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Anaplastic pancreatic cancer (APC) is a rare undifferentiated variant of pancreatic ductal adeno- carcinoma with poor overall survival (OS). The aim of this study ...
Clinical Characteristics and Overall Survival in Patients with Anaplastic Pancreatic Cancer CLANCY J. CLARK, M.D.,* JANANI S. ARUN, M.D.,* RONDELL P. GRAHAM, M.B.B.S.,† LIZHI ZHANG, M.D.,† MICHAEL FARNELL, M.D.,* KAYE M. REID-LOMBARDO, M.D.*

From the *Divisions of Gastroenterologic and General Surgery and †Anatomic Pathology, Mayo Clinic, Rochester, Minnesota Anaplastic pancreatic cancer (APC) is a rare undifferentiated variant of pancreatic ductal adenocarcinoma with poor overall survival (OS). The aim of this study was to evaluate the clinical outcomes of APC compared with differentiated pancreatic ductal adenocarcinoma. We conducted a retrospective review of all patients treated at the Mayo Clinic with pathologically confirmed APC from 1987 to 2011. After matching with control subjects with pancreatic ductal adenocarcinoma, OS was evaluated using Kaplan-Meier estimates and log-rank test. Sixteen patients were identified with APC (56.3% male, median age 57 years). Ten patients underwent exploration of whom eight underwent pancreatectomy. Perioperative morbidity was 60 per cent with no mortality. The median OS was 12.8 months. However, patients with APC who underwent resection had longer OS compared with those who were not resected, 34.1 versus 3.3 months (P 5 0.001). After matching age, sex, tumor stage, and year of operation, the median OS was similar between patients with APC and those with ductal adenocarcinoma treated with pancreatic resection, 44.1 versus 39.9 months, (P 5 0.763). Overall survival for APC is poor; however, when resected, survival is similar to differentiated pancreatic ductal adenocarcinoma.

(APC) is a rare undifferentiated variant of pancreatic ductal adenocarcinoma (PDA) first reported by Sommers et al. in 1954.1 Previous authors have described APC as undifferentiated carcinoma, pleomorphic carcinoma, giant cell carcinoma, undifferentiated pancreatic carcinoma with osteoclast-like giant cells (OCGCs), osteoclastoma, and mixed osteoclast and pleomorphic-type giant cell tumor.1–16 Despite numerous studies focused on histologic diagnosis and epithelial or mesenchymal origin,6, 17–23 few studies have investigated clinical outcomes for patients with APC. Prior reports have suggested that survival of patients with APC is poor relative to differentiated PDA.8, 13, 14, 16 In a populationbased study, we recently reported that survival is similar between resected APC and differentiated PDA.24 Undifferentiated pancreatic carcinoma with OCGCs is a subtype of APC with a distinct histologic morphology.25 First reported by Rosai et al. in 1968, it is characterized by discohesive, oval neoplastic spindle cells present in sheets with interspersed nonneoplastic

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Presented at the Americas Hepato-Pancreato-Biliary Association annual meeting, Miami, Florida, March 9, 2012. Address correspondence and reprint requests to Clancy J. Clark, M.D., Assistant Professor of Surgery, General Surgery, Wake Forest Baptist Health, Medical Center Boulevard, Winston-Salem, NC 27157. E-mail: [email protected].

multinucleated OCGCs.4, 9, 17, 26, 27 Survival for patients with this specific subtype of APC has been reported to be significantly better than other types of APC.16 The primary aim of this study was to describe our experience with APC in terms of presentation, histopathology, perioperative morbidity and mortality, and survival. Second, we compared the overall survival (OS) of patients with APC matched with similar patients with PDA. Materials and Methods Study Cohort

This retrospective cohort study was approved by the Mayo Clinic Institutional Review Board. All patients diagnosed with APC treated at the Mayo Clinic, Rochester, Minnesota, between 1987 and 2010 were identified. Paper and electronic medical records were reviewed to extract demographic information, presenting symptoms, tumor stage, method of diagnosis, and pathology findings. Perioperative data included type of operation, extent of lymph node dissection, number of positive lymph nodes, and perioperative 30-day morbidity and mortality. Preoperative imaging records were reviewed for tumor extension, tumor size, central necrosis, and metastases. When available, original staging computed tomography (CT) and magnetic resonance images were reviewed. Tumor stage was defined using

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the American Joint Committee on Cancer (AJCC), 7th Edition staging scheme for pancreatic cancer.28 The last date of follow-up was defined as the date of last contact with a physician or date of death as of December 14, 2011. Overall survival was defined as number of months from date of operation or pathologic confirmation in unresected patients to date of death or last follow-up. Pathology Confirmation

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Continuous data were reported as median with interquartile range and categorical data as count and per cent. Overall survival was evaluated using Kaplan-Meier estimates and log-rank test. Significance was defined as a P value # 0.05. Results Clinical Characteristics

To compare OS of patients with resected APC and PDA, we performed a case–control study. Patients with APC were matched 1:3 with a cohort of 394 patients with poorly, moderately, or well-differentiated PDA who underwent pancreatic resection at the Mayo Clinic in Rochester, Minnesota. Matching parameters were age, sex, year of operation, and the AJCC, 7th edition stage. One patient with APC and metastatic disease to periaortic lymph nodes (identified after resection) was not included in the survival analysis as a result of an inability to match with a similar Stage IV patient with PDA. Sensitivity analyses indicated that the survival estimates were not impacted by inclusion or exclusion of this patient from the final analysis.

Between 1987 and 2010, 16 patients with pathologyconfirmed APC were treated at the Mayo Clinic in Rochester, Minnesota. The majority of patients were male (56.3%) with a median age of 57 (range, 45 to 71 years) (Table 1). Abdominal pain and jaundice were the most common presenting symptoms. On review of CT imaging, radiographic evidence of a hypodense pancreatic mass suggesting central necrosis was present in five of eight (62.5%) patients (Fig. 1). Ten patients underwent exploratory laparotomy with pancreatic resection performed in eight patients. For the six patients who did not undergo resection, four patients presented with distant metastatic disease to the liver and two patients presented with preoperative imaging indicating locally advanced disease with major arterial involvement. Pancreaticoduodenectomy was performed in six patients and two patients underwent distal pancreatectomy with en bloc resection of the stomach (n 4 1) and left kidney (n 4 1), respectively. For patients treated with pancreatic resection, pathology demonstrated margin-negative resection (R0) in six patients and a microscopic positive margin (R1) in two patients. One patient treated with R0 resection was found to have metastatic disease to periaortic lymph nodes after resection on final pathology. Median tumor size was 4.0 cm (range, 3.9 to 5.0 cm). Positive lymph nodes were identified in five of the 10 (50.0%) patients who had lymph node staging at the time of exploration. For all patients who underwent exploratory laparotomy, 30-day perioperative morbidity was 60.0 per cent (n 4 6) with no mortality. Postoperative complications included pancreatic fistula (n 4 2); delayed gastric emptying (n 4 1); intra-abdominal abscess and biliary stricture (n 4 1); leak from feeding jejunostomy requiring reoperation (n 4 1); and duodenal ulcer resulting in a hemigastrectomy, vagotomy, and Roux-en-Y reconstruction performed at another institution (n 4 1).

Statistical Analysis

Pathologic Review

Statistical analyses were performed using SASÒ 9.1.3 (SAS Institute Inc., Cary, NC). Univariate comparison of APC and PDA groups was performed using x2 and Fisher’s exact test for categorical variables and Wilcoxon rank-sum test for continuous variables.

Based on tumor H&E morphology, cases with APC were subtyped as follows: anaplastic pancreatic carcinoma, not otherwise specified (31.3%); giant cell carcinoma (25.0%); mixed pleomorphic/giant cell carcinoma (18.8%); undifferentiated carcinoma with OCGCs

Hematoxylin and eosin-stained (H&E) slides were reviewed for each case independently by two pathologists (R.P.G. and L.Z.) to confirm the diagnosis of APC. After morphologic review, APC cases were descriptively subtyped. In cases with morphologic evidence of OCGCs, diagnosis of undifferentiated carcinoma with OCGCs was confirmed with cluster of differentiation (CD) 68 and cytokeratin. Immunohistochemistry for CD68 and cytokeratin was performed as follows. Four-micron-thick paraffin sections were cut from the formalin-fixed paraffin-embedded tissue blocks. Heatinduced epitope retrieval was performed with a steamer (95 to 99°C) in the case of the cytokeratin stain and Dako Target Retrieval Solution (Dako, Carpinteria, CA) in the CD68, both using previously validated methods. After pretreatment, monoclonal antibodies directed to cytokeratin (clone OSCAR, 1:40, CovanceÒ, Dedham, MA) and CD68 (clone KP1, 1:50-1:100; Dako) were applied to the tissue sections with 30-minute incubations and slide preparation completed. Appropriate controls were used. Identification of Matched Control Subjects

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TABLE 1. Clinical Characteristics of Patients with Anaplastic Pancreatic Cancer (APC) Variable Age (years) median (IQR) Male, no. (%) BMI (kg/m2), median (IQR)a Presenting symptom, no. (%) Abdominal pain Jaundice Pancreatitis Weakness Pathologic diagnosis, no. (%) Endoscopic cytology Percutaneous FNA or biopsy At the time of exploration Surgery, no. (%) Pancreaticoduodenectomy Distal pancreatectomy Bypass procedure None Pathologic assessment Tumor size (cm), median (IQR)a Negative resection margin, no. (%) Lymph nodes evaluated, no. (%) Node-positive, no. (%) Number of positive lymph nodes per patient, median (IQR) AJCC, 7th edition stage, no. (%) Ia Ib IIa IIb III IV Pathology, no. (%) Anaplastic, NOS Giant cell Mixed pleomorphic/giant cell Undifferentiated with osteoclast-like giant cells Undifferentiated Pleomorphic Follow-up (months), median (IQR)

All Patients with APC (n 4 16) 57.2 (45.0–70.8) 9 (56.3) 25.7 (23.1–28.4) 9 5 1 1

(56.3) (31.5) (6.3) (6.3)

4 (25.0) 2 (12.5) 10 (62.5) 6 2 2 6

(37.5) (12.5) (12.5) (37.5)

4.0 (3.9–5.0) 6 (75.0) 10 (62.5) 5 (50.0) 2 (1–2) 0 1 4 2 2 7

(0) (6.3) (25.0) (12.5) (12.5) (43.8)

5 4 3 2

(31.3) (25.0) (18.8) (12.5)

1 (6.3) 1 (6.3) 10.0 (1.6–25.5)

a Not available for three patients. IQR, interquartile range; BMI, body mass index; FNA, fine needle aspiration; AJCC, American Joint Committee on Cancer; NOS, not otherwise specified.

(12.5%); undifferentiated (6.3%); and pleomorphic (6.3%). In 10 of 16 cases, there was sufficient tissue for immunohistochemistry (IHC) for cytokeratin and CD68 staining. Immunohistochemistry for nine cases was characteristic of APC with no OCGC seen either on H&E or with the aid of CD68 IHC and with variable expression of cytokeratin. One case with morphologic features diagnostic of undifferentiated carcinoma with OCGCs displayed focal positivity for cytokeratin in the neoplastic undifferentiated cells and diffuse CD68 positivity in the OCGCs. This pattern of cytokeratin and CD68 staining confirmed a diagnosis of undifferentiated carcinoma with OCGCs (Fig. 2A–B). For the second patient with morphologic evidence of undifferentiated

FIG. 1. Computed tomography image of a patient with anaplastic pancreatic cancer demonstrating a hypodense mass with central necrosis (white arrow) in the body of the pancreas.

carcinoma with OCGCs, tumor tissue blocks with residual tissue were not available for cytokeratin and CD68 IHC. Survival

The median OS for all patients with APC was 12.8 months. One-, 3-, and 5-year OS for patients with APC was 56.3, 21.1, and 14.1 per cent, respectively. One-, 3-, and 5-year OS for patients with APC treated with pancreatic resection was 87.5, 43.8, and 29.2 per cent, respectively. Median OS was significantly longer in patients with resected APC compared with patients with unresected APC (34.1 vs 3.3 months, log-rank P 4 0.001) (Fig. 3). Two patients with pathologically confirmed undifferentiated carcinoma with OCGCs were alive with no evidence of recurrence at 57 and 80 months after resection. OS was significantly improved for patients with undifferentiated carcinoma with OCGCs when compared with other subtypes of APC (log-rank P 4 0.018). Comparison of clinical characteristics between matched patients with APC and PDA is summarized in Table 2. In the matched cohort of patients with differentiated PDA who underwent pancreatic resection during the same period, 1-, 3-, and 5-year OS was 83.9, 58.1, and 25.4 per cent, respectively. Median OS was similar between patients with resected APC and patients with differentiated PDA (44.1 vs 33.9 months, log-rank P 4 0.763) (Fig. 4). Discussion

Anaplastic pancreatic cancer is a rare variant of PDA with previously reported poor survival.7, 14, 16 In the

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FIG. 2. (A–B) Undifferentiated pancreatic carcinoma with osteoclast-like giant cells (OCGCs). (A) Hematoxylin and eosin stain demonstrating a discohesive sheet of malignant lump spindle cells with hyperchromatic irregular nuclei with scattered reactive larger multinucleated osteoclast-like giant cells. Inset black arrows indicate osteoclast-like giant cells. (B) Immunohistochemical staining with CD68 highlights strong cytoplasmic reactivity in the larger multinucleated osteoclast-like giant cells. The neoplastic smaller malignant cells are CD68-negative. Inset black arrows indicate osteoclast-like giant cells.

current study, we confirmed a diagnosis of APC in 16 patients with eight patients undergoing pancreatic resection over a 23-year period. In this cohort, OS was very poor in unresected patients (median OS, 3.3 months) and corroborates previous reports.8, 13, 14, 16 However, after matching on age, sex, year of operation, and AJCC, 7th edition stage, OS was similar between patients with APC and those with PDA treated with pancreatectomy. The current study supports our previous findings of similar survival between resected APC and PDA using population-based data.24 The median OS of 12.8 months reported in our study for all patients is substantially higher than prior reports. Compared with matched patients with PDA, patients with APC treated with pancreatic resection had similar

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median OS (44.1 vs 33.9 months, P 4 0.763). The improved survival can likely be attributed to several factors. First, median tumor size was smaller than prior reports. Second, margin-negative resection was achieved in six of eight patients. Positive margin resection is a recognized predictor of worse OS.29 Although two patients required multivisceral resection to obtain a R0 resection, no major vascular resections were required. Third, metastatic disease to regional lymph nodes was present in 50 per cent of patients with APC, which is lower than previous APC series. Yamaguchi et al.13 reported three of four patients had node-positive disease at time of resection. In the study by Strobel et al.,16 67 per cent of patients were node-positive. Previous studies of lymph node status in PDA indicate that negative lymph node status is a predictor of improved survival.29–31 Lastly, two of the three long-term survivors in the resected cohort had histology-confirmed undifferentiated pancreatic carcinoma with OCGCs. In 1969, Kay et al.5 first proposed that patients with undifferentiated pancreatic carcinoma with OCGCs may have better survival than other subtypes of APC. Based on an autopsy series, Jallol et al.10 also proposed improved survival with undifferentiated pancreatic carcinoma with OCGCs. The impact of OCGCs on the biology of pancreatic cancer and on patient prognosis remains unknown. By IHC, the giant cells observed in undifferentiated carcinoma with OCGCs have been shown to be histiocytic in nature and have also been confirmed as nonneoplastic.23, 32 Several publications including the World Health Organization in 2000 categorize undifferentiated carcinoma with OCGCs separate from APC.9, 25–27, 33 In the current study, there were only two patients with histologically confirmed undifferentiated pancreatic carcinomas with OCGCs. Both patients were deemed resectable and were still alive without evidence of disease at the time of follow-up. Several studies have reported similarly favorable prognoses for this rare subtype of pancreatic carcinoma.9, 32, 34, 35 In contrast, Molberg et al.22 reported that eight of nine patients with undifferentiated pancreatic carcinomas with OCGCs died within 1 year. Anaplastic pancreatic cancer has a radiographic finding of a hypodense lesion in the pancreas with associated central necrosis and contrast enhancement of the surrounding rim of tumor on portal phase CT.13, 16, 22 We observed tumors harboring central tumor necrosis for 63 per cent of patients with APC on diagnostic imaging. However, clinical history appears to be similar to PDA. Currently, clinical history, physical examination, and diagnostic imaging cannot reliably make a distinction between PDA and APC. The only way to confirm the diagnosis of APC is to perform percutaneous or endoscopic fine needle aspiration.11 In general, our practice is to perform preoperative biopsy through

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FIG. 3. Overall survival for patients with resected and unresected anaplastic pancreatic cancer (APC) (log-rank P 4 0.001).

endoscopic-guided fine needle aspiration if diagnostic imaging does not lend itself to a diagnosis or neoadjuvant chemotherapy is planned. The main limitations of the current study are a result of the rarity of the disease and the retrospective study design. First, we attempted to control confounders of survival for pancreatic cancer using a case–control analysis for resected patients. However, this small cohort limited our ability to control for multiple prognostic factors such as number of positive lymph nodes, multivisceral resection, and positive resection margin. Second, because we identified only two patients with undifferentiated pancreatic carcinoma with OCGCs, the comparison of survival with other subtypes of APC should be interpreted with caution. Lastly, as a result of the retrospective design and frequent follow-up at

outside institutions, we were not able to evaluate the use of adjuvant or palliative chemoradiotherapy for patients with APC. Conclusion

Anaplastic pancreatic cancer is an aggressive form of pancreatic cancer that carries a poor prognosis in the unresected patient. In this case–control study, OS for patients with APC treated with curative pancreatic resection is comparable to PDA. In the rare instance that a patient is diagnosed with undifferentiated pancreatic carcinoma with OCGCs, survival may be improved. Therefore, we believe that histologic or radiographic evidence suggesting APC should not negatively influence the decision to operate. Patients

TABLE 2. Clinical Characteristics of Patients with Anaplastic Pancreatic Cancer (APC) Compared with Matched Patients with Pancreatic Ductal Adenocarcinoma (PDA) Treated with Pancreatectomy Variable

APC (n 4 7)

PDA (n 4 21)

P Value

Age (years), median (IQR) Male, no. (%) BMI (kg/m2), median (IQR) Pathologic assessment Tumor size (cm), median (IQR) Node-positive, no. (%) AJCC 7th edition stage, no. (%) Ia Ib IIa IIb III IV Follow-up (months), median (IQR)

56.6 (42.2–66.7) 2 (28.6) 23.7 (21.3–27.3)a

56.1 (50.2–66.4) 6 (28.6) 25.6 (22.9–30.5)

0.675 >0.999 0.473

4.2 (3.0–6.0) 2 (28.6)

3.5 (3.0 –3.5) 6 (28.6)

0.248 >0.999

0 (0) 1 (14.3) 4 (57.1) 2 (28.6) 0 (0) 0 (0) 34.1 (7.2–57.4)

0 (0) 3 (14.29) 12 (57.14) 6 (28.6) 0 (0) 0 (0) 22.5 (8.3–40.0)

>0.999

a

Not available for one patient. IQR, interquartile range; BMI, body mass index; AJCC, American Joint Committee on Cancer.

0.713

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FIG. 4. Survival for patients with resected anaplastic pancreatic cancer and well-differentiated pancreatic ductal adenocarcinoma (log-rank P 4 0.763).

with APC who have a resectable lesion with no evidence of metastatic disease and who are fit for an operation should be offered exploration with the goal of a R0 resection. REFERENCES

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