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Keywords:

  • antidiuretic hormone;
  • ectopic ADH production;
  • inappropriate secretion of antidiuretic hormone;
  • prostate carcinoma

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case report
  5. Discussion
  6. References

Abstract The syndrome of inappropriate secretion of antidiuretic hormone (ADH) was recognized in a 68-year-old man with a poorly differentiated metastatic adenocarcinoma of the prostate. Elevated levels of ADH were found in the tissues of the primary tumor and lymph node metastasis. The patient's clinical course is detailed and the pathophysiology of this syndrome is discussed. To our knowledge, this case is the ninth reported case of syndrome of inappropriate secretion of ADH with adenocarcinoma of the prostate. Antidiuretic hormone activity was proven in only three cases including this case.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case report
  5. Discussion
  6. References

Inappropriate secretion of antidiuretic hormone (ADH) is frequently observed in tumors with ectopic hormone production. It is generally accepted that three clinical conditions are required as the criteria for a tumor with ectopic ADH production: (i) the syndrome of inappropriate secretion of ADH (SIADH) as a clinical symptom of hormone oversecretion (and improvement of the symptom after tumor excision); (ii) an increase in the serum ADH level; and (iii) proof of ADH activity in the tumor tissue. The original disease is lung cancer in approximately 80% of all cases and 90% of these are oat cell carcinoma or undifferentiated carcinoma.1,2

This report describes a patient in whom the syndrome developed in association with adenocarcinoma of the prostate.

Case report

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case report
  5. Discussion
  6. References

A 68-year-old man with the chief complaint of a bloody bowel was admitted to the Department of Surgery, Chiba University Hospital with suspected rectal cancer on 11 October 1998. He had difficulty in urination and a digital rectal examination revealed a goose egg-sized, stony hard and hemorrhagic mass in the prostate. His serum prostate specific antigen (PSA) level was 1550 ng/mL (Tandem-R kit, Hybritech, CA, USA), strongly suggesting the presence of prostate carcinoma. The pathological finding from a transrectal needle biopsy of the prostate was poorly differentiated prostatic adenocarcinoma, Gleason grade 4 + 5 (Fig. 1). A bone scan revealed multiple bone metastases.

image

Figure 1. Pathological findings of prostate biopsy showing poorly differentiated adenocarcinoma (H&E).

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The clinical course of the patient is shown in Fig. 2. The patient was treated with 250 mg of diethylstilbestrol diphosphate daily for 7 days from 20 October. This was followed by an injection of 3.6 mg of goserelin acetate. The serum PSA level decreased to 382 ng/mL 20 days after the initiation of hormonal therapy. The serum sodium level was 127 mEq/L (normal: 135–145) when he was admitted and decreased to 117 mEq/L by 29 October. No response was noted to a supplement of sodium and steroids. The laboratory tests demonstrated that the serum osmotic pressure and urinary osmotic pressure were 250 mOsm/kgH2O and 414 mOsm/kgH2O, respectively. Urinary sodium increased to 73–134 mEq/L (normal: < 20). The renal function was normal.

image

Figure 2. Clinical course and serum levels of sodium and prostate specific antigen in the patient. DES-DP, diethylstilbestrol diphosphate. ▪, Serum sodium (mEq/L); ◆, serum PSA (ng/mL).

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An examination of the endocrinological function revealed adrenocorticotrophic hormone 40.2 pg/mL (normal range: 10–60), cortisol 62.52 μg/dL (normal range: 5–20), aldosterone 20.0 pg/mL (normal range: 10–80), thyroid stimulating hormone 2.36 μU/mL (normal range: 0.5–50), free triiodothyronine 0.86p/mL (normal range: 1.45–4.65) and serum renin 0.15 ng/mL per h (normal range: 0.2–0.7). The serum ADH level was 9.0 pg/mL (normal range: 0.5–3.0).

From these results, the patient was diagnosed as SIADH with adenocarcinoma of the prostate and he was treated with fluid restriction (1000 mL per day). During this treatment local convulsion was noted. The patient responded well to fluid restriction and his serum sodium level increased to 133 mEq/L on 6 November. However, his condition deteriorated gradually and he died on 8 November.

Pathological findings at autopsy

The prostate gland was enlarged (9 × 7 × 7 cm) and replaced by a grayish tumor that invaded the bladder and rectum. Distant metastases extended to the bone, lymph nodes and right adrenal gland. The ADH concentrations in the tissues of the primary tumor and lymph node metastasis were 13.3 pg/wg and 20.0 pg/wg, respectively (cf. ADH concentration in prostate cancer tissue of another patient was less than detectable level), indicating ADH secretion from these tumors. There was no evidence of any other tumor type at the post-mortem examination. Also, there were no abnormal findings of the central nervous system.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case report
  5. Discussion
  6. References

Syndrome of inappropriate secretion of ADH is a disease leading to hyponatremia and occurs in patients with pulmonary diseases and central nervous system disorders. Some drugs (i.e. cyclophosphamide, chlorpromazine) that stimulate or potentiate ADH secretion can also induce this syndrome. Syndrome of inappropriate secretion of ADH often appears in patients with a malignancy, most of which are oat cell carcinoma or undifferentiated carcinoma of the lung. There have been occasional reports of SIADH secondary to cancers of the pancreas, colon and stomach. To our knowledge, nine cases of SIADH with adenocarcinoma of the prostate have been reported (Table 1) and ADH activity in prostate carcinoma was proven in only three cases including this case.3,4 In the present case, no evidence of another type of tumor was confirmed by post-mortem examination and the proof of ADH activity in the tumor tissues strongly suggests the oversecretion of ADH from prostate carcinoma cells.

Table 1.  Previous reports of prostate cancer patients with SIADH
YearReporterAgeStageHistological differentiationTreatmentOutcomeSerum ADH levelTumor ADH level
  • *

    ADH, concentration in lymph node metastatic tissue; ADH, antidiuretic hormone; LH, left hand; ND, not determined; RH, right hand; SIADH, syndrome of inappropriate secretion of ADH.

1969Sellwood51DPoorly adenocarcinomaSurgical castration + estrogenDied, 2 years 2.5 (μU/mL)*100 (μU/mg)
1975Sacks60DPoorly adenocarcinomaSurgical castration + estrogenDied, 1 month10.8 (μU/mL) 17.2 (μU/mg)
1977Heim71DPoorly adenocarcinomaEstrogen 27 (pg/mL)ND
1981Murakawa72DPoorly adenocarcinomaRadical prostatectomy + surgical castration + palliative radiation to bone metastasisDied, 1 year3.8 (pg/mL)ND
1981Vossli66DPoorly adenocarcinomaUnknownUnknownNDND
1986Mnaymneh73DModerately adenocarcinoma + small cell carcinomaLH-RH agonistDied, 3 monthsNDND
1993Gasparini59CModerately adenocarcinomaLH-RH agonistAlive3.3 (pg/mL)ND
1996Arias58DPoorly adenocarcinomaLH-RH agonistAliveNDND
Present case68DPoorly adenocarcinomaLH-RH agonist + estrogenDied, 3 weeks9.0 (pg/mL) 13.3 (pg/wg) *20.0 (pg/wg)

Characteristic laboratory findings of SIADH are serum hyponatremia and high urinary sodium concentrations and unimpaired renal and adrenal functions. Also, a tumor is generally regarded as having ectopic ADH production when ADH level in the tumor tissue is proven. Although the diagnosis of a tumor with ectopic ADH production is relatively difficult, serum propressophysin was noted in patients with an ectopic ADH producing tumor and suggested as the potential marker.5 Propressophysin is a high molecular weight (mw: 20000) neurophysin consisting of pro-hormone arginine vasopressin.

The basic treatment strategy for hyponatremia due to SIADH is fluid restriction regardless of the primary disease and its treatment.6 In most cases of a tumor with ectopic ADH production, hyponatremia is improved by the treatment for the primary tumor.6 However, it is also suggested that in some cases, it could be worsened after conservative treatment, such as, radiation and chemotherapy. In this patient, hyponatremia worsened after the start of hormonal therapy. This is possibly explained by the hypothesis that large quantities of ADH were released from the tumor cells killed through apoptosis at the commencement of hormonal therapy. Recently, a non-peptide ADH receptor blocker to be taken orally was developed as a treatment for SIADH and the efficacy has been proven by clinical trials.7 If radical treatment for the primary disease is difficult, such drugs may be useful in improving clinical symptoms and quality of life. Administration of a non-peptide ADH receptor blocker before hormonal therapy should be considered to prevent the release of large quantities of ADH from tumor cells, particularly in stage D cases with SIADH, such as the present patient.

Most ADH producing prostate carcinomas are poorly differentiated adenocarcinomas and the prognosis is very poor. The average lifetime of five patients with stage D prostate carcinoma with SIADH was 175 days, while the reason for the poor prognosis is unclear. Hormone-producing tumors of the prostate gland are usually poorly differentiated. Although the exact mechanism of ectopic hormonal production is still obscure, it is suggested that genetic abnormalities of hormone and/or pro-hormone in tumor cells might cause inappropriate secretion of the hormones. Since advanced prostate cancer contains an accumulation of genetic changes,8 poorly differentiated cases may be more likely to cause abnormal hormonal secretion.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case report
  5. Discussion
  6. References
  • 1
    Bartter FC. The syndrome of inappropriate secretion of antidiuretic hormone. Endocrine and Neuroendocrine Hormone Producing Tumors Year Book Medical Publishers, Chicago, 1973; 1159.
  • 2
    Vorherr H, Massry SG, Utiger RD, Kleeman CR. Antidiuretic principle in malignant tumor extracts from patients with inappropriate ADH syndrome. J. Clin. Endocrinol. 1968; 29: 1624.
  • 3
    Sellwood RA, Spencer J, Azzopardi JG, Wapnik S, Welbourn RB, Kulatilake AE. Inappropriate secretion of antidiuretic hormone by carcinoma of the prostate. Br. J. Surg. 1969; 56: 9336.
  • 4
    Sacks SA, Rhodes DB, Malkasian DR, Robenbloom AA. Prostatic carcinoma producing syndrome of inappropriate secretion of antidiuretic hormone. Urology 1975; 6: 48992.
  • 5
    Tisher CC. Correction of an inappropriate ADH synthesis by tumor resection. Arch. Intern. Med. 1968; 121: 1637.
  • 6
    North WG. Human neurophysin as potential tumor markers for small cell carcinoma of the lung: Application of specific radioimmunoassays. J. Clin. Endocrinol. Metab. 1980; 51: 8927.
  • 7
    Saito T, Ishikawa S, Abe K et al. Acute aquaresis by the nonpeptide arginine vasopressin (AVP) antagonist OPC-31260 improves hyponatremia in patients with syndrome of inappropriate secretion of antidiuretic hormone (ADH). J. Clin. Endocrinol. Metab. 1997; 82: 1054.
  • 8
    Ichikawa T, Suzuki H, Ito H. Role of chromosomal loss in the progression of prostate cancers. Int. J. Clin. Oncol. 2000; 5: 34554.