REVIEW
Bilateral Primary Adrenal Non-Hodgkin’s Lymphoma and Primary Adrenocortical Carcinoma - Review of the Literature Preoperative Differentiation of Adrenal Tumors
ALEXANDRA OZIMEK, JOACHIM DIEBOLD*, RAINER LINKE ** , JENS HEYN *** , KLAUS HALLFELDT AND THOMAS MUSSACK
Department of Surgery Innenstadt, University Hospital Munich-Campus Innenstadt Nussbaumstrasse 20, 80336 München, Germany
*Department of Pathology, University Hospital Munich-Campus Innenstadt Thalkirchner Str. 36, 80336 München, Germany
** Department of Nuclear Medicine, University Hospital Munich-Campus Innenstadt Ziemssenstrasse 1, 80336 München, Germany
*** Department of Anaesthesiology, University Hospital Munich-Campus Großhadern Marchioninistr. 15, 81377 München, Germany
Abstract. Most of the adrenal tumors that are incidentally detected are benign adenomas. The incidence of malignant adrenal tumors including adrenocortical carcinoma (ACC) and primary adrenal lymphoma (PAL) is rather low. As many patients with ACC and PAL are diagnosed at an advanced stage of disease, the overall survival time of both entities remains poor. The therapeutic strategies for both entities differ. Thus an early differentiation between ACC and PAL is necessary. Unfortunately hitherto preoperative diagnosis of potentially malignant adrenal masses is still a main problem in the treatment of adrenal tumors. We present the case of a 57-year-old male patient with ACC and the case of an 87-year-old male patient with PAL and provide a systematic comparison of the clinical and pathological features of both entities. In both cases clinical and radiological features resulted in an initially false diagnosis. Primary surgical therapy was performed in both patients. The patient with PAL died five months aftre initial surgery. The patient with ACC showed tumor progression with local and systemic recurrence despite adjuvant therapy with mitotane and additional surgical therapy. Prognosis of patients with ACC and PAL seems to be dependant on the ability to start accurate treatment without any time delay. We propose some guidelines for diagnosis and surgical management of adrenal tumors.
Key words: Adrenal tumor, Adrenocortical carcinoma, Primary adrenal lymphoma, Non-Hodgkin’s lymphoma, Bilateral adrenal masses
(Endocrine Journal 55: 625-638, 2008)
THE adrenal gland is a frequent site of neoplastic dis- ease. It is estimated that adrenal masses occur in about 9% of the entire population. Since the early 1980’s the detection of adrenal lesions has increased with the ex- panding use of high-resolution imaging procedures [1, 2]. Once discovered, every adrenal tumor has to be defined to exclude hormonal dysfunction and malig- nancy. Neoplastic involvement of the adrenal gland may result from primary tumors originating from the
adrenal cortex or the adrenal medulla. Primary malig- nant tumors are adrenocortical carcinomas (ACC), primary adrenal lymphomas (PAL) and malignant pheochromocytomas. In addition, the adrenal glands are frequent sites for metastatic disease.
Adrenocortcial carcinoma (ACC) is a rare endocrine neoplasm with a heterogeneous presentation. Diagno- sis and accurate treatment can be greatly delayed due to the absence of specific clinical symptoms. Thus prognosis of ACC is generally poor [3, 4]. The rarity of the tumor has made it difficult to establish treatment guidelines. In stages I-III complete operative resec- tion remains the only potentially curative treatment. However, local recurrence is frequent and particularly related to the violation of the tumor capsule. Adjuvant
treatment options have still not been convincingly established. Hitherto, the adrenolytic compound mito- tane (alone or in combination with cytotoxic drugs or tumor bed radiation) remains the treatment of choice. Traditional cytotoxic chemotherapy alone has generally produced disappointing responses, implying the need for new therapies for this disease [3].
Primary adrenal non-Hodgkin’s lymphoma (PAL) is a rare neoplastic disease with about 116 reports in the literature, so far. It should be considered in patients with bilateral enlargement of adrenal glands and rapid- ly progressive adrenal insufficiency [5-9]. Most of these tumors are highly aggressive and their treatment is still not satisfactory. Therapeutic modalities include multi-agent chemotherapy, surgery followed by che- motherapy and/or radiation therapy and central ner- vous system (CNS) prophylaxis [5, 7]. Usually, the prognosis of PAL patients is fatal with early death occurring during chemotherapy. However, complete and partial remissions with a longer mean duration of survival have been reported in some cases [5-7, 10].
Indeed the overall survival time in patients with theses tumors seems to be dependant on the ability to establish diagnosis early in order to start accurate treatment without any time delay. Unfortunately hith- erto preoperative differentiation between ACC and
PAL is still a main problem in the treatment of poten- tially malignant adrenal tumors.
Case Reports
Case 1
An 84-year-old male patient in good physical condi- tion was admitted to our department for evaluation of a six-month history of significant weight loss and lumbar pain. There was no past history of carcinoma. Laboratory investigations showed normochromic, nor- mocytic anaemia, increased CRP and increased lactate dehydrogenase serum levels (Table 1). Contrast- enhanced CT scan revealed splenomegaly and large bilateral adrenal masses without abdominal lymphade- nopathy. Thoracic CT scan excluded any hilar or me- diastinal lymphadenopathy. The additional 2-[(18)F] fluoro-2-deoxyglucose (FDG)-PET scan showed an intense FDG accumulation in both adrenal glands without abnormal FDG uptake in extraadrenal regions (Fig. 1). Considering a 10-year history of arterial hy- pertension, bilateral phaeochromocytomas were sug- gested, but endocrine evaluation revealed all serum hormones and fractionated urinary catecholamines
| Parameter | Value case 1 | Value case 2 | Normal range |
|---|---|---|---|
| Hemoglobin (g/dl) | 11.4 | 14 | 14-17 |
| Hematocrit (%) | 32 | 39.5 | 38-52 |
| Leukocytes (N=) | 5100 | 9000 | 4000-11000 |
| Thrombocytes (N=) | 296000 | 281000 | 150000-400000 |
| CRP serum level (mg/dl) | 2.54 | 4.83 | <0.5 |
| LDH (U/l) | 445 | 1221 | <250 |
| Lactat (mmol/l) | 0.9 | 1.1 | 0.5-2.2 |
| Potassium (mmol/l) | 3.9 | 3.6 | 3.5-5.0 |
| Aldosterone (pg/ml) | <10 | <10 | 10-160 |
| Estradiol (pg/ml) | 21.0 | 10 | <45.0 |
| Progesterone (ng/ml) | 0.6 | 0.5 | <0.5 |
| Testosterone (ng/ml) | 335 | 272 | 350-900 |
| LH (U/l) | 11.1 | 3.3 | 1-10 |
| FSH (U/l) | 8.9 | 7.9 | 1-10 |
| Prolactine (uU/ml) | 92.2 | 338 | 30-350 |
| Cortisol (ug/dl) | 12.7 | 6.4 | 4.0-19.0 |
| Cortisol after ACTH (µg/dl) | 14 | 20.1 | 23-58 |
| Cortisol after DEXA (µg/dl) | 0.9 | 0.3 | <2 |
C: APPLIED
Acc: RC 014432 05
Se
2005 Jun 22
Heart
Im 70M111
19:01
520002
Cor
1320
Kontra
arteriel
512
B10
R
L
120.0
0.0 mA Tilt 0.0 0.0 s
A
Lin:DCM/Lin:DCM/ Id:ID
W. 187 L:85
1
DFOV: 37.8 x 37.8cm
within normal ranges. However, both non-hyperfunc- tioning adrenal masses were highly suggestive of ma- lignancy because of the large diameter. Therefore fine needle aspiration (FNA) biopsy was avoided and open bilateral adrenalectomy with abdominal lymphadenec- tomy was performed. Histopathological examination revealed diffuse large cell non-Hogkin’s (NHL) lym- phoma according to the World Health Organization Classification. The tumor cells were negative for Epstein-Barr virus (EBV) latent membrane protein-1 (LMP-1) and EB encoded RNA (EBER). After an uneventful postoperative period the patient was dis- charged at day 12 after surgery in good physical con- dition. Adjuvant chemotherapy therapy according to the CHOP-regime (cyclophosphamide, doxorubicin, vincristine, prednisone) was started. During the follow-up, the patient suddenly worsened four months postoperatively, and died another four weeks later because of disseminated progressive disease and car- diopulmonary failure.
Case 2
A 57-year-old male patient in good physical con- dition was referred to our clinic with complaints of leftsided abdominal and lumbar pain of two months duration.
Laboratory investigations showed highly increased
0
(A)
(B)
(C)
2006Feb(
Mag: 5 6:
Acq Time 12 026
DW
(D)
T … 1. … 1… …
(E)
CRP and lactate dehydrogenase serum levels as well as moderately increased liver enzymes (Table 1). Con- trast-enhanced CT scan was performed and revealed a large adrenal tumor of the left adrenal gland with smooth margins but inhomogeneous enhancement after application of contrast medium. There was no evidence of abdominal lymphadenopathy (Fig. 2A). Thoracic CT scan did not show any hilar or mediasti- nal lymphadenopathy. A pheochromocytoma was ex- cluded because the medical history was uneventful and all serum hormones as well as fractionated metaneph- rines and free catecholamines in a 24-hour urine speci- men were within normal ranges. Due to the imaging studies showing localized disease without infiltrative growth or lymphadenopathy, a non-functioning inci- dentaloma was supposed and laparoscopic lateral adrenalectomy was performed. Intraoperatively, there
| Clinical features | PAL | ACC |
|---|---|---|
| Incidence | 116 cases worldwide (1961-2006) | 0.4/100 000 |
| Mean Age [years] Gender | 68 w : m=1:3 | 10 & 50 w : m = 1.5:1 |
| Bilateral involvement [%] | 70% | 10% |
| Presenting symptoms | · symptoms of adrenal insufficiency · symptoms of lymphoma · symptoms of central nervous system involvement · unusual involvement of extranodal organs · rare symptoms (AIHA or thrombocytopenia, skin hitching, hypercalcaemia) · B symptoms | · symptoms of endocrine excess · symptoms of large tumor (abdominal discomfort, abdominal pain / lumbar pain) · B symptoms |
| CT-Results | · large mass · variable density | · large mass · central necrosis or calcification · heterogeneous enhancement · infiltration of adjacent organs · lymph node or other metastases (lung and liver) |
| MRT-Results | · low signal intensity on T1 -weighted images · high signal intensity on T2 weighted images | · hyperintense on T1- and T2-weighted images |
| Diagnosis | · Percutaneous fine needle aspiration (FNA) biopsy (CT or US guided) | No FNA biopsy if ACC is suspected |
| Histolopathological examination | B-cell NHL Diffuse large B-cell NHL Mixed small and large cell NHL Small cell NHL B-cell-lymphoma not specified | Microscopic diagnostic score: Weiss score |
| T-cell-lymphoma NHL not specified | ||
| Others Natural killer cell lymphoma Burktitt-like Lymphoma | ||
| Immunhistochemical examination | CD45+ (B & T-cell NHL) CD3+/30+/43+/45RO+ (T-cell NHL) CD20 +/40 +(B-cell NHL) | Ki-67 LI > 5 % |
| Therapy Treatment of choice Alternative | Chemotherapy Sugical debulking in combination with chemotherapy and/or radiation therapy CNS prophylaxis | Open adrenalectomy Mitotane (o,p'-DDD) Chemotherapy in combination with mitotane |
| Adjuvant therapy | ||
| Outcome [median survival rate] | 3,6 -34 months | 18 months |
was no evidence of malignancy, too. Histopathologi- cal examination of the left adrenal gland revealed a tu- mor with high mitotic rate and microscopic necrosis, but without clear evidence for malignancy according to histological criteria. The resection was classified as R0 (complete removal of tumor tissue). Therefore, no
adjuvant therapy was administered. The patient had an uneventful postoperative period and was discharged in good physical condition.
During the follow up (11 months after initial surgery) abdominal contrast-enhanced CT detected a tumor (3.7 x 5.5 cm) located in the splenorenal left
region with invasion in the adjacent organs. 2-[(18)F] fluoro-2-deoxyglucose (FDG)-PET scan was performed and showed an intense FDG accumulation in the left- sided tumor mass without abnormal FDG uptake in ex- traadrenal regions (Fig. 2B-C). Again, there was no evidence of metastatic disease. As adrenocortical carcinom was suggested now, an open tumor resection including left nephrectomy, splenectomy and segmental resection of sigma was performed. Histological analy- sis confirmed the diagnosis of adrenocortical carcino- ma and showed an inflitration of the tumor in adjacent organs (T4 N1 M0 R1, WHO stage IV). Therefore, the patient was administered adjuvant external tumor-bed radiation (total dose 50.4 Gy after 6 weeks) and adre- nolytic medical treatment with high-dose mitotane.
After a five months period of clinical improvement the patient developed progression of ACC with dis- seminated intra-abdominal lymph node metastases. Because of infiltration of the left sided colon an open retroperitoneal tumor mass resection including sigmaresection and iliacal lymphonodoectomy was perfomed. Adrenolytic treatment with mitotane was continued. Chemotherapy was denied by the patient. 23 months after primary diagnosis CT-scans of the abdomen showed further progression disease with dis- seminated peritoneal and intra-abdominal lymph node metastases (Fig. 2D-E). Again, palliative tumor re- section and left-sided hemicolectomie were performed to avoid mechanic ileus. After reconvalescence, the patient was scheduled to receive polychemotherapy according to the FIRM-ACT study protocoll (“First International Randomized trial in locally advanced and Metastatic Adrenocortical Carcinoma Treatment”; Etoposid, Doxorubicin, Cisplatin, Mitotane vs. Strep- tozotocin + Mitotane).
Discussion
The differential diagnosis of adrenal neoplastic disease includes primary tumors originating from the adrenal cortex or the adrenal medulla as well as metastases from primary carcinomas.
Benign non-hyperfunctioning adenomas comprise the majority of incidentally detected, asymptomatic adrenal masses [2, 4]. Hormonal activity increases with tumor size and mainly refers to production of cortisol (5-47%) or mineralcorticoids (1.6-3.3%). Be- nign tumors secreting sex hormones are rare [4]. Once
adrenal incidentalomas are discovered, their nature and endocrine function has to be defined to exclude hormonal dysfunction and malignancy.
Primary malignant tumors are adrenocortical carci- nomas (ACC), primary adrenal lymphomas (PAL) and malignant pheochromocytomas. However, the inci- dence of these tumours is rather low [1-4]. Adrenal glands are more frequently the site of metastatic dis- ease caused by primary carcinomas. In contrast to pri- mary tumors, many metastases tend to invade both adrenal glands [1, 4, 10]. Although any primary can- cer can spread to the adrenals, lymphoma, lung cancer, melanoma, leukaemia, kidney and ovarian carcinoma account for the majority of adrenal metastases [1, 4].
The incidence of adrenocortical carcinoma is esti- mated to be 0.4/100 000. It increases with tumor size to 25/100 000 (median diameter >6 cm) [4]. ACC ac- counts for about 0.02-0.2% cancer-related deaths and for up to 14% of adrenal incidentalomas. It shows a bimodal age distribution with peak incidence in first and fifth decades of life [1, 3, 4]. Indeed an exception- ally high annual incidence of ACC has been reported for children in southern Brazil and is probably related to a TP53 tumor suppressor gene mutation. Women are more often affected than men (ratio 1.5) [3, 11]. Bilateral manifestation is found in only 10% of the cases reported [1]. Average tumor size is mainly 11.5-12 cm (range: 2-36 cm), with only 4.2% tumors smaller than 6 cm [3, 11].
The molecular mechanisms of adrenocortical tumor- genesis are still not well understood. Recent studies assessing the differential gene expression patterns of benign and malignant adrenocortical tumors by cDNA macroarray allow to identify new tumor-suppressor genes and proto-oncogenes underlying adrenocortical tumorigenesis. Inactivating mutations at the 17p13 locus including the TP53 tumor suppressor gene and alterations of the 11p15 locus leading to IGF-2 overex- pression are frequently observed. In-vitro experiments suggest that overexpressed IGF-2 acting via the IGF-1 receptor is relevant for adrenal cancer cell prolifera- tion. Thus, the IGF-2 IGF-1 receptor pathway is a promising target for future therapies in ACC. Other results indicate that Chromogranin B and early growth response factor, 1HSP-60, Ciclin D1, jun proto- oncogene and topoisomerase I may play a role in ACC pathogenesis, too. In fact, larger series of patients are necessary to confirm the biologic, diagnostic, prog- nostic and therapeutic implications of these findings
[3, 12,13].
PAL represents only 3% of extranodal lymphomas [1, 2, 5]. Secondary involvement of the adrenal gland with non-Hodgkin’s lymphoma (NHL) is more fre- quent and occurs in nearly 25% of patients during the course of disease. PAL occurs with a male : female ratio of 3 : 1 and a median age of 68 years (range 39- 89) [5, 7, 10]. In contrast to ACC, nearly 70% of PAL cases reveal a bilateral adrenal involvement with a median maximum diameter of 8 cm (range 4-17) at the time of diagnosis [7, 10]. Anyhow, considering the rather low incidence of PAL compared with the incidence of ACC and the fact that at least 10 % of all ACC cases show bilateral adrenal involvement every case with bilateral adrenal masses should be carefully evaluated for possible adrenocortical carcinoma. An accurate preoperative differentiation is absolutely nec- essary to ensure the correct treatment.
As human adrenal glands do not contain any lym- phoid tissue, it is suggested that PAL arises from pre- vious autoimmune adrenalitis. It seems to derive from haemopoetic tissue within a single adrenal gland and to gravitate to the microenvironment of the contralater- al gland. This “homing theory” may partly explain bilateral disease and absence of nodal and marrow involvement by PAL [7, 9, 14]. Immune dysfunction seems to be the most important predisposing factor. According to a review of 55 patients with PAL by Wang et al. in 1998, 4% of patients suffered from human immunodeficiency virus (HIV) infection, 13% from concommittant autoimmune diseases, and 15% showed a past history of carcinoma [7, 15]. The data also implicates, that EBV may be a possible causative agent in the genesis of PAL. In addition, recent mo- lecular analyses indicate that mutations of the p53 gene (53%) and the c-kit gene (71%) may play an ad- ditional role in adrenal lymphomagenesis [7, 15].
Clinical and laboratory findings
In contrast to our patient, many patients with ACC present with clinical symptoms of endocrine excess. Indeed, hormonally functioning tumors account for 26-94% of adrenocortical carcinomas [3, 4]. Rapid progressive hypercortisolism combined with virilisa- tion due to androgen secretion in women is the most frequent symptom. High concentration of DHEA-S may suggest ACC, too, whereas decreased serum DHEA-S concentrations are more typical of a benign
adenoma. All in all, single secretion of estrogens, androgens or mineralcorticoides is rather rare. In many patients with a seemingly endocrine inactive ACC high concentrations of steroid precursors like androstenedione or 17a-hydroxyprogesterone can of- ten be demonstrated [3, 4]. In the absence of hormonal activity, early diagnosis is uncommon. Most patients with ACC are diagnosed at an advanced stage of disease with large primary tumors (median tumor size at diagnosis >10 cm) and an invasion in adjacent or- gans. Main clinical symptoms as abdominal discom- fort (nausea, vomiting, abdominal fullness) or back pain are related to a mass effect of the large tumor. Remarkably, in patients with non-cortisol producing ACC well-being is often little affected, even in cases with large tumor size. Occasionally patients present with typical clinical tumor symptoms as fever, weight loss and anorexia [3, 4]
The clinical symptoms of PAL are quite variable and often related to the presence of lymphoma or adre- nal insufficiency. PAL patients typically show a low incidence of extra-adrenal disease and an absence of leukaemia [5, 7, 10]. In 50% of these cases, an adrenal insufficiency is observed even when the neoplasms are small [5, 9, 10]. Skin pigmentation, gastrointestinal symptoms, profound fatigue, hypotension and Addi- son’s disease have been mainly reported. Systemic symptoms as fever and weight loss as well as local lumbar pain have been described and could be found in our case as well. In some cases, rare symptoms including autoimmune haemolytic anaemia or throm- bocytopenia, severe and diffuse skin hitching, hyper- calcaemia or unusual involvement of extranodal organs such as eye, thyroid gland, pituitary gland, or testicles can be found [7, 10, 16]. The incidence of CNS involvement is determined by the extent and proliferation of the disease. Risk factors include a high LDH serum level, a high/intermediate or high- risk International Prognostic Index (IPI) and the in- volvement of more than one extranodal site including bone marrow [7].
Radiological examinations
All adrenal tumors detected have to be diagnosed for their malignancy potential and hormonal activity to perform timely and curative treatment. Radiological, microscopic and macroscopic criteria have been estab- lished to differentiate between benign and malignant
lesion. However, none of these variables have proven entirely reliable.
Abdominal US largely depends on operator skills and tumor diameter [4, 5]. Whereas conventional US detects 65% of tumors <3 cm in diameter, endoscopic US may show even smaller lesions with a diameter of 1-2 cm [4]. However, US cannot be recommended for distinguishing between benign and malignant masses.
Contrast-enhanced CT is considered to be the most appropriate imaging tool to detect suspicious adreno- cortical tumors and to differentiate between benign and malignant lesion [2, 4, 5, 17, 18]. Criteria of ma- lignancy including inhomogenity, irregularity of mar- gins and irregular shape generally delivered a poor test performance [4, 5, 18]. Thus, both the tumour size and growth have been proposed to be important determi- nants to distinguish benign from malignant adrenal masses. However, attenuation thresholds have shown a better performance to diagnose adrenal malignancy than the tumour size or subjective criteria. In a review on 299 adrenalectomies Hamrahian et al. propose a non-contrast computed tomography attenuation value of 10 HU as a safe cut-off value to differentiate ade- nomas or hyperplasias from non-adenomas [18]. In cases with tumors of 4 cm or smaller, particularly in cases without a history of malignancy, 20 HU may be an acceptable cut-off value [4, 18]. However, a recent study including 151 adrenal masses with histologically confirmed diagnosis indicates an overlap between malignant and benign tumors and proposes delayed contrast-enhanced CT analyzing wash out of contrast medium for better discrimination of lipid-poor ade- nomas from ACC [3, 17]. In conclusion, adrenal lesions with an attenuation value of >10 HU in unenhanced CT or an enhancement washout of <50% and a delayed attenuation of >35 HU (on 10-15 min delayed enhanced CT) are suspicious for malignancy [3,17].
As ACC and PAL are both malignant adrenal tu- mors they have a similar appearance on CT. Hence, the differentiation between both of them is difficult. The CT appearance of ACC is that of a large mass with central necrosis or calcification of the tumor in up to 30% of the cases. Enhancement is heterogeneous after administration of contrast medium. Venous ex- tension of the tumor into the left vein or inferior vena cava as well as lymph node or other metastases (lung and liver) are common in advanced ACC and can usu- ally be identified on contrast-enhanced images [1-4,
17-19]. In the majority of PAL cases, radiological appearance is not pathognomonic. CT demonstrates a complex mass with diffuse involvement of the gland and variable density of the lesion [1, 2, 5]. Whereas some cases appear as homogenous adrenal lesions, other cases exhibit cystic components due to areas of haemorrhage, cystic degeneration or necrosis. En- hancement after administration of intravascular con- trast medium is less than that of the aorta or inferior vena cava [1, 2, 5].
In general chemical shift MRI does not provide ad- ditional information, but may be useful in ambiguous cases [4]. In contrast to benign tumours, malignant masses appear isointense to liver on T1-weighted images and hyperintense on T2 weighted images due to their higher fluid content. Additionally, malignant tumors show a strong contrast enhancement with de- layed washout after injection of paramagnetic contrast [1-4, 17-19]. However, as MRI intensity mainly de- pends on the amount of intracytoplasmatic lipids in- side the tumor, several exceptions may exist, e.g. with lipid-poor adenomas [4, 19]. On MRI, carcinomas are usually heterogeneously hyperintense on both T1- and T2-weighted images, reflecting the frequent internal haemorrhage and central necrosis. Enhancement is also heterogeneous, revealing nodular areas of intense enhancement and other areas with no enhancement. Washout of gadolinium enhancement is usually slow [2, 3]. On MRI, PAL usually shows low signal inten- sity on T1 and high signal intensity on T2 weighted images [2, 5].
In cases of radiographically indeterminate adrenal masses or past cancer history nuclear imaging is rec- ommended for tumor diagnosis and selection of appro- priate therapy. The main contribution of radionuclide imaging consists of functional information for tumor characterization. Since malignant tumors show an enhanced glycolytic metabolism with increased FDG uptake, PET is proposed for diagnosis, staging and detecting recurrences of adrenal malignomas. A dif- ferentiation between malignant and benign adrenal lesion can be performed using 18 FDG-PET with more than 95% accuracy [4, 19]. In particular, it plays an important role in evaluating treatment response and residual posttherapy masses. Several studies show an clear increase of FDG activity in malignant adrenal tumors, reflecting high glucose metabolism [4, 19, 20]. Moreover, PET imaging agents can also target specific adrenal gland enzymes expressed in tumor cells, inde-
pendent of secretory activity [19]. However, data are still insufficient to justify the application of FDG-PET for diagnosis of clinically inapparent masses outside clinical studies [4].
Adrenocortical scintigraphy achieves a relatively high sensitivity (71-100%) with a varying specificity (50-100%) to differentiate between benign and ma- lignant adrenal masses [4, 20]. Today, the radiophar- maceuticals 123-I-MIBG and 131-I-MIBG (metajod- benzylguanidine) and hydroxyephedrine are mainly used for the identification and localization of sym- pathomedullary diseases (medullar chromaffine tis- sue), including pheochromocytomas and extraadrenal paragangliomas. Thereby, the sensitivity of MIBG for detecting pheochromocytoma ranges between 80-90% with a specificity of 90-100% [4, 20].
131-6ß-Iodomethylnorcholesterol (NP-59) scintig- raphy is useful for detecting adrenocortical tumor tis- sue. It has a high specifity (100%) and reasonable sensitivity (70%) for distinguishing benign functioning adrenocortical adenomas from other adrenal lesions [20, 21]. Disadvantages of adrenal scintigraphy with iodocholesterol analogues are its restricted availabili- ty, time consuming procedure (3-5 days) and its asso- ciation with relative high dosage of radiation. Thus, further larger studies are required to confirm the use of NP-59 scintigraphy for incidentally detected adrenal masses [20].
Recently, radiolabeled somatostatin analogs have been proposed in the diagnostic evaluation of several tumors. Malignant adrenal masses showed significant uptake of somatostatin analog, suggesting the presence of somatostatin receptors [20].
Angiographic findings are nonspecific and therefore not useful in diagnosis or follow-up of adrenal tumors [5]. In conclusion, preoperative differentiation be- tween benign and malignant tumors is still the main problem in treatment of adrenal tumors.
Establishment of diagnosis
Percutaneous fine needle aspiration (FNA) biopsies under CT or US guidance can only be recommended in case of suspicious PAL or metastasic adrenal disease [4, 10, 22]. In the patient with PAL presented an early CT guided biopsy would have been indicated to avoid an in retrospect primary unnecessary operation. How- ever, although its sensitivity to diagnose malignancy ranges between 81-100% with a specificity of 83-
100%, 6-50 % of the FNA biopsies are reported to be inconclusive [4]. Considering the risk of metastatic spread of cancer cells and the fact that a benign cyto- logical diagnosis does not exclude malignancy, FNA cannot be approved as a standard procedure in the di- agnostic workflow for suspicious adrenal masses [4]. Moreover, FNA should never be attempted before exclusion of pheochromocytoma by endocrine testing due to possible life-threatening hypertensive crises [4, 22].
Based on histopathological and immunophenotyp- ing examinations, about 90% of PAL cases are B cell lymphomas. Only few reports describe T cell lympho- mas with a suppressive or cytotoxic phenotype an ex- pression of T-cell markers, e.g. CD 30, CD 43 and CD 45RO [5, 7-10, 15, 23-27]. The most common histol- ogy is the diffuse large-cell B cell lymphoma [5, 10], showing positive expressions of common leukocyte antigen CD 45 and of B-cell marker CD 20. Less com- mon types are the small-cell lymphoma (11%, includ- ing cleaved-cell and non-cleaved-cell), the mixed small- and large-cell (9%) and the undifferentiated lymphoma [5, 7, 10]. Uncommon variants include anaplastic large-cell, angiotropic/intravascular or folli- cular grade I/II lymphoma [7, 28].
In our case of ACC, primary histological examina- tion showed no clear evidence for malignancy. As the histopathological diagnosis of ACC is occasionally difficult (particulary with stage I and stage II disease), pathological examination should be performed by an experienced pathologist. The differentiation between benign and malignant adrenal lesions is based on mac- roscopic and microscopic features [3, 29]. For adreno- cortical tumors the macroscopic classification system by Hough includes e.g. tumor weight >100 g, tumor cell necrosis, haemorrhage with vascular invasion or invasion of tumor capsule [30]. Hitherto, the Weiss score is the microscopic diagnostic score most widely used [31]. Nuclear atypia, atypical and frequent mito- ses (>5/50 high power fields), eosinophilic tumor-cell cytoplasma (>75% of tumor cells), vascular and capsular invasion and necroses are suggestive for malignancy. Additionally, broad fibrous bands are a characteristic feature separating ACC from benign tumors [3, 31]. Nevertheless, there are still special types of ACC to which Weiss criteria are not fully ap- plicable (e.g. pediatric adrenocortical tumors, oncozy- tomas, aldosterone-producing tumors of pure zona glomerulosa type) [30, 32]. Important additional in-
formation is gained from immunohistochemical stainig. The immunohistochemical proliferation marker Ki-67 is a nuclear protein expressed by proliferating cells that can be observed in paraffin -embedded material using the primary antibody MIB 1. The percentage of Ki-67-positive tumor cells determines the tumor’s proliferative activity. The Ki-67 labeling index or MIB1 (LI) is a simple and reproducible method in the differential diagnosis of adrenocortical tumors. Re- sults of several studies using Ki-67 labeling index for differential diagnosis between adrenocortical adenoma and carcinoma suggest a strong correlation between Ki-67 expression and the malignancy of adrenocortical tumors in adults [33]. In the great majority of the cas- es, a Ki-67 LI greater than 5% seperates benign lesions from adrenocortical carcinomas without overlap [34]. Moreover, Terzolo et al. observed that overall survival of patients with ACC was significantly reduced in case of high levels of the Ki-67 LI [35]. These find- ings suggest that the immunohistochemical marker Ki-67 may be of prognostic relevance concerning clinical outcome [36].
Other markers like D11, inhibin-a, melan A and chromogranin are helpful to define or exclude the adrenocortical origin of the tumor. Finally, several new markers (LOH at 17p13, IGF-2 overexpression, Cyclin E) have been proposed to separate benign from malignant adrenal lesions [3, 12]. Nevertheless, histo- pathological prognostic factors of ACC have not yet been fully established because of the rarity of the dis- ease [30].
In the cases presented immunhistochemical analysis of the tissue resected showed an increased Ki-67 label- ing index in case of adrenocortical carcinoma and CD45+ and CD20+ positive cells in case of primary adrenal lymphoma.
Treatment options
In general, surgery of adrenal tumors should be con- sidered in patients with functioning cortical tumors and clinical symptoms [4, 37-39]. Regarding non- functioning tumors, recommendations for treatment mainly refer to the tumor size. In general, clinically inapparent lesions smaller than 3 cm without any criteria of malignancy are not resected and should be followed up closely by CT or MR scan every 6 or 12 months [4, 37-39]. Both, a close follow-up or adrenalectomy are reasonable treatment options for
intermediate sized tumours between 3 and 6 cm. In these cases, imaging should be repeated every 3 to 6 months to avoid misclassification of a small ACC as benign neoplasia [4, 37-39]. For lesions that do not increase in size, there are no data to support further ra- diological examination. Endocrine evaluation should be continued once a year for a period of 4 years [4]. In case of increase in tumor size or suspicion of malig- nancy, adrenalectomy should be strongly considered. Hitherto, adrenal lesion larger than 6 cm have been generally associated with a higher risk of malignancy and should have been removed [4, 17, 37-39], as per- formed in the cases presented.
Considering the surgical approach to adrenal tumors, minimally invasive adrenalectomy has proved to be a safe and reliable procedure for benign adrenal tumors with a diameter smaller than 6 cm. Many ret- rospective studies demonstrate its association with less intraoperative blood loss, lower postoperative morbid- ity, a shorter hospital stay, greater patients satisfaction and fewer incisional hernia [37-48]. At the moment still controversy exsits about the appropriate surgical approach for tumors larger than 6 cm. Data suggest that at a size threshold of more than 4 cm, the likeli- hood of malignancy doubles (to 10%) and is more than nine fold higher for tumors larger than 8 cm (47%) [49]. However, in a recently published review on their experience with laparoscopic adrenalectomies Palazzo et al. have shown, that large size is not necessarily indicative of malignancy. Among 391 laparoscopic adrenalecomies performed, 19 solid cortical tumors were larger than 6 cm. Histological examination re- vealed adrenocortical carcinoma in only three cases [37].
Indications for an open adrenalectomy are a defini- tive or presumed diagnosis of primary adrenocortical carcinoma and circumstances technically obstructive to a minimally invasive approach. The maximum tumor size able to be successfully resected by LA is highly dependant on the skill of the surgeon [37-48]. Laparoscopic surgery performed for adrenal tumors >6 cm or for tumors that are preoperativley considered potentially malignant should be performed by an expe- rienced laparoscopic surgeon. In case of any intraop- erative features of malignancy conversion to an open approach should be performed in order to enable ex- tensive radical compartmental resection [3, 37-50].
Surgical resection as a solitary treatment in patients with PAL is associated with a poor outcome [7]. Thus,
surgery has to be combined with additional therapeutic modalities including combination chemotherapy and/ or radiation therapy and CNS prophylaxis [5, 7]. Sur- gical debulking of PAL in addition to chemotherapy may result in improved survival [7]. The regimes of chemotherapy comprise CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), CHOP in com- bination with Rituximab, CHO (cyclophosphamide, doxorubicin, vincristine), CVP (vincristine, pred- nisone) or MACOP (cyclophosphamide, doxorubicin, prednisone, methotrexate, bleomycin). According to a review published by Kumar et al., one third of the patients achieved a partial or complete remission dur- ing chemotherapy with a mean duration of survival of 34 ± 32 months [5]. Nevertheless, many PAL patients deceased due to tumour recurrence or severe infections within one year after diagnosis. In a recent review of 116 PAL cases between 1961 and 2006 we found information on primary treatment in 71 of the cases reported [unpublished data]. 47 (66%) of the patients received chemotherapy and 20 (28%) received sur- gery. Information on response on treatment and out- come was available in 102 (87.9%) patients. 64 (62.7%) patients had died, 22 (21.6%) patients showed complete and 16 (15.7%) patients showed partial re- mission. Mean overall-survival rate was 15.3 months. The role of radiation therapy on the adrenal gland is still unknown. The impact on long-term renal function when exposing both kidneys to irradiation and the likelihood of systemic spread of lymphoma cells gen- erally precludes treatment with radiation alone or in combination with chemotherapy. Finally, CNS pro- phylaxis should be considered in cases with increased LDH serum levels and high or very high IPI score. Prophylactic intrathecal methotrexate and hydrocorti- sone applications may reduce the incidence of CNS recurrence and improve long-term survival in patients with aggressive NHL [7].
Hitherto, no significant advances in the treatment of adrenocortical carcinoma have been developed [3, 50]. In the absence of efficacious adjuvant therapy surgery remains the mainstay for primary and recurrent dis- ease. Concerning the surgical approach open adrena- lectomy is the procedure of choice in case of definitive or presumed diagnosis of ACC. In stages I-III resec- tion including resection of invaded organs and lym- phadenectomy reduces local recurrence rate and thus is associated with a prolonged disease free interval and long term patient survival rate [3, 11, 50-52]. To se-
cure optimal oncologic management and to decrease risk of tumor spillage and local recurrence avoiding capsular disruption is of utmost importance. Cobb et al. have reviewed the literature and identified 25 cases of ACC removed by laparoscopic resection [46]. Lo- cal recurrence or intraperitoneal dissemination oc- curred in 40% of patients. High local recurrence and peritoneal carcinomatosis after laparoscopic adrena- lectomy was also observed in a recent series reported by Gonzalez et al. [41]. Incomplete resection of the primary tumor or metastatic disease not suitable to sur- gery is associated with a particular poor prognosis, too. Nevertheless, tumor debulking in cases of extended disease may help to control hormone excess and may facilitate other therapeutic options. Surgery for local recurrences or metastatic disease improves survival rates in retrospective studies [3, 47, 50].
Concerning adjuvant treatment for ACC, Mitotane (o,p’-DDD) has remained the only adrenal-specific agent available, showing modest effect concerning tu- mor regression in patients with unresectable, residual or metastatic disease. The percentage of significant tumor regression after Mitotane treatment varies between 25%-61% [3, 50, 53]. In the majority of patients additional control of hormone excess can be achieved. Mitotane has a specific cytotoxic effect on adrenocortical cells producing focal degeneration of the fascicular and particularly the reticular zone. Met- abolic activation is essential for its adrenolytic activi- ty. Mitotane has a narrow therapeutic window with adverse effects occurting in more than 80% of all pa- tients [3, 50, 53]. Side effects are often dose limiting and mainly refer to gastrointestinal or central nervous system. Generally, they are reversible after cessation of mitotane. As mitotane induces adrenal insufficien- cy and increases the metabolic clearance of glucocorti- coids, high-dose glucocorticoid replacement is needed during mitotane treatment. As not all patients respond to mitotane therapy, it is important to define the subset of patients likely to respond in order to avoid unneces- sary treatment of patients [3, 50, 53]. Traditional cyto- toxic chemotherapy for ACC has generally produced disappointing results, with only a minority of patients responding to current protocols. Cisplatin alone or in combination with etoposide seems to have some activ- ity in ACC. As some in-vitro studies have indicated that mitotane may reverse multidrug-resistance and enhances tumor responsivity to cytotoxic drugs cyto- toxic treatment may be combined with mitotane thera-
Adrenal neoplasm
Functioning
Adrenal tumor size
No
Yes
Adrenalectomy
Suspicion of ACC
No
Yes
< 3 cm
3 - 5 cm
> 5 cm
Laparoscopic adrenalectomy
Open adrenalectomy
· Localized primary tumors
· Preoperative signs of local invasion, lymphadenopathy, metastases
Follow-up
Bilateral
· No preoperative evidence of local invasion, lymphadenopathy, metastases
· Preoperative imaging features suspicious for malignancy
No
Yes
· No radiological signs of malignancy
· No intraoperative evidence of local invasion
· Family history of malignant pheochromocytoma
Consider ACC
Consider PAL
· All aldosteronomas
· Rapid onset of endocrine symptoms
No
· Young age
· Bilateral masses > 6 cm
. Most pheochromocytomas
· Multiple elaborated hormons
· Few comorbidities
· Short medical history
· Myelolipomas
· Suspicious imaging features
· Age > 60 years
. Most cortisol, sex steroid or mineralcorticoid producing tumors
· Growth on follow-up
· Gender: male
· History of cancer
· Adrenal insufficiency
· Isolated adrenal metastasis
· Patient’s preference
. No primary cancer detected
Yes
Percutaneous US/CT guided needle biopsy
PAL
Yes
Chemo
V No
py. Thus combination of mitotane with etoposide, doxorubicin, csiplatin or with streptozotocin have been proposed. Results differ concerning significant treat- ment toxicity and overall response rate (49% vs. 36%) [3]. Khan et al. recently reported a study on a second line cytotoxic chemotherapy regimen using a combina- tion of vincristine, cisplatin, temiposide and cyclo- phosphamide (OPEC) after failure of streptozotocin plus mitotane in 11 patients. They observed a partial response in 2 patients and stable disease in seven pa- tients with a median survival of 21 months after the start of OPEC [54]. The limited response to cytotoxic chemotherapy in ACC may be caused by high expres- sion of the multidrug-resistance gene mdr-1. This results in high concentrations of p-glycoprotein acting as a drug efflux pump. Thus, antagonists of p-glyco- protein may improve the efficacy of cytotoxic therapy. [3, 55]. Regarding hormone excess adrenostatic drugs like ketoconazole, metyrapone, aminoglutethimide and etomidate may be used used to block steroidogenic enzymes and to lower circulating steroid hormones in the normal range [3].
Although radiotherapy has been often considered in- effective for treatment of ACC newer reports describe tumor response rates up to 42% and indicate, that ACC is not resistant to radiation therapy. Thus, radiation therapy is recommended to control localized disease in cases not amenable to surgery. Moreover, radiation therapy is the treatment of choice for most bone (and brain) metastases. Concerning adjuvant radiotherapy recent results demonstrate reduced local recurrence in patients with adjuvant radiotherapy of the tumor bed [3].
In order to summerize our therapeutic recommenda- tions and to improve clinical differentiation between different primary malignant tumors of the adrenal gland we have extended the algorithms for surgical treatment of adrenal neoplasms pubished by Suzuki and Palazzo in 2006 [37, 39]. The approach presented in Fig. 3 includes clinical and radiological features suspicious of primary bilateral adrenal lymphoma and should help to establish diagnosis rapidly in order to start adequate therapy without any time delay.
Prognosis
In general, the prognosis of both tumor entities is poor. Adrenocortical carcinoma is associated with a short disease-free survival duration and a median sur- vival rate of 18 months [4, 41]. While older studies suggested an improved outcome for functional tumors in adult patients, this results couldn’t be confirmed in more recent studies [50]. Main problems in patients with localized, non-metastatic ACC are local recur- rence or peritoneal carcinomatosis [4, 41]. Prognostic factors include tumor stage (I & II vs. III & IV), Weiss criteria (</=6 vs. >6 criteria), mitotic index (</=20 vs.
>20) and extent of surgery. Extensive surgical resec- tion reduces local recurrence rate. Complete repeat resection of local recurrence improves survival rates, too [52].
Prognosis of patients with PAL is poor, too. In a re- cently published review by Kumar et al., many PAL patients deceased due to tumor recurrence or severe in- fections within one year [5]. One third of the patients reviewed achieved a partial or complete remission dur- ing chemotherapy. The mean duration of survival in these patients was 34 ± 32 months, whereas the mean duration of survival in patients without response to chemotherapy was only 3.6 ± 3.9 months [5].
References
1. Lyon SM, Lee MJ (2002) Imaging the non-hyperfunc- tioning adrenal mass. Imaging 14: 137-146.
2. Dunnick NR, Korobkin M (2002) Imaging of adrenal incidentalomas: current status. AJR American Journal Roentgenology 179: 559-568.
3. Allolio B, Fassnacht M (2006) Clinical review: Adrenocortical Carcinoma: Clinical Update. Journal of Clinical Endocrinology and Metabolism 91: 2027- 2037.
4. Mansmann G, Lau J, Balk E, et al. (2004) The clinically inapparent adrenal mass: update in diagnosis and man- agement. Endocrine Reviews 25: 309-340.
5. Kumar R, Xiu Y, Mavi A, et al. (2005) FDG-PET imaging in primary bilateral adrenal lymphoma: a case report and review of the literature. Clinical Nuclear Medicine 30: 222-230.
6. Mantzios G, Tsirigotis P, Veliou F, et al. (2004) Primary adrenal lymphoma presenting as Addison’s disease: case report and review of the literature. Annals of Hematology 83: 460-463.
7. Grigg AP, Connors JM (2003) Primary adrenal lym- phoma. Clinical Lymphoma 4: 154-160.
8. Fukushima A, Okada Y, Tanikawa T, et al. (2003) Primary bilateral adrenal intravascular large B-cell lymphoma associated with adrenal failure. Internal Medicine 42: 609-614.
9. Zargar A, Laway B, Bhat K, et al. (2004) Adrenal insufficiency due to primary bilateral adrenal non- Hodgkin’s lymphoma. Experimental and Clinical Endocrinology and Diabetes 112: 462-464.
10. Tumino S, Leotta ML, Branciforte G, et al. (2003) Bilateral adrenal non-Hodgkin lymphoma type B. Journal of Endocrinological Investigation 26: 1120- 1123.
11. Kebebew E, Reiff E, Duh QY, et al. (2006) Extent of disease at presentation and outcome for adrenocortical
carcinoma: have we made progress? World Journal of Surgery 30: 872-878.
12. Lombardi CP, Raffaelli M, Pani G, et al. (2006) Gene expression profiling of adrenal cortical tumors by cDNA macroarray analysis. Results of a preliminary study. Biomedicine and Pharmacotherapy 60: 189- 190.
13. Slater E, Diehl S, Langer P, et al. (2006) Analysis by cDNA microarray of gene expression patterns of human adrenocortical tumors. European Journal of Endocrinology 154: 587-598.
14. Ellis, RD, Read D (2000) Bilateral non-Hodgkin’s lymphoma with adrenal insufficiency. Postgraduate Medical Journal 76: 508-509.
15. Wang J, Sun NCJ, Renslo R, et al. (1998) Clinical silent primary adrenal lymphoma: A case report and review of the literature. American Journal of Hematol- ogy 58: 130-136.
16. Terpos E, Theocharis S, Panitsas F, et al. (2004) Autoimmune hemolytic anemia with myelodysplastic features followed by bilateral adrenal non-hodgkin lymphoma: a case report and review of the literature. Leukemia and Lymphoma 45: 2333-2338.
17. Fassnacht M, Kenn W, Allolio B (2004) Adrenal tumors: how to establish malignancy? Journal of Endocrinological Investigation 27: 387-399.
18. Hamrahian AH, Ioachimescu AG, Remer EM, et al. (2005) Clinical utility of noncontrast computed tomog- raphy attenuation value (hounsfield units) to differenti- ate adrenal adenomas/hyperplasias from nonadenomas: Cleveland Clinic experience. Journal of Clinical Endo- crinology and Metabolism 90: 871-877.
19. Pacak K, Eisenhofer G, Goldstein DS (2004) Functional imaging of endocrine tumors: role of positron emission tomography. Endocrine Reviews 25: 568-580.
20. Maurea S, Klain M, Mainolfi C, et al. (2001) The diag-
nostic role of radionuclide imaging in evaluation of patients with nonhypersecreting adrenal masses. Jour- nal of Nuclear Medicine 42: 884-892.
21. Imperiale A, Olianti C, Manelli M, et al. (2005) Tomo- graphic evaluationof 131I-60-Iodomethyl-norcholesterol standardised uptake trend in clinically silent monolater- al and bilateral adrenocortical incidentalomas. The Quarterly Journal of Nuclear Medicine and Molecular Imaging 49: 287-296.
22. Nurnberg D (2005) Ultrasound of adrenal gland tumors and indications for fine needle biopsy. Ultraschall in der Medizin 26: 458-469.
23. Levy NT, Young WF, Habermann TM, et al. (1997) Adrenal insufficiency as a manifestation of disseminated non-Hodgkin’s lymphoma. Mayo Clinic Proceedings 72: 818-822.
24. Pimentel M, Johnston J, Allan D, et al. (1997) Primary adrenal lymphoma associated with adrenal insufficiency: a distinct clinical entity. Leukemia and Lymphoma 24: 363-367.
25. Xu A, Xiao X, Ye L, et al. (2003) Primary adrenal lym- phoma. Leukemia and Lymphoma 44: 739-740.
26. Tsai W, Hsieh C, Cheng M, Lin CK (2006) Adrenal insufficiency in T-cell lymphoma. International Jour- nal of Urology 13: 794-797.
27. . May F, Bachor R, Hack M, et al. (1998) Primary adrenal non-Hodgkin’s lymphoma: long-term survival. Journal of Urology 160: 487.
28. Frankel WL, Shapiro P, Weidner N (2000) Primary anaplastic large cell lymphoma of the adrenal gland. Annals of Diagnostic Pathology 4: 158-164.
29. Aiba M, Fujibayashi M (2005) Histopathological diagnosis and prognostic factors in adrenocortical carcinoma. Endocrine Pathology 16: 13-22.
30. Hough A, Hollifield J, Page D (1979) Prognostic fac- tors in adrenal cortcial tumors. American Journal of Clinical Pathology 72: 390-399
31. Weiss LM (1984) Comparative histologic study of 43 metastasizing and nonmetastasizing adrenocortical tumors. American Journal of Surgical Pathology 8: 163-169.
32. Pohlink C, Tannapfe A, Eichfeld U, et al. (2004) Does tumor heterogenity limit the use of the Weiss criteria in the evaluation of adrenocortical tumors? Journal of Endocrinological Investigation 27: 565-569.
33. Goldblum JR, Shannon R, Kaldjian EP, et al. (1993) Immunohistochemical assessment of proliferative activity in adrenocortical neoplasms. Mod Pathol 6: 663-668.
34. Wachenfeld C, Beuschlein F, Zwermann O (2001) Discerning malignancy in adrenocortical tumors: are molecular markers useful? Eur J Endocrinol 145: 335- 341.
35. Terzolo M, Boccuzzi A, Bovio S (2001) Immuno- histochemical assessment of Ki-67 in the differential
diagnosis of adrenocortical tumors. Urology 57: 176- 182.
36. Sasano H, Imatani A, Shizawa S, et al. (1995) Cell proliferation and apoptosis in normal and pathologic human adrenal. Mod Pathol 8: 11-17.
37. Palazzo FF, Sebag F, Sierra M, et al. (2006) Long-term outcome following laparoscopic adrenalectomy for large solid adrenal cortex tumors. World Journal of Surgery 30: 893-898.
38. Valeri A, Bergamini C, Manca G, et al. (2005) Adrenal Incidentaloma: The influence of a decision-making algorithm on the short-term outcome of laparoscopy. Journal of Laparoendoscopic and Advanced Surgical Techniques 15: 451-459.
39. Suzuki H (2006) Laparoscopic adrenalectomy for adre- nal carcinoma and metastases. Current Opinion in Urology 16: 47-53.
40. Sturgeon C, Kebebew E (2004) Laparoscopic adrena- lectomy for malignancy. The Surgical Clinics of North America 84: 755-774.
41. Gonzalez RJ, Shapiro S, Sarlis N, et al. (2005) Laparo- scopic resection of adrenal cortical carcinoma: A cau- tionary note. Surgery 138: 1078-1086.
42. MacGillivary D, Whalen G, Malchoff C, et al. (2002) Laparoscopic resection of large adrenal tumors. Annals of Surgical Oncology 9: 480-485.
43. Lombardi CP, Raffaelli M, De Crea C, Bellantone R (2006) Role of laparoscopy in the management of adre- nal malignancies. Journal of Surgical Oncology 94: 128-131.
44. Gagner M, Lacroix A, Bolte E (1992) Laparoscopic adrenalectomy in Cushing’s syndrome and pheochro- mozytoma. New England Journal of Medicine 327: 1033.
45. Porpiglia F, Fiori C, Tarabuzzi R, et al. (2004) Is laparoscopic adrenalectomy feasible for adrenocortical carcinoma or metastasis? BJU International 94: 1026- 1029.
46. Cobb WS, Kercher KW, Sing RF, Heniford BT (2005) Laparoscopic adrenalectomy for malignancy. Journal of American Surgery 189: 405-411.
47. Tsuru N, Ushiyama T, Suzuki K (2005) Laparoscopic adrenalectomy foe primary and secondary malignant adrenal tumors. Journal of Endourology 19: 702-709.
48. Walz MK, Petersenn S, Koch JA, et al. (2005) Endo- scopic treatment of large primary adrenal tumours. British Journal of Surgery 92: 719-723.
49. Sturgeon C, Shen WT, Clark OH, Duh OY, Kebebew E (2006) Risk assessment in 457 adrenal cortical carcino- mas: How much does tumro size predict the likelihood of malignancy? Journal of the American College of Surgeons 202: 423-430.
50. Roman S (2006) Adrenocortical carcinoma. Current Opinion in Oncology 18: 36-42.
51. Schulick R, Brennan M (1999) Long-term survival
after complete resection and repeat resection in patients with adrenocortical carcinoma. Annals of Surgical Oncology 17: 26-34.
52. Causeret S, Monneuse O, Mabrut J, et al. (2002) [Adrenocortical carcinoma: prognostic factors for local recurrence and indications for reoperation. A report on a series of 22 patients]. Annales de Chirurgie 127: 370-377.
53. Hahner S, Fassnacht M (2005) Mitotane for adrenocor-
tical carcinoma treatment. Current Opinin in Investiga- tional Drugs 6(14): 2407-2417.
54. Khan TS, Sundin A, Juhlin C, et al. (2004) Vincristine, cisplatin, teniposide, and cyclophoshamide combina- tion in the treatment of recurrent or metastatic adreno- cortical cancer. Medical Oncology 21: 167-177.
55. Kirschner L (2006) Emerging treatment istrategies for adrenocortical carcinoma: a new hope. Journal of Clinical Endocrinology and Metabolism 91: 14-21.