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Keywords:

  • adrenal glands;
  • adrenalectomy;
  • adrenocortical function;
  • renal cell carcinoma;
  • radical nephrectomy

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

OBJECTIVE

To determine the value of ipsilateral adrenalectomy with radical nephrectomy, by investigating the clinical aspects of adrenal involvement and adrenocortical function in patients with renal cell carcinoma (RCC).

PATIENTS AND METHODS

The demographic, clinical and pathological data of adrenal involvement were reviewed in 247 patients with RCC. To evaluate adrenocortical function, 14 patients (adrenalectomy in eight, adrenal-sparing in six) had a rapid adrenocorticotropic hormone (ACTH) stimulation test before and 2 weeks after surgery.

RESULTS

There was adrenal involvement with RCC in seven of the 247 (2.8%) patients (a solitary adrenal metastatic tumour in four and direct extension into the adrenal gland in three). All adrenal involvement was detectable on abdominal computed tomography before surgery, and these patients had a large primary renal tumour of > pT2 and/or distant metastasis. Plasma cortisol levels declined significantly more in response to the rapid ACTH stimulation test in those treated by adrenalectomy than in those with spared adrenal glands at 2 weeks after surgery (P < 0.05), while there was no significant difference between the groups before surgery.

CONCLUSIONS

These results suggest that unconditional ipsilateral adrenalectomy with radical nephrectomy for RCC should be avoidable, and thus preserve the reserve of adrenocortical function, as preoperative imaging, especially thin-slice multidetector helical computed tomography, can detect adrenal involvement with RCC in most cases. Unilateral adrenalectomy might cause an irreversible impairment of the reserve of adrenocortical function.


Abbreviations
IA

ipsilateral adrenalectomy

ACTH

adrenocorticotropic hormone

17-OHCS

17-hydroxycorticosterone

INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

Advances in imaging methods and the spread of health examinations has considerably increased of the detection of small and low-stage RCC [1]. This higher prevalence of incidentally discovered low-stage disease has provoked greater consideration of a more conservative surgical approach. Radical nephrectomy including ipsilateral adrenalectomy (IA), as established by Robson et al.[2], is still a common surgical procedure for RCC, but the need for IA during radical nephrectomy has been controversial over the last decade. Several recent studies suggest that IA during radical nephrectomy is unnecessary, particularly when preoperative imaging is negative, as adrenal involvement is unlikely in patients with localized and low-stage RCC [3–6].

However, Nakada et al.[7] reported that the reserve of adrenocortical function was impaired in patients with primary aldosteronism treated by adrenalectomy compared with those who had an aldosterone-producing adenoma enucleated, and surgery to spare adrenocortical tissue appeared to be an option not only in adrenocortical adenoma but also in phaeochromocytoma. Therefore, IA during radical nephrectomy might impair the reserve of adrenocortical function in patients with RCC. Thus to determine the value of IA during radical nephrectomy, we investigated the clinical aspects of adrenal involvement and adrenocortical function in patients with RCC.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

Institutional Review Board approval was obtained from our institute to conduct this study. In a retrospective cohort study, the outcome was assessed from a chart review of the demographic, clinical and pathological data in patients with RCC. The records of 247 patients (from January 1985 to December 2001) at the authors’ institution were reviewed (170 men, 69%, and 77 women, 31%; median age 60 years, range 24–84). The primary renal tumour was on the right, left and bilateral in 110, 130 and seven patients, respectively. The surgery consisted of 224 radical nephrectomies, 11 partial nephrectomies, two enucleations of renal tumour, one open renal tumour biopsy and two ultrasonography-guided renal tumour biopsies in 240 patients with unilateral RCC. In seven patients with bilateral RCC, five had a bilateral radical nephrectomy, one a bilateral partial nephrectomy and one a right radical nephrectomy and left partial nephrectomy.

Tumour stage was determined according to the fifth edition of the TNM classification [8]. Histological tumour types were classified as clear cell, granular cell or other (not classifiable), and histological grades and forms of infiltration were also classified. Abdominal CT, operative and pathology reports were used to assess any adrenal involvement.

To assess adrenocortical function, before and 2 weeks after surgery the plasma levels of adrenocorticotropic hormone (ACTH) and cortisol, and 24-h urinary excretion of 17-hydroxycorticosterone (17-OHCS) were measured, and the rapid ACTH stimulation test used in 14 patients (adrenalectomy in eight, adrenal spared in six). In this test the plasma levels of cortisol were measured before and 1 h after the intravenous administration of tetracosactide 0.25 mg (Daiichi Pharmaceutical, Tokyo, Japan).

All data are expressed as the median (95% CI); for statistical analysis the unpaired t-test and the chi-square test were used to compare groups, with statistical significance indicated at P < 0.05.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

There was adrenal involvement with RCC in seven of the 247 patients (2.8%); Table 1 shows the demographic, clinical and pathological results from these patients. All tumours were stage ≥ pT2 and four patients had distant metastases in lung, bone and/or lymph node. Four patients with a solitary adrenal metastatic tumour and three with direct extension into the ipsilateral adrenal gland were detected on preoperative abdominal CT, and those imaging findings were consistent with the findings in the operative reports. No adrenal involvement was detected at surgery in patients with negative findings on preoperative abdominal CT.

Table 1.  Demographic, clinical and pathological findings in patients with RCC and adrenal involvement (all men)
FindingsPatient
1234567
Age78525168484852
Metastatic sideContraIpsiIpsiContraIpsiIpsiContra
CT findings of adrenal lesionTumourInvasionInvasionTumourInvasionTumourTumour
Location of RCCCranialCranialCranialMiddleCranialMiddleWhole
pTNM stagepT3aN0M1pT3bN1M1pT3cN2M1pT3aNxM1pT3bN2M1pT4N0M1pT2NxM1
Other site metastasesLungLung, boneLungLungNoneNoneNone

The primary tumour in patients with adrenal involvement was significantly larger than in those with no such involvement (Table 2). A significantly higher proportion of patients with adrenal involvement had advanced tumour stages, histological grades and forms of histological infiltration, while there was no significant difference in age, gender and histological tumour types (Table 2).

Table 2.  Clinicopathological characteristics and descriptive statistics in 247 patients with or without adrenal involvement
Characteristic, median (95% CI) or NAdrenal involvementP
withwithout
N 7240 
Age52 (46–67) 60 (59–61)0.449
Gender (M/F)  7/0163 : 770.163
Primary tumour (cm)11.0 (7.2–12.4) 5.0 (5.2–6.0)0.001
Cell type  0.289
Clear cell 4185
Granular cell 124
Other 231
Histological grade  0.001
Grade 1 079
Grade 2 4144
Grade 3 313
Grade X 04
Histological infiltration  0.010
Interferon-α 2150
Interferon-β 484
Interferon-γ 13
not available 03
pT category  0.001
pT1 0148
pT2 143
pT3 542
pT4 14
pTx 03

There was no significant difference in the plasma levels of ACTH and cortisol and 24-h urinary excretion of 17-OHCS before and 2 weeks after the surgery, except that the plasma levels of ACTH in patients treated by adrenalectomy were significantly higher at 2 weeks after than before surgery (Table 3).

Table 3.  The results of the adrenocortical function tests
Median (95% CI)Before surgeryat 2-weeksP
  1. *P < 0.05 vs after ACTH in adrenalectomy at 2-weeks.

Adrenalectomy (eight)
Plasma ACTH, pg/mL54 (40–69)78 (54–125)0.022
Plasma cortisol, µg/mL
before ACTH16 (14–17)18 (13–21)0.500
after ACTH28 (26–31)24 (22–28)0.082
Urinary 17-OHCS, mg/day 4.7 (3.5–5.4) 4.6 (3.1–7.9)0.375
Adrenal-sparing patients (six)
Plasma ACTH, pg/mL40 (22–72)63 (43–85)0.310
Plasma cortisol, µg/mL
before ACTH20 (15–22)22 (15–28)0.456
after ACTH31 (26–38)35 (25–42)*0.980
Urinary 17-OHCS, mg/day 4.0 (2.4–6.6) 4.7 (2.5–8.5)0.453

In the rapid ACTH stimulation test before surgery, the plasma levels of cortisol before and 1 h after the administration of tetracosactide are shown in Table 3; there was no significant difference in the response between patients treated with IA or not, but 2 weeks after surgery the plasma levels of cortisol before and 1 h after stimulation declined significantly more in patients treated by IA than in those who were not (P < 0.05).

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

Robey et al.[9] reported no significant difference in 5- and 9-year survival between patients with RCC treated by IA and those who were not, suggesting that the ipsilateral adrenal gland need not be removed routinely as part of radical nephrectomy for RCC. Furthermore, several studies suggest that metastatic RCC (not by direct extension) in the ipsilateral adrenal gland should be regarded as stage M+ (distant metastasis), and that the need and benefit of IA during surgery for RCC are extremely limited [10–12].

In keeping with other results [3–6,10–13], the incidence of adrenal involvement with RCC was 2.8% in the present study. Siemer et al.[14] reported that adrenal metastasis was found in a significantly higher proportion of patients with advanced stage disease (≥pT3b, N+, M+), and adrenal metastasis was diagnosed in 77% by CT or MRI, with no false-positive findings when the primary tumour was ≤ 4 cm. In the present study, all adrenal involvement was also found in patients with advanced stage (≥ pT2) disease with direct extension into the adrenal, or a large adrenal solitary tumour; CT before surgery detected all adrenal involvement. Taking these findings together, adrenal involvement with RCC is rare if preoperative imaging shows clinical stage T1N0M0 with normal adrenal glands, as noted in several previous reports [3–6]. Furthermore, recent advances in imaging, especially thin-slice multi-detector helical CT, will improve the precision of detecting adrenal lesions in patients with RCC.

However, Nakada et al.[4] reported that enucleating aldosterone-producing adenoma is preferable to unilateral adrenalectomy, as the response of plasma cortisol to ACTH administration in patients with an aldosterone-producing adenoma enucleated was more sensitive than in those after adrenalectomy, even 5 years after surgery. In keeping with these findings, in the present study the reserve of adrenocortical function 2 weeks after surgery was impaired in patients treated by IA compared with those after adrenal-sparing surgery. Furthermore, the plasma levels of ACTH tended to be slightly higher 2 weeks after IA than after adrenal-sparing surgery. This also suggests that patients treated by IA had a potential hypo-functioning adrenal. Therefore, IA during radical nephrectomy for low-stage RCC might be harmful rather than beneficial, as IA may cause an irreversible impairment of the reserve of adrenocortical function. Even in patients with advanced-stage disease we might consider adrenal-sparing surgery with radical nephrectomy if the patient had distant metastases (N+ or M+) and a radical operation could not be expected, as there is ≥ 20% risk of later adrenocortical insufficiency in patients with metastatic hypernephroma, although the study did not note the primary sites [15].

A limitation of the present study is that it is retrospective, so there was no central pathological review and the specimens were not step-sectioned. Another limitation is that adrenal function was evaluated only before and 2 weeks after surgery; thus, to determine whether the compensatory mechanism adjusts for the lack of a proper adrenocortical response to ACTH stimulation, a prospective study including a long-term follow-up of adrenal function is needed.

In conclusion, to preserve adrenocortical function, unconditional IA with radical nephrectomy for RCC should be avoidable, as the benefit of IA is extremely limited, especially in patients with small and low-stage disease, as preoperative imaging, especially thin-slice multi-detector helical CT, could detect adrenal involvement with RCC in most cases, and IA might cause an irreversible impairment of the reserve of adrenocortical function.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES