Gynecologic Oncology Reports 2 (2012) 112–114

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Case Report

Amylase-producing ovarian carcinoma: A case report and a retrospective study☆ Tetsuya Kawakita a,⁎, Hiromasa Sasaki a, Tsutomu Hoshiba a, Akihiro Asamoto a, Evan Williamson b a b

Department of Obstetrics and Gynecology, Ishikawa Prefectural Central Hospital, 2‐1, Kuratsuki-Higashi, Kanazawa, Ishikawa 920‐8530, Japan Department of Pathology, U.S. Naval Hospital Okinawa, PSC 482, FPO AP 96362, Okinawa, Japan

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Article history: Received 1 May 2012 Accepted 9 June 2012 Available online 17 June 2012 Keywords: Amylase Tumor marker Ovarian cancer

Introduction Since Weiss et al. (1951) first reported an association between hyperamylasemia and lung carcinoma in 1951, and Tsunashima et al. (1976) reported amylase-producing ovarian carcinoma in 1976, several reports of amylase-producing tumors have been documented. Amylase is an enzyme that catalyzes the breakdown of starch, and it is coded by two different loci: AMY1 (salivary-type) and AMY2 (pancreatic-type) localized on the short arm of the chromosome at the 1p21 position (Zabel et al., 1983). AMY2A is a possible tumorsuppressor gene and its deletion may be associated with carcinogenesis (Kang et al., 2010). Although amylase itself may not be associated with carcinogenesis, amylase may potentially be useful as a tumor marker. Here we report a case of amylase-producing ovarian carcinoma, and we also conduct a retrospective study investigating the association between hyperamylasemia and ovarian carcinoma. Case study In September 2011, a 49-year-old nulliparous woman was admitted to our hospital presenting with 1-week abdominal distension and sudden onset epigastric pain. She had no significant past medical history. Physical examination revealed prominent ascites and a pelvic mass. Laboratory tests revealed slightly elevated leukocyte counts, mild liver dysfunction, and hyperamylasemia with serum amylase of 7515 U/L (normal range 33–120) with salivary-type dominant (99%). Serum lipase was within ☆ Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request. ⁎ Corresponding author. Fax: + 81 76 238 2337. E-mail address: [email protected] (T. Kawakita). 2211-338X/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.gynor.2012.06.002

normal limits, and urine amylase was markedly elevated (6551 U/L/ day) with salivary-type dominant (88%). The amylase/creatinine clearance ratio (ACCR) was 1.0 (normal range 1–5). Abdominal and pelvic computer tomography (CT) scans exhibited a normal pancreas, ascites, and a right adnexal tumor (10.2× 6.6 cm). Pelvic magnetic resonance imaging revealed an adnexal mass with fluid-attenuated cystic and solid components, which was suspected to be rupture of ovarian carcinoma. Serum carbohydrate antigen 19‐9 (CA19-9) was slightly elevated (55.5 U/mL), while CA125 was within normal limits. She underwent surgery with peritoneal washing cytology, total abdominal hysterectomy, bilateral salpingo-oophorectomy, and omentectomy. After detailed and careful discussion, she refused lymphadenectomy based on her concerns about complications such as lymphedema. Serous ascites and minor rupture of the right adnexal mass were observed. Tumor metastasis to adjacent organs was not noted, but peritoneal washing cytology was positive for atypical cells with large nuclei. Histology of the right ovary showed serous adenocarcinoma (high grade, pT1c) without evidence of metastasis (Fig. 1A). Immunohistochemically, cytoplasmic staining for amylase was more apparent, compared with negative control (Fig. 1B, C). Based on the FIGO criteria of ovarian carcinoma, she was diagnosed as having serous adenocarcinoma with FIGO stage Ic disease. Within 24 h after surgery, this patient's serum and urine amylase returned to normal. She received 6 cycles of combination chemotherapy at the following doses: docetaxel (70 mg/m2 iv) and carboplatin (AUC 5). Her last follow-up was April 2012, and there was no sign of recurrence. Materials and methods This retrospective study was approved by the institutional review board of our hospital. Written informed consent was obtained from all patients. Data on women undergoing salpingo-oophorectomy from 2007 to 2011 was evaluated. All patients were ethnically Japanese. Patients with endometrial cystic lesions were excluded from the study. To avoid confounding macroamylasemia, patients with renal failure were excluded. We stratified the women into two groups: group 1 with ovarian malignancy and group 2 with benign ovarian tumors. All serum amylase, CA19-9, and CA125 levels were measured prior to surgery. Hyperamylasemia is defined as serum amylase > 2 standard deviation (SD) above the upper range of normal. We assessed the incidence of hyperamylasemia and correlation between amylase and CA19-9/CA125. Results were analyzed by JMP (version 10, SAS institute, Tokyo, Japan). Differences in categorical variables were assessed by Fisher's exact test or chi-square test. Differences in continuous variables were analyzed using the Student's t test or one-way ANOVA. The

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Fig. 2. Serum amylase level. Malignant = ovarian carcinoma (group 1), benign = benign ovarian tumor (group 2), serous = serous adenocarcinoma, others = ovarian carcinoma except for serous adenocarcinoma, dotted line = upper normal range of serum amylase, solid line = median of serum level of each group.

and other carcinomas (41/70) (S1). Fig. 2 indicates the distribution of serum amylase levels. There was no significant difference in serum amylase levels between group 1 and group 2 (199 U/L±891 U/L, median 68.5 U/L vs 83 U/L ±76 U/L, median 73 U/L; P=0.11). However, group 1 had a significantly higher incidence of hyperamylasemia (15/70, 21.4%), compared with group 2 (10/158, 6.3%) (sensitivity 21.4%; specificity 93.5%; OR, 4.03; 95% CI, 1.71–9.52; Pb 0.002). After adjusting for age, the OR was 3.48 (95% CI, 1.43–8.74; Pb 0.0059). Patients with serous carcinoma had a significantly higher incidence of hyperamylasemia (11/29, 38%) compared with other carcinomas (4/41, 9.8%) and benign tumors (10/158, 6.3%) (Pb 0.001). After adjusting for age and stage, there was also a significant difference between serous adenocarcinoma and other carcinomas (P= 0.01). Serum amylase level was significantly higher in patients with serous adenocarcinoma (382 U/L ±1376 U/L, median 86 U/L) than patients with other ovarian carcinoma (69 U/L ± 37 U/L, median 63 U/L) and benign tumor (83 U/L ±76 U/L, median 73 U/L) (Pb 0.01). Fig. 3 displays the correlations between amylase and CA19-9/CA125 in patients with ovarian carcinoma. CA19-9 showed a negative correlation with amylase (Spearman r= −0.35, Pb 0.005). There was no demonstrable correlation between amylase and CA125 (Spearman r= −0.007, P=0.96). Discussion Fig. 1. Histology of the right ovary showing serous adenocarcinoma. A. Hematoxylin and eosin stain, 200× magnification. B. Immunohistochemical staining for salivary-type amylase, 200× magnification. C. Negative control of immunohistochemical staining for salivary-type amylase, 200× magnification.

Spearman test was used to assess correlations between amylase and CA19-9/CA125 in patients with ovarian carcinoma. Descriptive statistics were used and presented as mean, SD, and frequency. Multivariate logistic regression was used to explore the relationships between malignancy and hyperamylasemia; the results of the analysis were expressed as an odds ratio (OR) with 95% confidence interval (CI). P b 0.05 was considered statistically significant. Results Group 1 consisted of 70 women aged 20–87 with ovarian carcinoma. Group 2 consisted of 158 women aged 20–89 with benign ovarian tumors. The women in group 1 were older than those in group 2 (55±14 vs 44 ±16; Pb 0.001). Group 1 included serous adenocarcinoma (29/70)

Amylase is mainly produced by pancreatic and salivary gland tissues, but the AMY1 and AMY2 genes are also expressed in lung, trachea, ovary, fallopian tubes, and uterine cervix (Seyama et al., 1994). It is also a well-known nonspecific marker for pancreatitis. As this patient had epigastric pain and hyperamylasemia, acute pancreatitis was initially suspected. However, salivary-type amylase was dominant, and lipase, which is more specific to the pancreas, was normal. Abdominal and pelvic CT scans detected a pelvic mass and ascites, and not pancreatitis. Hyperamylasemia, normal ACCR, and serous adenocarcinoma immunohistochemically positive for amylase confirmed the diagnosis of amylase-producing ovarian carcinoma. This entity sometimes mimics pancreatitis. Few studies have investigated the association between hyperamylasemia and ovarian carcinoma. Zakrezewska and Pietrynczak (1996) reported that 39% of patients with ovarian carcinoma had hyperamylasemia, with salivary-type dominant. They also found that amylase was significantly elevated in women with ovarian carcinoma. However, their study did not assess age differences. Ueda et al. (1994) reported that serum amylase increases with age. Age was probably a confounding

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Fig. 3. Correlation between serum amylase and CA19-9/CA125 level in patients with ovarian carcinoma.

factor. In our study, even after adjusting for patient age, the OR was still high. The sensitivity of serum amylase was rather low with 79.6% ovarian carcinoma patients having a normal amylase and the benign tumor group having higher median amylase levels than those patients with ovarian carcinoma. However, the specificity of serum amylase was very high, with 93.5% of ovarian carcinoma patients exhibiting elevated serum amylase levels. Many well-known tumor markers such as CA125 and CA19-9 are sensitive, but not specific. Therefore, amylase, particularly in conjunction with existing markers may represent a promising tumor marker (Zakrezewska & Pietrynczak, 1996). This may be especially true for serous adenocarcinoma with significantly higher serum amylase levels. It is interesting that serum amylase in ovarian carcinoma negatively correlates with serum CA19-9. The pathophysiology of this is not clear, but serum amylase may represent a potential tumor marker in CA19-9 negative patients. The mechanism of this high amylase level is still unclear. Sayama et al. (1994) reported that the AMY1 gene (salivary-type) was exclusively and highly expressed in the salivary glands and in amylase-producing lung adenocarcinomas. It is also reported that AMY2A (pancreatic-type) may be associated with carcinogenesis (Kang et al., 2010; Watanabe et al., 2010). Neoplastic transformation of cells may result in expression of AMY1 gene and biosynthesis of salivary-type amylase. There are several limitations to our study. First, group 1 included women with various stages of carcinoma (S1). To assess the level of serum amylase according to the stage, we need larger study groups. Other limitations are retrospective design and short observational period. We need longer observation if we assess serum amylase as a possible marker for recurrence. At this time, we can only say that serum amylase is a possible diagnostic marker. In conclusion, amylase-producing tumors sometimes mimic pancreatitis. Since hyperamylasemia is common in ovarian carcinoma, we should be aware of the possibility that patients with hyperamylasemia (especially salivary-type) may have ovarian carcinoma after excluding other common etiologies. Hyperamylasemia may be associated with

ovarian carcinoma, and measurement of serum amylase in conjunction with existing tumor makers may represent a more specific screening regimen. Conflict of interest statement All authors declare that there are no conflicts of interest.

Acknowledgement We thank Dr. Tetsuji Kurokawa for immunohistochemical analysis and Dr. Hiroshi Kawamura for assistance in data collection. Appendix A. Supplementary data Supplementary data to this article can be found online at http:// dx.doi.org/10.1016/j.gynor.2012.06.002. References Kang, J.U., Koo, S.H., Kwon, K.C., Park, J.W., 2010. AMY2A: a possible tumor-suppressor gene of 1p21.1 loss in gastric carcinoma. Int. J. Oncol. 36, 1429–1435. Seyama, K., Nukiwa, T., Takahashi, K., Takahashi, H., Kira, S., 1994. Amylase mRNA transcripts in normal tissues and neoplasms: implication of different expressions of amylase isogenes. J. Cancer Res. Clin. Oncol. 120, 213–222. Tsunashima, T., Arima, T., Onashi, J., 1976. Hyperamylasemia in a case of ovarian cancer. Nihon Shokakibyo Gakkai Zasshi 73, 907–909. Ueda, M., Araki, T., Shiota, T., Taketa, K., 1994. Age and sex-dependent alterations of serum amylase and isoamylase levels in normal human adult. J. Gastroenterol. 29, 189–191. Watanabe, T., Miura, T., Degawa, Y., Fujita, Y., Inoue, M., Kawaguchi, M., Furihata, C., 2010. Comparison of lung cell cancer cell lines representing four histopathological subtypes with gene expression profiling using quantitative real-time PCR. Cancer Cell Int. 10, 2. Weiss, M.J., Edmondson, H.A., Wertman, M., 1951. Elevated serum amylase associated with bronchogenic carcinoma; report of case. Am. J. Clin. Pathol. 21, 1057–1061. Zabel, B.U., Naylor, S.L., Sakaguchi, A.Y., Bell, G.L., Shows, T.B., 1983. High resolution chromosomal localization of human genes for amylase, proopiomelanocortin, somatostatin, and a DNA fragment (D3S1) by in situ hybridization. Proc. Natl. Acad. Sci. U. S. A. 80, 6932–6936. Zakrezewska, I., Pietrynczak, M., 1996. The activity of alpha-amylase and its salivary isoenzymes in serum and urine of patients with neoplastic diseases of female reproductive organs. Rocz. Akad. Med. Bialymst. 41, 492–498.

Amylase-producing ovarian carcinoma: A case report and a retrospective study.

► Amylase-producing ovarian carcinoma may mimic pancreatitis. ► Hyperamylasemia is common in ovarian carcinoma. ► Serum amylase may be a promising tum...
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