Parathyroid Hormone-related Protein-Secreting ...

Jpn J Clin Oncol 2006;36(2)113–115 doi:10.1093/jjco/hyi215

Parathyroid Hormone-related Protein-Secreting Uterine Endometrioid Adenocarcinoma Yukio Kinugasa1, Ken-ichiro Morishige1, Shoji Kamiura1, Yoshitane Tsukamoto2 and Fumitaka Saji3 1

Department of Gynecology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, 2Department of Pathology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, 3National Hospital Organization, Kure Medical Center, Kure, Hiroshima, Japan

Received June 21, 2005; accepted November 14, 2005; published online January 17, 2006

Key words: humoral hypercalcemia of malignancy – endometrioid adenocarcinoma – endometrial cancer – parathyroid hormone-related protein

INTRODUCTION

CASE REPORT

Humoral hypercalcemia of malignancy (HHM) is a common paraneoplastic syndrome occurring in up to 10% of patients with solid tumor (1), but is uncommon in patients with gynecological malignancies. HHM caused by endometrial cancer is very rare and only few cases of paraneoplastic hypercalcemia associated with endometrial cancer have been reported previously (2–4). In the report by Hiller et al. (2), two HHM cases were clear cell adenocarcinoma of uterus, whereas the cause of hypercalcemia was not identified. The case of Buller (3) had a prominent squamous cell component within areas of the adenocarcinoma, which expressed ectopic parathyroid hormone. Furthermore, the case of Sachmechi was serous papillary carcinoma associated with parathyroid hormonerelated protein (PTHrP)-induced hypercalcemia (4). We report a case of endometrioid adenocarcinoma of the uterine corpus with hypercalcemia, due to an elevated serum level of PTHrP, resulting in a suppressed level of serum intact PTH. Immunohistochemical study showed a PTHrP production in the tumor.

A 32-year-old Japanese nulligravida woman, with a history of irregular genital bleeding, was referred to our hospital because of malignant cytology from the endometrium. The physical examination was unremarkable, and laboratory studies showed normal urinalysis, serum electrolytes, and hepatic and renal functions. There were no palpable lymph nodes and she had a normal-sized uterus. Magnetic resonance imaging of the pelvis before surgery revealed a normal uterus with intact junctional zone. Both ovaries were of normal size and appearance. No evidence of ascites or lymph node swelling was demonstrated. Endometrial sampling under dilatation and curettage revealed Grade 2 endometrioid adenocarcinoma. Total hysterectomy and bilateral salpingo-oophorectomy were carried out. Abdominal exploration revealed a normal, smooth-surfaced uterus with grossly unremarkable ovaries and fallopian tubes. Peritoneal cytology was negative and no paraaortic or pelvic lymph node swelling was identified. An intraoperative pathological examination revealed Grade 1 endometrioid adenocarcinoma, without myometrial invasion. Post-operatively, the serum calcium was normal: preoperative and post-operative laboratory data are presented in Table 1. Microscopic examination confirmed the presence of a well-differentiated endometrioid adenocarcinoma with a minimal degree of myometrial invasion. There was no permeation of myometrial lymphatics and vessels by tumor cells. The patient was staged as Ib endometrioid cancer. The patient

For reprints and all correspondence: Ken-ichirou Morishige, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-3 Nakamichi, Higashinari-ku, Osaka City 537-8511, Japan. E-mail: morisige-ke@mc.pref.osaka.jp

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The diagnosis of parathyroid hormone-related protein (PTHrP)-secreting metastatic uterine endometrioid cancer was made in a 32-year-old Japanese woman with humoral hypercalcemia of malignancy. The primary endometrial cancer had been removed, and the tumor was diagnosed as Grade 1 endometrioid adenocarcinoma with shallow myometrial invasion. Salvage chemotherapy (paclitaxel and calboplatin) was started from 5 months after surgery when recurrent tumors were detected in the peritoneum and liver. Despite the salvage chemotherapy, the tumor progressed and hypercalcemia became evident with elevated PTHrP whereas no bone metastasis was identified. To the best of our knowledge, this is the first reported case of hypercalcemia due to PTHrP secretion in uterine endometrioid adenocarcinoma.

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PTHrP in uterine endometrioid adenocarcinoma

Table 1. Calcium-related laboratory data from pre-operation to identification of hypercalcemia Parameter Standard values Calcium

8.6–10.5 mg/dl

Phosphate 2.4–4.3 mg/dl ALP

127–380 IU/l

Albumin

3.8–5.3 g/dl

PTH

10–65 pg/ml

PTHrP

13.8–55.3 pmol/dl

Pre-operation Post-operation Hypercalcemia noticed 10.3 4.5

9.7

21.3

–

6.4

–

–

5.1

5

2.7

–

–

6

–

–

4550

132

IMMUNOHISTOCHEMICAL STUDIES We performed the immunohistochemical staining as described before (5). The antibody to PTHrP was kindly provided by Chugai Pharmaceutical Co. (Kamakura, Japan) (6). The normal endometrium was slightly positive for PTHrP in accordance with previous studies (5,7) (Fig. 2A). We confirmed the specificity of PTHrP-immunoreactivity comparing with the immunoreactivity without a primary antibody. The primary tumor in this case showed slightly stronger staining than normal endometrium (Fig. 2B). The histological appearances of primary and recurrent tumors were almost identical and well differentiated. However, sections of the recurrent tumor exhibited strongly positive immunohistochemical staining for PTHrP, compared with the slight staining of the primary tumor (Fig. 2C). Positive staining was characterized by brown cytoplasmic granules.

DISCUSSION HHM is characterized by excessive serum calcium, the absence of bone metastases and low concentrations of immunoreactive parathyroid hormone (8). In the original report of HHM (9), hypercalcemia of uterine cancer was described in the absence of bone metastases, which was a case of anaplastic carcinoma of the endometrium. Sachmechi et al. described the first report of HHM due to PTHrP in endometrial cancer, although the histological type was papillary serous carcinoma (4). This is the first reported case of HHM due to PTHrP in endometrioid adenocarcinoma of the endometrium. Levels of PTHrP were not examined pre-operatively or postoperatively because this patient did not exhibit hypercalcemia. At the time of recurrence, the patient had increased serum immunoreactive PTHrP in the presence of a high serum calcium level. The hypercalcemia in our patient was possibly caused by a PTHrP-mediated mechanism, because the serum

Figure 1. Abdominal computerized tomography scan. Left: Multiple liver metastases, Right: A large enhanced mass at the right abdomen.


received no adjuvant therapy post-surgically and remained clinically disease-free for 3 months, but the CA 19-9 level subsequently elevated. At 5 months after surgery, a right lower abdominal mass was seen on an ultrasound exam. Fine-needle biopsy of the mass revealed metastatic adenocarcinoma, compatible with the original endometrioid adenocarcinoma. Computerized tomography of the abdomen and pelvis revealed a large, heterogeneously enhanced, right lower abdominal mass and multiple metastasis to the liver (Fig. 1). A bone scintigraphy showed no evidence of skeletal metastasis. The patient started chemotherapy, with two courses of paclitaxel (175 mg/m2) and carboplatin (AUC; 5) given 4 weeks apart. At the time of the second course of chemotherapy, unknown fever developed. Four weeks after the second chemotherapy, the serum calcium elevated to 21.3 mg/dl. The serum PTHrP level was extremely high (4550 pmol/l) (Table 1). Hypercalcemia was partially controlled to calcium levels of 13.1 mg/dl with hydration, diuretics and intravenous alendronate therapy. However, the serum calcium elevated again and renal dysfunction progressed. She died of cancer 7 days after hypercalcemia was noticed.

Jpn J Clin Oncol 2006;36(2)

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level of PTHrP was elevated and native PTH was suppressed. Although the primary tumor might not have expressed sufficient PTHrP protein inducing hypercalcemia, the recurrent tumor expressed a much higher level of PTHrP and induced severe hypercalcemia (Fig. 2). Paraneoplastic hypercalcemia is most often associated with squamous cell carcinoma but occasionally adenocarcinoma accompanying with small cell lineage (9). In the tumor of this patient, neither squamous nor small cell elements were demonstrated histologically. In summary, we report a patient with recurrent endometrioid adenocarcionoma associated with paraneoplastic hypercalcemia due to PTHrP secretion. Sections of the recurrent tumor exhibited positive immunohistochemical staining for PTHrP.

Figure 2. Immunoreactive PTHrP localization in the normal endometrium (A), the tumor at primary surgery (B) and the recurrent tumor (C). The recurrent tumor shows significantly stronger immunostaining for PTHrP than the primary uterine tumor.

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