ADRENOCORTICAL CARCINOMA WITH INTRACAVAL EXTENSION
SEAN P. HEDICAN AND FRAY F. MARSHALL*
From the James Buchanan Brady Urological Institute, The Johns Hopkins Hospital, Baltimore, Maryland
ABSTRACT
Purpose: We describe the presenting features, treatment approach and prognosis of adreno- cortical carcinoma with intracaval extension of tumor thrombus.
Materials and Methods: In addition to 3 patients with adrenocortical carcinoma associated tumor thrombus treated at our institution, we reviewed an additional 26 patients described in the literature from 1972 to 1997 with regard to presentation, management and outcome.
Results: We identified 23 female and 6 male patients 6 to 77 years old (mean age 41.3). Of the lesions 24 originated in the right adrenal gland. Mean tumor size was 10.1 cm. and 89% of lesions were at least 9 cm. in greatest dimension. Tumor thrombus extended to the atrium in 15 patients, retrohepatic cava in 7 and subhepatic cava in 7. Flank or abdominal discomfort was the most common presenting complaint and abnormal steroid metabolism was documented in 76% of patients. Cardiac bypass techniques were used in 14 patients and none of the 3 intraoperative mortalities, 2 thromboemboli and 1 exsanguination, occurred using this approach. Eight patients received postoperative mitotane, 6 of whom had no evidence of residual disease at the time of case description.
Conclusions: All patients with large adrenal tumors, especially those arising from the right gland, should undergo careful evaluation of the vena cava for thrombus. The best chance for survival is via complete surgical extirpation which is facilitated by the use of cardiac bypass techniques. There is evidence to support the early use of postoperative mitotane if there is a suspicion of residual or recurrent disease.
KEY WORDS: adrenal gland neoplasms, thrombosis
Carcinoma of the adrenal cortex is a rare but extremely aggressive disease with a reported incidence of 2 cases per million.1 These tumors are highly malignant with 50 to 70% exhibiting locally advanced lesions at the time of presenta- tion.2 The prognosis for untreated adrenocortical carcinoma is dismal, with a median survival of 2.5 months.3 Extension of tumor thrombus into the vena cava is a phenomenon well recognized in patients with renal cell carcinoma4,5 and has been described in association with Wilms tumor,6 retroperi- toneal leiomyosarcoma,7 testicular cancer,8 thyroid cancer,9 and, most notably, adrenocortical carcinoma.1º Evidence sug- gests that as many as a third of primary adrenocortical cancers may develop tumor thrombus within the vena cava.11 Thrombus may be asymptomatic or become manifest as as- cites, the nephrotic syndrome, hepatomegaly, acute tricuspid valve failure or the Budd-Chiari syndrome.12
The identification of intracaval thrombus is paramount to the successful treatment of adrenocortical carcinoma since complete local excision is the best therapy for advanced local disease.13 The recent use of cardiopulmonary bypass and circulatory arrest has facilitated the surgical extirpation of renal cell carcinomas extending into the vena cava and this approach is now being used for adrenal cancers.5.14 Bypass maneuvers allow bloodless dissection and inspection of the vena cava, and help reduce the risk of intraoperative exsan- guination and tumor thromboembolus. With the exception of conflicting reports regarding the use of the adrenolytic agent mitotane (o,p’-DDD), the treatment of residual or recurrent postoperative adrenocortical carcinoma tends to be dismal due to the chemoresistant nature of the tumor.15-17 We ex- amined our experience and the literature in an effort to Accepted for publication May 9, 1997.
* Requests for reprints: James Buchanan Brady Urological Insti- tute, Marburg 1st Floor, Johns Hopkins Hospital, Baltimore, Mary- land 21287-2101.
identify patient demographics, presenting features and suc- cess of various treatment approaches to adrenocortical carci- noma with intracaval thrombus extension.
CASE HISTORIES
Case 1. M. A., a 51-year-old white man, presented in April 1990 with a chief complaint of right upper quadrant and testicular discomfort. Ultrasound and computerized tomog- raphy (CT) revealed a 12 cm. right adrenal tumor (fig. 1). Presenting laboratory evaluations were significant for ele- vated serum levels of lactate dehydrogenase 1,599 IU/. (nor- mal 80 to 200) and alkaline phosphatase 290 IU/l. (normal 40
to 250), and 24-hour urinary levels of free cortisol 412 mcg. (normal 20 to 90), 17-ketosteroids 31.6 mg. (normal 9 to 22) and 17-hydroxycorticosteroids 16.5 mg. (normal 2 to 11).
Magnetic resonance imaging (MRI) confirmed the presence of a 10 × 11 cm. right adrenal mass with medial displace- ment of and possible intraluminal involvement of the vena cava. Inferior venacavogram demonstrated a well defined filling defect in the vena cava between the hepatic and renal veins (fig. 2). On April 16 the patient underwent right adre- nalectomy with excision of vena caval tumor thrombus under cardiopulmonary bypass with 17 minutes of circulatory ar- rest at 20C. The final specimen weighed 1,300 gm. and meas- ured 12 × 19 cm. Histopathology revealed adrenocortical carcinoma with associated tumor thrombus.
The patient was free of disease until 1 year postoperatively when CT demonstrated several small lesions within the liver associated with an elevation of the serum transaminases. He was treated initially with 20 mg. gossypol b.i.d., and, later 300 mg./m.2 paclitaxel, 75 mg./m.2 cisplatin, 5 mcg./kg. granulocyte-colony stimulating factor daily were added due to disease progression. After 4 courses of therapy progressive neuropathy developed without significant disease regression, and so 2 to 4 gm. mitotane daily were initiated. The patient had improvement of the hepatic lesions after 6 months of therapy and the mitotane was discontinued. Mitotane was later reinitiated in April 1993 when followup CT revealed enlargement of the hepatic lesions. However, biopsies did not demonstrate cancer, and so mitotane was discontinued. In December 1995 he again had evidence of hepatic metastases, and exploratory laparotomy was performed with biopsy and cryoablation of the lesions. Adrenocortical carcinoma was identified in 1 of the pre-ablation biopsies. Currently, it has been 6 years and 8 months since the original surgery and there is no evidence of disease.
Case 2. J. I., a 29-year-old white woman, presented in August 1989 with progressive malaise, lower extremity edema, 30 pound weight gain and worsening dyspnea. An echocardiogram revealed a nonhomogeneous mass filling the right atrium. Further evaluation included ultrasound and CT which demonstrated a 12.7 cm. right adrenal mass with
intraluminal thrombus in the vena cava. MRI confirmed intracaval tumor thrombus extending from the adrenal to the level of the right atrium. There was no evidence of metastatic disease.
At operation the patient was extremely ill having gained 80 pounds from edema fluid. She underwent right adrenalec- tomy with excision of vena caval tumor thrombus. Trans- esophageal echocardiography helped to delineate the intra- cardiac tumor and facilitated the placement of intravenous monitoring lines. The patient was placed on cardiopulmonary bypass with 45 minutes of circulatory arrest at 18C while tumor was extracted from the right atrium and hepatic veins with the aid of dental mirrors. The specimen weighed 570 gm. and pathology revealed a primary adrenocortical carci- noma. Postoperatively hepatorenal failure and a consump- tive coagulopathy developed. She was reexplored 10 days postoperatively due to a persistently elevated white blood count and septic parameters but no collections were identi- fied. The patient died 4 days following reexploration of mul- tisystem organ failure.
Case 3. M. M., a 52-year-old white woman, presented in 1980 with Cushing’s syndrome. Abdominopelvic CT revealed a large right adrenal tumor with intracaval tumor thrombus. Venacavogram confirmed the presence of thrombus in the subhepatic vena cava. The patient underwent right adrena- lectomy with extraction of the intracaval thrombus without the use of bypass techniques by clamping above the cephalad extent of the thrombus. The patient did well during the initial postoperative period but within 1 month diffuse pul- monary and intra-abdominal metastases developed. Mito- tane was initiated but despite aggressive treatment she died of diffuse disease 8 months later.
RESULTS
In addition to our 3 cases, 26 cases of adrenocortical car- cinoma with intracaval tumor thrombus were reported in the literature from 1972 until 1997. Individual patient demo- graphics, tumor location and size, thrombus extent, surgical approach, chemotherapy and treatment outcome are summa- rized in table 1. Female patients are known to have a higher incidence of primary adrenocortical carcinoma and, indeed, a 3.8:1 female-to-male ratio was noted among patients with intracaval tumor extension. Patient age ranged from 6 to 77 years (mean 41.3). The majority of tumors were on the right side with only 5 arising from the left adrenal gland. Mean tumor size was 10.1 cm. (± 5.6) and 89% of described lesions were 9 cm. or greater. Thrombus extended to the atrium in 15 patients, retrohepatic cava in 7 and subhepatic cava in 7.
Clinical presentation varied, however, the most common presenting complaint for male and female patients was local flank or abdominal discomfort (table 2). Clinical or biochem- ical evidence of abnormal adrenal steroid production was noted in 70% of female patients and 100% of male patients. Nonfunctional tumors were noted more commonly in older patients with a mean age of 62 years (range 51 to 77) versus 36 years (range 6 to 72) for patients with functional tumors (table 3).
Cardiac bypass techniques were used in 14 cases (table 1). Bypass was initiated after tumor thromboembolus in 2 of these patients (5 and 29) and both died intraoperatively. The third patient (6) was placed on emergency bypass after tumor thrombus fractured and lodged against a proximally placed Rumel clamp. The patient survived the operation and lived another 3 years following suramin therapy and resection of a pulmonary metastasis. Gross evidence of residual tumor was noted in 3 patients, 2 of whom (17 and 20) were not placed on bypass during resection, and in the third case (15) the use or nonuse of bypass techniques was not discussed. The only other intraoperative death occurred in a patient (27) who
| Pt. No. | Reference | Age-Sex | Lesion Side | Size (cm.) | Thrombus Level | Incision | Cardiac Bypass | Circulatory Arrest | Complications | Additional Therapy | Followup |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 2 | Present series Present series | 51-M 52-F | Rt. Rt. | 12 Not re- ported | II 1 | Thoracoabdominal Thoracoabdominal | Yes No | Yes No | Rt. femoral deep venous thrombosis None | Gossypol 4 mos., paclitaxel, cisplatin-4 mos., mitotane- begun at 2 yrs. after liver metastasis developed, con- tinued for 6 mos. Mitotane after extensive me- tastasis | No evidence of disease 80 mos. Died of metastasis at 8 mos. |
| 3 | Present series | 29-F | Rt. | 12.7 | III | Thoracoabdominal | Yes | Yes | Postop. multisystem organ failure | None | Died of multisystem organ failure at 2 wks. |
| 4 | Siegelbaum et al23 | 23-F | Rt. | 18 | I | Thoracoabdominal | No | No | None | Mitotane after pulmonary metastasis | No evidence of disease 60 mos. |
| 5 | " | 72-F | Lt. | Not re- ported | I | Lt. subcostal/me- dian sternotomy | Yes, after tu- mor embolus | Not reported | Possible intraop. tumor embolus | - | Died intraop. |
| 6 | Moul et al21 | 33-M | Lt. | 16 | III | Bilat. subcostal/ median sternot- omy | Yes, after tu- mor embolus | Yes | None | Suramin 2 cycles, pulmonary metastasis resected | Progressing pulmonary metastasis at 36 mos. |
| 7 | Concepcion et al8 | 38-F | Rt. | Not re- ported | II | Rt. subcostal/me- dian sternotomy | No | No | Intraop. hypotension | Not reported | Died of metastasis at 18 mos. |
| 8 | " | 27-F | Rt. | 9 | III | Midline/median sternotomy | No | No | None | Mitotane started 2 days postop. | No evidence of disease 17 mos. |
| 9 | * | 55-F | Rt. | 20 | III | Midline/median sternotomy | Yes | No | None | Mitotane | No evidence of disease 12 mos. |
| 10 | Decker and Kuehner16 | 41-F | Rt. | 20 | II | Not reported | No | No | Not reported | Not reported | Died of metastasis at 21 mos. |
| 11 | * | 48-F | Rt. | 14.5 | III | Not reported | Yes | Yes | Not reported | Not reported | Died of metastasis at 2 mos. |
| 12 | Cheung and Thompson 27 | 22-F | Rt. | 14 | III | Rt. subcostal/me- dian sternotomy | Yes | Yes | Postop. bleeding/reex- ploration | Mitotane low dose | No evidence of disease 12 mos. then committed suicide |
| 13 | Shahian et al28 | 51-F | Rt. | 12 | III | Bilat. subcostal/ median sternot- omy | Yes | Yes | Rt. hemothorax, deep ve- nous thrombosis | None | No evidence of disease 10 mos. |
| 14 | Carbonnel et al29 | 28-F | Rt. | Not re- ported | III | Not reported | Yes | No | Postop. coma | None | Died postop. day 2 |
| 15 | Brabrand and Soreide30 | 72-F | Rt. | 6 | II | Thoracoabdominal | Not reported | Not reported | Persistent 2 cm. thrombus below diaphragm | Not reported | Died diffuse pulmonary metastasis at 3 mos. |
| 16 | Pritchett et al31 | 72-F | Rt. | Not re- ported | III | Thoracoabdominal | Not reported | Not reported | Not reported | Not reported | Not reported |
| 17 | Ritchey et al32 | 44-M | Rt. | 10 | I | Not reported | No | No | Unresectable | Not reported | Died of metastasis at 10 mos. |
| 18 | Hugh et al12 | 18-F | Rt. | 12 | II | Midline/median sternotomy | Yes | No | Rt. basal lung collapse | None | Died of metastasis at 14 mos. |
| 19 | ₦ | 43-F | Rt. | 15 | III | Midline/median sternotomy | Yes | No | Bilat. lung collapse, deep venous thrombosis | None | No evidence of disease 15 mos. |
| 20 | Schramek et al33 | 52-F | Rt. | 15 | III | Not reported | No | No | Residual tumor | 5-Fluorouracil | Died of metastasis at 5 mos. |
| 21 | Martorana et al34 | 45-F | Lt. | Not re- ported | I | Bilat. subcostal | No | No | None | 5-Fluorouracil/doxorubicin/ cyclophosphamide | No evidence of disease 5 mos. |
| 22 | Geelhoed et al18 | 22-F | Rt. | Not re- ported | III | Not reported | Yes | Not reported | Not reported | None | No evidence of disease 36 mos. |
| 23 | " | 23-F | Lt. | Not re- ported | II | Not reported | No | No | None | Mitotane begun at 18 mos. after pulmonary recurrence | No evidence of disease 22 mos. |
| 24 | " | 27-M | Lt. | Not re- ported | II | Not reported/me- dian sternotomy | No | No | Not reported | Not reported | No evidence of disease 24 mos. |
| 25 | Javadpour et al14 | 22-F | Rt. | Not re- ported | III | Thoracoabdominal | Yes | Yes | Rt. hemothorax with ex- ploration, disseminated intravascular coagula- tion | 5-Fluorouracil/mitotane | No evidence of disease 12 mos. |
| 26 | Cahill and Sukov11 | 67-F | Rt. | 9 | I | Not reported | No | No | None | None | No evidence of disease 5 mos. |
| 27 | Scully et al36 | 37-M | Rt. | 12 | III | Midline/median sternotomy | No | No | Exsanguinated | - | Died intraop. |
| 28 | Shons and Gamble19 | 77-F | Rt. | Not re- ported | Down C. iliac | None, died prior to surgery | - | - | - | - | Died 11 days after diagnosis |
| 29 | Castleman et al10 | 6-M | Rt. | 8 | III | Thoracoabdominal | Yes after embo- lus | No | Intraop. tumor pulmonary thromboembolus | - | Died intraop. |
| Endocrine Status* | No. Women (%) | Mean Age + SD | No. Men (%) | Mean Age + SD | Total No. Pts. (%) | Mean Age + SD |
|---|---|---|---|---|---|---|
| Functional tumor | 16 (70) | 37 ± 16 | 6 (100) | 33 ± 14 | 22 (76) | 36 ± 16 |
| Nonfunctional | 6 (26) | 62 ± 10 | 0 | - | 6 (21) | 62 ± 10+ |
| tumor | ||||||
| Unknown status | 1 (4) | 29 | 0 | - | 1 (3) | 29 |
* All patients with clinical or laboratory evidence of abnormal adrenal steroid metabolism were considered to have functional tumors.
t p = 0.05 paired Student’s t test.
| Presenting Signs or Symptoms | No. Women (%) | No. Men (%) |
|---|---|---|
| Cushing's syndrome | 7 (30) | 1 (17) |
| Virilization/feminization | 3 (13) | 0 |
| Menstrual irregularities | 5 (22) | 0 |
| Precocious puberty | 0 | 1 (17) |
| Abdominal mass | 3 (13) | 0 |
| Abdominal/flank pain | 8 (35) | 3 (50) |
| Ascites/distension* | 3 (13) | 2 (33) |
| Peripheral edema | 7 (30) | 1 (17) |
| Dyspnea/shortness of breath | 3 (13) | 0 |
| Wt. loss | 2 (9) | 0 |
| Wt. gain | 1 (4) | 0 |
| Hypertension | 0 | 2 (33) |
* Includes patients complaining of early satiety.
exsanguinated during another procedure in which bypass techniques were not used. Of 8 patients who received post- operative mitotane 6 (9, 25, 8, 23, 4, and 1) exhibited no evidence of residual disease at the time of the report (12 months, 12 months, 17 months, 22 months, 5 years, and 6 years 8 months, respectively). One of the remaining 2 pa- tients (12) was free of disease at 12 months but committed suicide, while the other (2) died of diffuse metastases 8 months following surgery.
DISCUSSION
Intracaval extension of tumor by adrenocortical carcinoma was first described in 1972 by Castleman et al.10 Due to the rarity of this cancer, the exact incidence of vena caval in- volvement is not known although some authors hypothesize that it may be present in as many as 30% of patients.11 The intracaval tumor thrombus consists of an independently vas- cularized collection of malignant cells within a latticework of clotting elements. These lesions tend to arise most commonly from the right adrenal gland (82.8% in our review), presum- ably due to the more direct route into the vena cava via the short right adrenal vein. Primary tumors tend to be large with a mean size of 10.1 cm. (range 6 to 20) and our review demonstrated that 89% of described lesions were 9 cm. or greater in largest dimension. As a result of these observa- tions, we recommend that MRI or venacavogram be per- formed to evaluate the vena cava for tumor thrombus in any patient with a primary adrenal tumor that is 9 cm. or larger, especially those originating from the right gland. These ad- ditional imaging modalities should also be used in any pa- tient, regardless of primary tumor size, whose initial studies suggest compression or distension of the vena cava.
Clinical presentation varied but the majority of patients complained of local discomfort or pain. Review of the clinical and laboratory data from these patients revealed a much higher incidence of hypersecreting (that is functional) tumors (76% versus 29 to 59% reported in the literature), for adrenal lesions not associated with intracaval thrombus.15.17 A pos-
sible explanation for this observation is that hypersecretion may reflect the more direct injection of steroid products into the blood stream from malignant cells trapped within intra- caval thrombus versus an encapsulated tumor.18 Similar to organ confined lesions,19 we found that nonfunctioning tu- mors presented more commonly in older patients (mean age 62 years ± 10) versus patients with functional tumors (mean age 36 years ± 16). The reported female-to-male ratio for adrenocortical carcinoma varies from 1:1.3 to 1.4:1 depending on the series.17,20 In our review we noted a pronounced fe- male predilection with a 3.8:1 female-to-male ratio. This may be due, in part, to the increased likelihood of clinically de- tectable steroid hypersecretion among female patients with resultant seeking of medical attention.
The use of cardiac bypass techniques has improved the safety and efficacy of removing large retroperitoneal tumors with intracaval tumor thrombus.5-8 Javadpour et al were the first to report the use of these techniques in the management of an adrenocortical cancer with a malignant vena caval thrombus.14 Although direct vascular wall invasion by these tumors has been reported, the majority of these lesions spread via intraluminal extension only due to the barrier effect of the intimal layer of the vena cava. Intracaval tumor can quickly achieve a supradiaphragmatic position and grow in a mushroom fashion within the right atrium. In our study 52% of thrombi attained this level making complete extrac- tion from a subhepatic cavotomy dangerous. Unlike the con- densed thrombi of renal cell carcinoma, intracaval thrombus from adrenocortical lesions is gelatinous and friable much like the primary tumor.21 Attempts at extraction or clamping of the vena cava without knowledge of the superior extent of the thrombus can result in massive thromboembolus, intra- vascular collapse and probable death.22 Two patients identi- fied in this review experienced this complication and died intraoperatively as a result, while a third nearly suffered the same fate but was saved using emergency cardiac bypass. Other authors have advocated the use of cardiac bypass only for tumor thrombus extending above the subhepatic vena cava21 but in our review 1 of the 2 patients who died intra- operatively as a result of a tumor thromboembolus had tumor extending within the subhepatic vena cava only. This finding may reflect the extreme friability of these lesions and sug- gests that early proximal vena caval control and occlusion are critical for subhepatic lesions extracted without the ad- vantage of cardiac bypass.
Sublethal emboli and residual intracaval tumor can prove to be just as deadly as the more dramatic saddle embolus, since independent vascularization of the intracaval tumor allows growth following embolization from the primary le- sion.22 Not only does cardiac bypass help guard against the threat of thromboembolism but it allows for a more meticu- lous, bloodless dissection of the vena cava. In 1 of our cases we used dental mirrors to inspect the ostium and lumen of each hepatic vein for residual thrombus during circulatory arrest. Cardiac bypass also reduces the risk of significant hemorrhage and alleviates the need to occlude the porta hepatis, ligate lumbar veins or cross-clamp the aorta to de- crease bleeding.7 In our review 1 patient who exsanguinated intraoperatively was never placed on bypass. No intraopera-
tive mortalities occurred among patients resected while on cardiac bypass. Since complete surgical extraction affords the best survival in patients with adrenocortical carcinoma (49% 5-year survival for a complete versus 9% for a subtotal resec- tion)17 and cardiac bypass improves the ability to remove all intracaval tumor while minimizing the risks, cardiovascular surgeons should be available to provide bypass capabilities for these tumors. Preoperative planning is critical, and the images (coronal and sagittal) provided by MRI are excellent for predicting adjacent organ involvement and cranial extent of intracaval tumor.23
The survival impact of intracaval tumor extension is un- known, however, 5-year survival rates of 60 to 70% have been reported for similar patients with renal cell carcinoma asso- ciated thrombus following complete resection.4 Unlike renal cell carcinoma, 1 chemotherapeutic agent, mitotane, has shown impressive although somewhat controversial efficacy in the treatment of adrenocortical carcinoma. Several studies indicate that mitotane may improve survival following sub- total tumor resection or recurrence.17,24 Additional studies also advocate the use of adjuvant mitotane therapy following apparent complete tumor resection25,26 while other authors have shown no significant improvement in cancer control rates.17 Significant long-term survival (mean 74 ± 33 months) was shown in a series of 8 patients with recurrent disease treated with mitotane alone (2 patients) or mitotane and repeat surgery (6 patients).24 In the 2 longest survivors in our review (5 years or more) and in 1 patient who was disease-free after 22 months mitotane was initiated only after there was evidence of metastatic disease. Of the other 5 patients who received mitotane 4 had no evidence of disease at 12 months or more. Although statistically significant con- clusions cannot be based on these few patients, our results, in addition to the findings of Schteingart et al, suggest that the use of postoperative mitotane is efficacious and can likely be delayed until there is biochemical or radiographic evidence of recurrence.24 Careful radiographic, serum and urine fol- lowup studies are an important feature of this treatment approach.
CONCLUSIONS
Adrenocortical carcinoma with intracaval extension of tumor thrombus is found most commonly in association with large right lesions. Our review of the litera- ture8, 10-12, 14, 16, 18, 19, 21, 23,27-35 indicates that the majority of patients are women and most often present with local dis- comfort or evidence of abnormal steroid production. Throm- bus tends to be friable and rapidly achieves a supradiaphrag- matic position. The mainstay of therapy is complete surgical excision, which is facilitated using cardiac bypass tech- niques. Evidence supports the use of postoperative mitotane in the treatment of presumed residual or recurrent tumor.
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