contents
14.1 Epidemiology . . . 143 14.2 Clinical Features . . . 143 14.3 Surgical Treatment . . . 145 14.4 Medical Therapy . . . 146 14.5 Prognosis . . . 146
14.6 Recurrence and Laparoscopic Surgery . . . 146 14.7 Case Report . . . 146
References . . . 149
One of the reasons that make this tumor such a threat- ening disease (actually the second most lethal en- docrine neoplasm after anaplastic thyroid carcinoma) is its proneness to both recurrences and distant metas- tases, very often synchronous with the recurrence it- self. In spite of the most careful surgery at the time of first operation in more than 60% of the cases, adreno- cortical carcinoma (ACC) recurs involving several ad- jacent and even distant organs. Since it is well known that medical therapy has very poor efficacy (if any) in treating these patients [14], surgery remains the only option, if not for cure, for an acceptable survival in the presence of a recurrent disease.
14.1 Epidemiology
According to the Memorial Sloan-Kettering Cancer Center experience [21], resection of a local or distant recurrence was performed in 47 of 113 patients, with almost half undergoing a third operation; one patient underwent a seventh resection! Similar experiences have been quoted by most surgeons who are familiar with this often fatal illness. The high number of repeat operations is an important point to focus on because it expresses the growth of the tumor. As in any other malignancy the possibility of recurrence is related to the stage of the disease at presentation. In fact, Sulli-
van, who introduced a Staging System which is widely used [22], reported a 5-year survival rate of 100% for Stage I disease, an 80% rate in Stage II, 20% in Stage III and 0% in Stage IV.According to others [7], even in the presence of a complete resection of the carcinoma as many as 68% of the patients will develop a local re- currence.It is easy to understand that survival is linked in most of the cases with recurrence, which is general- ly the crucial occurrence in the natural history of treated disease.
The relapse time between first surgery and recur- rence is also an important factor because it is an ex- pression of the aggressiveness of the disease; a very early recurrence is often related to a poor prognosis.
Most authors [2, 9, 18] agree that recurrence occurs most often 1–2 years after the operation. Late recur- rences have also been described from 5 to even 14 years after the first operation [13].
The organs more often involved are respectively the kidney, liver, great vessels, spleen, pancreas and stom- ach together with retroperitoneal fat tissue and di- aphragm (Figs. 1, 2). A very common site is unfortu- nately the peritoneal serosa,where several nodules can be found: this constitutes a dreadful situation because it makes surgical radicality a very difficult challenge.
Port site metastases are a common site as well and they will be more thoroughly discussed when discussing laparoscopic access [8].
As for distant metastases repeat resection is per- formed in more than 50% of the cases for lung metas- tases, in one-third for liver and more rarely for bones [21]. Other sites such as skin or brain are exceptional.
14.2 Clinical Features
The clinical pattern of recurrent disease differs in ac- cordance with the functional status of the primary tu- mor. The onset in the case of a functioning malignan- cy is generally, if not always, unveiled by the presence Paolo Miccoli, Pietro Iacconi
of characteristic stigmata that can be divided into three types according to the type of hormone in excess:
steroid, sexual and mineralocorticoid hormones. The patients usually recognize quite easily their symptoms and stigmata having experienced them before. This can be very simple in the first two instances but not in the third (mineralocorticoid) because the latter,which is exceptionally rare in malignant tumors, may cause minimal symptoms.The clinical suspicion will be con- firmed by adequate hormonal serum and urinary measurements addressed by the morphologic changes which have occurred. In these patients the diagnosis is easily achieved and there is no need for measurements of hormonal markers of malignancy such as DHEA-S [17]. In contrast imaging studies should be initiated immediately to determine the exact site of the recur- rence or distance metastasis. Although abdomen ul- trasonography can be an excellent tool initially in par- ticular when the liver is involved, computed tomogra- phy (CT) [12] must be considered the procedure of choice to determine the presence and the extension of a recurrence. A contrast-enhanced CT of abdomen and chest is mandatory and it will give important in-
Gallbladder
Liver
Liver
Bile duct Recurrence
Transverse colon Kidney
Inferior vena cava Duodenum
Fig. 1. Recurrent right adrenocortical carcinoma involving the liver, right kidney
Fig. 2. CT showing right recurrent adrenocortical carcinoma infiltrating the diaphragm
formation about the functioning status of the con- tralateral kidney,since the homolateral kidney is often affected by the recurrence and thus may have to be in- cluded in the resection [21, 15].
When dealing with nonfunctioning tumors the re- currence is more often revealed by imaging studies routinely performed during follow-up because a tight surveillance by means of echography and CT is high- ly recommended in these patients,in particular during the first 3–5 years after primary operation. In these cases symptoms can be completely absent or nonspe- cific such as fever, anemia or unexplained weight loss.
Pain in the flank or palpable masses are only present if the recurrent mass is very large or is invading sur- rounding structures and in particular nerve trunks in the retroperitoneum. In these patients the most accu- rate imaging workup must be accomplished before re- peat surgery. Magnetic resonance imaging (MRI) might be complementary to CT when an intravascular extension of the mass is suspected: in these cases MRI is probably irreplaceable [15] and it has reduced the role for venography,which should be reserved only for patients with large masses on the right side either if some doubt about great vessels involvement still exists [19] or if a venous bypass has to be planned before op- eration [1]. As for fine-needle aspiration biopsy, prob- ably everyone agrees that if it is not useful in ACC it should be excluded from the preoperative workup in these patients, having no role at all in a disease, such as recurrent ACC, where the nature of the lesion cannot be misunderstood.
14.3 Surgical Treatment
At present reoperative surgery remains the most ef- fective, if not the only, therapeutic option for these patients. This is true for both the palliation of symp- toms induced by hormonal hypersecretion in func- tioning tumors and to prolong the survival in all cases.
In fact it is well demonstrated in all the largest series dealing with repeat surgery for ACC that surgical treatment proved to be superior in terms of life expectancy in comparison to any medical treatment [7, 18, 9, 4]. Pommier [18] demonstrated that, in his cohort of 73 cases treated in a single institution, mean survival time was 56 months for patients reoperated versus 19 months for patients who had undergone only medical therapy. Furthermore in the Cleveland Clinic’s experience mitotane proved to be as effica- cious as no therapy at all in treating locoregional re- currences [3].
Unfortunately, in spite of certain efficacy, repeat surgery falls short in curing these patients: Jensen et al.
evaluated the NIH series of 32 cases, concluding that none of them was cured, only 20% had a 5-year sur- vival and median survival from the time of diagnosis was less than 2 years [11]. The same authors assume that the results do not change even in the presence of the most extensive surgery. These disappointing con- clusions though must not refrain surgeons from an ag- gressive operative attitude: there is a general agree- ment [21, 18, 9, 19, 4, 11] that surgery is able to improve survival dramatically and may thereby control the ad- verse effects of hormonal excess better than mitotane.
Thus, the decision to operate on these patients should be made in all the patients where no important medical contraindications exist: surgical contraindi- cations consist either of extensive metastatic disease or of involvement of major arterial vessels [21].In all oth- er cases large debulking attempts are justified. In spite of such aggressive approaches the perioperative mor- tality is surprisingly low, ranging from 0% [2, 11] to 3.6% [21]. Morbidity of course cannot be negligible in such complex surgery: the complications occurring more often are bleeding and abdominal abscesses, but they are very rarely life-threatening [11].
Another characteristic indicating the difficulty of this surgery is the high rate of incomplete resections:
one-third of the cases in the Memorial Sloan-Kettering Cancer Center series [21] and 36% of the patients in our institution underwent a resection that was not complete.More often the metastases’resection (69% in the same series) appeared to be radical, thus confirm- ing the high tendency of this tumor to infiltrate local- ly. The natural consequences of the phenomenon are the different outcome of the patients according to the completeness of the resection: a median survival of 74 months among those undergoing a complete resec- tion and only 16 months among those undergoing an incomplete removal of the recurrence [21].
Laparotomic access is generally the favorite access for large debulking operations, particularly on the right side, where the presence of the liver makes the thoraco-phreno-abdominal approach not particular- ly useful. Furthermore, it does not violate the pleural cavity and is less limiting in operating on the opposite side of the peritoneal cavity where synchronous metastases can occur (e.g. liver metastases in a recur- rence on the left side). We favor bilateral subcostal in- cisions versus midline incisions, but sometimes the first operative incision might restrict the surgeon’s choice. In our opinion it offers an optimal view of the contralateral side with the above-mentioned advan-
tages and a better exposure of the upper abdomen, where generally the regional recurrences, more diffi- cult to approach, are located. This is the case for infil- trations of the spleen, stomach, diaphragm, kidneys, pancreas and left colon flexure.Thoracoabdominal ac- cess remains mandatory when venous bypass is re- quired and the superior vena cava must be ap- proached; access to chest can also be obtained extend- ing superiorly the abdominal incision to the sternum (sternotomy).
14.4 Medical Therapy
The very limited efficacy of medical treatment has al- ready been stressed in this and in other specific chap- ters. The only drug which has been utilized widely is mitotane, but its value as adjuvant therapy in the pa- tients operated for ACC was excluded [24] and its im- portant side-effects were prohibitive. In recurrences where surgery cannot be accomplished though, this drug is still used. If its response could be objectively demonstrated in terms of real mass reduction (CT measurement,autopsies,etc.),its results would be even more disappointing and there is no demonstration that this supposed response correlates with prolonged survival [25].The intended efficacy in nonoperable pa- tients is by consequence in terms of partial control of endocrine symptoms and it must be associated with a replacement therapy with corticosteroids. It seems that in no more than one-third of these patients can medical therapy really palliate functional symptoms.
14.5 Prognosis
It has already been stated that prognosis is dismal in these patients and very prolonged survivals, if not real cures, are so exceptional as to be considered more as episodic reports rather than as a matter of discussion.
In fact, long-term survivors (from 15 to even 20 years) have been described [11, 16, 20], but this is not enough to induce optimistic hopes when operating on these patients. We have already seen that a better prognosis can be expected when the operation has accomplished a complete resection. In the same way resections seem to have a better outcome in patients with a longer dis- ease-free interval [11].
The overall median survival from the time of diag- nosis is less than 2 years [11]. In a series by The Italian National Registry for Adrenal Cortical Carcinoma, 23% of the patients who underwent reoperation were
alive 3 years after the recurrence diagnosis [2]. This confirms that repeat surgery should in any case be re- garded as an absolute indication, being the only valid therapeutic option.
14.6 Recurrence and Laparoscopic Surgery
It should not be necessary to repeat that no role can ex- ist for laparoscopic surgery when treating ACC, let alone when treating its recurrences. Thoracoscopy might be useful if an isolated lung metastasis has to be removed, but this represents an exceptional and episodic situation.
Vice versa this is a good opportunity to stress once again the responsibilities of laparoscopic adrenalec- tomies in the occurrence of peritoneal implants which must be regarded as real disasters.Although peritoneal recurrences can be present after traditional surgery, trocar port site seeding and the fair number of reports of such a situation [5, 6, 8, 10, 23] leave no doubt that this complication must be considered as a specific complication of laparoscopic removal of ACC. One of the characteristics of this kind of recurrence is their tendency to present quite early after first surgery [10];
this is a further confirmation of our concern about this dreadful occurrence. The greatest caution should be taken when deciding to operate laparoscopically on patients who present even a faint suspicion of malig- nancy.
14.7 Case Report
A 34-year-old female patient was admitted to our de- partment in October 2000 with a history of recent ap- pearance of hirsutism and a cushingoid appearance.
On US, the left adrenal gland was 7¥5¥5 cm. CT con- firmed the US report (Fig.3).With the suspicion of ad- renal carcinoma the patient underwent a traditional open approach. Histology confirmed ACC. In July 2001, for recurrent symptoms and stigmata a CT showed a locoregional recurrence involving the spleen and the left lobe of the liver (Fig. 4a, b). The mass was removed “en bloc” with apparent radicality. The fol- lowing October the patient underwent an exploration with the suspicion of a uterine myomatoma (Fig. 5).
The mass proved to be an ovarian metastasis. In Feb- ruary 2002 the third recurrence involving the left kid- ney and part of the left diaphragm was removed. In March 2003 the patient underwent a fifth operation
Fig. 3. CT showing a left adrenal tumor measuring up to 7 cm maximum diameter
Fig. 4a, b. CT showing recurrence of left adrenocortical carcinoma involving the spleen and left lobe of the liver
Fig. 5. CT showing an ovarian metastasis of a previously operated recurrent adrenocortical carcinoma
Fig. 6. CT showing extensive re-recurrence of adrenocortical carcinoma involving the psoas muscle
Pancreas Kidney
Kidney Left renal vein
Treitz
Tumor recurrence in the posterior wall Recurrence invading the psoas m.
Inferior vena cava Duodenum Duodenum Inferior vena cava
Pancreas
Treitz (divided)
Recurrent adreno-cortical carcinoma infiltrating psoas m.
Thrombus
M. psoas
Fig. 7
Fig. 8
References
1. Baumgartner F, et al. (1996) Modified venous bypass for resection of renal and adrenal carcinomas with involve- ment of the inferior vena cava. Eur J Surg 162:59–62 2. Bellantone R, et al. (1997) Role of reoperation in recur-
rence of adrenal cortical carcinoma: results from 189 cas- es collected in the National Italian Registry for Adrenal Cortical Carcinoma. Surgery 122:1212–18
3. Bodie B,et al.(1989) The Cleveland Clinic experience with adrenal cortical carcinoma. J Urol 141:257–60
4. Crucitti F, et al. (1996) The Italian Registry for Adrenal Cortical Carcinoma: analysis of a multiinstitutional series of 129 patients. Surgery 119:161–70
5. Deckers S, et al. (1999) Peritoneal carcinomatosis follow- ing laparoscopic resection of an adrenocortical tumor causing primary hyperaldosteronism. Horm Res 52:
97–100
6. Dackiw AP,et al.(2001) Adrenal cortical carcinoma.World J Surg 25:97–100
7. Didoklar MS, et al. (1981) Natural history of adrenal cor- tical carcinoma: a clinicopathologic study of 42 patients.
Cancer 47:2153–61
8. Iacconi P, et al. (1999) Re: A case of Cushing’s syndrome due to adrenocortical carcinoma with recurrence 19 months after laparoscopic adrenalectomy. J Urol 161:
1580–1
9. Icard P, et al. (1992) Adrenocortical carcinoma in surgi- cally treated patients: a retrospective study of 156 cases by The French Association of Endocrine Surgery. Surgery 112:972–80
10. Iino K,et al.(2000) A case of adrenocortical carcinoma as- sociated with recurrence after laparoscopic surgery. Clin Endocrinol 53:243–48
11. Jensen CJ, et al. (1991) Recurrent or metastatic disease in select patients with adenocortical carcinoma. Arch Surg 126:457
(Fig. 6) to remove a recurrence involving the psoas muscle and the stump of the renal vein (with a throm- bus reaching the vena cava) (Figs. 7, 8). The patient died in July 2002, with symptoms of hypercortisolism and cerebral and pulmonary metastases. She refused any medical therapy.
12. Korobkin M, et al. (1996) Differentiation of adrenal ade- nomas from nonadenomas using CT attenuation values.
Am J Roentgenol 166:531–36
13. Kunieda K, et al. (2000) Recurrence of giant adreno- cortical carcinoma in the contralateral adrenal gland 6 years after surgery: report of a case. Surg Today 30:
294–97
14. Luton J, et al. (1990) Clinical features of adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy. N Engl J Med 322:1195–01
15. Miccoli P, Bernini GP (2001) Adrenocortical carcinoma.
In: Doherty GM, Skogseid B (eds) Surgical endocrinolo- gy. Lippincott, Williams and Wilkins, Philadelphia 16. Orlando R, et al. (2003) Adrenocortical carcinoma:
a 15-year survival after complete resection and repeated resection. A retrospective study in a patient with an expected poor prognosis. Anticancer Res 23:2929–31 17. Osella G, et al. (1994) Endocrine evaluation of incidental-
ly discovered adrenal masses (incidentalomas). J Clin En- docrinol Metab 79:1532–38
18. Pommier RF, Brennam MF (1992) An eleven-year experi- ence with adrenocortical carcinoma. Surgery 112:963–71 19. Pommier RF, Brennan MF (19921) Management of adre-
nal neoplasms. Curr Probl Surg 28:677–96
20. Sakamoto K, et al. (1995) Metastatic adrenocortical carci- noma treated by repeat resection: a case report of long- term survival over 18 years. Int J Urol 2:50–2
21. Schulick RD, Brennan MF (1999) Long-term survival af- ter complete resection and repeat resection in patients with adrenocortical carcinoma.Ann Surg Oncol 6:719–26 22. Sullivan M, et al. (1978) Adrenal cortical carcinoma. J Urol
120:660–65
23. Ushiyama T, et al. (1997) Case of Cushing’s syndrome due to adrenocortical carcinoma with recurrence 19 months after laparoscopic adrenalectomy. J Urol 157:2239 24. Vassilopoulou-Sellin R, et al. (1993) Impact of adjuvant
mitotane on the clinical course of patients with adreno- cortical cancer. Cancer 71:3119–23
25. Wooten MD, King KD (1993) Adrenal cortical carcinoma.
Cancer 72:3145–55
