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Synchronous renal and adrenal masses: an analysis of 80 cases

Armita Bahrami MDa, Luan D. Truong MDa, b, Steven S. Shen MD, PhDb and Bhuvaneswari Krishnan MDa, c, Corresponding Author Contact Information, E-mail The Corresponding Author

aBaylor College of Medicine, Houston, TX, USA

bThe Methodist Hospital, Weill Medical College of Cornell University, Houston, TX, USA

cMichael E. DeBakey VA Medical Center, Houston, TX, USA

Available online 5 September 2008.

Abstract

Synchronous renal and adrenal masses are uncommon. Although adrenal masses in the context of renal cell carcinoma (RCC) are often suspected as metastasis, other adrenal lesions with different therapeutic and prognostic implications may coexist with RCC. In a retrospective review of 550 radical nephrectomies with ipsilateral adrenalectomy, 80 cases of coexisting renal and adrenal masses were identified. The renal masses included 76 RCCs, 3 oncocytomas, and 1 malignant pheochromocytoma of adrenal gland involving the kidney. Although the gross pathologic impression of adrenal masses in the presence of RCC was metastasis, on histologic examination, 56% of them were found to be benign lesions (mostly adrenal adenoma/hyperplasia), whereas malignant involvement from RCC was seen in 43%. The benign and malignant nature of the adrenal lesions in the context of RCC could not be discriminated based on the size of adrenal mass. Because of the prognostic implication of direct or metastatic involvement of adrenal gland in the setting of RCC and the possibility of finding small metastatic foci, a meticulous gross and microscopic examination of adrenal glands is emphasized. Rare unusual combinations of renal and adrenal lesions such as RCC and adrenal histoplasmosis, RCC and adrenal myelolipoma, renal oncocytoma, and adrenal pheochromocytoma are also described.

Keywords: Renal cell carcinoma; Adrenal tumors; Synchronous renal and adrenal tumors; Renal tumors; Benign adrenal tumors; Malignant adrenal tumors; Adrenal metastasis

Article Outline

1. Introduction
2. Materials and methods
3. Results
4. Discussion
References

1. Introduction
Simultaneous renal and adrenal masses at presentation are uncommon. Because approximately 80% to 85% of isolated renal masses represent renal cell carcinomas (RCCs), the detection of both adrenal and renal masses is generally considered metastatic RCC in the adrenal gland. On the other hand, a high prevalence of asymptomatic adrenal tumors has been reported in autopsy series where adrenal adenomas greater than 1 cm were seen in 1.5% to 7% of cases [1]. With the advent of sensitive imaging techniques and their increased clinical utility, small lesions of both the kidney and adrenal gland are often discovered. In view of the common existence of benign adrenal masses, the likelihood of metastasis in the setting of simultaneous renal and adrenal masses has not been previously analyzed.

2. Materials and methods

The pathology reports of 550 radical nephrectomy specimens performed at The Methodist Hospital and Michael E. DeBakey VA Medical Center in Houston, Tex, between January 1988 and August 2006 were reviewed for synchronous renal and adrenal lesions. Only grossly and/or radiologically detected lesions, which on subsequent microscopic examination were found to represent distinct pathological entities, were considered for the study. The demographic data and pathological characteristics of these cases were subsequently reviewed.
3. Results

Of the 550 radical nephrectomy specimens, 80 (15%) had simultaneous adrenal and renal lesions. The patients included 67 men and 13 women, ranging from 35 to 77 years of age (mean, 63 years). The incidence of primary benign lesions of the adrenal gland was 8.1% (45/550), whereas the incidence of metastatic tumor and direct extension from RCC were 3.5% (19/550) and 2.7% (15/550), respectively.

The most frequent combinations of renal/adrenal lesions included RCC and adenoma/hyperplasia (37/80, 44%), RCC and adrenal metastasis (19/80, 24%), and RCC and contiguous spread to adrenal gland (15/80, 19%). Unusual coexisting renal and adrenal masses were also encountered, including RCC and histoplasmosis of the adrenal gland, RCC and adrenal myelolipoma, oncocytoma and pheochromocytoma, and a malignant pheochromocytoma invading the kidney. The details of these cases are summarized in Table 1.
Table 1.

Histologic characteristics of synchronous renal and adrenal masses
Adrenal masses (no. of cases) [size range] Renal Masses (no. of cases) [size range]
Cortical adenoma or hyperplasia (37) [0.5-3.5 cm] Clear cell (27), papillary (6), chromophobe (2), oncocytoma (2) [2-22 cm]
Metastatic RCC (19) [0.5-9 cm] Clear cell (17), papillary (2) [2.5-12 cm]
Contiguous spread of RCC (15) Clear cell (11), unclassified (2), papillary (1), collecting duct (1) [4-18 cm]
Pheochromocytoma (4) [2.8-3.3 cm] Clear cell (2) [1.5-4.5 cm], oncocytoma (1) [1.8], pheochromocytoma invading kidney (1) [10 cm]
Myelolipoma (1) [6.5 cm] Clear cell (1) [2.5 cm]
Histoplasma infection (1) [8 cm] Clear cell (1) [7.5 cm]
Hemangioma (2) [0.5 cm, 1.6 cm] Clear cell (2) [8 cm, 8.5 cm]
Benign cyst (1) [1.5 cm] Clear cell (1) [4 cm]
Full-size table

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The renal lesions included 62 (79%) conventional clear cell RCC, 9 (11%) papillary RCCs, 2 (2.5%) chromophobe RCCs, 3 (3.75%) oncocytomas, 2 (2.5%) unclassified RCCs, 1 (1%) collecting duct carcinoma, and 1 (1%) adrenal pheochromocytoma with direct extension to the kidney (Table 1). The overall mean size of renal tumor was 8.1 cm (range, 1-22 cm). The average size of RCCs without simultaneous adrenal involvement was 5.3 cm (range, 1-14.9 cm), the mean size of RCCs with adrenal metastasis was 8.7 cm (range, 2.5-12 cm), and the average size of RCCs with direct extension to adrenal gland was 10.5 cm (range, 5-18 cm), which reflects combined measurement of the renal and adrenal tumors. The tumor stage among RCCs included T1a, 22 cases; T1b, 9 cases; T2, 4 cases; T3a, 22 cases; T3a and T3b, 10 cases; T3b alone, 3 cases; T3c, 3 cases; and T4, 3 cases. Interestingly, all the patients with T4 tumors also had direct extension of RCC into the adrenal gland. Among the 3 cases with T3c tumors, 1 case also had direct adrenal invasion (T3a) and 2 cases had adrenal metastasis.

The adrenal lesions included 37 (46%) cases of cortical adenoma or hyperplastic nodule, 19 (24%) metastatic RCCs, 15 (19%) contiguous spread of RCC, 4 (5%) pheochromocytomas, and 5 (6%) other lesions, including 2 hemangiomas, 1 myelolipoma, 1 histoplasma infection, and 1 benign cyst (Table 1). Among 19 patients with metastatic RCC, isolated contralateral and bilateral involvement were seen in 1 and 2 cases, respectively. The average size of benign adrenal tumor was 1.7 cm (range, 0.5-8 cm), and the average size of metastatic RCC was 3.7 cm (range, 0.5-9 cm).

The tumor stages of 35 RCCs associated with adrenal adenoma/hyperplasia were as follows: T1a in 20 cases, T1b in 8 cases, T2 in 1 case, T3a (with perirenal and hilar fat invasion) in 5 cases, and T3b (renal vein invasion) in 1 case. The RCCs in 15 cases with direct adrenal extension (T3a) also showed renal vein invasion in 3 (T3b) inferior vena cava involvement above the diaphragm in one (T3c) and tumor invasion beyond the Gerota fascia in 3 (T4). The details of these cases are shown in Table 2. Among the 19 cases with adrenal metastasis, most of the cases showed higher tumor stage (T3) with invasion of the neoplasm into the perirenal adipose tissue. Of the 19 cases, 10 showed invasion of the RCC into the renal vein/inferior vena cava. There was only one T2 and one T1a stage tumor with metastatic adrenal tumor. The details of these cases are shown in the Table 3.

Table 2.

Renal cell carcinomas with direct extension into the adrenal glands
RCC variant Tumor size Tumor stage Tumor grade
Clear cell 5 cm T3a G2
Clear cell 12 cm T3a and T3b G4
Clear cell 17.5 T3a G3
Collecting duct carcinoma 6 cm T3a G4
Clear cell 18 T3a G3
Clear cell 12 T3a, also lung metastasis G4
Papillary type 2 10 cm T4 G4
RCC, unclassified 10.1 cm T3a and T3c G3
RCC, unclassified 8.5 cm T4 G4
Clear cell 9.5 cm T3a G4
Clear cell 8.4 cm T3a G4
Clear cell 9.1 cm T3a, T3b G3
Clear cell 11 cm T3a G3
Clear cell N/A T4 G3
Clear cell 8.3 cm T3a, T3b, lymph node metastasis G3
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Table 3.

Cases of RCC with adrenal metastasis
RCC variant RCC size Adrenal mass Tumor stage Nuclear grade
Clear cell 2.5 0.6 T3a G2
Clear cell 8.5 5 T3a and T3b G3
Clear cell 12 N/A T3a and T3b G3
Clear cell 10.5 N/A T3c G2
Clear cell 12 0.5 T3c G2
Clear cell 4.2 2.2 T3a,T3b, omental metastasis G4
Clear cell 11.7 8.5 T3a andT3b G4
Clear cell 11 3.5 T3a G4
Clear cell 8.5 3.7 T3a G4
Clear cell 11.5 2 T3a G3
Clear cell 11 0.8 T3a and T3b G3
Clear cell 4 0.9 T1a G4
Clear cell 9a N/A T3a and T3b G3
Clear cell 11b N/A T3a and T3b G3
Clear cell 6 0.5 T3a and T3b G3
Clear cell 10.5 9 T3a also lung metastasis G3
Papillary 5.5 0.7c T3a G3
Clear cell 9.8b 7 and 2 cm T2 G3
Papillary Multiple 2-3 cm N/A T3a, lymph node metastasis G3
Full-size table
a Isolated contralateral adrenal metastasis.
b Metastasis also to contralateral adrenal gland.
c Hemorrhagic mass with foci of micrometastasis.

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4. Discussion

Ipsilateral adrenal metastasis has been reported in 1.2% to 10% of RCCs [2], [3], [4], [5], [6], [7], [8], [9], [10] and [11]. Although ipsilateral adrenal removal has been traditionally performed routinely in conjunction with radical nephrectomy, the benefit of this practice has long been under scrutiny [3], [5], [7] and [12]. Several authors have advocated against concomitant adrenalectomy as a standard procedure for smaller renal tumors with grossly normal adrenal gland and without radiographic evidence of adrenal disease. These conclusions were based on the low incidence of malignant involvement on pathologic examination of grossly unremarkable adrenal glands and the relatively high sensitivity of imaging modalities in detecting adrenal lesions [3], [4], [5], [13], [14], [15] and [16]. The habitual practice of unilateral adrenalectomy in renal surgery has also been discouraged due to the likelihood of irreversible impairment of the adrenocortical functional reserve [17]. Based on these observations, most authors advise adrenal sparing nephrectomy, unless there is a clear indication, including positive radiography for adrenal involvement, a large upper pole renal tumor, or a gross adrenal lesion seen at the time of nephrectomy [2], [3], [5], [6], [7], [12], [16], [18], [19] and [20] R. von Knobloch, F. Seseke and H. Riedmiller et al., Radical nephrectomy for renal cell carcinoma: is adrenalectomy necessary?, Eur Urol 36 (1999), pp. 303–308. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (34)[20].

Although detecting a gross adrenal mass during renal surgery is a clear indication for concomitant ipsilateral adrenalectomy, the odds of adrenal malignant involvement by RCC when a gross lesion is discerned has not been previously discussed. Although in our series, the gross pathologic impression of adrenal masses in the presence of a primary renal neoplasm was mainly metastasis from RCC, histologically, we found that most of these lesions (43/77, 56%) represented other entities, among which adrenal adenoma/hyperplasia was the most common. On the other hand, malignant invasion, either as a direct extension or as a result of hematogenous spread, accounted for less than half of the cases (43%).

As demonstrated in Table 1, there was no correlation between the size of adrenal lesions and their benign or malignant nature. Of note, in 2 of the adrenal metastatic tumors, the size of gross lesions was only 0.5 cm in diameter, supporting the notion that careful examination of any suspicious adrenal lesion, regardless of its size, is essential. In addition, because of the lack of reliable distinctive gross features, microscopic evaluation is mandatory to determine the nature of these lesions. Although the initial design of our study specifies inclusion of only cases of grossly and/or radiologically detectable adrenal lesions, we did not find any cases of metastasis detected by microscopic examination that was not observed on gross examination.

The likelihood of adrenal metastasis has been shown to be higher in RCCs of higher stage and larger size. In a study of 511 patients undergoing radical nephrectomy with ipsilateral adrenalectomy for RCC, the probability of adrenal spread correlated with tumor stage, with T4, T3, and T1-T2 tumors accounting for 40%, 7.8%, and 0.6% of cases, respectively [3]. Consistent with these findings, in our series, 17 of the 19 cases with adrenal metastasis were stage T3 RCCs; whereas only 1 case of T2 lesion and 1 case of T1a lesion showed metastasis, the latter in fact was a Fuhrman's nuclear grade 4 RCC. In our case series, the mean size of renal tumor with adrenal metastasis was 8.7 cm, which was significantly larger than the mean size of tumors without adrenal involvement (5.3 cm) (P value<.01). Li et al [8] in their study of 129 RCCs found no adrenal invasion by tumors of less than 5 cm in diameter. All the patients with adrenal involvement were either grade 3 or 4 with pT2 or T3 lesions. In our series, 3 of the 19 adrenal metastases were derived from RCCs smaller than 5 cm in diameter; the smallest of which was a 2.5 cm RCC associated with a 0.6-cm focus of adrenal metastasis. In 2 of these cases, although the tumors were small (2.5 and 4.2 cm), they were T3a lesions with invasion into the perirenal fat, and one of them also had vena cava invasion (T3b). The third case was a T1a lesion but showed a nuclear grade of 4 (Table 3). Our findings indicate that the nuclear grade and tumor stage are better predictors of adrenal metastasis than simply the size of tumor.

Adrenal involvement in the setting of RCC has important prognostic implications. Ipsilateral adrenal invasion by direct extension is classified as a pT3a in the American Joint Committee on Cancer staging system, whereas involvement by hematogenous route defines a stage IV or metastatic tumor. In general, the presence of adrenal metastasis has been shown to be associated with a poor outcome in patients with RCC [4], [5], [6] and [10]. In the follow-up on 4 of our patients with adrenal metastasis, 3 patients died of disease within 1 to 2 years of diagnosis, whereas 1 patient with a T3a tumor and a very small (0.9 cm) adrenal metastasis was alive with no evidence of disease, 15 years after the nephrectomy. Although a number of studies have found some improvement in the survival of a subset of patients with RCC who had an isolated adrenal metastasis and underwent metastasis removal [18], [21], [22] and [23], others experienced no significant benefit in patients' survival from ipsilateral adrenalectomy [14] and [19].

In the current American Joint Committee on Cancer staging system RCC, invasion into the perirenal fat, renal sinus, and direct invasion of the adrenal gland are considered as pT3a tumors. There is significant controversy about combining all 3 in 1 category as pT3a tumors. Han et al [24] have shown that direct invasion of RCC into the adrenal gland has a worse prognosis than perinephric fat or renal sinus invasion. They suggested considering direct extension of RCC into the adrenal gland as a T4 tumor instead of T3a because its prognostic characteristics were similar to that of T4 tumors [24]. In addition, tumors with renal sinus invasion showed more aggressive behavior than those with perinephric fat invasion [25] and [26]. From these studies, it appears that the T3a tumors are heterogeneous and should be further subclassified based on the site of invasion.

The incidence of adrenal gland involvement by RCC is very low. In our study of 550 RCCs, there was a 2.7% incidence of direct extension of RCC and a 3.5% incidence of adrenal metastasis. Given the fact that the patients with both direct adrenal invasion and metastasis had dismal prognosis, a large number of cases must be studied to determine if there is any difference in the prognosis in these groups.

We found an overall higher incidence of adrenal pathologic abnormalities (15%) compared with the 6.5% incidence reported from Antonelli et al [22], in a study of 914 radical nephrectomy specimens. This discrepancy may be due to inclusion of both gross and/or radiological abnormalities in our study and the inclusion of only radiologically detected adrenal lesions in their study. The patients' mean age in their series (61.5 years) was comparable to that in our study (62 years). The prevalence of benign pathologic entities of the adrenal gland and the incidence of metastatic adrenal and direct infiltration from a renal primary in their study were reportedly 3%, 2.7%, and 0.8%, respectively.

We observed some uncommon findings in our series, including a case of an isolated contralateral metastasis to the left adrenal gland from a 9-cm right RCC. Very few examples of contralateral adrenal metastasis from RCC have been reported in the literature. The largest series was reported from the Mayo Clinic of 11 patients, 2 with synchronous and 9 with metachronous metastases [8], [27], [28] and [29]. Although the most common sites of metastatic RCC are the lungs, abdominal organs, bones, and brain [30], the contralateral adrenal gland is the sole metastatic site in only 2.5%, according to an autopsy study of more than 400 patients with RCC [31]. Our series also included 2 cases of an uncommon bilateral involvement of adrenal glands [32] and [33] from a 7-cm and an 11-cm RCC.

There were also a number of uncommon coexisting renal and adrenal lesions in our series. Although only a handful of ipsi- or contralateral adrenal myelolipoma associated with RCC have been reported in the literature [34], [35], [36], [37] and [38], our report adds 2 additional examples: a case of adrenal myelolipoma presenting as a 6.5-cm lesion in association with a 2.5-cm RCC (Fig. 1A-C) and another case of an incidental microscopic focus of adrenal myelolipoma. The later was, however, not included in the study because no gross abnormalities were seen in the adrenal gland. Myelolipoma can be an incidentaloma of the adrenal gland or can also present as a large mass. Hemorrhage is a complication of large myelolipomas. The pathogenesis of myelolipoma is not definitively known, but recently, a clonal proliferation of both hematopoietic elements and adipose tissue has been demonstrated in this entity [39].



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Fig. 1. (A) Gross photograph of radical nephrectomy containing a partly cystic RCC and a myelolipoma in the adrenal gland. (B) The neoplasm in the kidney showing clear cell RCC, with rich vascularity and the neoplastic cells with clear cytoplasm. (C) The concomitant adrenal mass showing myelolipoma in the ipsilateral adrenal gland. Myeloid and erythroid precursors admixed with megakaryocytes and scant adipose tissue is present.

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One of the nephrectomy contained a 7.5-cm RCC and an 8-cm histoplasma granuloma in the ipsilateral adrenal gland, characterized by a granulomatous inflammation associated with histoplasma organisms. Although an infrequent cause of adrenal mass, adrenal histoplasmosis may unusually affect immunocompetent hosts and exhibit variable imaging features [40]. They can present as unilateral or bilateral adrenal masses and rarely cause adrenal insufficiency. Histoplasmosis, therefore, should be included in the differential diagnosis of incidentally discovered adrenal masses.

The coexistence of RCC and adrenal pheochromocytoma is infrequent. The combination of pheochromocytoma and multiple clear cell RCC in a young patient should always raise the possibility of Von Hippel Lindau (VHL) syndrome. In this study, a 36-year-old man with VHL syndrome had multiple clear cell RCC and bilateral adrenal pheochromocytomas. This combination of multiple RCC and pheochromocytoma is seen in type 2b VHL syndrome (Fig. 2A-B) [41]. Von Hippel Lindau disease is an autosomal dominant hereditary syndrome, characterized by a germline mutation in the VHL gene. The carriers are predisposed to tumors in multiple organs, including hemangioblastoma in the retina and central nervous system, RCC, pheochromocytoma, and islet cell tumors of the pancreas. Clear cell RCC has been found to occur in up to 70% of these patients [42]. In a germline mutation, analysis performed in a large study of 469 families with VHL from North America, Europe, and Japan, the various cancer phenotypes included RCC without pheochromocytoma, RCC with pheochromocytoma, and pheochromocytoma alone [43]. Based on the earlier reports, metastatic RCC has been a common cause of death in patients with VHL [44].



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Fig. 2. Concurrent RCC and adrenal pheochromocytoma. (A) Clear cell RCC in the kidney. The adjacent normal kidney is also seen. (B) The adrenal mass showing a pheochromocytoma with a nested pattern and rich vascularity. Adjacent normal adrenal gland is seen.

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Two other pheochromocytomas in our series were sporadic tumors. One was in a 59-year-old man with a 1.5-cm grade 2 clear cell RCC and a 2.8-cm adrenal pheochromocytoma. The second case was from a 77-year-old man with a 1.8-cm oncocytoma and a 3.3-cm adrenal pheochromocytoma (Fig. 3A-C). This combination of renal and adrenal tumors is extremely rare, and to the best of our knowledge, only 2 such cases have been previously reported [45] and [46]. Our series also included a very rare case of malignant adrenal pheochromocytoma with invasion into the kidney. No primary renal tumor was found in the kidney.



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Fig. 3. Concurrent renal oncocytoma and adrenal pheochromocytoma. (A) Renal oncocytoma showing solid islands and dilated tubules with cells containing eosinophilic granular cytoplasm. A loose scant cellular stroma is present. (B) adrenal pheochromocytoma with a solid pattern. Adjacent normal adrenal gland is present. (C) Higher magnification of the adrenal tumor showing some spindled cells with abundant granular cytoplasm. The cytoplasm has a brownish hue due to the presence of melanin.

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In summary, although less than half of the grossly discovered adrenal lesions in association with RCC in our series were found to represent malignant involvement by RCC, due to the significant prognostic consequence of adrenal metastasis and the possibility of small metastatic foci in adrenal glands, meticulous gross and microscopic examination of adrenal glands removed during renal surgery is crucial. Nevertheless, other pathologic entities, including benign or malignant adrenal primaries, as well as nonneoplastic lesions, should also be included in the differential diagnosis. When the adrenal mass is larger than the renal mass, pathological entities other than metastatic RCC should be considered.
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