Adrenal Carcinoma

Adrenocortical carcinomas (ACs) are uncommon malignancies that can have protean clinical manifestations. A majority of cases are metastatic at the time of diagnosis, with the most common sites of spread being the local periadrenal tissue, lymph nodes, lungs, liver, and bone. ACs are virtually always unilateral. One review suggested that 2-10% of cases may be bilateral at initial diagnosis[4] ; however, this finding has not been replicated. (See Etiology, Pathophysiology, and Workup.)

Adrenocortical masses are common; approximately 2% of the general adult population (7% of those over age 70 years) may have adrenal incidentalomas, biochemically and clinically asymptomatic adrenal masses found incidentally during unrelated imaging investigations, such as abdominal computed tomography (CT) scanning or magnetic resonance imaging (MRI). Only a small number of adrenal incidentalomas (up to 10%) are functional, and only about 2% prove to be ACs.[5] Ectopic adrenocortical tumors are exceedingly rare.[6]

The management of adrenal incidentalomas, therefore, focuses on the following:

1. Identifying functional masses and treating them appropriately (including surgical removal)
2. Identifying ACs early, with the intent of attempting complete surgical extirpation
3. Reassuring patients whose masses are neither functional nor malignant and arranging for follow-up examinations.

Classification of adrenal malignancies

Adrenocortical carcinomas

These include the following:

• Functional
• Nonfunctional
• Well differentiated
• Intermediate
• Poorly differentiated to anaplastic

Metastatic adrenal tumors

The most common potential primaries include the following:

• Lung
• Breast
• Melanoma
• Renal cell carcinoma
• Extra-adrenal lymphoma
• Leukemias
• Pancreatic carcinoma
• Colonic carcinoma
• Ovarian carcinoma

Adrenomedullary tumors

These include the following:

• Malignant pheochromocytoma
• Ganglioneuroblastoma
• Neuroblastoma
• Neuroendocrine carcinoma

Stromal malignancies

These include the following:

• Neurofibrosarcoma
• Angiosarcoma
• Liposarcoma
• Fibrosarcoma
• Leiomyosarcoma
• Myxosarcoma
• Malignant teratoma

Adrenal malignancies in the setting of familial predisposing syndromes

The associated syndromes include the following:

• Li-Fraumeni syndrome
• Familial polyposis coli
• Gardner syndrome
• Turcot syndrome
• Cowden syndrome
• Beckwith-Wiedemann syndrome (possible)
• Carney complex (possible)
• Carney triad
• Multiple endocrine neoplasia type 1 (MEN1)

Other

These include primary adrenal lymphomas, which can be unilateral or bilateral. Adrenal malignancies can also be classified as composite tumors and mixed tumors.

Functional and nonfunctional tumors

Adrenal tumors are classified in several ways. One popular method, which has great clinical relevance, is to divide them into functional or nonfunctional, depending on the elaboration of adrenocortical hormones (glucocorticoids, mineralocorticoids, androgens, estrogens; rarely, a host of possible peptides).

Nonfunctional variants of AC were previously reported to be far less common than the functional types; older reports suggested that approximately 50-80% of ACs are functional (patients present mainly with Cushing syndrome). Subsequent reports, however, have suggested that nonfunctional ACs may be more common than previously thought.

Sporadic and syndromic tumors

Another classification method is to subdivide ACs into sporadic and syndromic variants. The syndromic variants occur with multiple cancer predisposition syndromes, including Gardner syndrome, Beckwith-Wiedemann syndrome (associated with hemihypertrophy), multiple endocrine neoplasia type 1, the SBLA syndrome (sarcoma, breast, lung, and adrenal carcinoma and other tumors within several kindreds, which have not been clearly associated with localization to a single gene), and Li-Fraumeni syndrome.

Cellular origin

Adrenal tumors can also be classified based on their cellular origin. Included here are primary ACs, primary adrenal lymphomas, soft-tissue sarcomas of the adrenal, malignant pheochromocytomas, and secondary metastatic adrenal tumors (the common primaries of which are tumors of the breast, kidney, lung, and ovary, as well as melanoma, leukemia, and lymphoma). Only the ACs typically are included in discussions of adrenal cancers, and this monograph will be restricted to those. (See Pathophysiology and Etiology.)

Authorities also report rare composite adrenal tumors, which are different histologic variants of the same embryologic origin (eg, coexisting neuroblastoma and malignant pheochromocytoma), and mixed adrenal tumors (typically, mixtures of pheochromocytomas, spindle cell sarcomas, and adrenocortical carcinomas).

Endocrine syndromes associated with AC include the following:

• Cushing syndrome (30%)
• Virilization and precocious puberty (22%)
• Feminization (10%)
• Primary hyperaldosteronism (2.5%)
• Combined hormone excess (35%)
• Polycythemia (< 1%)
• Hypercalcemia (< 1%)
• Hypoglycemia (< 1%)
• Adrenal insufficiency (particularly from primary adrenal lymphomas)
• Non–glucocorticoid-mediated insulin resistance
• Catecholamine excess due to rare instances of coexisting pheochromocytoma
• Cachexia (usually preterminal)

The exact etiopathogenesis of sporadic AC is unclear, but analysis of syndromic variants of the condition gives some insight. The role of tumor suppressor gene mutations is suggested by their association with Li-Fraumeni syndrome, which is characterized by inactivating germline mutations of the TP53 gene (a vital tumor suppressor gene, or antioncogene) on chromosome 17. This syndrome also is associated with a predisposition to other malignancies, including breast carcinoma, leukemias, osteosarcomas, and soft-tissue sarcomas.

A few reports describe an association between AC and familial adenomatous polyposis, which also is due to an inactivating germline mutation of a tumor suppressor gene (in this case, the adenomatous polyposis coli gene, APC).[7] However, such mutations have not been found in sporadic APC cases.

Hyperplasia

Suggestions have been made that adrenal hyperplasia predisposes patients to develop AC.[8] A few cases of congenital adrenal hyperplasia are associated with functional adrenocortical adenomas but not carcinoma. A few cases of AC are also associated with primary hyperaldosteronism, in which the adrenal tissue has portions showing adrenocortical hyperplasia. However, definitive proof of a sequence in which hyperplasia leads to adenoma, which then leads to carcinoma—similar to a sequence that produces colonic neoplasms—is lacking.

Carney triad

The association of AC with the Carney triad (GI stromal tumor, pulmonary chondromas, extra-adrenal paraganglioma) is far less defined. Since the Carney triad is so rare, there are very few reported cases.

Genetic mechanisms

Potential mechanisms for adrenocortical tumorigenesis include the following:

• Activation of various proto-oncogenes: Ras, PKC, C myc, C fos, G proteins, and G protein-coupled receptors (eg, for vasoactive intestinal peptide [VIP], gastric-inhibitory peptide [GIP], luteinizing hormone [LH], catecholamines)

• Inactivation of tumor suppressor genes (antioncogenes): TP53, TP57, TP16, H19, retinoblastoma gene, APC gene, and various deoxyribonucleic acid (DNA) repair ̶ enzyme genes

• Inhibition of senescence and/or apoptosis: Mutations involving telomerase and/or BCL-2 genes

• Changes in adrenocortical tissue-specific factors: Mutations involving the genes for StaR, SF-1 (steroidogenic factor), and Dax-1 transcription factor

• Aberrant expression of receptors to normal adrenocorticotropic agents and ligands: Adrenocorticotropic hormone, angiotensin 2, catecholamines, and endorphins

• Ectopic expression of receptors on adrenocortical cells to atypical trophic factors and ligands: Cytokines, growth factors, and neurotransmitters

Among the putative pathogenetic mechanisms that may function in concert with each other are alterations in intercellular communication, paracrine and autocrine effects of various growth factors, cytokines elaborated by the tumor cells, and promiscuous expression of various ligand receptors on cell membranes (causing the cells to be in a state of perpetual hyperstimulation). This is presumed to lead to clonal adrenal cellular hyperplasia, autonomous proliferation, tumor formation, and hormone elaboration.

Some molecular studies of adrenocortical tumor cells show in situ mutations of the TP53 and TP57 genes (both antioncogenes) and increased production of insulinlike growth factor 2 (IGF-2). TP53 gene mutations are the most common mutant genes in human cancer. A potential role for this gene in sporadic AC is suggested by the frequent finding of loss of heterozygosity at the 17p13 locus in cases of sporadic AC. Definite germ cell mutations of the TP53 gene have also been demonstrated in more than 90% of children with AC from southern Brazil, which has the highest prevalence of sporadic AC in the world. Amplification of steroidogenic factor-1 expression has also been described in this population.

Another genetic locus of interest is the 11p chromosomal region that may also harbor a tumor suppressor gene and has been implicated in linkage studies in subjects with the Beckwith-Wiedemann syndrome. Loss of heterozygosity at band 11p15 and overexpression of IGF-2, whose gene is carried on this genetic locus, have been described in cases of sporadic AC.

Other studies demonstrate that some of AC cells express menin (the aberrant gene product in patients with multiple endocrine neoplasia type I [MEN1]); in other cases, the hybrid gene is associated with glucocorticoid-responsive aldosteronism (GRA).

Several reports suggest that, while benign adrenal tumors retain expression of the type 2 MHC antigens, these are lost in adrenocortical carcinoma cells. Furthermore, while adrenal adenomas can be monoclonal (43%), polyclonal (28%), or mixed (28%), virtually all ACs are monoclonal.

The fact that the normal adrenal cortex has multiple areas of adrenomedullary cells (often forming large cell nests) and that adrenocortical cells also are scattered in the adrenal medulla suggests a close interaction between the two groups of cells, despite their distinct phylogenetic and embryonic origins. The relevance of the paracrine interactions of these cells in the etiopathogenesis of AC and adrenal tumors as a whole is still being actively investigated.

AC tumors are uncommon, having an incidence of approximately 0.6-1.67 cases per million persons per year. In southern Brazil, however, the incidence of adrenal tumors is 10-15 times that of the general population, a difference that has been associated with a mutation in the P53 gene.

Sex- and age-related demographics

The female-to-male ratio for ACs is approximately 2.5-3:1. The accumulation of data, especially in international registries, revealed the incidence of adrenal tumors to be higher in female individuals than had previously been thought, particularly in those aged 0-3 years and those over 13 years. Nonfunctional ACs are distributed equally between the sexes.

AC occurs in 2 major peaks: in the first decade of life and again in the fourth to fifth decades. While, functional tumors are more common in children, however, nonfunctional tumors are more common in adults.

Based on data from the International Pediatric Adrenocortical Tumor Registry, the median age at which children develop adrenal carcinomas is 3.2 years; 60% are younger than four years, and 14% are older than 13 years.[9]

AC is relatively rare, accounting for just 0.02-0.2% of all cancer-related deaths. The most important predictive clinical parameters of prognosis are as follows:

• Disease stage at diagnosis
• Completeness of resection at surgery
• Presence or absence of metastasis at the time of diagnosis

Follow-up data from large centers, such as the MD Anderson Cancer Center and the Memorial Sloan-Kettering Cancer Center, suggest a temporal improvement in clinical survival of patients with AC since the late 1980s and early 1990s.

Male patients tend to be older and have a worse overall prognosis than do female patients. Female patients are more likely than male patients to have an associated endocrine syndrome. Although still somewhat controversial, some suggest that children with AC have a better prognosis than do adults; favorable clinical outcome has been reported in 70% or more of pediatric cases.[10]

Detection of tumors at an early clinical stage is crucial for curative resection; total resection offers the only prospect for cure. The estimated overall five-year survival rate for patients with AC is approximately 20-35%. For cases in which total surgical resection is achieved, this rate is estimated to be approximately 32-47%, while in cases in which total surgical extirpation has not been possible, the five-year survival rate is estimated to be 10-30%.[11]

Even after apparently complete surgical resection, however, local or distant relapse occurs in nearly 80% of cases. Documented cases exist of AC recurrence more than 10 years after presumed curative surgery. Recurrent or relapsing AC is usually a bad omen. Although symptoms of hormonal excess can often be medically managed in this setting, cure is virtually unknown.

The presence of distant metastasis generally is another sign of an especially poor outcome. Estimates suggest that as many as 50% of such patients are dead within 12 months of detecting metastatic deposits, regardless of treatment. Indeed, patients with functional AC may have a better prognosis because they present earlier, unlike patients with nonfunctional variants, who invariably present when the tumors are very large or are associated with distant metastasis.

Estrogen receptor (ER)–negative status also confers a worse prognosis in AC. In a study of 17 patients, Shen et al found that one- and five-year survival rates were 86% and 60%, respectively, for patients with ER-positive tumors, versus 38% and 0% for those with ER-negative tumors.[12]

The prognosis for cases of AC occurring in pregnancy is also grim; however, the fetal prognosis in these cases remains excellent.

Patients who show no response to mitotane or who relapse are probably best served by referral to a major cancer center, where they can be enrolled in one of several ongoing combination chemotherapeutic/radiation and/or surgical resection protocols. AC is too uncommon for most tertiary hospitals to have enough expertise to manage these patients adequately.

In 2016, Kim and colleagues published nomograms to predict recurrence-free survival (RFS) and overall survival (OS) after curative resection of adrenocortical carcinoma (ACC). The nomograms were created using a multi-institutional cohort of 148 patients who underwent curative-intent surgery for ACC at 13 major US institutions.[13]  

The prediction model for RFS is based on the following 5 independent prognostic factors[13] :

• Tumor size (< 12 or ≥12 cm)
• Nodal status (N0, N1, or Nx)
• T stage (I/II or III/IV)
• Cortisol-secreting tumor
• Capsular invasion.

The nomogram to predict OS is based on the following 3 independent prognostic factors[13] :

• Tumor size (< 12 or ≥12 cm) 
• Nodal status (N0, N1, or Nx)
• Resection margin (R0 or R1)

Higher total points based on the sum of the assigned number of points for each factor in the nomograms were associated with a worse prognosis.[13]

Potential complications associated with AC can be subclassified as follows:

• Local tumor invasion: Including the potential for tumor thrombus formation, which can embolize similar to renal cell carcinoma
• Hormone excess syndromes (eg, Cushing syndrome, hyperaldosteronism, hirsutism, virilization, hypertension)
• Paraneoplastic syndromes (eg, cachexia)
• Local pain in patients with bone metastases

While AC accounts for only approximately 5-10% of cases of Cushing syndrome, approximately 40% of patients with both Cushing syndrome and an adrenal mass also have a malignant tumor. Virtually all feminizing adrenal tumors in men are malignant.

Unfortunately, most patients with adrenocortical carcinoma (AC) present with advanced disease that is characterized by multiple abdominal or extra-abdominal metastatic masses (stage IV disease); therefore, distinguishing potential AC from adrenal incidentalomas is crucial (and controversial).

Nonfunctional variants

These hormonally silent tumors account for approximately 40% of patients with AC. Nonfunctional variants of AC tend to be more common in older patients and appear to progress more rapidly than functional tumors do. Although in some cases, they are found incidentally, during either examination or radiologic imaging, nonfunctional ACs typically present with any of the following:

• Fever
• Weight loss
• Abdominal pain and tenderness
• Back pain
• Abdominal fullness
• Symptoms related to metastases

Hormonally active variants

The hormonally active variants of AC constitute approximately 60% of cases. Approximately 30-40% of adult patients with these present with the typical features of Cushing syndrome, while 20-30% present with virilization syndromes.

More than 80% present of pediatric patients, however, present with virilization syndromes. Isolated Cushing syndrome is much less common, occurring in approximately 6% of pediatric cases. Virilization (in girls) or precocious puberty (in boys) is the most common endocrine presentation of a functional AC.

Hirsutism, facial acne, oligo/amenorrhea, and increased libido all are possible presenting symptoms. Feminization as a presentation of AC is quite rare. Other modes of presentation include profound weakness, hypertension, and/or ileus from hypokalemia related to hyperaldosteronism and hypoglycemia.

Physical findings almost always include a palpable mass in the abdomen; the mass is hard and nonmovable.[14]

Virilization

In pediatric patients, findings in boys include premature puberty with enlargement of the penis and scrotum, pubic hair, acne, and deepening voice. Findings in girls include premature appearance of pubic and axillary hair, clitoral hypertrophy, acne, deepening voice, premature increase in growth velocity, lack of appropriate breast development, and lack of menarche.

Cushing syndrome

Signs of Cushing syndrome include the following[15] :

• Round face
• Double chin
• Buffalo-hump fat distribution
• Generalized obesity
• Failure of growth velocity in children
• Hypertension

Feminization

In rare cases, feminization may occur. Findings in male patients include gynecomastia and hypertension; findings in female patients include precocious sexual development and hypertension.

A full evaluation is advised in all patients with a distinct adrenal nodule or tumor larger than 1 cm, in order to determine whether the tumor is functional. The general agreement is that all functional masses should be removed.

Laboratory results may also help in distinguishing between a neoplasm of the adrenal cortex and a neuroblastoma. Adrenocortical tumors should not be confused with adrenal medullary tumors, also known as pheochromocytomas, which, like neuroblastomas, secrete catecholamines.

Compared with imaging findings in pediatric patients with neuroblastoma, adrenocortical carcinoma (AC) can be highly suspected when adrenal lesions have a thin tumoral capsule, a stellate zone of central necrosis, and evidence of the production of adrenocortical hormone.[16]

The following are the major imaging features that serve as red flags for a possible AC on adrenal imaging[17] :

• Irregular shape
• Large size (larger than 4 cm in diameter)
• Intralesional calcification
• Tumor heterogeneity on both plain and contrast enhancement, which may indicate intralesional hemorrhage, necrosis, or both (Inhomogeneous density estimates by computed tomography [CT] in various parts of the tumor on both plain and contrast-enhanced images may also indicate intralesional hemorrhage.)
• Unilateral location
• High CT attenuation values (especially with > 20 Hounsfield units [HU])
• Evidence of tumor invasion of local structures or extension into major vessels

While some reports suggest an increased predilection for the left adrenal gland in AC, most studies indicate no side preference.

Laboratory studies for AC include determinations of the following:

• Serum glucose
• Serum cortisol
• Serum adrenal androgen
• Urine adrenal hormone
• Urine vanillylmandelic acid (VMA)
• Urine homovanillic acid (HVA) levels

Include screening tests that can exclude excess hormone production when evaluating all primary adrenal masses.

Cushing syndrome

The best screening tests for Cushing syndrome are the standard 1-mg dexamethasone suppression test and the 24-hour urinary cortisol excretion test. The recognition of the relatively high prevalence of subclinical Cushing syndrome in patients with adrenal incidentalomas (some reports suggest a prevalence as high as 5-8%) that may otherwise appear hormonally silent informs the policy of some experts to perform more in-depth testing of the hypothalamic-pituitary-adrenal (HPA) axis in patients with identified adrenal masses. Such testing would include the screening tests mentioned, as well as the following:

• Diurnal rhythm evaluation with 8 am and midnight serum or salivary cortisol estimations
• Corticotropin-releasing hormone (CRH) stimulation test
• Serum adrenocorticotropic hormone (ACTH) estimations (generally found to be low)
• Serum dehydroepiandrosterone (DHEAS) levels (also generally found to be suppressed)

Alternatively, 24-hour urinary cortisol and its metabolites can be measured.

Pheochromocytoma

The evaluation of adrenal masses must also include screening for possible pheochromocytoma, including, at a minimum, a 24-hour urinary estimation of catecholamines (epinephrine, norepinephrine, dopamine) and metabolites (particularly metanephrines and normetanephrines). In addition, plasma metanephrines and catecholamines can be assayed.

Other screens

Evaluation of adrenal masses also includes screens for the following:

• Hyperaldosteronism: Screen for hyperaldosteronism by using simultaneous aldosterone and renin levels to compute aldosterone-to-renin ratios

• Virilization syndromes: Screen for virilization syndromes using serum adrenal androgens (androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate), serum testosterone, and 24-hour urinary 17-ketosteroids.

• Feminization syndromes: Plasma estradiol and/or estrone tests can help to screen for feminization syndromes

Computed tomography and magnetic resonance imaging

Adrenal CT scanning and magnetic resonance imaging (MRI) are the imaging studies of choice in AC. The typical case is characterized by a large unilateral adrenal mass with irregular edges. The presence of contiguous adenopathy serves as corroborating evidence. (See the image below.)

The National Italian Study Group review of adrenal incidentalomas demonstrated that 90% of AC cases had diameters of 4 cm or larger on radiologic imaging. This study, based on a cohort of 887 patients, showed that using the 4 cm cutoff resulted in 90% sensitivity but poor specificity.[18]

Targeted CT scans of the adrenal using 3- to 5-mm sections offer the best resolution and are particularly useful in detecting tumors that are 1 cm or smaller.

Intravenous contrast generally is not necessary for localization of adrenal masses but is useful for demonstrating vascularity and clarifying sites of metastases. Some reports have also shown that in comparison with ACs, adrenal adenomas have a much earlier washout of contrast enhancement and that this may be of diagnostic utility. The contrast washout at 5 minutes postinjection is approximately 50% in adenomas, versus 8% in nonadenomas; at 15 minutes, the contrast washout is approximately 70% versus 20%, respectively.[19]

Accumulating evidence suggests that low attenuation values on unenhanced CT scans can distinguish benign adrenal adenomas from AC or metastatic adrenal deposits that have attenuation values generally greater than 20 Hounsfield units (HU). Authorities suggest that adenomas have HU values of 10 or less. (However, many caveats significantly limit the clinical utility of this.)[20]

Authorities also suggest using norms for HU values in intravenous contrast studies to assist in distinguishing adrenal adenomas from AC. A study by Hamrahian et al found that the sensitivity and specificity for the 10- and 20-HU cutoffs in distinguishing adenomas from nonadenomas, including AC and pheochromocytoma, were 40.5% and 100% for adenomas and 58.2% and 96.9% for nonadenomas.[21] These numbers suggest that, while limited as a screening instrument, the HU score has considerable utility in making definitive diagnoses when the scores are either less than 10 HU or greater than 20 HU.

MRI, in particular, shows significant utility in distinguishing AC from nonfunctional adenomas and pheochromocytomas. The malignant lesions tend to be of intermediate to high density on T2 imaging, while the nonfunctional adenomas are low intensity, and pheochromocytomas have a very high signal intensity. On gadolinium–diethylenetriamine penta-acetic acid (DTPA) contrast-enhanced MRI scans, adenomas generally demonstrate mild enhancement with rapid contrast washout, while ACs show rapid and intense enhancement with sluggish washout. The relatively higher fat content of adrenal adenomas compared with ACs has been used in the new chemical shift imaging (CSI) MRI protocols to further enhance the distinguishing capacity of these studies.

Chest CT scanning should be performed when metastatic disease is present. Affected lung parenchyma strongly suggests an AC over a neuroblastoma.

Ultrasonography has less sensitivity in detecting adrenal tumors and is highly user-dependent with regard to the interpretation and quality of results. It has particular utility, however, in the follow-up of previously detected incidentalomas. Abdominal and retroperitoneal ultrasonography is usually followed with abdominal CT scanning and MRI.

Bone scanning

Bone scanning should be performed to detect metastatic disease. However, the presence of bone disease does not allow for the differential diagnosis of malignancies.

Other

Iodocholesterol scans rarely are indicated in suspected cases of AC; the findings generally are negative in this setting, unlike in steroid-secreting adrenal adenomas.

Arteriography and venography currently have very little, if any, place in the diagnostic evaluation of adrenal masses suspected to be AC.

Because the histologic analysis of these masses may be unreliable, and owing to the potential for tumor seeding into the retroperitoneum, fine-needle aspiration and core tissue biopsies (percutaneous route) generally are not recommended.[22] Presently, the only setting where these biopsies are justified is in the evaluation of patients with a known malignancy, in order to exclude adrenal metastases.[23] The biopsies may be CT- or ultrasonographically guided.

Fine-needle aspirations should not be performed on any adrenal mass until pheochromocytoma has been definitively excluded; otherwise, the procedure may precipitate a potentially fatal crisis.

A specific histologic diagnosis of AC may be difficult in a case that is lacking clinical evidence of metastasis. Some of the macroscopic features of an AC that suggest malignancy include a weight of more than 500 g, the presence of areas of calcification or necrosis, and a grossly lobulated appearance. Histologic findings also include numerous mitoses, scant cytoplasm, and none of the rosettes observed in neuroblastoma.

In the Weiss system, which is considered the standard for determining malignancy in adrenocortical tumors, each of the following features is awarded one point; a total score > 3  suggests AC[24, 25] :

• Nuclear Grade 3 or 4
• Mitotic rate > 5 per 50 HPF
• Presence of atypical mitosis
• Clear cells in ≤25% of the tumor
• Diffuse architecture in more than one third of the tumor
• Necrosis
• Venous invasion
• Sinusoidal invasion
• Capsular invasion

As an adjunct to the Weiss score, Soon et al studied the use of microarray gene expression profiling to discriminate between adrenocortical adenomas and carcinomas; they found that the combination of insulinlike growth factor–2 (IGF-2) and Ki-67 overexpression identified ACs with 96% sensitivity and 100% specificity.[26]

Sbiera et al reported that steroidogenic factor-1 (SF-1), a transcription factor involved in adrenal development, can be valuable for the differential diagnosis of adrenal masses and for predicting prognosis in AC. In their study, SF-1 mRNA expression was present in all 91 adrenocortical tumors analyzed, and absent in all nonsteroidogenic tumors. Strong SF-1 protein expression significantly correlated with poor clinical outcome, independent of stage.[27]

Adrenocortical tumors

These typically have a yellowish brown appearance on the cut surface. Pathologic features suggestive of malignancy are the large size of the primary tumor (tumor weights > 100 g suggest malignancy), high mitotic rate, atypical mitoses, high nuclear grade, large areas of necrosis, low percentage of clear cells, diffuse cellular architecture, and evidence of capsular, lymphatic, or vascular invasion.[28]

Tumors may have broad fibrous bands separating them into nodules, and they often have a variegated appearance, a zona glomerulosa–like appearance, or a fascicular and reticulated appearance. Still, other areas may show near-total dedifferentiation.

Most of the cells are lipid-poor compared with typical adrenocortical cells, and they have an eosinophilic cytoplasm. Bizarre-looking, pleomorphic cells and multinucleate giant cells also may be evident. Predicting the hormonal products of a particular tumor based on histologic appearance is impossible.

Distinction between adrenocortical and adrenomedullary tumors

These two types of tumors have distinctive histologic appearances and immunohistochemical staining patterns. While adrenomedullary tumors stain positive for neuroendocrine markers (eg, synaptophysin, neuron-specific enolase, chromogranin A), adrenocortical cells stain positive for D11, with very little overlap.

The AC staging tumor-node-metastasis (TNM) criteria, as delineated by the Union for International Cancer Control (UICC),[29] are outlined below.

Tumor criteria are as follows:

• TX: Primary tumor cannot be assessed
• T0: No evidence of primary tumor
• T1: Tumor diameter of 5 cm or less with no extra-adrenal invasion
• T2: Tumor diameter greater than 5 cm with no extra-adrenal invasion
• T3: Tumor of any size with local extension but not involving adjacent organs (ie, kidney, diaphragm, great vessels [renal vein or vena cava), pancreas, liver)
• T4: Tumor of any size with local invasion of adjacent organs

Lymph node criteria are as follows:

• NX: Regional lymph nodes cannot be assessed
• N0: No regional lymph node involvement
• N1: Positive regional node(s)

Metastasis criteria are as follows:

• M0: No distant metastasis
• M1: Distant metastasis

Staging for AC follows the stage I-IV pattern used for most solid tumors. See the Table below.

Table. Stage Grouping for Adrenal Cortex Carcinomas (Open Table in a new window)

Fassnacht et al have argued that the UICC’s staging criteria have limited prognostic value. After reviewing 492 patients in the German AC registry who were diagnosed between 1986 and 2007, these researchers proposed that the prognostic value would be improved if stage III disease were defined by the presence of positive lymph nodes, infiltration of surrounding tissue, or venous tumor thrombus, and if stage IV were restricted to patients with distant metastasis.[30]

Because adrenocortical carcinomas (ACs) are so rare, clinical series are small and there has been only limited prospective evaluation of treatment strategies. Therefore, significant controversy over therapy exists, and very few, if any, universally accepted treatment standards have been determined. Current practices are strongly influenced by expert consensus opinion from a few medical centers that specialize in ACs.

When feasible, total resection remains the modality of choice for the definitive treatment of AC. It also remains the only potentially curative therapy.

Medical care in patients with AC, which can be supportive or adjuvant to surgical resection, encompasses the following:

• Treatment of endocrine excess syndromes
• Use of mitotane or several multiagent chemotherapy regimens
• Treatment and prevention of potential complications
• Strategies for palliative and terminal care issues, including symptom relief and management

Management of nonfunctional tumors

Virtually all authorities agree that because of the significant potential cancer risk, all nonfunctional adrenal tumors of 6 cm or greater should be removed. Authorities also generally agree that nonfunctional adrenal tumors of 3 cm or less have a very low probability of being adrenal cancer; therefore, they can be observed safely.

The management strategy for adrenal masses larger than 3 cm and less than 6 cm is disputed. Some authorities suggest lowering the threshold for surgical removal of nonfunctional masses from 6 cm to 4-5 cm. Others individualize the follow-up of these patients depending on their clinical status, CT scan characteristics, and age. Particularly important is the fact that these criteria do not apply to children, who generally have smaller ACs.

A review of the available data suggests that the incidence rate of malignancy is small (< 0.03%) in all adrenal incidentalomas that are 1.5-6 cm. However, this rate increases considerably with tumors larger than 6 cm (up to 15%). The smallest identified AC associated with metastasis reported in the literature was 3 cm in diameter.

When feasible, total resection remains the treatment of choice for the definitive management of AC. It also is still the only potentially curative therapy. Following surgery, management shoudld focus on pathologic verification of the diagnosis, evaluation of prognostic markers, and genetic evaluation to guide discussion of adjuvant therapy.[25]

Open versus laparoscopic surgery

While open laparotomy for adrenalectomy represents the standard of care, several reports suggest a role for laparoscopic resection if the adrenal tumor is small and there is no evidence of metastatic disease preoperatively.[31, 32, 33] The most common sites for metastases are the lungs, liver, bone, and lymph nodes. Contiguous spread to the kidney and liver (if the primary is on the right side) and tumor extension into the venous drainage system of the adrenals and the inferior vena cava are common.

A study by Agha et al suggested that laparoscopic adrenalectomy can be effectively performed even on larger tumors (> 6 cm). Data from 279 patients who underwent the minimally invasive procedure (227 with tumors of 6 cm or smaller and 52 with tumors > 6 cm) showed that although the mean duration of surgery, estimated blood loss, intraoperative bleeding rate, conversion rate, and postoperative complication rate were greater in the patients with larger tumors, the two tumor groups each had only one major complication.[34]

Recurrent and metastatic tumor management

Recurrent local and metastatic tumors are common in AC, even in patients who undergo a successful complete resection. In such settings, the only effective treatment is attempted reoperation.[35, 36] Case reports indicate that repeated thoracotomy can allow for more than 10 years of high-quality survival despite recurring crops of metastatic disease. Moreover, a large, retrospective series showed that pulmonary metastasectomy may be beneficial in carefully selected patients.[37] In that study, by Kemp et al, median overall survival was 40 months and 5-year actuarial survival was 41%, following resection of pulmonary metastasis.

A study from Memorial Sloan-Kettering Cancer center found that in patients with AC, aggressive primary surgical removal and aggressive surgical treatment of local or distant relapse led to long-term survival rates far superior to those reported in previous studies, regardless of patient age. One important feature of this study was that patients who underwent a complete second resection had a median survival of 74 months (5-y survival rate, 57%).[38]

Mitotane

Mitotane remains the major chemotherapeutic option for the management of AC because it is a relatively specific adrenocortical cytotoxin. It is used as primary therapy, as adjuvant therapy, and as therapy in recurrent or relapsing disease.[39]

Mitotane apparently causes adrenal inhibition without cellular destruction. The exact mechanism of action is unknown. It inhibits cholesterol side-chain cleavage and 11-beta-oxyhydrase reactions. It also appears to reduce the peripheral metabolism of steroids. Alteration of extra-adrenal metabolism of cortisol reduces measurable 17-hydroxy corticosteroid while stimulating the formation of 6-beta-hydroxy cortisol. Plasma levels of corticosteroids do not fall.

This drug may be considered in the treatment of inoperable adrenal cortical carcinoma (functional and nonfunctional). It controls endocrine hypersecretion in 70-75% of patients. While objective tumor responses often are cited in as many as 20-25% of patients, a study has yet to be conducted with modern imaging techniques and response criteria accepted by clinical oncologists. Tumor response has been reported to correlate with serum levels and often requires several months of continuous therapy. Assaying mitotane levels during therapy is valuable because therapeutic efficacy depends on achieving serum levels of at least 15 mcg/mL.

Approximately 40% of the drug is absorbed, and approximately 10% of the dose is recovered in the urine as a water-soluble metabolite. Active metabolite excreted in the bile varies from 1-17%. The balance apparently is stored in tissues. Autopsy data indicate that fat tissue is the primary storage site, but the active metabolite is found in most tissues. After therapy, plasma terminal half-life varies from 18-159 days.

Experience suggests that the best approach is continuous treatment with the maximum possible dosage. If the dose is tolerated and an improved clinical response appears possible, increase the dose until adverse reactions interfere. The aim is to achieve doses as high as 10-20 g/day.

Efficacy

Mitotane’s major beneficial effect is on symptoms; treatment benefits are generally short-lived, and long-term survivors on this therapy are rare. 

El Ghorayeb et al.reported a rapid and complete remission of metastatic AC with mitotane monotherapy 2 years after a right adrenalectomy for stage III nonsecreting AC. The patient remained disease-free with good quality of life on a low maintenance dose of mitotane during the subsequent 10 years.[40]

Postoperative/adjuvant therapy

Adjuvant therapy with mitotane remains controversial. A retrospective study by Terzolo et al examining adjuvant mitotane therapy in patients who underwent radical surgery for AC found evidence that mitotane can significantly increase recurrence-free survival. The study included 47 Italian patients who received mitotane postoperatively and control groups of 55 Italian patients and 75 German patients.

In the Italian patients, baseline features were similar in the treatment and control groups; the German patients were significantly older and had more stage I or II disease than did patients in the mitotane group. Median recurrence-free survival was 42 months in the mitotane group, as compared with 10 months in the Italian control group and 25 months in the German control group. Multivariate analysis indicated that mitotane treatment had a significant advantage for recurrence-free survival.[41]

A meta-analysis that included 1249 patients from five studies concluded adjuvant mitotane led to significantly longer recurrence-free survival and overall survival and concluded that adjuvant mitotane is an effective postoperative strategy.[42] In contrast, a US Adrenocortical Carcinoma Group review of 207 patients who underwent resection of AC, 88 (43%) of whom received adjuvant mitotane, found that adjuvant mitotane was not associated with improved recurrence-free or overall survival.[43]

Based on data so far, adjuvant therapy can be recommended for patients with high risk for recurrence based on positive margins, ruptured capsule, large size of the primary tumor, or high mitotic rate. Adjuvant mitotane therapy can be considered after resection of AC.[44]  It should be noted that patients treated with mitotane usually require lifelong steroid replacement therapy, due to the adrenolytic nature of that agent. 

Chemotherapy and mitotane in metastatic disease

Typically, the choice of systemic therapy consists of mitotane alone or in combination with chemotherapy. Various agents have been combined with mitotane, including cisplatin, carboplatin, etoposide, doxorubicin, and streptozocin. Response rates reported with mitotane monotherapy is on the order of 10-30%.

The First International Randomized Trial in Locally Advanced and Metastatic Adrenocortical Carcinoma Treatment (FIRM-ACT) study of first -line therapy for AC reported that patients who received mitotane and EDP (etoposide, 100 mg/m2 on days 2-4; doxorubicin, 40 mg/m2 on day 1, and cisplatin, 40 mg/m2 on days 3 and 4) had higher response rates and longer median progression-free survival than patients treated with mitotane plus streptozocin (5 mo vs 2.1 mo, respectively). Toxicity rates for both of the combinations were similar. Overall survival in the entire group was not significantly better; however, the study revealed that for those patients who did not receive alternative second-line therapy, overall survival was better in the EDP-mitotane group.[45]

Pembrolizumab was reported to produce a 23% objective response rateRR and median OS of 24.9 months. A second study showed 15% response rate.  Pembrolizumab can be utilized as a single agent or combination with mitotane[46, 47] .  Several studies are investigating combined immune checkpoint blockade with anti-CTLA4 and anti-PD-L1 agents and other novel combinations. Other targeted therapies studies include insuline like growth factor 1, VEGF, EGFR, mTOR inhibitors but no clear evidence of benefit and no firm conclusions can be drawn.

There is evidence of mitotane plasma levels and efficacy. 55-66% response rates were reported in patient with plasma levels greater than 14 mg/L.  Lower levels were associated with decreased efficacy. Adverse events are also associated with higher plasma levels. Higher-dose regimens therefore are preferred for mitotane monotherapy and a lower-dose regimen is best when used in combination with chemotherapy.[48]

Second-line and subsequent treatment

Despite the superiority of EDP plus mitotane (EDP-M) in first-line therapy, the overall outlook still remains poor. In patients whose AC progresses after EDP-M therapy, second-line treatments to consider include streptozocin plus mitotane and gemcitabine plus capecitabine. The response rates reported with second-line regimens tend to be low (~10%).

Ronchi et al found that, as with other types of cancer, expression of excision repair cross-complementing group 1 (ERCC1) by ACs predicts resistance to platinum-based chemotherapy. Median overall survival after platinum treatment was 8 months in patients with high ERCC1 expression, versus 24 months in those with low ERCC1 expression.[49]

In the future, the treatment of adrenal carcinoma may utilize novel chemotherapeutic agents, vascular growth inhibitors, and small-molecule therapy based on a better understanding of the molecular pathways involved in tumorigenesis.

Management of endocrine syndromes

In functional tumors, management of the endocrine syndromes is often important because the associated systemic effects may significantly impact patient well-being.

Therapeutic options for Cushing syndrome include mitotane, ketoconazole, metyrapone, aminoglutethimide, RU 486 (mifepristone), and intravenous etomidate, alone or in various combinations.

For hyperaldosteronism, the major therapeutic options are spironolactone, eplerenone, amiloride, triamterene, and various antihypertensives, especially long-acting dihydropyridine calcium channel blockers.

For hyperandrogenism or hyperestrogenism, several options are available if adverse effects from androgen or estrogen significantly affect patient well-being. Antiestrogens may include the following:

• Clomiphene citrate
• Tamoxifen
• Toremifene
• Danazol

Potential antiandrogens include the following:

• Flutamide
• Cyproterone acetate
• Bicalutamide (Casodex)
• Nilutamide
• Megestrol acetate

Ketoconazole, spironolactone, and cimetidine also have a significant antiandrogen effect. The various aromatase inhibitors (eg, testolactone, anastrozole, letrozole, fadrozole) have some antiandrogen effect as well; therefore, they may be used. Controlled studies have not yet been performed to assess which of these agents, either alone or in combination, achieves the best metabolic control. The choice of medication often is guided by cost, availability, patient preference, adverse effects, and tolerance.

In the rare setting of mixed carcinoma associated with pheochromocytoma components, high-dose, radiolabeled metaiodobenzylguanidine (MIBG) has a potential role.

The management of blood pressure elevation in endocrine syndrome from adrenal cancer is similar to that in pheochromocytoma, with use of long-acting alpha blockers (usually phenoxybenzamine), followed by long-acting beta blockers (eg, propranolol) and, finally, metyrosine. There is no evidence suggesting that a combination of radiotherapy with mitotane (or any other chemotherapeutic regimen, for that matter) confers any survival benefit.

Patients treated with mitotane may present with features of both glucocorticoid and aldosterone insufficiency requiring replacement therapy.

Stem cell transplantation

Autologous hematopoietic stem cell transplantation for rescue after high-dose chemotherapy is an established approach in several hematologic malignancies and certain solid tumors. A single case report describes the successful use of a combination of adrenalectomy, chemotherapy, surgical debulking of lung metastases, and autologous transplantation in a three-year-old girl with AC.[50]

Some experts recommend that the use of radiation therapy be restricted to palliation of local disease, such as symptomatic metastases to the bone and local luminal obstructive disease.[51] Percutaneous radiofrequency ablation may provide control of local symptoms related to local compression by an invasive tumor.

In contrast, a review of 865 cases of adrenocortical carcinoma concluded that medically fit patients with stage III, node-negative disease should receive adjuvant radiation after surgical resection, as this has been associated with significantly improved overall survival, compared with surgery alone.[52] The American Association of Clinical Endocrinology recommends considering radiation therapy or radiofrequency ablation as part of a multidisciplinary approach in patients with advanced or recurrent disease.[25]

A meta-analysis by Polat et al suggested that radiotherapy to the tumor bed may be considered in patients at high risk for local recurrence. These researchers recommended administering a total dose of more than 40 Gy, with single fractions of 1.8-2 Gy (including a boost volume to reach from 50-60 Gy in individual patients).[51]

Ambulatory follow-up should be performed every month for the first 2 years after treatment because repeat resection of locally recurring disease and resection of metastatic lung disease can substantially improve long-term survival.

Scanning of the local area in the abdomen or pelvis and of sites of metastatic disease should continue as follows:

• First 2 years: every 3 months
• Third and fourth year: every 4 months
• Fifth year: every 6 months 

Patients should be monitored for the reappearance of adrenocortical hormone hyperactivity, along with scanning, unless their history suggests that Cushing syndrome or autonomous adrenocortical hormonal production is present. If this is the case, the physician should immediately search for recurrence.

No definitive guidelines exist for all nonfunctional adrenal masses being followed serially. A suggested follow-up regimen is to perform repeat adrenal CT or MRI scans 3-6 months after the initial evaluation, then yearly (some suggest every 6 mo for the first few years) in order to detect any change in tumor size. Accompany these with periodic checks of hormonal profiles (after 1 y, then every 1-2 y thereafter).

European Society of Endocrinology

Clinical practice guidelines for the management of adrenocortical carcinoma (AC) in adults were released in 2018 by the European Society of Endocrinology.[53]  

Diagnosis

Perform a detailed hormonal workup of all patients with suspected ACC to identify potential autonomous excess of glucocorticoids, sex hormones, mineralocorticoids, and adrenocortical steroid hormone precursors.

Perform a chest CT in addition to an abdominal-pelvic cross-sectional imaging (CT or MRI) in any case where there is high suspicion for AC.

Do not use adrenal biopsy in the diagnostic workup of patients with suspected AC unless there is evidence of metastatic disease that precludes surgery.

Surgery

Complete en bloc resection of all adrenal tumors suspected to be AC is recommended. Enucleation and partial adrenal resection is not recommended.

Open surgery for all tumors with radiological findings suspicious of malignancy and evidence for local invasion is recommended.

Routine loco-regional lymphadenectomy should be performed with adrenalectomy for highly suspected or proven AC. At a minimum, it should include the periadrenal and renal hilum nodes. All suspicious or enlarged lymph nodes identified on preoperative imaging or intraoperatively should be removed.

Perioperative hydrocortisone replacement in all patients with hypercortisolism who undergo surgery for AC is recommended.

Pathological work-up:

• Use immunohistochemistry for steroidogenic factor 1 (SF1) for the distinction of primary adrenocortical tumors and non-adrenocortical tumors.
• Use the Weiss system for the distinction of benign and malignant adrenocortical tumors.
• Use Ki67 immunohistochemistry for every resection specimen of an adrenocortical tumor.

Adjuvant therapy:

• Adjuvant therapy is not recommended for adrenal tumors with uncertain malignant potential.
• Adjuvant mitotane treatment is recommended for those patients without macroscopic residual tumor after surgery who have a high risk of recurrence.
• Administer adjuvant mitotane for at least 2 years, but not longer than 5 years, in patients without recurrence.

Treatment of recurrent and/or advanced AC:

• For advanced AC not amenable to complete surgical resection, local therapeutic measures (eg, radiation therapy, radiofrequency ablation, chemoembolization) are of particular value .
• Routine use of adrenal surgery in case of widespread metastatic disease at the time of first diagnosis is not recommended.
• In patients with advanced AC at the time of diagnosis who do not qualify for local treatment, either mitotane monotherapy or mitotane plus EDP (etoposide, doxorubicin, cisplatin) is recommended.
• Surgery is recommended for patients with recurrent disease that arises after a disease-free interval of at least 12 months.

Pregnancy and AC:

• Prompt surgical resection is recommended when an adrenal mass suspected to be an AC is diagnosed in a pregnant patient.
• Patients should avoid pregnancy while on mitotane treatment.

National Comprehensive Cancer Network

When an adrenal gland tumor is found on an imaging study, in patients with no history of prior or current malignancy and no risk, or suspicion, of adrenal metastasis, National Comprehensive Cancer Network (NCCN) recommendations for evaluation include an adrenal protocol: non-contrast CT (if Hounsfield units [HU] < 10, the tumor is probably benign and no further imaging is recommended; if > 10 HU, proceed with contrast CT with washout); or MRI with and without contrast.

The NCCN also recommends a biochemical workup for the following, in addition to the workup for AC[44] :

• Hyperaldosteronism
• Hypercortisolemia
• Pheochromocytoma
• Androgen excess

In patients with suspected AC, the NCCN recommends the following studies, to evaluate for metastases and local invasion:

• Fluorodeoxyglucose (FDG) PET/CT
• Chest CT with or without contrast
• Abdominal/pelvic CT or MRI with contrast
• Biochemical workup

Patients with resectable disease should undergo adrenalectomy, with the choice of open versus minimally invasive surgery based on tumor size, degree of concern regarding potential malignancy, and local surgical expertise. If AC is found, the patient should undergo genetic counseling and testing for inherited cancer syndromes, and consideration of microsatellite instability (MSI), mismatch repair (MMR), and tumor mutational burden (TMB) testing.

For localized AC, recommended treatment is resection of the tumor and adjacent lymph nodes, preferably by open adrenalectomy. If there is high risk for local recurrence (eg, positive margins, Ki-67 > 10%, rupture of capsule, large size, high grade), external-beam radiation therapy (EBRT) to the tumor bed should be considered. Adjuvant mitotane therapy may also be considered, although this is a category 3 recommendation (ie, there is major NCCN disagreement that the intervention is appropriate).

For patients with locoregional unresectable or metastatic disease, the NCCN recommends considering the following options:

• Observation for clinically indolent disease with imaging and biomarkers (if functional) every 12 weeks
• Resection of primary tumor and metastases if > 90% removable, particularly if functional
• Local therapy (ie, stereotactic body radiation therapy [SBRT], thermal ablative therapies, liver-directed therapy)
• Systemic therapy, preferably in a clinical trial

For systemic therapy, preferred regimens are cisplatin or carboplatin plus etoposide ± doxorubicin ± mitotane. Other recommended regimens are pembrolizumab ± mitotane or mitotane monotherapy; streptozocin ± mitotane is useful in certain circumstances.

Adjuvant or palliative treatment for adrenocortical carcinoma (AC) has been studied by using mitotane, cisplatin, etoposide, and doxorubicin. Mitotane leads to autodestruction of the adrenal cortex. Therefore, it is used in almost all protocols in the hope that it will decrease any autonomous hormone production and suppress tumor growth. Chemotherapy has focused on 3 antineoplastics—cisplatin, etoposide, and doxorubicin—given alone or in combination; studies have focused on the regimen etoposide and cisplatin and on etoposide, doxorubicin, and cisplatin.

Class Summary

These agents inhibit cell growth and proliferation. Cancer chemotherapy is based on an understanding of tumor cell growth and how drugs affect it. After cells divide, they enter a period of growth (phase G1), followed by DNA synthesis (phase S). The next phase is a premitotic phase (phase G2). Finally, a period of mitotic cell division (phase M) occurs.

Rates of cell division vary for different tumors. Most common cancers grow slowly compared with normal tissues, and the rate may decrease if tumors are large. This difference allows healthy cells to recover from chemotherapy more quickly than do malignant cells, and this is the rationale for current cyclic dosage schedules.

In interfering with cell reproduction, some antineoplastic agents are specific to certain phases of the cell cycle, whereas others (eg, alkylating agents, anthracyclines, cisplatin) are not phase specific. Cellular apoptosis (ie, programmed cell death) is another potential mechanism of many antineoplastic agents.

Mitotane (Lysodren)

Mitotane is an option for the management of AC because it is a relatively specific adrenocortical cytotoxin. It decreases the production of cortisol by causing adrenal atrophy and affecting mitochondria in adrenocortical cells. No pediatric standards or dosages have been established; doses in children must be individualized.

Cisplatin

Cisplatin inhibits DNA synthesis and, therefore, cell proliferation, by causing DNA cross-linking and denaturation of the double helix.

Doxorubicin (Adriamycin)

Doxorubicin, a cytotoxic anthracycline antibiotic isolated from cultures of Streptomyces peucetius var. caesius, is mutagenic and carcinogenic. It blocks DNA and RNA synthesis by inserting between adjacent base pairs and binding to the sugar-phosphate backbone of DNA, inhibiting DNA polymerase. The drug binds to nucleic acids presumably by specific intercalation of the anthracycline nucleus with the DNA double helix. It can also cause DNA strand breakage, because of its effects on topoisomerase II.

Doxorubicin is a powerful iron chelator; the iron-doxorubicin complex induces the production of free radicals that can destroy DNA and cancer cells.

Doxorubicin's maximum toxicity occurs during the S phase of cell cycle. The drug has a multiphasic disappearance curve, with half-lives of up to 30 hours. This agent does not cross blood-brain barrier but is taken up rapidly by the heart, lungs, liver, kidney, and spleen. The dosage is related to body surface area.

Antiproliferative drugs may be useful for palliating symptoms in patients with diffuse metastases. Liposomes in different drug products can vary in chemical and physical properties, which can substantially affect functional properties.

Etoposide (Toposar)

Etoposide is a glycosidic derivative of podophyllotoxin that exerts a cytotoxic effect by stabilizing the normally transient covalent intermediates formed between the DNA substrate and topoisomerase II. The drug leads to single-stranded and double-stranded DNA breaks that arrest cellular proliferation in the late S or early G2 phase of cell cycle.

Pembrolizumab (Keytruda)