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 (). 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 [6
]. 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
, 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 [1
Histology of pancreatic cancer. (A): Ductal adenocarcinoma. (B): Acinar cell carcinoma.
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 [1
]. 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 [8
]. 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
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 [9
]. 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 [10
]. 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
]; 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 () [2
]. We report a median survival time of 56.9 months for patients presenting with localized disease amenable to surgical resection (). 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.
Previously reported series of acinar cancer
Survival by stage. The median survival time for patients with localized (L) disease was 56.9 months and the median survival time for patients with advanced (A) disease was 19.6 months.
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 (). 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 [2
]. 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
]. 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.