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Clinical Characteristics and Outcomes From an Institutional Series of Acinar Cell Carcinoma of the Pancreas and Related Tumors

From the Memorial Sloan-Kettering Cancer Center, Gastrointestinal Oncology Service, Department of Medicine, Department of Epidemiology and Biostatistics, Department of Pathology, and Gastric and Mixed Tumor Service, Department of Surgery, New York, NY 10021.

Address reprint requests to Leonard B. Saltz, MD, Memorial Sloan-Kettering Cancer Center, Gastrointestinal Oncology Division, Howard Bldg 917, 1275 York Ave, New York, NY 10021; email: saltzl{at}mskcc.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: Acinar cell carcinoma is a rare tumor of the exocrine pancreas. Clinical features such as prognostic information, survival, and treatment outcomes are unknown. We present the largest retrospective review to date.

PATIENTS AND METHODS: Thirty-nine patients with pathologically confirmed acinar neoplasms of the pancreas were identified between August 1981 and January 2001. Demographic data, tumor characteristics, and treatment information were obtained by chart review. Survival probabilities were estimated by using the Kaplan-Meier method and compared using the log-rank test.

RESULTS: The median survival for all patients was 19 months. On the basis of a univariate analysis, the patients’ stage of disease correlated significantly with survival. The median survival of patients with localized disease was 38 months, versus 14 months for those presenting with metastases (P = 0.03). Patients who could be treated with surgery as first-line therapy had a longer survival time (36 months) compared with those who did not have surgery (14 months). Two of 18 patients who received chemotherapy and three of eight patients who received radiation had a major response.

CONCLUSION: The survival curves suggest a more aggressive cancer than pancreatic endocrine neoplasms but one that is less aggressive than ductal adenocarcinoma of the pancreas. Those patients who present with localized disease have a much better prognosis than those who present with metastases. There is a high recurrence rate after complete surgical resection, suggesting that micrometastases are present even in localized disease and that adjuvant therapies may be indicated. Chemotherapy and radiation afford disappointing results, however, and novel therapies are needed.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
ACINAR CELL carcinomas (ACCs) are rare tumors of the exocrine pancreas, accounting for up to 1% of all pancreatic tumors.^1-5 ACC is defined as a carcinoma exhibiting evidence of pancreatic enzyme production by the neoplastic cells, although these tumors also have highly characteristic histologic features (Fig 1). According to data from the American Cancer Society, in the year 2000 there were roughly 300 patients with ACC in the United States. This tumor has been described elsewhere in multiple case reports dating from 1950 and earlier,^6-13 with two small series by Webb¹⁴ and Klimstra¹⁵ reviewing 11 and 28 patients with ACC, respectively, collected from multiple institutions. These studies emphasized the pathologic characteristics of acinar cell carcinoma. Another series, by Hoorens et al,¹⁶ analyzed cell lineage markers, p53 expression, and K-ras mutations of ACCs, demonstrating that they constitute an entity different from ductal adenocarcinoma or endocrine tumors. Other pancreatic neoplasms with predominantly acinar differentiation include mixed acinar-endocrine carcinoma (a tumor with both acinar and endocrine differentiation in > 25% of the cells) and pancreatoblastoma (a tumor most commonly affecting young children). Both mixed acinar-endocrine carcinoma and pancreatoblastoma have biologic properties similar to acinar cell carcinoma when they occur in adulthood.^17,18

View larger version (155K): [in this window] [in a new window]   Fig 1. Light microscopic appearance of acinar cell carcinoma. The tumor is hypercellular, with cords of cytologically uniform cells with granular eosinophilic apical cytoplasm reflecting the accumulation of zymogen granules.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Selection and Staging
We searched the pathology records of the Memorial Sloan-Kettering Cancer Center from 1980 to 2001 for pancreatic neoplasms with features of acinar differentiation. Tumor types included were acinar cell carcinomas, mixed acinar-endocrine carcinomas,² and pancreatoblastomas occurring in adults.² The last two tumors were included because they are closely related to acinar cell carcinoma, both in terms of cellular differentiation and biologic behavior.^17,18 Cases found dated from August 1981 to January 2001. Pathologic material included biopsies of metastatic lesions or specimens obtained after full or partial pancreatectomy. The light microscopic features of all cases were highly suggestive of acinar differentiation. These included a hypercellular low-power appearance with a relatively circumscribed periphery and minimal desmoplastic stroma within the tumors. The cells were arranged in nests and cords. Characteristic pinpoint lumina punctuated solid regions; these acinar formations recapitulated the morphology of nonneoplastic pancreatic acini (Fig 1). The cytoplasm was moderate in amount, eosinophilic, and focally granular. The nuclei generally showed only moderate atypia. They were commonly oriented toward the basal aspect of the cells, and single prominent nucleoli were often present. Immunohistochemical staining confirmed the light microscopic impression of acinar differentiation and excluded the alternative diagnosis of pancreatic endocrine neoplasm in all patients with ACC. All patients with ACC showed positivity for one of the pancreatic enzymes trypsin or chymotrypsin, generally for both. In four patients with ACC, a minor component of endocrine differentiation was detected as focal positivity for synaptophysin (four patients) or chromogranin (two of these four patients).

Two of the identified patients with ACC showed light microscopic features similar to those of pure acinar cell carcinomas, but in addition to having widespread staining for the acinar markers trypsin and chymotrypsin, these tumors showed a less prominent endocrine component. In each case, there was positive staining for synaptophysin (both patients) or chromogranin (one patient) in roughly 30% of the tumor cells. These tumors were classified as mixed acinar-endocrine carcinomas.

In addition, there were two adult patients with pancreatoblastomas. These tumors had similar microscopic features to the ACCs but, in addition, exhibited squamoid corpuscles (circumscribed, whorled nests of spindle-shaped squamous cells with larger nuclei than the surrounding acinar elements and more abundant cytoplasm). Both of these tumors stained for trypsin and chymotrypsin and had minor components with endocrine differentiation.

All of the 39 cases of acinar neoplasms identified were from surgical specimens (ie, no cases diagnosed exclusively by cytology were included). We obtained clinical information from the patients’ charts; however, four cases involved specimens sent to Memorial Sloan-Kettering solely for review by the pathology department. In these cases, the patients’ treating physicians were called for clinical information. Complete clinical information was obtained for 37 patients with ACC; two patients were from outside the United States, and their information could not be attained. We have mortality data on 37 patients with ACC and treatment information on 33 patients.

Response to Therapy
Surgery was uniformly employed for the 16 patients who had limited, resectable disease. Resectable disease was defined as no radiographic or laparoscopic evidence of distant metastases or major vessel involvement. Two patients received postoperative adjuvant chemotherapy and/or radiation. Systemic treatment included single-agent chemotherapy, combination chemotherapy, and combined modality treatment with radiation and chemotherapy. For those with more extensive disease or disease recurrence, chemotherapy was the most common treatment. There were a variety of different types of chemotherapy administered.

For this review, response criteria were defined as the following: Complete response (CR) was defined as the disappearance of the primary lesion and all metastases. Partial response (PR) was defined as a 30% decrease in the longest dimension of the largest lesion, taking as a reference the baseline longest dimension of the largest lesion. Progressive disease (PD) was defined as a 20% increase in the longest dimension of the largest lesion, taking as a reference the baseline longest dimension, or the appearance of one or more new lesions. Stable disease (SD) was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as a reference the baseline longest dimension of the largest lesion. For SD to occur, the reference lesion must have been measured at least 3 months after the baseline lesion was measured. The longest diameter was recorded for the primary tumor or the largest metastatic lesion, whichever was larger. All measurements were performed using a caliper or ruler and were recorded in metric notation in centimeters. The same method of assessment and the same technique were used to characterize the primary tumor or the largest lesion at baseline and during follow-up. Computed tomographic scans and magnetic resonance imaging were the methods used for tumor assessments.

Statistical Analysis
Survival probabilities were estimated using Kaplan-Meier methods. Potential prognostic factors were treated univariately using the log-rank test from date of confirmation by pathology to last follow-up or date of death. Time to first treatment failure is defined as the time from end of first-line treatment to date of first treatment failure or last follow-up.

	RESULTS

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Demographics
Demographic data were available for all 39 patients. The patient demographics and disease characteristics are summarized in Table 1. The median age of this population was 60 years, with the youngest at age 15 years and the oldest at age 87 years. Seventy-seven percent of the patients were men; 23% were women. Most of the patients in the series were white, non-Hispanic (82%), with 3% African-American, 5% Asian-Pacific islander, and 11% Hispanic.

Presenting Signs and Symptoms
The most common initial symptom was abdominal pain or bloating, accounting for 19 patients’ presenting complaints. A few others had a change in stools, from diarrhea to bloody stools. Some of the most common signs at presentation were a palpable abdominal mass, elevated liver enzymes, jaundice, and anemia. Three patients in this series had subcutaneous nodules, a manifestation of elevated lipase secreted by the tumor (lipase hypersecretion syndrome). All three of these patients with subcutaneous nodules had elevated lipase levels. Only nine patients in this series had a documented lipase level. Four had normal levels, four had elevated levels (at 607, 1,230, 7,100, and 10,600 U/L), and one patient had a slightly elevated lipase at 77 U/L (normal range, 7 to 60 U/L). Only four patients had a documented alpha-fetoprotein levels. Two were elevated at 22,751 and 44.7 ng/mL (normal range, 0.0 to 15.0 ng/mL), and two patients were normal.

Treatment Type and Response Rates
Among the 39 patients identified, 25 (64%) have died from their disease; one (3%) died from causes unrelated to acinar cell carcinoma, and two (5%) were lost to follow-up. The two patients lost to follow-up were excluded from further statistical analysis. Of the 37 remaining patients, the first-line treatments were as follows: 16 underwent surgery, eight received chemotherapy, two received concurrent chemotherapy and radiation therapy, two received sequential radiation followed by chemotherapy, and nine received no treatment or unknown treatment. Table 2 lists the response rates for those patients who underwent chemotherapy or radiation.

There were 22 different chemotherapy regimens administered to 18 different patients. There were no CRs, two PRs, and seven patients with SD. The PRs were seen with two different regimens. The first was a combination of irinotecan, fluorouracil (FU), and leucovorin. This patient died in a car accident 7 months after the initiation of therapy while in a PR. The other PR was with an experimental regimen of cytarabine, cisplatin, and caffeine. This patient had a PR after 3 months of treatment and then progression of disease on a follow-up computed tomographic scan after 6 months of treatment. The most common chemotherapy treatment associated with SD was FU.

Only a few patients in this series received radiation therapy. The responses, however, were favorable. One of the two evaluable patients who received concurrent FU and radiation benefited from a PR, the other had SD for 6 months. Similarly, of the two patients who received sequential radiation followed by chemotherapy, one patient had a PR and the other had SD. One patient received radiation only; this patient had a PR. In both cases of concurrent chemotherapy and radiation, 5,040 Gy radiation was used with three daily bolus infusions of FU during the first and last weeks of radiation.

Overall Survival and Time to Treatment Failure
As of March 2001, the median duration of follow-up from the date of diagnosis was 32 months, with a range of 2 to 64 months. The median overall survival was 19 months, with a 95% confidence interval of 14 to 30 months.

Of the seven patient characteristics analyzed univariately for correlation with survival (Table 3), only two were statistically significant: sex (P = .04) and metastases at presentation (P = .03). Males were 3.72 times more likely to die than females (median survival was 15 v 45 months, respectively). There was a statistically significant difference between those who presented with local-regional disease and those with metastases. Patients presenting with disease confined to the pancreas (n = 18) had a median survival of 38 months, whereas patients with metastatic disease had a median survival of 14 months (P = .03). The Kaplan-Meier survival curve for metastases at presentation is shown in Fig 2. The slight differences in the survival profiles for age, race, tumor size, tumor location, and type of first-line treatment did not reach statistical significance. Even though the survival curves between the types of first-line treatments were not statistically significant, there is a notable difference. If the patient underwent surgery as their initial therapy, their median survival was 36, versus 14 months for those who did not have surgery as a first-line treatment.

View larger version (11K): [in this window] [in a new window]   Fig 2. Overall survival, Kaplan-Meier curve. Median survival, 19 months.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
This study, representing 20 years of experience at Memorial Sloan-Kettering Cancer Center, is the most comprehensive series to date describing the clinical characteristics, treatment outcomes, and survival of 37 patients with pancreatic acinar cell carcinoma and the related tumors (mixed acinar-endocrine carcinoma and adult pancreatoblastoma).

Our patients presented with any of a constellation of different signs and symptoms. On imaging, a heterogeneous mass arising from the pancreas was usually seen. Frequently, there is evidence of metastatic disease, the most common site being the liver. Interestingly, these tumors can secrete lipase and occasionally present with signs related to excess lipase secretion, manifested by high serum lipase levels, diffuse subcutaneous nodules, and polyarthropothies. The skin nodules are often mistaken for metastatic disease—a mistake that can have profound implications in the management of this disease. This lipase hypersecretion syndrome is uncommon but has been a frequently reported paraneoplastic syndrome.^6-13,22,23

Pathologic review of the pure acinar cell carcinoma yields two predominant cellular patterns of growth: the acinar pattern consisting of cells growing in well-formed acini, and the solid pattern characterized by sheets and cords of cell separated by a thin fibrovascular stroma.¹⁵ These cells also display a unique immunohistochemical staining pattern: strongly positive for trypsin and chymotrypsin and negative or only focally positive for synaptophysin and chromogranin. The mixed acinar-endocrine carcinomas are histologically similar to the pure ACCs but have more than 25% endocrine cells when analyzed by immunohistochemistry. In this study, both of the mixed acinar-endocrine carcinomas showed predominantly acinar differentiation. Pancreatoblastomas are also fundamentally acinar neoplasms, showing consistent expression of the enzymes trypsin and chymotrypsin.¹⁸ In addition, pancreatoblastomas commonly have endocrine ductal differentiation and exhibit characteristic squamoid corpuscles, which is the histologic hallmark of the entity that allows separation from acinar cell carcinomas. Patients with pancreatoblastomas have been reported to have a similar clinical course as those with acinar cell carcinomas, which justifies their inclusion in this study.

Although this study was not designed as a direct comparison, it is interesting to note that the overall survival for acinar cell carcinoma in this series (19 months) lies between ductal adenocarcinoma of the pancreas (with a median survival of 6 months) and pancreatic endocrine neoplasms (with a median survival of between 40 and 60 months)^24,25 when compared with historical controls and other institutional series.

A matched analysis was performed using the pancreatic cancer database at Memorial-Sloan Kettering Cancer Center. Cases of acinar cell carcinoma of the pancreas were matched with cases of ductal adenocarcinoma in terms of age and sex. The median age was 60 years in this group (range 26 to 85 years), and there were nine women and 30 men, similar to the group with acinar cell carcinoma. The median overall survival for the matched cases of ductal adenocarcinoma was 8 months (95% confidence interval, 6.9 to 13.5; n = 39), substantially less than the survival we noted for acinar cell carcinoma.

Those patients with confined disease have a better prognosis than those who present with metastases; this finding also is similar to the data on ductal adenocarcinoma. The median survival for acinar cell carcinoma in our study is similar to the survival in the series presented by Klimstra et al¹⁵ (18 months). In that study, the size of the tumor and patient age also correlated with survival; however, our analysis did not suggest similar correlations.

Women outlived men by approximately 30 months. There is little reason to believe that the biology of acinar cell carcinoma is different in men versus women. This difference is likely caused by a confounding factor, specifically, the presence of metastatic disease. Only three of the eight women presented with metastatic disease. Such confounders can only be identified with a multivariate analysis, which is precluded by the small sample size.

For the few patients who had an elevation of lipase levels, this did not seem to correlate with either the extent of disease or with a better or worse prognosis. Lipase levels, when elevated, may be a useful marker to assess response to therapy and should be checked in those patients diagnosed with acinar cell carcinoma.

Surgical management of acinar cell carcinoma remains the best therapy for those patients with local, resectable disease. Those who were able to undergo surgical resection had a survival of 36 months. This compares favorably with the data on ductal adenocarcinoma of the pancreas; published reports on survival after resection estimate a median survival of 12 to 18 months.²⁶ The survival for the surgically resected patients in our series was much higher than the survival for patients who did not undergo surgery. This comparison is subject to selection bias because only fit patients are selected for surgical resection and these patients all have locally confined disease. As mentioned above, those with local disease had a statistically significant survival advantage (P = .03) compared with the patients who presented with metastatic disease.

Unfortunately, surgical management is not curative in the majority of patients. We noticed a high frequency of recurrent disease among the patients who underwent a surgical resection (72%), many of whom experienced distant metastases as opposed to local recurrences. The trend toward distant recurrence compared with local recurrence correlates with the gross findings on pathologic review. Acinar neoplasms are usually well circumscribed, making an R0 resection more common. As expected, of the few patients who remained disease free after surgery, most (80%) were those with negative margins. The high frequency of distant recurrences suggests the presence of micrometastases even in those presenting with organ-confined disease and indicates that adjuvant chemotherapy may play a role. It is difficult to determine which chemotherapy regimen is most appropriate for adjuvant treatment and what should be the duration of such therapy. Most adjuvant therapies are modeled after therapies with favorable response rates in the metastatic setting.

In our patients with metastatic disease, the response rates with chemotherapy were disappointing at best. Only two of 18 patients had a PR to chemotherapy. These two regimens were different. One contained cisplatin, cytarabine, and caffeine, a toxic experimental therapy. The other regimen, irinotecan, FU, and leucovorin, commonly used for metastatic colon cancer,²⁷ is better tolerated. It is notable that ACCs tend to respond to FU and combination therapies that are commonly used to treat colon cancer. A recent molecular analysis of both ACCs and pancreatoblastomas found abnormalities in the APC/ß catenin pathway similar to those found in colorectal cancer. ACCs and pancreatoblastomas had none of the gene abnormalities that are commonly found in ductal pancreatic adenocarcinomas.²⁸ Perhaps administration of newer agents with activity in metastatic colorectal cancer (ie, oxaliplatin or capecitabine) should be attempted to improve the unsatisfactory results noted with current therapies.

For those patients with unresectable yet locally confined disease, chemoradiation may be the best treatment option. Although the numbers are small, they are impressive. All eight patients treated with radiation had either a PR or SD. Because of the finding that many patients who presented with local disease eventually had distant recurrences, it is reasonable to recommend a radiation course that includes some chemotherapy, either concomitant or sequential, for better control of likely distant metastatic disease. FU was the only radiosensitizing agent used in this series.

Despite the somewhat improved survival compared with ductal adenocarcinoma, acinar neoplasms remain difficult to treat. Because they are rare tumors, there is a paucity of information available, and randomized trials comparing treatment strategies are impossible. It is useful, however, to observe that responses to treatment exist and can be durable. Patients who are fit to undergo surgical resection have the best survival. Radiation therapy affords good responses in those with regional, unresectable disease. Chemotherapy results are disappointing, and novel therapies are needed. The information gained from this series will assist the practitioner in estimating prognosis and will help guide treatment decisions.

	NOTES

 
Submitted February 1, 2002; accepted July 11, 2002

	REFERENCES

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Holen, K. D. Articles by Saltz, L. B. Search for Related Content PubMed PubMed Citation Articles by Holen, K. D. Articles by Saltz, L. B. Social Bookmarking                            What's this?