit of systemic therapy observed in this series than in our previously published series of 10 years ago may be explained by the greater use of combination chemotherapy regimens incorporating oxaliplatin and irinotecan over the last decade . Regimens used included combinations of drugs known to have activity in both PDA and colon cancer, including irinotecan, oxaliplatin, erlotinib, gemcitabine, and 5-fluorouracil, along with the three-drug combination regimen GTX. The identification of shared genetic alterations between ACC and CRC offers a biologic rationale for the use of agents active in CRC in the management of ACC. The combination regimen of infusional 5-fluorouracil, irinotecan, and oxaliplatin has been shown to produce a survival advantage for patients with metastatic PDA, compared with gemcitabine, and has also been demonstrated to produce high response rates and long survival times in patients with metastatic CRC [23, 24]. Given the activity of these agents administered as doublet chemotherapy regimens reported here, this three-drug combination offers the potential for significant activity in ACC patients; however, to our knowledge this regimen has not yet been tried in a patient with ACC.
To summarize, the observed activity of combination chemotherapy in patients with metastatic ACC offers support for the use of gemcitabine- or 5-fluorouracil–based combination therapy incorporating irinotecan, a platinum analog, or docetaxel in patients with advanced disease. The benefit of adjuvant therapy remains unproven. We report cases of ACC occurring in a male BRCA1 germline mutation carrier and in a female with HNPCC. The association of ACC with hereditary genetic cancer predisposition syndromes is an area of ongoing research. These observations in patients with a known predisposing genetic background offer insight into the key molecular events leading to the development of ACC. We anticipate that further study of ACC may help elucidate the sequence of genetic events leading to sporadic ACC and so provide new molecular targets for intervention.
Presented in part at the 2010 American Society of Clinical Oncology Gastrointestinal Symposium.
Conception/Design: Eileen M. O'Reilly, David S. Klimstra, Maeve A. Lowery
Provision of study material or patients: Eileen M. O'Reilly, David S. Klimstra, Jinru Shia, Kenneth H. Yu, Peter J. Allen, Murray Brennan
Collection and/or assembly of data: Kenneth H. Yu, Maeve A. Lowery
Data analysis and interpretation: Eileen M. O'Reilly, Jinru Shia, Murray Brennan, Maeve A. Lowery
Manuscript writing: Maeve A. Lowery
Final approval of manuscript: Eileen M. O'Reilly, David S. Klimstra, Jinru Shia, Kenneth H. Yu, Peter J. Allen, Murray Brennan, Maeve A. Lowery