ELSEVIER SAUNDERS
Renal and adrenal tumors in children
Stephen A. Zderic, MD
Pediatric Urology, University of Pennsylvania School of Medicine, Children’s Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Robert Wood Center, 3rd Floor, Philadelphia, PA 19104-4399, USA
Although tumors of the kidney in children had been described sporadically in the medical litera- ture, Max Wilms, a German surgeon, described their common histologic features. Before 1930, the outlook for these patients was poor, and most died of their disease or attempted surgical intervention. Ramon Guiteras [1] noted in his textbook of urology in 1913 that tumors of the kidney in a child were virtually always fatal. At the start of the new millennium, survival rates for these pa- tients approach 90%, even for the most advanced stages of disease. The path of the past 50 years that improved survival dramatically is worth retracing [2].
Advances in anesthetic and surgical technology and techniques made an incredible difference in the ability of children to survive the surgical pro- cedure. Even today, under more optimal condi- tions, the surgical management of large lesions remains challenging [3]. Sidney Farber’s [4] obser- vation that chemotherapy could eradicate tumor was a quantum leap forward. Some patients with pulmonary metastases were administered actino- mycin D, but died of their advanced disease. At autopsy, however, the pulmonary lesions con- tained fibrosis and no evidence of tumor, giving medical oncologists hope that such treatment would benefit future patients. With the develop- ment of additional chemotherapeutic regimens and the use of radiation therapy, survival rates began to improve dramatically for these children [2], and it became evident that not all patients would require intensive therapy. Hence, the need for carefully designed trials. With only 400 cases of Wilms’ tumor presenting each year in the United
States, it was apparent that only a national, co- operative study could provide answers in a timely fashion. The National Wilms’ Tumor Study (NWTS) was organized in response, and has conducted four long-term studies [5-8] addressing how adjunctive therapy may be tailored optimally to maximize survival and minimize the exposure to chemotherapy and radiation therapy.
Diagnostic imaging
Radiographic studies are essential to identify in advance special circumstances in which the surgi- cal approach will differ from the traditional simple nephrectomy. Such conditions would include the presence of tumor extension into the vena cava, bilateral disease, or a malignancy in a solitary kidney. The evaluation of these patients usually begins with an abdominal pelvic ultrasound or- dered by a referring physician. Whenever possible, the radiologist should be consulted in advance as to the suspected diagnosis, so that additional views may be taken of the inferior vena cava to establish the presence or absence of tumor thrombus. A CT scan with contrast establishes the presence of function in the contralateral kidney and rules in any evidence of bilateral disease. Chest films with oblique views or a CT scan of the chest are in- dicated to rule out pulmonary metastases.
Staging
Despite the impressive advances in diagnostic imaging, the staging of Wilms’ tumor is based on clinical observations made in the operating room and ultimately in the pathology suite. It was crucial to the success of the NWTS that a common terminology existed for patient stratification (Table 1). Despite the size of the tumors and
| NWTS stage | Description | Chemotherapy | Radiation | Survival RFS (overall) |
|---|---|---|---|---|
| I | Completely contained within renal parenchyma | AMD + VCR 18 weeks | No | 90% (97%) |
| II | Capsular margin (+) | AMD + VCR 18 weeks if favorable histology Add DOX + CPM and etoposide if histology shows anaplasia | No Except if unfavorable histology | 89% (93%) |
| III | Nodes (+) | AMD + VCR + DOX 24 weeks if favorable histology Add CPM and etoposide if histology shows anaplasia | Yes | 74% (85%) |
| IV | Visceral/pulmonary metastases | AMD + VCR + DOX 24 weeks if favorable histology Add CPM and etoposide if histology shows anaplasia | Yes | 69% (81%) |
| V | Bilateral renal involvement | Biopsy to confirm, then AMD + VCR 8-12 weeks Repeat CT scan Add third agent if no response | Yes | 75% (73%) |
Abbreviations: AMD, actinomycin D; DOX, doxorubicin; CPM, cyclophosphamide; RFS, recurrence-free survival (tumor-free survival) VCR, vincristine.
Data from: Refs. [12,13,20,21].
changes in lymph nodes, final staging is determined by histologic analysis of the renal margins and nodal status. These two parameters greatly affect subsequent adjuvant therapy. It is important that the contralateral kidney is examined with direct visual inspection of the anterior and posterior surface to search for evidence of nephrogenic rests and small tumors that may evade detection by CT or MRI in up to 7% of cases (although with current imaging, this point is debated) [9].
Surgical considerations
Additional preoperative testing should include a complete blood cell count, electrolytes with blood urea nitrogen and creatinine, liver function tests, and type and crossmatch. No matter how routine the nephrectomy may appear on a CT scan, acute hemorrhage can be rapid, and blood always must be available. These tumors typically present as large abdominal masses, and the surgi- cal approach to the renal artery often is compli- cated by numerous dilated veinous collaterals. The
traditional surgical approach to these patients is transperitoneal with an incision large enough to allow for exploration of the contralateral kidney. Upon entering the peritoneum, the opposite kid- ney is exposed and inspected for small capsular lesions that may have evaded detection by pre- operative imaging. Although CT and MRI have made it possible to detect more than 95% of contralateral lesions, the NWTS continues to advocate contralateral exploration given the dif- ference in management for patients with bilateral disease. Therefore, any suspicious lesions in the contralateral kidney should be biopsied before proceeding with nephrectomy.
Once the contralateral kidney is cleared as normal, attention is directed to identifying the major vessels leading to the ipsilateral affected kidney. The vein should be inspected carefully to ensure that no tumor thrombus is present. After ligation of the artery followed by the vein, a ne- phrectomy is performed, with the surgical team noting the extent of the tumor margins. Upon removal of the specimen, a sampling of the lymph
nodes should be taken, with a special emphasis on any enlarged nodes, 50% of which will contain tumor on histologic examination. All specimens should be delivered to the pathology suite with a detailed map showing the locations of the primary tumor, a description of the margins, and from where the lymph nodes were sampled.
Surgical management of Wilms’ tumor is chal- lenging because of the large size of the primary lesions. Because pretreatment with chemotherapy may lead to understaging of patients, management in the United States has called for exploration, nephrectomy, and lymph-node sampling as the initial management. Even in the fourth NWTS, 11% of patients experienced surgical complica- tions, most commonly hemorrhage and bowel obstruction postoperatively [10]. Another impor- tant surgical goal is to avoid tumor rupture and spillage because it increases local recurrence rates up to sixfold [11]. In summary, the surgeon’s goals are to (1) eliminate or diminish tumor burden, (2) accurately stage the extent of disease, and (3) minimize the need for additional chemotherapy or radiation therapy by avoiding tumor spillage.
Adjunct therapy stage by stage
A major achievement of the NWTS has been survival rates of over 80% for all stages, and continuing to minimize the toxicity of chemother- apy and radiation therapy. The decisions about adjunctive therapy are made by considering the stage and histologic grade, and Table 1 summa- rizes the current NWTS 5 recommendations. For patients with stage I or II favorable histology, an 18-week course of actinomycin D and vincristine has produced survival rates of 100%. If the pathologist reports the presence of anaplasia, the complexity of the regimen increases, and radiation therapy is added irrespective of stage. The use of doxorubicin is restricted to patients with stage-III disease or higher, or those with anaplasia. Another goal of the current NWTS is to validate molecular markers, such as the loss of heterozygosity for chromosomes 16q and 1p, that can better predict which patients are at greater risk for relapse and identify new potential markers [12].
National Wilms’ Tumor Study versus International Society for Pediatric Oncology trials
The approach to a patient with Wilms’ tumor varies among institutions; most European centers
have adopted a trial of biopsy followed by chemotherapy upfront (International Society for Pediatric Oncology-SIOP trial). Following med- ical reduction of the tumor burden, a nephrectomy and lymph-node sampling is performed. This is in contrast to most American institutions, in which the approach advocated by the NWTS is stan- dard. How do outcomes compare between these two approaches?
D’Angio [13] has outlined the major advantages and disadvantages of both approaches succinctly. The two trials cannot be compared directly because the patients in the NWTS are staged surgically. This is a crucial point. It does not matter which approach is taken for patients who have true stage- I disease because for these two trials, the therapy is the same. For patients who have stage-III disease, however (ie, those with positive lymph nodes), failure to treat patients with positive nodes has resulted in a higher rate of local recurrence. A major concern with up-front chemotherapy is that positive lymph nodes will be rendered tumor-free, thus preventing accurate staging. The SIOP trial addresses this concern by treating all patients with capsular extension (stage II) with a course of anthracyclines, even if their lymph nodes are negative. Thus, critics of the SIOP approach argue that many patients with true stage-II disease are subjected to the potential toxicity of anthracylines without a benefit. This argument is countered by proponents of preoperative chemotherapy, who point out that there is a higher risk for tumor spillage during a nephrectomy performed as first- line therapy, which in turn increases the risk for local recurrence by 10% [11]. This increase, however, did not translate into a significant in- crease in mortality.
Both of these trials have produced remarkable occurrence-free and total survival. The NWTS approach is favored in the United States because it can obtain a more exact surgical staging that allows therapy to be tailored to minimize long-term side effects. This is crucial because long-term follow-up in this patient population is 60 to 80 years. In one study of long-term outcomes follow- ing doxorubicin administration, the incidence of congestive heart failure (CHF) was 20% approxi- mately 20 years after therapy [14]. Will this per- centage increase as this cohort of patients ages? Will these rates of CHF decline as the doses of doxoru- bicin are dropped to the lowest levels possible?
Another study has shown that adult survivors of Wilms’ tumor are more likely to develop a second malignancy [15]. Another recent report
described four adult patients who developed a tumor in their remaining kidney years after their initial therapy for Wilms’ tumor [16]. These authors questioned if the incidence of such findings will increase as more long-term survivors reach adulthood, and speculated that if there is a rise in such findings, an argument could be made for partial nephrectomy as the initial management for these children. This report describes a highly selected patient population because it comes from a center known for its expertise in nephron-sparing surgery. Further long-term outcomes studies must examine the frequency with which such tumors develop in the contralateral kidney in a complete cohort of NWTS patients. Currently, with an experienced surgical, anesthesia, and medical on- cology team in place, an argument can be made for an up-front nephrectomy and lymph-node sampling [13]. It is equally important to remember when exceptions to this approach should be taken, and a SIOP-type protocol adopted, as in the following examples.
Special surgical considerations
Rarely, special circumstances such as caval extension, bilateral disease, or a tumor in a solitary kidney arise in which the patient should be pre- treated with chemotherapy before definitive surgi- cal resection. Pretreatment dramatically reduces tumor thrombus for patients with caval extension, which will reduce substantially the surgical mor- bidity [17]. Patients with bilateral disease or tumor in a solitary kidney should be managed with a biopsy, and under certain circumstances, a lymph-node sampling followed by chemotherapy. Chemotherapy administered up-front usually reduces tumor burden substantially, making the
partial nephrectomies simpler to perform. Several cases illustrate the application of these general principles.
A 5-year-old boy presented with a solid mass in his right lower quadrant. A CT scan revealed an 8-cm solid mass in the kidney that was a crossed fused ectopia (Fig. 1). An open biopsy and lymph- node sampling confirmed Wilms’ tumor and that the nodes were tumor-free. The patient was treated up-front with actinomycin D and vincristine, and there was a substantial reduction in tumor burden at 10 weeks. A partial nephrectomy was performed and the specimen’s margins were tumor-free.
A 6-year-old boy presented with a slowly ex- panding mass in his right kidney; 1 year earlier, he had undergone a left nephrectomy for Wilms’ tumor (Fig. 2). The presumptive diagnosis was that this also represented Wilm’s tumor, and the de- cision was made to proceed with a partial nephrec- tomy. Following mobilization of the kidney, the vessels were isolated, mannitol was administered, and regional hypothermia was applied with an ice slush contained within a rubber dam [18]. Once the parenchyma was cooled, the vessels were clamped, the tumor was excised, and the size of the cavity was measured. A Foley catheter balloon was inflated to these dimensions, and placed within the cavity, which was then closed over the balloon. Three days later, the tumor bed was treated with brachtherapy administered through the catheter in the form of iridium seeds. The dosimetry calculation was based on of the dimensions of the cavity and Foley balloon, which had been determined intraopera- tively [19]. Despite negative tumor margins on the specimen, the decision was to proceed with the brachytherapy because of the possibility of sampling error, and concerns for local recurrence. Eight years later, this patient remains tumor-free with a normal serum creatinine.
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A 3-year-old girl presented with a huge abdom- inal mass that on CT scan was shown to represent bilateral renal tumors (Fig. 3). The presumptive diagnosis of Wilms’ tumor was made, and the decision was made to proceed with chemotherapy
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without a biopsy. Despite an aggressive regimen of chemotherapy, there was no change in the size of these masses 8 weeks later, and the decision was made to proceed with bilateral partial nephrecto- mies. Bilateral indwelling catheters were left to administer brachytherapy postoperatively, and the patient remained free of residual tumor for 2 years. She presented to the emergency department 2 years later, however, with facial edema and was hyper- tensive with a serum creatinine of 7.0. No element of obstructive uropathy could be detected, and microscopic hematuria and massive proteinuria were noted on urinalysis.
A clinical diagnosis of end stage renal disease secondary to Deny’s Drasch syndrome was made, which was confirmed on pathologic examination of the kidneys that were removed when her peritoneal dialysis catheter was placed. Histopathologic eval- uation of the kidneys showed signs of diffuse mesangial sclerosis. The classic triad of the Deny’s Drasch syndrome includes genital ambiguity, a progressive glomerulopathy, and the develop- ment of Wilm’s tumor. This syndrome is diagnosed more readily in males as a result of the evaluation of ambiguous genitalia. As this case illustrates, it
can present in females, most often as bilateral Wilms’ tumors. Given the known mutation in the WT-1 gene that has been mapped to chromosome 11p13, a molecular diagnosis should allow more effective management of these patients, including the use of up-front nephrectomies before the onset of malignancy. The challenge of identifying this syndrome in the rare genotypic and phenotypic female will remain.
In summary, children with solitary kidneys or bilateral disease may be managed with nephron- sparing techniques and achieve equivalent survival to other patients in the NWTS [20]. In a review of the Children’s Hospital of Philadelphia’s experi- ence with nephron-sparing surgery, the key de- terminant of patient survival was the histologic classification of the tumors [21]. Patients whose tumors were characterized as having unfavorable histologic elements fared more poorly than their counterparts with favorable histology, irrespective of stage. Another factor to be considered is the frequency of recurrences. Several rare instances have been noted of patients who, despite initial favorable histology, had several recurrences until the histology changed to unfavorable elements. It is hoped that with a better understanding of the molecular biology of these tumors, this subset of patients can be identified reliably and undergo up-front nephrectomies and transplantation in the future.
Sarcoma and rhabdoid variants
In years past, sarcoma and rhabdoid variants were included in the category of Wilms’ tumors, but it is now clear that they have differing cellular origins. These tumors have differing metastatic potential, and a far more ominous prognosis [22].
The classic location for clear cell metastases is bone; in contrast, rhabdoid tumors may metasta- size to brain. The rhabdoid renal tumor accounts for 2% of pediatric renal tumors. This highly malignant tumor presents in young patients with a mean age of 13 months, and is cured reliably only in the early stages. For patients with a rhabdoid tumor and positive lymph nodes, the 2-year sur- vival rate is reported to be as low as 10% [23], although recently several long-term survivors have been reported [24]. Patients with a rhabdoid tumor often present with gross hematuria and may exhibit hypercalcemia and calcifications within the kidney that are often prominent (Fig. 4) [25].
Renal-cell carcinoma
Renal-cell carcinoma is observed in childhood, and is the more likely diagnosis when a patient presents with a renal mass after 8 years of age. Gross hematuria is more common with this tumor than with Wilms’ tumor. As in adults, radical nephrectomy offers the only effective means of management. There is no effective medical adju- vant therapy for patients with renal-cell carcinoma, irrespective of age.
Angiomyolipoma
Angiomyolipoma is a rare renal tumor most likely to present in children who carry a known diagnosis of the tuberous sclerosis complex (TSC) [26]. Although these tumors are benign, they may cause substantial morbidity if their size may cause hemorrhage. For this reason, annual ultrasound examinations are recommended. In older patients, obesity may prevent the use of ultrasound, and serial MRIs may become needed for follow-up
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studies (Fig. 5). Studies have shown that over 50% of patients with TSC develop angiomyolipomas by an average of 7 years of age [27]. For lesions greater than 4 cm in diameter, the risk for hemorrhage increases [28], and the use of selective embolization has been effective. On occasion, open exploration with partial nephrectomy will be required for a lesion whose growth persists despite emboliza- tion. Careful follow-up is important because rare cases of renal-cell carcinoma (see Fig. 5) will appear in this population [29].
Adrenal tumors
Neuroblastoma
Neuroblastoma is the most common extracranial solid neoplasm found in children. One of the more intriguing features of this tumor is the frequency with which it is identified in fetal adrenal specimens. Studies suggest that in early fetal development, all adrenals contain focal areas with histology consis- tent with neuroblastoma [30]. The much lower incidence of clinical neuroblastoma suggests that most of these lesions will involute. Clinical presen- tations may include the finding of an abdominal mass, bone pain secondary to a metastasis, or anemia caused by bone-marrow tumor infiltration. Although most neuroblastomas arise from the adrenal glands, these tumors may develop any- where along the sympathetic chain, which accounts for the occasional symptoms that are secondary to catecholamine release. Thoracic lesions, pelvic
masses arising from the organ of Zuckerkandl, and direct compression of the spinal cord are also possible presenting sites.
Most patients will have an initial ultrasound evaluation that documents the presence of an adrenal mass. CT scans of the abdomen, pelvis, and chest document the degree of spread and lymphatic involvement. The use of I-131 metaio- dobenzylguanadine has been described as a func- tional imaging approach to detect lymphatic spread. Urinary levels of vanillylmandelic acid and homovanyllic acid are elevated in 90% or more of these patients at the time of presentation, and these levels drop with therapy, which offers oncologists a noninvasive means of searching for recurrences.
The traditional means of staging these patients was based on anatomic considerations, such as whether the tumor was localized or spread across the midline, lymph-node status broken down as local or distant, and whether the lesion was deemed unresectable. This traditional scheme worked well for patients with minimal or advanced stages of disease, but it failed to predict the outcome adequately for many patients. Shimada [31] de- veloped a histologic classification system to further stratify these patients into those at higher risk for recurrence [32].
In the 1980s, neuroblastoma samples were analyzed for expression of the N-myc oncogene, which was increased in patients with advanced disease [33]. Despite this association, there are still
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many patients with advanced disease who present with no increase in N-myc expression, implying that there is a substantial degree of tumor hetero- geneity. Clearly, however, N-myc amplification is associated with a poor prognosis independent of the patient’s age or stage at presentation. In recent years, pediatric oncologists have relied on a strat- egy to categorize patients into low-, intermediate-, and high-risk groups by using traditional staging, patient age, N-myc amplification status, the DNA index (a measure of dipoloid versus the tetraploid states), and the Shimada histopathology grade. This risk scale better selects patients in need of maximal adjuvant therapy, and allows exclusion of patients in whom a surgical resection alone will prove curative.
The surgical excision of the tumor in a patient 1 year of age or younger with stage-1 disease and no N-myc amplification results in disease-free survival rates of 90% [34,35]. For these patients, chemo- therapy and radiation therapy are indicated only for recurrences, which are rare. For patients with lymphatic involvement, or disease that has crossed the midline, an aggressive surgical resection will be followed by chemotherapy. This aggressive pursuit of tumor burden, however, should never come at the expense of normal adjacent structures. If surgical resection will compromise adjacent organs or large vessels, then the best debulking that can be attained or a biopsy should be followed by chemotherapy (Fig. 6). After repeat imaging to monitor the degree to which tumor burden has been diminished, a second laparotomy may be undertaken to provide the maximal degree of resection possible.
As the number of risk factors increases, the patient will be classified into the high risk of
recurrence group, for whom the most aggressive chemotherapy is administered, as well as radiation therapy. In selected cases, intraoperative radiation therapy has been used. In some centers, autologous bone-marrow transplantation has been used as a last resort for patients in whom established chemotherapy regimens have failed [36]. For pa- tients with stage-IV disease, an unfavorable Shi- mada classification, and an increase in N-myc copy numbers, the survival rate at 4 years is 20%, which underscores the need for such aggressive therapy.
An unusual manifestation of neuroblastoma is seen in the neonate who presents with stage-IV disease. Neonatal patients will have an abdominal mass, positive lymph nodes, subcutaneous tumor nodules, and evidence of hepatosplenomegally. Despite the findings of widespread disease, these patients often show spontaneous regression, even in the absence of any therapy [37]. With the application of modern molecular tools to these tumors, it seems that these patients have favorable prognostic factors. These patients with stage-IV disease must represent a different molecular etiol- ogy because their survival rate is 85% to 90% compared with the 20% rate seen in older patients with stage-IV disease.
Adrenocortical carcinoma
Adrenocortical carcinoma rarely presents in childhood, but its unique endocrine manifestations should be reviewed [38]. One third of patients with adrenocortical carcinoma will present with Cush- ing’s syndrome, a manifestation of excess adrenal activity characterized by combinations of obesity, abdominal striae, moon facies, acne, fractures (secondary to osteoporosis), hypertension, and
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virilization (clitoromegally in females and exces- sive phallic development in males) [39]. This constellation of findings should result in an endo- crine workup to distinguish among the various possible etiologies of this syndrome. The workup will include an ultrasound of the gonads and retroperitoneum [40] to localize any masses that would be responsible for the syndrome. In many instances, both adrenal glands are enlarged sym- metrically, which is consistent with a diagnosis of Cushing’s disease if seen in conjunction with an elevated corticotropin level. Upon administration of high-dose dexamethasone or metyrapone (a blocker of 11-ß-hydroxylase), serum cortisol levels drop in these patients. Cushing’s disease is caused by a corticotrophin-secreting pituitary adenoma, and is managed by neurosurgical techniques. The only other cause of elevated corticotropin in this setting is ectopic corticotropin secretion by another malignancy.
In the event that the corticotropin level is decreased, there may be non-corticotrophin- dependent bilateral hyperplasia (both adrenal glands should be enlarged equally), or there is an adrenal tumor that should be apparent on sonog- raphy or CT scan. Plasma cortisol levels in these instances are not suppressed by administration of either dexamethasone or metyrapone (as opposed to the suppression that is seen with Cushing’s disease). These lesions are managed by surgical removal of the affected adrenal accompanied by a lymph-node sampling. In recent years, several groups have described a laparscopic approach to pediatric adrenalectomy [41]. It is critical to re- member that an active adrenal tumor may induce contralateral adrenal suppression. This means that in the postoperative period, the patient may experience the signs and symptoms of adrenal insufficiency. This can be prevented with preoper- ative administration of hydrocortisone followed by a slow postoperative steroid tapering and moni- toring of serum cortisol levels. It remains difficult for pathologists to determine whether these tumors are benign or malignant using histopathologic criteria. The presence of spread to the lymph nodes or adjacent or distant organs is the criterion by which malignancy is determined. In general, tu- mors less than 5 cm in diameter will be confined to the adrenal and are amenable to surgical cure [42].
Pheochromocytoma
Pheochromocytoma in the pediatric population is also extremely rare, and presents several chal-
lenges in diagnosis, medical, and surgical manage- ment that will be reviewed briefly. (The reader is referred to a recent review of pediatric pheochro- mocytoma management [43].) A bewildering array of presenting symptoms is possible for these patients. Flushing, headache, or the detection of hypertension in an emergency department or pediatrician’s office often will trigger the workup. Rarely, these lesions will be present at other sites along the sympathetic chain; if near the bladder, patients have been reported to describe headaches with voiding. Several case reports describe patients presenting with strokes [44,45]. CT will localize most of these lesions, although more recent pub- lications describe the use of positron emission tomography to identify nonadrenal sites [46]. These patients must be managed with alpha-block- ers and simultaneous volume repletion in prepara- tion for surgery [47]. This is critical because these patients are severely volume-depleted secondary to the vasoconstriction. Intraoperative fluctuations in blood pressure can be dramatic, and call for careful monitoring with an arterial line. A rapidly acting vasodilator, such as nipride, must be ready for use at any moment. Most of these lesions will be benign, and patients will recover fully after surgical removal. As with adrenal cortical tumors, there are no realiable histopathologic criteria to distinguish which lesions are malignant. These are defined by their metastatic spread, and although rare, usually are fatal [48].
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