Common Childhood Tumors. Денис Овечкін

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1 Common Childhood Tumors Денис Овечкін 2016

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3 Зміст 3 Зміст Common Childhood Tumors RHABDOMYOSARCOMA Etiology and pathogenesis Epidemiology Clinical presentation Clinical Group Outcomes LIPOMATOUS TUMORS FIBROUS TUMORS OSTEOSARCOMA (OSTEOGENIC SARCOMA) Incidence Classification Clinical Presentation Outcomes EWING S FAMILY OF TUMORS Classification Incidence Causes Staging Clinical findings Differential diagnosis Prognosis NEPHROBLASTOMA (WILM`S TUMOR) Etiology Pathology Clinical Presentation Differential diagnosis Outcome Recurrent Wilms` tumor NEUROBLASTOMA Incidence Etiology Pathology Clinical Presentation Staging

4 Зміст 4 23 Outcomes 24 TERATOMAS 25 Sacrococcygeal Teratoma 26 Ovarian Teratoma 27 Testicular Teratomas 28 Retroperitoneal Teratomas 28 Mediastinal Teratomas 29 Head and Neck Teratomas 29 Intracranial Teratomas 29 Other Head and Neck Teratomas 29 Dermoid cyst 30 LYMPHOMA 30 Hodgkin's Lymphoma (or Hodgkin's disease) 31 Non-Hodgkin's Lymphoma 35 MEDIASTINAL MASSES 38

5 Common Childhood Tumors 5 Common Childhood Tumors Rhabdomyosarcoma Etiology and pathogenesis Epidemiology Clinical presentation Clinical Group Outcomes Lipomatous Tumors Fibrous Tumors Osteosarcoma (Osteogenic sarcoma) Incidence Classification Clinical Presentation Outcomes Ewing s family of tumors Classification Incidence Causes Staging Clinical findings Differential diagnosis Prognosis Nephroblastoma (Wilm`s tumor) Etiology Pathology Clinical Presentation Differential diagnosis Outcome Recurrent Wilms` tumor Neuroblastoma Incidence Etiology Pathology Clinical Presentation Staging Outcomes Teratomas Sacrococcygeal Teratoma Ovarian Teratoma Testicular Teratomas Retroperitoneal Teratomas Mediastinal Teratomas Head and Neck Teratomas Intracranial Teratomas Other Head and Neck Teratomas Dermoid cyst Lymphoma Hodgkin's Lymphoma (or Hodgkin's disease) Non-Hodgkin's Lymphoma Mediastinal Masses

6 Common Childhood Tumors 6 Common Childhood Tumors RHABDOMYOSARCOMA Rhabdomyosarcoma (RMS) is a malignant tumor of mesenchymal origin. RMS is a type of cancer, specifically a sarcoma (cancer of connective tissues), in which the cancer cells are thought to arise from skeletal muscle progenitors. It can also be found attached to muscle tissue, wrapped around intestines, or in any anatomic location. Most occur in areas naturally lacking in skeletal muscle, such as the head, neck, and genitourinary tract. The two major histologic subtypes of RMS [26]: embryonal (more common in younger children, the cancer cells resemble those of a typical 6- to-8-week embryo); alveolar (more common in older children and teenagers, they resemble those of a typical 10- to-12-week embryo). Embryonal RMS (ERMS) is the most common type of RMS, affecting two thirds of all patients with disease. ERMS occur more frequently in the head and neck region as compared with the extremities. Alveolar RMS (ARMS) occurs in older children, and tumors are most commonly located on the trunk or extremities. Prognosis is worse in ARMS than ERMS, with a 5-year survival rate of 54%. Etiology and pathogenesis The exact nature of the pathogenesis of RMS is unclear; however, many hypotheses exist. It is largely thought that RMS arises as a consequence of regulatory disruption of skeletal muscle progenitor cell growth and differentiation [11]. Epidemiology Rhabdomyosarcoma is the most common type of soft tissue sarcoma diagnosed during the first 2 decades of life, accounting for 4,5% of all cases of childhood cancer [14]. It is the third most common extracranial solid tumor of childhood after Wilms' tumor and neuroblastoma. Age at presentation follows a bimodal distribution, with peak incidences between 2 and 6 years and again between 10 and 18 years of age. This distribution reflects the incidences of the two major histologic subtypes of RMS. The incidence of embryonal RMS is highest at birth and extends through childhood before declining, while alveolar RMS peaks during childhood and adolescence. Approximately 65% of all RMS cases occur in children younger than 6 years of age. Slightly more males (58,4%) are affected than females (41,6%) [14, 26]. Clinical presentation Clinical presentation varies with the site of origin. Orbital tumors produce chemosis, a mass on the conjunctiva or eyelid or proptosis. Progression to blindness and ophthalmoplegia may result.

7 Common Childhood Tumors 7 Tumors originating in the nasopharynx, paranasal sinuses, middle ear and mastoid (parameningeal tumors) present with pain, discharge, epistaxis, cranial nerve palsies, voice changes and airway obstruction. Tumors arising from the soft tissues of the head and neck produce an asymptomatic firm mass. Bloody vaginal discharge or a red polypoid friable lesion at the introitus is highly suggestive of RMS of the vagina. Bladder tumors may mimic an infection with urinary frequency or other difficulties with urination. Prostatic lesions block urinary outflow, necessitating catheterization. Since prostatic lesion bulges into the rectum, digital rectal examination is diagnostic. Trunk or extremity lesions are visible as firm, fixed subcutaneous masses. Ultrasound, CT and MRI can be used to better define the anatomic relationships of the primary tumor. Metastatic evaluation includes chest radiographs, abdominal and chest CT scan, bone scan, skeletal survey, bone marrow aspirate and biopsy. Depending upon the site and size of the tumor, diagnosis is made by incisional or excisional biopsy. It is imperative that enough tissue be obtained to run the special tests including analysis of fresh tissue for cytogenetic and molecular characteristics. N B : When an entire lump or suspicious area is removed, the procedure is called an excisional biopsy. When only a sample of tissue is removed with preservation of the histological architecture of the tissue s cells, the procedure is called an incisional biopsy or core biopsy. When a sample of tissue or fluid is removed with a needle in such a way that cells are removed without preserving the histological architecture of the tissue cells, the procedure is called a needle aspiration biopsy. Clinical Group The extent of residual disease after resection is one of the most important prognostic factors in RMS (Table 9.3). This system differs from TNM staging in that determination of each patient's clinical group is based on the extent of the surgical resection instead of tumor size and site. Table 9.3 Clinical grouping for RMS patients [14, 43] Group Criteria 5-Year Survival I Localized disease, completely resected origin: regional nodes not involved A. Confined to organ or muscle of origin B. Infiltrating outside organ or muscle of 85% Compromised or regional resection including: A. Grossly resected tumors with microscopic residual tumor B. Regional disease, completely resected, II with nodes involved and/or tumor extension into an adjacent organ 40% C. Regional disease, with involved nodes, grossly resected, but with evidence of microscopic residual tumor III Incomplete resection or biopsy with gross residual disease remaining 40% IV Distant metastases present at outset 35% for RMS consists of chemotherapy, radiation therapy and sometimes surgery [26]. Surgery to remove the tumor may be difficult or impossible depending on the location of the tumor. Unresectable tumors should be treated preoperatively with chemotherapy. Reduction of the tumor burden may permit adequate resection thus allowing reduction in radiation therapy. If there is no evidence of metastasis, surgery combined with chemotherapy and radiation offers the best prognosis. Patients whose tumors have not metastasized usually have a good chance for long-term

8 Common Childhood Tumors 8 survival, depending on the subtype of the tumor. All children with RMS are assumed to have microscopic metastasis at the time of diagnosis because hematogenous spread occurs early. This is the rationale for use of chemotherapy in all patients [26, 38]. Outcomes The overall survival rate of children with RMS depends upon site of origin and histology. About one-third of newly diagnosed patients falls into the low risk group and have a cure rate of 85 to 95%. About one-fifth of patients have metastatic disease at the time of diagnosis. Their 5-year survival rate is only 20% [14, 26]. LIPOMATOUS TUMORS Benign lipomas, so often seen in adults, are uncommon in children. Infiltrating lipomas and lipoblastomas are the more common benign fatty tumors in children. Complete resection is necessary but it may not be feasible in all locations. Liposarcomas are very rare in children and wide resection is essential for cure. FIBROUS TUMORS There is a wide spectrum of lesions represented in the category of fibrous tumors. Differentiating benign from malignant can be very difficult. Benign fibroma is a rare small lesion in subcutaneous tissues that is treated with wide local excision. Fibromatoses may appear benign under the microscope but behave aggressively because of their location or invasiveness. They can only be cured by wide local excision; however, mutilating surgery is not recommended unless the tumor becomes "aggressive." Fibrosarcoma can present at any age. The most common locations are the trunk, extremities, face and neck. The tumor presents as a rapidly growing, firm, painless mass. The primary site is imaged with CT or MRI, combined with metastatic evaluation with chest radiography and chest CT scanning. Complete surgical excision is essential for cure. Chemotherapy and radiation therapy are ineffective. OSTEOSARCOMA (OSTEOGENIC SARCOMA) Osteogenic sarcoma (OS) is an aggressive cancerous neoplasm arising from primitive transformed cells of mesenchymal origin that exhibit osteoblastic differentiation and produce malignant osteoid. It is the most common histological form of primary bone cancer. NB: Two main types of cells in our bones help them stay strong and keep their shape: Osteoblasts help build up bones by forming the bone matrix (the connective tissue and minerals that give bone its strength). Osteoclasts prevent too much bone matrix from building up and help bones keep their proper shape. By depositing or removing minerals from the bones, osteoclasts also help control the amount of these minerals in the blood. Like osteoblasts of normal bone, the cells that form this cancer make bone matrix. But the bone matrix of an OS is not as strong as that of normal bones. Incidence OS derives from primitive bone-forming mesenchymal cells and is the most common primary bone tumor. Among childhood cancers, OS occurs eighth in general incidence and in the following order: leukemia (30%), brain and other nervous system cancers (22.3%), neuroblastoma (7.3%), Wilms tumor (5.6%),

9 Common Childhood Tumors 9 Non-Hodgkin lymphoma (4.5%), rhabdomyosarcoma (3.1%), retinoblastoma (2.8%), osteosarcoma (2.4%), and Ewing sarcoma (1.4%). OS has a bimodal age distribution, having the first peak during adolescence and the second peak in older adulthood [11, 38]. The first peak is in the year-old age group, coinciding with the pubertal growth spurt. This suggests a close relationship between the adolescent growth spurt and osteosarcoma. The second peak is in adults older than 65 years of age; it is more likely to represent a second malignancy, frequently related to Paget s disease. There is a preference for origination in the metaphyseal region of tubular long bones. Most often it affects the proximal end of tibia or humerus, or distal end of femur. Osteosarcoma tends to affect regions around the knee in 60% of cases, 15% around the hip, 10% at the shoulder, and 8% in the jaw (Image 9.11). Causes The exact cause of OS is not known, but genetics may play an important role. Children and adults with other hereditary abnormalities, including exostoses (bony growths), retinoblastoma, Ollier's disease, osteogenesis imperfecta, polyostotic fibrous dysplasia, and Paget's disease, have an increased risk for developing osteosarcoma. Image 9.11 Predilections of osteosarcoma (Image by Mikael Häggström, 2008). Pathology The tumor is solid, hard, irregular ("fir-tree," "moth-eaten" or "sun-burst" appearance on X-ray examination) due to the tumor spicules of calcified bone radiating in right angles [14]. These right angles form what is known as Codman's triangle (Image 9.12). Surrounding tissues are infiltrated. NB: Codman triangle (previously referred to as Codman's triangle) is the triangular area of new subperiosteal bone that is created when a lesion, often a tumour, raises the periosteum away from the bone. It is a type of periosteal reaction. The main causes for this sign are osteosarcoma, Ewing's sarcoma, etc. Microscopically: The characteristic feature of osteosarcoma is presence of osteoid (bone formation) within the tumour. Tumor cells are very pleomorphic (anaplastic), some are giant, numerous atypical mitoses. These cells produce osteoid describing irregular trabeculae (amorphous, eosinophilic/pink) with or without central calcification (hematoxylinophilic/blue, granular) tumor bone. Tumor cells are included in the osteoid matrix. Image 9.12 X-ray features of tumors: Codman's triangle Classification Based on how they look under the microscope, osteosarcomas can be classified as high grade,

10 Common Childhood Tumors 10 intermediate grade, or low grade [11, 17, 38]. Some of these subtypes have a better prognosis (outlook) than others. The grade of the tumor plays a role in determining its stage and the type of treatment used. Clinical Presentation Many patients first complain of pain that may be worse at night, and may have been occurring for some time. If the tumor is large, it can appear as a swelling. The affected bone is not as strong as normal bones and may fracture with minor trauma (a pathological fracture). However, each child may experience symptoms differently. Symptoms may include, but are not limited to, the following: pain (sharp or dull) at the site of the tumor swelling (mass) and/or redness at the site of the tumor increased pain with activity or lifting limping decreased movement of the affected limb The symptoms may have been present over a short period of time or may have been occurring for six months or more. The route to osteosarcoma diagnosis usually begins with an x-ray, continues with a combination of scans (CT scan, PET scan (Positron emission tomography), MRI) and ends with a surgical biopsy. Films are suggestive, but bone biopsy is the only definitive method to determine whether a tumor is malignant or benign [43]. There are two main types of biopsy: a needle aspiration and a surgical biopsy. The location, incision and technical aspects of the biopsy can affect a patient s treatment options and outcome. usually starts after a biopsy of the tumor. Osteosarcoma is often treated with a combination of therapies that can include surgery, chemotherapy and radiation therapy [38]. Current standard treatment is to use neo-adjuvant chemotherapy (chemotherapy given before surgery) followed by surgical resection [11]. Surgery is used after chemotherapy to remove any remaining tumor. In most cases, surgery can remove the tumor while saving the affected limb. This is called limb-salvage surgery. In rare cases, more involved surgery (such as amputation) is necessary. Though radiation therapy is not widely used in osteosarcoma treatment, it can be effective and is occasionally recommended, especially when a tumor is difficult to remove surgically or when residual tumor cells remain after surgery. Types of Surgery Surgery for osteosarcoma involves biopsy, surgical removal of the tumor, bone grafts, limb salvage procedures, amputation, and/or reconstruction. The type of surgery will depend on the size and location of the tumor, and whether the cancer has spread. Limb-salvage surgery: it is sometime necessary to remove all or part of a limb. In most cases, however, limb-salvage surgery is used to avoid amputation. Through limb-salvage surgery, all of the bone and cartilage involved with the tumor, including some degree of muscle surrounding it, is removed, while nearby tendons, nerves and vessels are saved. The bone that is removed is replaced with a bone graft or with a metal prosthesis (Image 9.13). Subsequent surgery may be needed to repair or replace the reconstruction which can become loose or break. Patients who have undergone limbsalvage surgery need intensive rehabilitation. It may take as long as a year for a patient to

11 Common Childhood Tumors 11 Image 9.13 Prosthesis replacing. regain full use of a limb following limbsalvage surgery. Amputation: in some cases, if the tumor cannot be removed because, for example, it involves the nerves and blood vessels, amputation is the only option. The advantages of an amputation are that it is a simple operation with minimal chances of surgical complication and it definitively removes the local tumor. The functional outcome is good with the modern prostheses available today. Rotationplasty: this operation preserves the lower leg and uses the ankle as a knee joint (Image 9.14). In this procedure, the patient functions more like a below knee amputee rather than an above knee amputee. It is especially useful in very young children where limb length would be an issue. Image 9.14 Rotationplasty Outcomes Tumor staging, presence of metastases, local recurrence, chemotherapy regimen, anatomic location, size of the tumor, and percentage of tumor cells destroyed after neoadjuvant chemotherapy have effects on the outcome. The overall 5-year survival rate for osteosarcoma is 68%, without significant gender difference [14, 43]. EWING S FAMILY OF TUMORS The Ewing s family of tumors (EFT) or a tumor of the Ewing s family (TEF) is a group of cancers that start in the bones or nearby soft tissues that share some common features. They can develop at any age, but these tumors are most common in early teenage years. Classification There are 3 main types of Ewing tumors:

12 Common Childhood Tumors 12 v Ewing sarcoma of bone: Ewing sarcoma that starts in the bone is the most common tumor in this family. This type of tumor was first described by Dr. James Ewing in 1921, who found it was different from the more common bone tumor, osteosarcoma. Its cells looked different from osteosarcoma cells when seen under a microscope. It was also more likely to respond to radiation therapy. v Extraosseous Ewing tumor (EOE): Extraosseous Ewing tumors start in soft tissues around bones, but they look and act very much like Ewing sarcomas in bones. They are also known as extraskeletal Ewing sarcomas. v Peripheral primitive neuroectodermal tumor (PPNET): This rare childhood cancer also starts in the bone or soft tissue and shares many features with Ewing sarcoma of bone and EOE. Peripheral PNETs that start in the chest wall are known as Askin tumors. NB: Peripheral PNETs are similar to, but not quite the same as, PNETs of the brain and spinal cord. Researchers have found that the cells that make up Ewing sarcoma, EOE, and PPNET are very similar. They tend to have the same DNA (gene) abnormalities and share similar proteins, which are rarely found in other types of cancers. That s why these 3 cancers are thought to develop from the same type of cells in the body. There are slight differences among these tumors, but they all get the same treatment. Of the tumors in this family, Ewing s tumor of bone represent around 87%, while EOE (at 8%) and PNET (at 5%) are much rarer [14]. Incidence TEF can occur at any age, but they are most common in teens and are less common among young adults and young children (the peak between 10 and 20 years of age). They are rare in older adults. Ewing sarcoma occurs most frequently in male teenagers, with a male/female ratio of 1.6:1 [14, 26]. Ewing tumors occur most often in whites (either non-hispanic or Hispanic). They are less common among Asians. The reason for this is not known [43]. Most Ewing tumors occur in the bones. The most common sites are the pelvis (hip bones), the chest wall (such as the ribs or shoulder blades), and the legs, mainly in the middle of the long bones. (In contrast, osteosarcoma usually occurs at the ends of the long bones, especially around the knees.) Extraosseous Ewing tumors can occur almost anywhere. Causes The exact cause of Ewing sarcoma is not fully understood. There seems to be no known risk factors or prevention measures avaliable. However, researchers have discovered chromosomal changes in a cell's DNA that can lead to Ewing sarcoma formation. These changes are not inherited. They develop in children after they are born for no apparent reason [11, 14, 38]. Staging A TEF is staged as either localized (involving only the site of origin and nearby tissues) or metastatic (involving spread to distant parts of the body). The formal (and more detailed) staging system for Ewing tumors is the American Joint Committee on Cancer (AJCC) system for bone cancer. Clinical findings The following are the most common symptoms of Ewing's sarcoma. However, each child may experience symptoms differently. Symptoms may include, but are not limited, to the following: pain around the site of the tumor swelling (mass) and/or redness around the site of the tumor fever weight loss, decreased appetite fatigue paralysis and/or incontinence (if the tumor is in the spinal region ) symptoms related to nerve compression from tumor (i.e., numbness, tingling, paralysis, etc.)

13 Common Childhood Tumors 13 At this time unfortunately, there are no special tests that can help with early detection of Ewing s and PNET [14, 45]. The diagnosis of a TEF begins with recognition of certain signs and symptoms suggesting the disease might be present. The most common symptom of a TEF of the bone is pain. Pain occurs in about 85% of patients. Because these signs and symptoms are also typical of normal bumps and bruises or bone infections, some cases are not easily recognized. Only after the child s condition does not resolve quickly or is not improved by antibiotics is the diagnosis questioned [43]. In addition to a complete medical history and physical examination of your child, diagnostic procedures for Ewing's sarcoma may include: Imaging tests (such as x-rays, MRI, CT, and PET scans) create pictures of the inside of the body. On conventional radiographs, the most common osseous presentation is a permeative lytic lesion with periosteal reaction. The classic description of lamellated or "onion skin" (or "onion peel") type periosteal reaction is often associated with this lesion (Image 9.15). Plain films add valuable information in the initial evaluation or screening. The wide zone of transition (e.g. permeative) is the most useful plain film characteristic in differentiation of benign versus aggressive or malignant lytic lesions. MRI should be routinely used in the work-up of malignant tumors. MRI will show the full bony and soft tissue extent and relate the tumor to other nearby anatomic structures (e.g. vessels). CT can also be used to define the extraosseous extent of the tumor, especially in the skull, spine, ribs and pelvis. Both CT and MRI can be used to follow response to radiation and/or chemotherapy. Image 9.15 Onion peel. A anteroposterior and B lateral views. Classically described in Ewing s tumor but it is not pathognomonic (sometimes also seen in osteomyelitis or osteogenic sarcoma). Biopsy of the tumor. The results of imaging tests may strongly suggest a Ewing tumor, but a biopsy is the only way to be certain. A biopsy is also the best way to tell Ewing tumors from other types of cancer. There are a couple of ways to get a sample of the tumor to diagnose Ewing tumors: excisional biopsy and incisional biopsy. Bone marrow aspiration the tests aren t usually done to diagnose Ewing tumors, but they may be done once the diagnosis is made because it is important to know if the tumor has spread to the bone marrow. Bone marrow aspiration and biopsy are usually done at the same time. In most cases the marrow samples are taken from the back of both of the pelvic (hip) bones. These tests may be done as a separate procedure, or they may be done during the surgery to biopsy or treat the main tumor (while the child is still under anesthesia). A small piece of bone and marrow is removed with a slightly larger needle. Testing the biopsy samples:

14 Common Childhood Tumors 14 Immunohistochemistry Cytogenetics Reverse transcription polymerase chain reaction (RT-PCR) NB: No blood test can be used to diagnose Ewing tumors. But certain blood tests may be helpful once a diagnosis has been made. A blood test for levels of an enzyme called lactate dehydrogenase (LDH) is typically done at diagnosis (high LDH level indicates the cancer may be harder to treat) [14, 43]. Differential diagnosis Other entities that may have a similar clinical presentation include osteomyelitis, osteosarcoma and eosinophilic granuloma. Soft tissue neoplasms such as malignant fibrous histiocytoma that erode into adjacent bone may also have a similar appearance. Most patients with Ewing tumors are treated in clinical trials according to national treatment guidelines called protocols. The types of treatment that can be used in TEF include [11]: Chemotherapy Surgery Radiation therapy High-dose chemotherapy followed by a stem cell transplant Chemotherapy is almost always the first treatment. Localized therapy (surgery and/or radiation therapy) is next, often followed by more chemotherapy. A stem cell transplant might be an option for some patients with Ewing tumors that are unlikely to be cured with other treatments. Surgery for Ewing sarcoma involves surgical removal of the tumor, bone/skin grafts, limb salvage procedures, amputation, and/or reconstruction. The type of surgery will depend on the size and location of the tumor, and whether the cancer has spread. lengths vary depending on location and stage of the disease at diagnosis. Radical chemotherapy may be as short as 6 treatments at 3 week cycles; however most patients will undergo chemotherapy for 6 12 months and radiation therapy for 5 8 weeks. Transplantation of normal stem cells from another person is used to help restore normal blood production in patients whose own ability to make any or all of these blood cells has been compromised by cancer, intensive cancer treatment, or other types of damage or abnormality. The use of cells from another individual is called allogeneic transplantation. Stem cells collected form patients themselves prior to intensive treatment can also be used to supplement the recovery of the patient's own cells after particularly aggressive course of chemotherapy or radiation therapy. The use of a patient's own cells is referred to as autologous transplantation. In the past, this type of treatment was often called a bone marrow transplant. If a stem cell transplant is considered as part of the initial treatment plan for a Ewing tumor, the patient first gets standard doses of chemotherapy, then local treatment of the tumor (surgery and/or radiation therapy), followed by high-dose chemotherapy and a stem cell transplant. In the past, the stem cells were often collected from the child s bone marrow, which required a minor operation. But researchers have found that these cells can be taken from the bloodstream using a procedure similar to a blood donation. Instead of going into a collecting bag, the blood goes into a special machine that filters out the stem cells and returns the other parts of the blood to the person s body. The stem cells are then frozen until the transplant. This may need to be done more than once. Once the stem cells have been frozen and stored, the child gets high-dose chemotherapy, sometimes along with radiation therapy. When the treatment is finished, the patient s stem cells are thawed and returned to the body in a blood transfusion. The stem cells travel through the bloodstream and settle in the bone marrow. Over the next 3 or 4 weeks, they start to make new, healthy blood cells [11].

15 Common Childhood Tumors 15 Until this happens, the child is at high risk of infection because of a low white blood cell count, as well as bleeding because of a low blood platelet count. To avoid infection, protective measures are taken, such as using special air filters in the hospital room and having visitors wear protective clothing. Blood and platelet transfusions and treatment with antibiotics may also be used to prevent or treat infections or bleeding problems [11]. Prognosis Localized tumors With current treatment, the overall 5-year survival rate for patients with Ewing tumors that are still localized when they are first found is around 70% [14]. Metastatic tumors When the cancer has already spread at the time of diagnosis, the 5-year survival rate is about 15% to 30%. The survival rate is slightly better if the cancer has only spread to the lungs as opposed to having reached other organs [14, 43]. Factors other than the stage of the cancer can also affect survival rates. Factors that have been linked with a better prognosis include [11, 26]: Smaller tumor size Main tumor is on an arm or leg (as opposed to chest wall or pelvis) Normal blood LDH level Good tumor response to chemotherapy Age younger than 10 NEPHROBLASTOMA (WILM`S TUMOR) Renal tumors account for 6.3% of cancer diagnoses for children younger than 15 years of age, with a reported incidence of 7.9 per million. Including adolescents younger than 20 years of age, this drops slightly to 4.4% of cancer diagnoses, with an incidence of 6.2 per million [14, 43]. The five most common pediatric renal tumors are [43]: Wilms' tumor (90-95%), clear cell sarcoma (6%), rhabdoid tumor (2%), congenital mesoblastic nephroma, nephroblastomatosis. Wilms' tumor (also referred to as nephroblastoma or renal embryoma) is the most common primary malignant renal tumor of childhood [26, 43]. Wilms' tumor (WT) typically occurs in children, rarely in adults. Its common name is an eponym, referring to Dr. Max Wilms, the German surgeon ( ) who first described this kind of tumor. WT affects about 1 in 10,000 live births. 60% present before the age of three years. Most nephroblastomas are unilateral, being bilateral in less than 5% of cases [11, 43, 38]. The majority (75%) occur in otherwise normal children; a minority (25%) is associated with other developmental abnormalities. It is highly responsive to treatment, with about 90% of patients surviving at least five years. Etiology Genetic analysis of WT shows the chromosomes within the tumor cells to be normal, mutated, or mosaic. The relationship between Wilms' tumor and chromosomal mutations is based on the "two hit hypothesis" of Knudson. According to this model, individuals inherit a maternal and paternal set of chromosomes. Children with WT are born with a mutation in the tumor suppressor gene on one chromosome, thereby losing heterozygosity (LOH) at this locus (the first hit). Mutation at the same location on the other chromosome leads to tumor formation (second hit). Interestingly, studies of tumors with LOH show the vast majority are maternal. This tendency of LOH to favor the maternal or paternal allele is termed genomic imprinting. Somatic mosaicism has also been described in children with WT [14].

16 Common Childhood Tumors 16 Several chromosomal deletions have been described in WT. The etiology of clear cell sarcoma, rhabdoid tumors and congenital mesoblastic nephroma are unclear. Pathology The histology of Wilms' tumor is either favorable or unfavorable. Favorable histology is more common (89%) and is characterized by the presence of three components: stroma blastema epithelial elements Unfavorable histology is less common (3% to 13%, increasing with age) and defined by the presence of anaplasia. Wilms' Tumor Staging Stage Criteria Stage Criteria The tumor is limited to the kidney and has been completely resected. The tumor was not ruptured or biopsied prior to I removal. There is no penetration of the renal capsule or involvement of renal sinus vessels. The tumor extends beyond the capsule of the kidney but was completely resected with no evidence of tumor at or II beyond the margins of resection. There is penetration of the renal capsule or invasion of the renal sinus vessels. Gross or microscopic residual tumor remains postoperatively, including inoperable tumor, positive III surgical margins, tumor spillage surfaces, regional lymph node metastases, positive peritoneal cytology, or transected tumor thrombus. The tumor was ruptured or biopsied prior to removal. IV Hematogenous metastases or lymph node metastases outside the abdomen (e.g., lung, liver, bone, brain). V Bilateral renal involvement is present at diagnosis, and each side may be considered to have a stage.

17 Common Childhood Tumors 17 Image 9.16 Wilms' Tumor Staging. Clinical Presentation Most children with WT present between the ages of 2 and 4 years with an asymptomatic abdominal mass, often discovered by either a parent or pediatrician (Image 9.17). Nonpalpable tumors are typically discovered by ultrasonography during evaluation for abdominal pain. Gross hematuria has been reported in 18.2% of patients and microscopic hematuria in 24.4%. 10% of children with WT have coagulopathy, and 20-25% present with hypertension because of activation of the renin-angiotensin system [14, 43]. Fever, anorexia, and weight loss occur in 10%. Extension of tumor thrombus into the renal vein can obstruct the spermatic vein and result in a left varicocele and, in rare cases, tumor extension into the atrium may produce cardiac malfunction. Tumor rupture and hemorrhage are also infrequent events that can present as an acute abdomen.

18 Common Childhood Tumors 18 Image 9.17 Asymptomatic abdominal mass in patient with Wilms` tumor Differential diagnosis The differential diagnosis for an abdominal mass includes neuroblastoma, hepatoblastoma, rhabdomyosarcoma, and lymphoma. NB: Neuroblastoma is the most common solid abdominal tumor in children [43]. One clinical observation to help distinguish between WT and neuroblastoma is that children with neuroblastoma are often ill because of extensive metastatic disease at presentation. In contrast, children with WT are generally healthy toddlers with a palpable abdominal mass. After an abdominal mass is identified, radiographic imaging is performed to determine the anatomic location and extent of the mass. The diagnostic workup includes a chest x-ray and an abdominal ultrasound. The chest x-ray is done to evaluate for the presence of pulmonary metastasis. Additional studies include urinalysis, abdominal plain film, and computed tomography (Image 9.18). The urine may contain red blood cells (20% of cases) or hyaluronic acid. The abdominal x-ray may show eggshell calcifications. This is in contrast to the speckled calcifications seen in neuroblastoma and the popcorn calcifications seen in teratomas [11, 43].

19 Common Childhood Tumors 19 Image 9.18 CT scan in a patient with a right-sided Wilms` tumor with favorable histology. Although MRI avoids radiation exposure, it has not been shown to be superior to CT scanning in standard assessments. MRI is currently being evaluated as a method to help distinguish nephrogenic rests from WT and may be the preferred method to follow children with bilateral WT after resection [11, 14, 43]. F-fluorodeoxyglucose positron emission tomography (FDG PET) has not been fully delineated in pediatric cancers. It is recognized that FDG PET has an established role in Hodgkin lymphoma and increasingly in sarcomas in children, but its role in WT is unclear [11, 26]. The main types of treatment that can be used for WT are: Surgery Chemotherapy Radiation therapy for WT is based mainly on the stage of the cancer and whether its histology. Surgical therapy is a primary component in the multidisciplinary treatment of WT or other neoplastic renal lesions [43]. If there is bilateral disease and wedge/partial resection of all tumors will result in removal of greater than one-third of the total renal mass, biopsy is done and the operative area is closed. Afterward, the child is treated with chemotherapy and re-explored in 6 weeks [14]. All children with WT receive postoperative chemotherapy. Those with Stage I and II lesions and favorable histology are treated with actinomycin D and vincristine. Children with Stage III and IV lesions and favorable histology and children with Stage II or III disease and focal anaplasia are treated with actinomycin-d, vincristine and adriamycin (doxorubicin) and postoperative abdominal irradiation [14]. Indications for preoperative chemotherapy include Stage V disease, IVC involvement above the hepatic veins, massive tumor and cytoreductive therapy if other organs are at risk [11]. Indications for postoperative radiation therapy include gross residual tumor, tumor spill, positive lymph nodes, peritoneal involvement, Stage IV disease and unfavorable histology [11]. Children with congenital mesoblastic nephroma do not require adjuvant therapy. Outcome The overall survival for children with favorable histology is 90%. Children with favorable histology, Stage I lesions have a 97% long-term survival. This drops to 60% for children with favorable histology, Stage IV lesions [14].

20 Common Childhood Tumors 20 Overall survival for children with unfavorable histology is 50%. Children with unfavorable histology, Stage I lesions have an 89% long-term survival. This drops to 14-55% for children with unfavorable histology and any other Stage disease [14]. Congenital mesoblastic nephroma is a benign lesion with an excellent prognosis. Recurrent Wilms` tumor The prognosis and treatment for children with WT that recurs (comes back after treatment) depends on their prior treatment, the cancer s histology (favorable or unfavorable), and where it recurs. The usual treatment for these children is surgery to remove the recurrent cancer (if possible), radiation therapy (if not already given to the area), and chemo, often with different drugs than those used during first treatment. NEUROBLASTOMA Neuroblastoma (also known as an "infantile neuroblastoma," and "neuroepithelioma") is the most common extracranial solid cancer in childhood and the most common cancer in infancy. The term neuro refers to nerves, while blastoma refers to a cancer that affects immature or developing cells. It is a neuroendocrine tumor, arising from any neural crest element of the sympathetic nervous system (SNS). It most frequently originates in one of the adrenal glands, but can also develop in nerve tissues in the neck, chest, abdomen, or pelvis. NB: Neuroblastoma is one of the few human malignancies known to demonstrate spontaneous regression from an undifferentiated state to a completely benign cellular appearance. Neuroblastoma is a tumor derived from neuroblasts. A neuroblast is a dividing cell that will develop into a neuron often after a migration phase. Neuroblasts are derived from neural crest cells and migrate during fetal development to form the autonomic nervous system. NB: Autonomic nervous system part of the nervous system also controls body functions we are rarely aware of, such as heart rate, breathing, blood pressure, digestion, and other functions. There are two paths of migration [14]: along developing nerves to form the sympathetic plexuses, where they form ganglion cells and to the adrenal gland to form the medulla. Tumors of the neuroblasts can be either malignant or benign. There is a wide spectrum of how neuroblastomas can behave. Some grow and spread quickly, while others grow slowly. Sometimes, in very young children, the cancer cells die without any cause and the tumor goes away on its own. In other cases, the cells sometimes mature on their own into normal ganglion cells and stop dividing. This causes the tumor to become a ganglioneuroma. Incidence Neuroblastoma is responsible for 7-10% of all childhood tumors and 15% of all cancer deaths. This tumor occurs in approximately 1 in live births. There is no ethnic prevalence [11, 14, 43]. There is a slight male predominance with a ratio of 1.2:1 (male to female) [26]. The median age at diagnosis is months, and 97% of neuroblastomas are diagnosed in children less than 10 years of age. The incidence is biphasic with a peak at less than 1 year of age and a second peak at 2-4 years [38, 43, 45]. Prenatal or postnatal exposure to drugs, chemicals or radiation has not been unequivocally demonstrated to increase the incidence of neuroblastoma [14]. Etiology The etiology of neuroblastoma is not well understood. Although most cases of neuroblastoma are thought to be sporadic, there is a subset of patients that exhibit a predisposition to develop disease in an

21 Common Childhood Tumors 21 autosomal dominant pattern. About 22% of neuroblastomas are thought to be the result of a germinal mutation. Heredity In about 1% to 2% of all neuroblastomas, children may have inherited an increased risk of developing neuroblastoma. But the vast majority of neuroblastomas do not seem to be inherited. Pathology Neuroblastomas arise from the primitive pluripotential sympathetic cells that are derived from neural crest cell and normally differentiate to form tissues of the sympathetic nervous system. All fetuses have neuroblastic nodules between weeks gestational age. Most regress before birth or shortly thereafter. Neuroblastoma in situ is frequently found in infants 3 months or younger dying from other causes. Therefore the cells that form neuroblastoma may be fetal remnants that fail to regress [14, 43, 45]. Neuroblastomas belong to a group of tumors classified as the small round blue cell tumors. Others in this category include Ewing s sarcoma, non-hodgkin s lymphoma, primitive neuroectodermal tumors (PNETs) and undifferentiated soft tissue sarcomas such as rhabdomyosarcoma. Neuroblastomas can be differentiated from other tumors in this category by using immunohistochemistry. Clinical Presentation Tumors arise anywhere there are sympathetic nerves from the brain to the pelvis. Neuroblastoma is a tumor with multiple clinical manifestations related to the site of the primary tumor, the presence of metastases, and the production of certain metabolic tumor byproducts. Most primary tumors occur in the abdomen (65%). The tumor may be hard, nodular, fixed, and painful on palpation. The frequency of adrenal tumors is slightly higher (40%) in children compared to infants (25%). Infants have more thoracic and cervical primary tumors [14]. The clinical presentation depends on the location of the primary. Often the symptoms are few and general. Generalized symptoms include weight loss, failure to thrive, abdominal pain and distention, fever, and anemia. Neoplasms arising in the upper mediastinum or neck may involve the stellate ganglion (or cervicothoracic ganglion or inferior cervical ganglion is a sympathetic ganglion) and cause Horner s syndrome, which is characterized by ptosis (drooping of the upper eyelid from loss of sympathetic innervation to the superior tarsal muscle); miosis (small pupils); enophthalmos, anhidrosis (decreased sweating on the affected side of the face); and heterochromia of the iris on the affected side [14, 43]. Those with thoracic primaries are diagnosed after a mass is found on a routine chest radiograph. The parents often find abdominal tumors when they are bathing the child. Abdominal tumors are more irregular than Wilms tumors and more often cross the midline. Pelvic tumors may result in obstructive symptoms (urethral or colonic). Rarely they compress or infiltrate the iliac veins and/or arteries and present with lower extremity edema. Tumors that extend intraspinal in any of these locations may present with neurologic symptoms. Acute cerebellar ataxia, characterized by opsomyoclonus and nystagmus ("dancing eye syndrome"), has been observed. This syndrome is seen more frequently (> 60%) in patients with primary mediastinal tumors. Rarely, patients with neuroblastoma present with profuse watery diarrhea if the tumor secretes vasoactive intestinal peptide (VIP). The diarrhea resolves once the tumor is removed % of tumors are biologically active secreting vanillymandelic acid (VMA) or homovanellic acid (HVA) or other catecholamine metabolites. HVA represents degradation products of the dopamine pathway. More differentiated tumors produce norepinephrine and epinephrine that give rise to VMA. The VMA:HVA ratio has some prognostic implication with levels > 1 indicating tumors with a more favorable prognosis. 10% of neuroblastomas secrete acetylcholine and not catecholamines; these tumors tend to be more malignant [11, 14, 26]. Hypertension is found in 25% of cases and is related to the production of catecholamines by the tumor. Neuroblastoma may spread by direct extension into surrounding structures, lymphatic infiltration, or

22 Common Childhood Tumors 22 hematogenous metastases. Regional and distant lymph nodes, liver, bone marrow, and bone cortex are frequently involved. Patients with bone cortex metastases have an ominous prognosis. Bone metastases occur in sites containing red marrow and involve the metaphyseal areas of long bones in addition to the skull, vertebral column, pelvis, ribs, and sternum. Bone lesions may cause extreme pain and may be first identified when a child refuses to walk because of leg pain [14, 26]. Hematogenous metastases to the brain, spinal cord, and heart are unusual. Brain metastases usually manifest in older children with headaches and seizures. Lung metastases are found on chest radiographs in only 4% of patients. This may be the result of direct extension to the lung from mediastinal lymph nodes or diffuse hematogenous spread, presenting with a radiographic pattern that may be confused with pulmonary edema or interstitial pneumonia [14]. Occasionally, patients with advanced disease present with a bleeding diathesis related to thrombocytopenia from extensive involvement of bone marrow and interference with hepatic production of clotting factors by liver metastases. Multiple subcutaneous skin nodules and hepatomegaly may occur in infants with stage IV-S neuroblastoma. Metastases to the bony orbit may produce proptosis or bilateral orbital ecchymosis often referred to as "panda eyes" or "raccoon eyes". Staging The stage of a cancer is one of the most important factors in choosing treatment. The stage of the neuroblastoma is based on results of physical exams, imaging tests, and biopsies of the main tumor and other tissues, which were described in the section. International Neuroblastoma Staging System (INSS) Since the mid-1990s, most cancer centers have used the INSS to stage neuroblastoma. In simplified form, the stages are: Stage 1: Localized tumor with complete gross excision, with or without microscopic residual disease; representative ipsilateral lymph nodes negative for tumor microscopically (i.e., nodes attached to and removed with the primary tumor may be positive). Stage 2A: Localized tumor with incomplete gross excision; representative ipsilateral nonadherent lymph nodes negative for tumor microscopically. Stage 2B: Localized tumor with or without complete gross excision, with ipsilateral nonadherent lymph nodes positive for tumor. Enlarged contralateral lymph nodes must be negative microscopically. Stage 3: Unresectable unilateral tumor infiltrating across the midline, with or without regional lymph node involvement; or localized unilateral tumor with contralateral regional lymph node involvement; or midline tumor with bilateral extension by infiltration (unresectable) or by lymph node involvement. The midline is defined as the vertebral column. Tumors originating on one side and crossing the midline must infiltrate to or beyond the opposite side of the vertebral column. Stage 4: Any primary tumor with dissemination to distant lymph nodes, bone, bone marrow, liver, skin, and/or other organs, except as defined for stage 4S. Stage 4S (also called special neuroblastoma): Localized primary tumor, as defined for stage 1, 2A, or 2B, with dissemination limited to skin, liver, and/or bone marrow (by definition limited to infants younger than 12 months). Marrow involvement should be minimal (i.e., <10% of total nucleated cells identified as malignant by bone biopsy or by bone marrow aspirate). More extensive bone marrow involvement would be considered stage 4 disease. The results of the MIBG (metaiodobenzylguanidine) scan, if performed, should be negative for disease in the bone marrow. Recurrent: While not formally part of the staging system, this term is used to describe cancer that has come back (recurred) after it has been treated. The cancer may come back in the area where it first started or in another part of the body. International Neuroblastoma Risk Group Staging System A risk-group staging system now coming into use is known as the International Neuroblastoma Risk Group Staging System (INRGSS). It is similar to the INSS, but it does not use the results of surgery to help define the stage. This lets determine a stage before surgery, based on the results of imaging tests (usually a CT or MRI scan, and an MIBG scan), as well as exams and biopsies. The stage can then be used to help predict how resectable the tumor is that is, how much of it can be removed with surgery. The INRGSS uses image-defined risk factors (IDRFs), which are factors seen on imaging tests that might mean the tumor will be harder to remove (Table 9.4). This includes things like the tumor growing into a nearby vital organ or growing around important blood vessels.

23 Common Childhood Tumors 23 The INGRSS divides neuroblastomas into 4 stages [11]: L1: Localized tumor not involving vital structures as defined by the list of image-defined risk factorsa and confined to one body compartment. L2: Locoregional tumor with presence of one or more IDRFs. M: Distant metastatic disease (except MS). MS: Metastatic disease in children younger than 18 months with metastases confined to skin, liver, and/or bone marrow. Table 9.4 Image-Defined Risk Factors (IDRFs) in Neuroblastic Tumors Ipsilateral tumor extension within two body compartments Neck Neck-chest, chest-abdomen, abdomen-pelvis Tumor encasing carotid and/or vertebral artery and/or internal jugular vein Tumor extending to base of skull Tumor compressing the trachea Cervico-thoracic junction Thorax Tumor encasing brachial plexus roots Tumor encasing subclavian vessels and/or vertebral and/or carotid artery Tumor compressing the trachea Tumor encasing the aorta and/or major branches Tumor compressing the trachea and/or principal bronchi Lower mediastinal tumor, infiltrating the costo-vertebral junction between T9 and T12 Thoraco-abdominal Tumor encasing the aorta and/or vena cava Abdomen/pelvis Tumor infiltrating the porta hepatis and/or the hepatoduodenal ligament Tumor encasing branches of the superior mesenteric artery at the mesenteric root Tumor encasing the origin of the coeliac axis, and/or of the superior mesenteric artery Tumor invading one or both renal pedicles Tumor encasing the aorta and/or vena cava Tumor encasing the iliac vessels Pelvic tumor crossing the sciatic notch Intraspinal tumor extension whatever the location provided that: More than one third of the spinal canal in the axial plane is invaded and/or the perimedullary leptomeningeal spaces are not visible and/or the spinal cord signal is abnormal Infiltration of adjacent organs/structures Pericardium, diaphragm, kidney, liver, duodeno-pancreatic block, and mesentery Conditions to be recorded, but not considered IDRFs Multifocal primary tumors

24 Common Childhood Tumors 24 Pleural effusion, with or without malignant cells Ascites, with or without malignant cells The diagnosis of neuroblastoma is based on the clinical signs and symptoms discussed previously. To assess for metastases, a bone scan and a plain chest radiograph are obtained. The child s urine is sent for HVA and VMA. The primary tumor is usually assessed with CT scan which helps determine the extent of disease, invasion into surrounding structures, and lymph node involvement. In children with a primary abdominal tumor, involvement of the liver with tumor can also be assessed. For patients who present with neurologic symptoms, MRI can be helpful to define involvement of the spinal canal or cord. MIBG scan is a compound resembling norepinephrine that binds to norepinephrine sites and is stored in neural crest cells. When this substance is labeled with 123 I or 131 I it can define the tumor or identify metastases even in those few patients with normal catecholamine levels [14]. Some neuroblastomas are easily recognized when looked at by doctors experienced in testing children s tumor samples. But some cases may be hard to tell apart from other types of children s cancers. In these situations, special tests such as immunohistochemistry must be done. For this test, a portion of the sample is treated with special proteins (antibodies) that attach to substances in neuroblastoma cells but not in other cancers. Chemicals (stains) are then added so that cells containing these substances change color and can be easily seen under a microscope. This lets the pathologist know that the tumor is a neuroblastoma. Bone marrow aspiration and biopsy Neuroblastoma often spreads to the bone marrow. If blood or urine levels of catecholamines are increased, then finding cancer cells in a bone marrow sample is enough to diagnose neuroblastoma (without getting a biopsy of the main tumor). If neuroblastoma has already been diagnosed by a biopsy done elsewhere in the body, bone marrow testing is done to help determine the extent of the disease [11]. A bone marrow aspiration and biopsy are usually done at the same time. In most cases the samples are taken from the back of both of the pelvic (hip) bones. The diagnosis of neuroblastoma is confirmed by: 1. Biopsy with unequivocal diagnosis of neuroblastoma by light microscopy, or 2. Bone marrow biopsy or aspirate with unequivocal tumor cells and increased serum or urine catecholamines. The approach to treatment of neuroblastoma depends on the stage of the cancer, the child's age, and other factors such as the prognostic markers mentioned previously. The types of treatment used may include [11, 38]: Surgery Chemotherapy Retinoid therapy (retinoids are chemicals that are related to vitamin A; retinoids such as 13- cis-retinoic acid (isotretinoin) have reduced the risk of recurrence after treatment in children with high-risk neuroblastoma) Radiation therapy High-dose chemotherapy/radiation therapy and stem cell transplant Immunotherapy (monoclonal antibodies are man-made versions of immune system proteins that can be made to attack a very specific target)

25 Common Childhood Tumors 25 In many cases, more than one type of treatment is needed. for neuroblastoma is largely based on which risk group a child falls into [11]: v Low risk Children at low risk can often have surgery as their only treatment. Even in cases where some neuroblastoma is left behind after surgery, the child can usually be watched carefully without further treatment because the remaining tumor will often mature or go away on its own. Chemotherapy is typically given after surgery if much of the tumor can t be removed or if it has some unfavorable features. A common chemotherapy regimen is a combination of carboplatin, cyclophosphamide, doxorubicin, and etoposide. But other combinations may be used. Infants with stage 4S disease and no symptoms can often be watched carefully with no treatment, because these cancers typically mature or go away on their own [11]. If the tumor causes problems such as an enlarged liver, which can be life-threatening for very young infants, chemotherapy that is less intense may be used to shrink the tumor. Radiation therapy may be used if chemo does not shrink the liver right away. v Intermediate risk Surgery is an important part of treatment for children at intermediate risk, but it is rarely enough on its own. Children are typically given 4 to 8 cycles (about 12 to 24 weeks) of chemotherapy before or after surgery. The chemotherapy drugs used are usually the same as for low-risk disease, although the doses may be higher. Radiation therapy may be used if chemotherapy is not effective. If chemotherapy is used after surgery, a second look surgery may be done to see if there is any cancer remaining and, if there is, remove it if possible. This may be followed by radiation therapy, if needed. v High risk Children at high risk require more aggressive treatment, which often includes chemotherapy, surgery, and radiation. is often divided into 3 phases. Induction: The goal of this phase is to get the cancer into remission by destroying or removing as much of it as possible. usually starts with chemotherapy, using more drugs and at higher doses than what is used in other risk groups. Surgery may be done after this to try to remove any tumors that are still visible. Consolidation: This phase uses more intensive treatment to try to get rid of any cancer cells that remain in the body. High-dose chemotherapy is given (often along with radiation therapy), followed by a stem cell transplant. Maintenance: This phase of treatment is given to try to lower the chance that the cancer will come back. The retinoid drug 13-cis-retinoic acid (isotretinoin) is often given for 6 months after other treatments are completed. Immunotherapy with the monoclonal antibody ch14.18, along with immuneactivating cytokines (GM-CSF and IL-2), is often given as well. v Recurrent neuroblastoma If neuroblastoma comes back after initial treatment, it is known as a recurrence or relapse. at this point will depend on many factors, including the initial risk group, where the cancer recurs, and what treatments have been used. For low- and intermediate-risk neuroblastomas that recur in the same area where they started, surgery with or without chemotherapy may be effective. For higher-risk cancers or those that recur in distant parts of the body, treatment is usually more intense, and may include a combination of chemotherapy, surgery, and radiation therapy (such as MIBG radiotherapy). Chemotherapy might include drugs that weren't used during the initial treatment. In some relapsed cases, intensive treatment with high-dose chemotherapy/radiation therapy followed by a stem cell transplant may be used. Because these cancers can be hard to treat, clinical trials of experimental treatments, such as monoclonal antibodies or new anti-cancer drugs, may be another reasonable option. Outcomes When considered alone, the two most important clinical variables for predicting outcome in neuroblastoma patients are the disease stage and the patient age at diagnosis. Disease free survival of all patients with stages 1, 2, or 4S is 75-90%. Infants less than one year of age with stage 3 and 4 have cure rates of 80-90% and 60-75%, respectively. Those children older than one year of age with stage 3 and 4 disease have 3-year survivals of 50% and 15%, respectively [14, 26, 43].

26 Common Childhood Tumors 26 TERATOMAS The word teratoma comes from classical Greek and means roughly "monstrous tumor". A teratoma is an encapsulated tumor with tissue or organ components resembling normal derivatives of all three germ layers. There are rare occasions when not all three germ layers are identifiable. NB: Teratomas have been reported to contain hair, teeth, bone and very rarely more complex organs such as eye, torso, and hands, feet, or other limbs. Sometimes, the teratoma has within its capsule one or more fluid-filled cysts and when a large cyst occurs there is a potential for the teratoma to produce a structure within the cyst that resembles a fetus. Because they are encapsulated, teratomas are usually benign, although several forms of malignant teratoma are known and some of these are common forms of teratoma. A mature teratoma is typically benign and found more commonly in females, while an immature teratoma is typically malignant and is more often found in males [43]. Teratomas are thought to be present at birth (congenital), but small ones often are not discovered until much later in life. Pathophysiology Teratomas belong to a class of tumors known as non-seminomatous germ cell tumor (NSGCT). The term "malignant teratoma" has sometimes been used as a synonym for NSGCT. All tumors of this class are the result of abnormal development of pluripotent (totipotential) cells: germ cells and embryonal cells Teratomas of embryonal origin are congenital; teratomas of germ cell origin may or may not be congenital (this is not known). Primordial germ cells appear during the third week of gestation in the wall of the yolk sac near the allantois. They move along the dorsal mesentery of the hindgut, reaching the genital ridges by about the sixth week of gestation. Germ cells that do not complete this journey can develop into teratomas. While the totipotential nature of germ cells and their path of migration explain the location and pathology of the more common teratomas (sacroccygeal and gonadal), intracranial and mediastinal locations are more difficult to explain. Localization The kind of pluripotent cell appears to be unimportant, apart from constraining the location of the teratoma in the body. NB: Whereas in adults 90% of germ cell tumors are at gonadal locations, in childhood, the extragonadal site is more common until puberty, at which time the gonadal sites are more common [14, 26]. Teratomas derived from embryonal cells usually occur on the body midline: in the brain, elsewhere inside the skull, in the nose, in the tongue, under the tongue, and in the neck (cervical teratoma), mediastinum, retroperitoneum, and attached to the coccyx. However, teratomas may also occur elsewhere: very rarely in solid organs (most notably the heart and liver) and hollow organs (such as the stomach and bladder), and more commonly on the skull sutures. Embryonal teratomas most commonly occur in the sacrococcygeal region: sacrococcygeal teratoma is the single most common tumor found in newborn babies. Of teratomas on the skull sutures, approximately 50% are found in or adjacent to the orbit [43]. Incidence Teratomas are interesting but uncommon lesions, probably occurring in 1 in 20,000-40,000 live births. The exact incidence is difficult to ascertain [43]. The anatomic distribution of these lesions varies between reporting institutions, but the sacrococcygeal lesion appears to be most common. Sacrococcygeal teratomas account for the majority of cases (45-65%). The next most common locations are: gonadal (10-35%), mediastinal (10-12%), retroperitoneal (3-5%), cervical (3-6%), presacral

27 Common Childhood Tumors 27 (3-5%), and central nervous system (2-4%) [14]. Approximately 20% of pediatric germ cell tumors are malignant, and they represent 1% to 3% of all malignant tumors in childhood and adolescence [26, 43]. Sacrococcygeal Teratoma Tumors of the sacrococcygeal region, referred to as sacrococcygeal teratomas (SCTs) in most reports, generally present in two distinct fashions: neonates with large predominantly external lesions, which are detected in utero or at birth and are rarely malignant; older infants and children who present with primarily hidden pelvic tumors with a much higher rate of malignancy. SCTs are the most common extragonadal tumor in neonates, accounting for up to 70% of all teratomas in childhood. Interestingly, 75% occur in females [10, 14, 43]. Associated anomalies occur in 10-15% of cases and include imperforate anus, anorectal stenosis, anorectal agenesis, sacral hemivertebra, absence of the sacrum and coccyx, and anterior meningocele [14]. Currarinos triad is the association of a pre-sacral mass with anorectal stenosis and a sacral deformity. Classification SCT are classified based on the location of the lesion (Image 9.19). Type I lesions are external with a small presacral component (45% of reported cases). Type II lesions have an external and a significant presacral component (34%). Type III lesions have a small external component with the majority of the tumor being retroperitoneal (9%). Type IV lesions have no external component, being entirely presacral (10%) [43]. Image 9.19 Classification of sacrococcygeal teratomas based on Altman's study [43]. On examination, the visible portion of the lesion is skin covered and posterior to the anus (Image 9.20). In some patients all or part of the lesion may be in the retrorectal space and/or the retroperitoneum. In these cases, patients will present with rectal pain, constipation, and/or a mass.

28 Common Childhood Tumors 28 Image 9.20 Sacrococcygeal teratoma. The diagnosis of SCT is usually made by physical examination. In neonates presenting with large external masses, the degree of pelvic and abdominal involvement should be assessed preoperatively with ultrasonography, CT, or magnetic resonance imaging (MRI), and these studies may also offer a clue as to the characteristics of the vascular supply. A chest x-ray is obtained to rule out metastatic disease. Ultrasonography is useful to determine the nature of the lesion (solid vs. cystic), and the presence of liver involvement [14]. Alpha-fetoprotein (AFP) and beta human chorionic gonadotropin (beta-hcg) are serum tumor markers associated with teratomas and should be obtained preoperatively and followed postoperatively [43, 45]. Differential diagnosis The differential diagnosis is quite long and includes lipoma, myelocystocele, pilonidal cysts, sacral dimple, diastematomyelia, meningocele, epidermal sinus, sacral agenesis, fetus in fetu, parasitic twin, hamartoma, hemangioma, neuroblastoma, chordoma, rectal duplication, and sarcoma [10, 14, 43]. SCTs should be completely excised. Surgery (which has been undertaken in utero as fetal surgery) is the cornerstone of successful therapy and cure rates exceed 95% [10, 14, 45]. If the lesion is benign (97%), no further therapy is indicated. These children should be evaluated every 3 months for the first 2 years with emphasis on rectal examination and AFP levels. If the lesion is malignant, adjuvant chemotherapy with cisplatin, bleomycin and vinblastine is indicated [14, 43]. Ovarian Teratoma Ovarian tumors are one of the more common germ cell tumors in female children and adolescents. Of all ovarian masses, most (80%) are benign (epithelial cysts, teratomas, immature teratomas) often with predominantly cystic components [11, 43]. Ovarian and sacrococcygeal teratomas occur with near equal frequency in infants. In older children, however, ovarian teratomas are more common. Since 50% of ovarian tumors are teratomas and >90% of these are benign [14]. Children's Oncology Group ovarian staging system Stage I: Limited to ovary (ovaries) peritoneal washings negative; Stage II: Microscopic residual; peritoneal washings negative for malignant cells, tumor markers positive or negative. Stage III: Lymph node involvement; gross residual or biopsy only; contiguous visceral involvement (omentum, intestine, bladder); peritoneal washings positive for malignant cells; tumor markers positive or negative. Stage IV: Distant metastases, including liver. Abdominal pain, mass and vomiting are the most common presenting complaints. With the child supine, the mass is often visible and movable. If torsion (1-3%) has occurred, the abdomen may be

29 Common Childhood Tumors 29 tender with 1-3% of the torsion group spontaneously rupturing [14]. Ultrasonography and CT can determine the organ of origin, assess the contralateral ovary, and determine whether the lesion is solid or cystic. Abdominal x-rays may show displacement of the normal gas pattern and/or calcifications within the tumor. Serum AFP and beta-hcg levels should be measured. The differential diagnosis includes pregnancy, ovarian torsion, omental or mesenteric cyst, lymphangioma and lymphoma. The tumor should be removed. In addition, the peritoneum and contralateral ovary should be evaluated to rule out metastasis and bilateral lesions, respectively. The treatment algorithm for malignant ovarian tumors is surgery and observation for stage I and surgery and chemotherapy for higher-stage tumors. Many adolescents present with primarily cystic lesions and most of these are benign. Laparoscopy has been widely utilized in the management of ovarian lesions in childhood, adolescents, and adults. The main controversy surrounds the ability to perform a cancer type procedure in cases where the exact tumor histology (benign vs. malignant) cannot be determined preoperatively. If the lesion is primarily solid or if the serum markers are elevated, an open procedure is indicated. If the serum markers are normal and the lesion is primarily cystic, particularly if there is a very large cystic component, a less invasive technique may be considered; however, avoidance of tumor spill must be assured. Testicular Teratomas Testicular germ cell tumors in children are one of the rarer germ cell tumor types, with an incidence of 0.5 to 2.0 per 100,000 [43]. The bimodal age distribution of testes tumors, with a small peak in the first 3 years of life and a much larger peak in young adults, suggests a difference in the tumors of these age groups. The malignant germ cell tumors in the younger group are predominantly yolk sac tumors, whereas most adolescent and adult testes tumors are seminomas and mixed tumors. Testicular tumors are rare in boys prior to puberty, and during this time non-germ cell Sertoli tumors and paratesticular rhabdomyosarcomas are more common, whereas germ cell tumors predominate in pubertal and adult males. Paratesticular neuroblastoma has also been reported arising from an embryonic adrenal rest along the spermatic cord. They usually present as a painless testicular mass. Ultrasound may show calcifications. Serum AFP and beta-hcg should be drawn preoperatively. Current Children's Oncology Group staging system for childhood testes cancer: I. Limited to testis (testes), completely resected by high inguinal orchiectomy; no clinical, radiographic or histologic evidence of disease beyond the testes. II. Transscrotal biopsy; microscopic disease in scrotum or high in spermatic cord (<5 cm from proximal end). Tumor markers fail to normalize or decrease with an appropriate half-life. III. Retroperitoneal lymph node involvement, but no visceral or extraabdominal involvement. Lymph nodes > 4 cm by CT; or > 2 cm and < 4 cm with biopsy proof. IV. Distant metastases, including liver. A preoperative elevation of AFP indicates the presence of yolk sac tumor and thus precludes consideration of testes-sparing surgery, and a radical orchiectomy is performed with ligation of the cord at the internal ring (the standard approach consists of an inguinal incision) [14, 43]. If the AFP is normal, there is a much greater chance that the mass represents a benign lesion. A retroperitoneal lymph node dissection is not indicated. Patients with malignant teratomas should receive chemotherapy. Retroperitoneal Teratomas Retroperitoneal teratomas occur with equal frequency between the genders.

30 Common Childhood Tumors 30 Children usually present with gastrointestinal symptoms or abdominal mass. In addition to chest x-ray, abdominal plain films, and ultrasound, a CT scan may be useful to determine the relationship of the tumor to other retroperitoneal structures and distinguish it from a primary renal or adrenal tumor. The differential diagnosis includes those listed for ovarian teratomas as well as Wilms tumor, neuroblastoma, and sarcoma. Retroperitoneal teratomas should be removed. The vast majorities are benign and require no further treatment [14, 26]. Patients with malignant lesions and those with high-grade immature elements should be treated with cisplatin-based chemotherapy. Mediastinal Teratomas Mediastinal teratomas may arise in the mediastinum, the pericardium, or the heart. The latter two are mentioned only for completeness. Mediastinal teratomas occur with equal frequency between the genders. They usually present with respiratory symptoms or chest pain. A small portion of boys with mediastinal teratomas may present with precocious puberty as a result of a beta-hcg secreting tumor [14, 43]. The differential diagnosis includes thymoma, parathyroid adenoma, bronchogenic cysts, cystic hygroma, duplications, aneurysms, lymphoma, lipoma, myxoma, and thyroid goiter. Chest radiograph and CT scan are necessary to confirm the presence of a mass and define its relationship with other intrathoracic structures. AFT and beta-hcg levels should be drawn preoperatively and followed in the postoperative period. Boys with beta-hcg secreting mediastinal teratomas should have chromosomal analysis as there is an association between these lesions and Klinefelter s syndrome [14]. The treatment is surgical resection. Children with malignant lesions and those with tumors containing high-grade immature elements also receive cisplatin-based chemotherapy. Head and Neck Teratomas Intracranial Teratomas Intracranial teratomas have a bimodal distribution occurring in infants < 2 months and children years. They usually originate from the pineal gland and increase the intracranial pressure [14]. In the newborn this is manifest as obstructive hydrocephalus and in the child as headaches, visual changes, seizures, and vomiting. On CT or MRI, teratomas are typically calcified, supratentorial, midline lesions. In newborns, most of these lesions are benign. In older children, the majority are malignant. Complete resection, although rarely possible, is the only chance for long-term survival. Partial resection will provide palliation of symptoms in some cases. Other Head and Neck Teratomas Teratomas involving the neck or areodigestive tract are rare, gender nonspecific lesions. They can obstruct the

31 Common Childhood Tumors 31 oropharynx leading to polyhydramnios and pulmonary hypoplasia in the fetus and respiratory distress in the newborn. They may involve the neck (thyroid teratoma), the oropharynx, or the nasopharynx. The differential diagnosis includes cystic hygroma, lymphangioma, branchial cleft cyst, goiter, and neuroblastoma. Plain films show calcifications, while CT and/or MRI demonstrate the extent of the lesion. The majorities are benign and complete resection is the treatment of choice. Image 9.21 Neck teratoma. Dermoid cyst A dermoid cyst is a mature cystic teratoma containing hair (sometimes very abundant) and other structures characteristic of normal skin and other tissues derived from the ectoderm. A dermoid cyst can occur wherever a teratoma can occur, since they are categorically classified as such. The term is most often applied to teratoma on the skull sutures and in the ovaries of females. Because it grows slowly and contains mature tissue, a dermoid cyst is almost always benign. The rare malignant dermoid cyst usually develops squamous cell carcinoma in adults; in infants and children it usually develops an endodermal sinus tumor. for dermoid cyst is complete surgical removal, preferably in one piece and without any spillage of cyst contents. LYMPHOMA Lymphoma is a type of blood cancer that occurs when B or T lymphocytes divide faster than normal cells or live longer than they are supposed to. Lymphoma may develop in the lymph nodes, spleen, bone marrow, blood or other organs and eventually they form a tumor. Typically, lymphoma presents as a solid tumor of lymphoid cells. These malignant cells often originate in lymph nodes, presenting as an enlargement of the node (a tumor). It can also affect other organs in which case it is referred to as extranodal lymphoma. Extranodal sites include the skin, brain, bowels and bone. NB: Lymphomas are closely related to lymphoid leukemias, which also originate in lymphocytes but typically involve only circulating blood and the bone marrow and do not usually form static tumors. There are many types of lymphomas, and in turn, lymphomas are a part of the broad group of diseases called hematological neoplasms. Lymphomas are the third most common pediatric malignancy [11, 14, 45]. Lymphomas account for 11% of all cancers diagnosed in children and more than twice as many cases are diagnosed in boys as in girls. Lymphomas are rare before the age of two and incidence increases with age thereafter such that lymphomas account for nearly a fifth (19%) of all childhood cancers diagnosed in year-olds. Because the whole system is part of the body's immune system, patients with a weakened immune system such as from HIV infection or from certain drugs or medication also have a higher incidence of lymphoma. Lymphoma is the most common form of hematological malignancy, or "blood cancer", in the developed world. Classification Several classification systems have existed for lymphoma. These systems use histological findings and other findings to divide lymphoma into different categories. Lymphomas are divided into two broad categories, depending on the appearance of their cancerous

32 Common Childhood Tumors 32 Lymphomas are divided into two broad categories, depending on the appearance of their cancerous (malignant) cells. These are known as Hodgkin's lymphoma (HL) and non-hodgkin lymphoma (NHL). Together, they are the third most common type of cancer in children. Classification systems generally classify lymphoma according to: Whether or not it is a Hodgkin lymphoma. Whether the cell that is replicating is a T-cell or B-cell. The site that the cell arises from. WHO classification The current accepted definition is the WHO classification, updated in 2008, is the latest classification of lymphoma and is based upon the foundations laid within the "Revised European-American Lymphoma classification" (REAL). This system attempts to group lymphomas by cell type (i.e. the normal cell type that most resembles the tumor) and defining phenotypic, molecular or cytogenetic characteristics. There are three large groups: the B-cell, T-cell, and natural killer cell tumors. Subtypes according to the WHO classification: Mature B-cell neoplasms Mature T-cell and natural killer (NK) cell neoplasms Hodgkin Lymphoma Immunodeficiency-associated lymphoproliferative disorders Signs and symptoms Lymphoma presents with certain non-specific symptoms. If symptoms are persistent, lymphoma needs to be excluded medically. Lymphadenopathy or swelling of lymph nodes It is the primary presentation in lymphoma. Systemic symptoms (B symptoms) can be associated with both HL and NHL. They consist of: - Fever - Night sweats - Weight loss Other Symptoms : - Loss of appetite or anorexia - Fatigue - Respiratory distress or dyspnoea - Itching Lymphoma is definitively diagnosed by a lymph node biopsy, meaning a partial or total excision of a lymph node that is then examined under the microscope [11, 14, 28]. This examination reveals histopathological features that may indicate lymphoma. After lymphoma is diagnosed, a variety of tests may be carried out to look for specific features characteristic of different types of lymphoma. These include: Immunophenotyping (this is a technique used to study the protein expressed by cells) Flow cytometry (this is a laser-based, biophysical technology employed in cell counting, cell sorting, biomarker detection and protein engineering, by suspending cells in a stream of fluid and passing them by an electronic detection apparatus) FISH testing (Fluorescent in situ hybridization (FISH) is a cytogenetic technique that is used to detect and localize the presence or absence of specific DNA sequences on chromosomes. FISH uses fluorescent probes that bind to only those parts of the chromosome with which they show a high degree of sequence complementarity). Hodgkin's Lymphoma (or Hodgkin's disease) HL is a malignant disease of the lymphatic system characterized by the presence of Reed-Sternberg cells in the lymphomatous tissue (Image 9.22) [26, 43, 45]. The Reed-Sternberg cell is a large cell which is either multinucleated or has a multilobulated nucleus. In most cases it arises from B-cells of the germinal center. Unlike many other cancers, the adult and pediatric forms have similar biology and natural history. Pediatric HL accounts for 12% of all HL cases [43].

33 Common Childhood Tumors 33 HL accounts for 6% of all pediatric malignancies, with an incidence of about 6 cases per 1 million, with a bimodal distribution with peaks in adolescence (15 to 19 years) and after age 55 years. HL is exceedingly rare in children less than 5 years of age [11, 26, 43]. In younger children it is more common in boys, but during adolescence the sex ratio is equalized. Image 9.22 Hodgkin Lymphoma: Nodular Sclerosis. Classic Reed- Sternberg cell is 20 to 50 microns in size, with acidophilic or amphophilic cytoplasm, large bilobed or multilobed nucleus with vesicular or coarse chromatin. A large, round, eosinophilic central nucleolus is always present. History HL is named after Thomas Hodgkin, a British pathologist, who in 1832 described the disease. 150 years later, with the advent of microscopic histology, Sternberg (1898) and Reed (1902) described the distinctive multinucleated giant cell with the prominent nucleoli that are characteristic of Hodgkin s disease. Etiology The exact etiology of HL is unknown; however, an infectious cause has been suggested. It is likely associated with the Epstein-Barr virus (EBV). This concept is supported by the presence of EBV in serologic studies and biopsy material from Hodgkin's lymphoma patients. Immune system dysfunction is hypothesized to be one of the primary causes for HL. Classification The current WHO classification system separates HL into two broad categories: v Classical v Lymphocyte predominant Classical HL has four subtypes: lymphocyte depleted, nodular sclerosing, mixed cellularity, and classical lymphocyte rich. Classical HL accounts for 90% of all cases. For children, nodular sclerosis is the most common subtype, accounting for 65% of cases. Staging Staging has both clinical and pathologic features. The Ann Arbor staging system and its Cotswolds modification remain the standard for adult and pediatric HL (Table 9.5). Clinical staging is dependent on: (1) involvement of single or multiple lymph node regions, (2)

34 Common Childhood Tumors 34 involvement of single or multiple extra-lymphatic organs, and (3) presence of disease on one or both sides of the diaphragm [43]. Table 9.5 Hodgkin Lymphoma Staging: Ann Arbor Classification with Cotswolds Modification Stage I Involvement of a single lymph node region or lymphoid structure (e.g., spleen, thymus, Waldeyer ring) or involvement of a single extralymphatic site Stage II Involvement of two or more lymph node regions on the same side of the diaphragm Stage III Indicates that the cancer has spread to both sides of the diaphragm, including one organ or area near the lymph nodes or the spleen With or without involvement of splenic, hilar, celiac, or portal nodes; with involvement of paraaortic, iliac, and mesenteric nodes Stage IV Indicates that the cancer has spread to both sides of the diaphragm, including one organ or area near the lymph nodes or the spleen Clinical presentation HL must be considered in any child with lymphadenopathy. Involved nodes are described as firm, nodular, and painless (Image 9.23). Children and adolescents most frequently present with cervical and or supraclavicular lymphadenopathy (80%). Patients presenting primarily with enlarged axillary nodes (25% of all cases) or inguinal nodes (5%) are far less common. Associated mediastinal disease is found in up to 75% of adolescents and 33% of children [14, 43]. The presence of facial swelling or distended cervical veins alerts the physician to mediastinal disease and the possibility of airway obstruction. Axillary and inguinal lymph nodes can be involved, but primary axillary or inguinal tumors are uncommon.

35 Common Childhood Tumors 35 Image 9.23 Hodgkin's lymphoma. The most common childhood presentation of HL is painless cervical or supraclavicular adenopathy. Systemic symptoms (B symptoms) occur in approximately one-third of children at the time of diagnosis and indicate advanced disease. Systemic symptoms include: recent (<6 months) loss of greater than 10% body weight, drenching night sweats, fever exceeding 38 C. These symptoms are not specific to HL and can occur in non-hodgkin lymphoma. The presence or absence of B symptoms, which occur in up to a third of children, has prognostic significance and is reflected in the staging of HL. Splenomegaly and/or hepatomegaly indicate more advanced disease. Depending on the primary site of the disease and its extent, patients may present with airway obstruction, pleural or pericardial effusion, hepatocellular dysfunction, anemia, neutropenia, thrombocytopenia and/or nephrotic syndrome. Respiratory distress due to mediastinal lymph node enlargement is much less common in children with HL than in children with NHL but it should always be considered prior to general anesthesia and biopsy [14, 43]. At present there is no specific laboratory test for HL. An excisional biopsy of a suspicious lymph node should be the initial step to diagnosis. depends on histologic evaluation and identification of Reed-Sternberg cells, hence biopsy is mandatory. An adequate amount of tissue should be excised for analysis and, if possible, several lymph nodes should be evaluated histologically. In the absence of palpable peripheral lymph nodes in a child with mediastinal disease, mediastinoscopy or thoracoscopy/thoracotomy are necessary to obtain tissue for diagnosis. Differential The differential diagnosis includes systemic infections, infectious lymphadenopathy, NHL, Langerhan's histiocytosis, mononucleosis and other causes of generalized or localized lymphadenopathy. Any child with unexplained lymphadenopathy should receive a careful history and physical examination and a chest radiograph to rule out the presence of a mediastinal mass prior to lymph node biopsy. The role of surgery in the initial diagnosis and staging for HL has been reduced [14, 26, 43]. With the wide application of chemotherapy in all stages of HL, surgical staging has become irrelevant, because the additional information it provides does not alter treatment. The surgeon's primary role is to obtain tissue for diagnosis. Biopsies should be taken from the most easily accessible site, and adequate tissue must be obtained and sent fresh to pathology for immunohistochemistry, immunopheno-typing, cytogenetics, and flow cytometry. Fine-needle aspiration is generally discouraged, because it is inaccurate and inadequate tissue is obtained to properly stage

36 Common Childhood Tumors 36 and classify the patient. for HL is based largely on the stage of the disease. But other factors, including a person s age and general health, and the type and location of the disease, may also affect treatment options. Several types of treatment can be used for Hodgkin disease [11]: Chemotherapy Radiation therapy Monoclonal antibodies High-dose chemotherapy and stem cell transplant The 2 main methods of treating HL are chemotherapy and radiation therapy. Depending on the situation, one or both of these treatments might be used. Monoclonal antibodies and high-dose chemotherapy with stem cell transplants may be used for certain patients, especially if other treatments haven t worked. Except for biopsy and staging, surgery is rarely used to treat Hodgkin disease. Outcomes Newer protocols obtain close to 95% overall five-year survival in children [11, 43]. The youngest patients have the best prognosis. Histologically, the lymphocyte depleted subtype has the worst prognosis, but it is very unusual in children. The lymphocyte predominant subtype has the best prognosis. Non-Hodgkin's Lymphoma Non-Hodgkin lymphomas (NHLs) comprise a heterogeneous group of tumors that has a constantly evolving classification system. The current WHO pathologic classification identifies almost 60 unique subtypes based on morphologic, immunophenotypic, and genetic differences, as well as clinical behaviour [28]. NHL can be broadly divided based on the cell of origin (B-cell or T-cell) or on clinical behavior (indolent, aggressive, or highly aggressive) [28, 43]. There are distinct differences between adult and pediatric NHL, with a strong bias toward precursor B- lymphoblastic and T-lymphoblastic lymphoma, anaplastic large cell lymphoma, and Burkitt lymphoma in childhood [28, 43]. Incidence NHL is less common than HL and accounts for less than 5% of pediatric malignancies. NHL is more common in males. The male to female ratio of involvement is 3:1 [11, 14, 43]. Children at any age can get NHL, but kids ages 7 to 11 are affected most often. NHL is rare at less than 5 years of age, with an incidence of 2.8 per million cases but increases dramatically after age 20 [26]. The African endemic form often appears at the orbit or in the jaw (>70%) while the sporadic form almost always presents as abdominal disease. The endemic form has a peak incidence at around 7 years of age and the sporadic form affects children from a broader age distribution. Etiology The etiology of NHL is unknown. DNA and RNA viruses are thought to play an important role in the pathogenesis of NHL. The link between Epstein-Barr virus (EBV) and endemic forms of Burkitt's lymphoma observed in Africa and New Guinea is well known. EBV deoxyribonucleic acid (DNA) and nuclear antigens have been identified in 95% of African Burkitt's lymphoma tumor cells [14]. Classification In children with NHL, more than 90% of tumors belong to three histological subtypes: v Lymphoblastic lymphoma; v Small non-cleaved cell lymphoma (including Burkitt's and non-burkitt's lymphomas); v Large cell lymphoma (histiocytic). Each of these categories is subdivided on the basis of histology and/or immunophenotype. Lymphoblastic lymphomas account for 30% of childhood NHL and are mainly tumors of thymocytes (i.e., T-cell) origin. They consist of lymphoblasts that are morphologically identical to T-lymphoblasts of

37 Common Childhood Tumors 37 acute leukemia. Small non-cleaved cell lymphomas (Burkitt's and non-burkitt's) account for 40-50% of childhood NHL. Small noncleaved cell lymphomas originate from B-cells. Large-cell lymphomas (LCL), formerly histiocytic lymphoma, account for 20-25% of childhood NHL. There are three subtypes based on reactivity to T- or B-cell antibodies: B-lineage, T-lineage, or indeterminate lineage. Staging Although several staging schemes exist, the most widely used staging system is the one used at the St. Jude's Children's Hospital (Table 9.6). Table 9.6 St. Jude's staging system Stage for childhood non-hodgkin's lymphoma Single tumor or nodal area outside the abdomen or I mediastinum Single tumor with regional node involvement Two or more tumors or nodal areas on one side of the II diaphragm Primary gastrointestinal tumor (resected) with or without regional node involvement Tumors or lymph node areas on both sides of the diaphragm III Any primary intrathoracic disease or extensive intraabdominal disease Any paraspinal or epidural tumors Any bone marrow or CNS involvement regardless of other IV sites of involvement Clinical Presentation In children, NHL occurs predominantly in the chest and abdomen. All NHL tumors grow rapidly and have a tendency for widespread systemic dissemination. All lymphatic tissue may be involved including that of lymph nodes, Peyer's patches, the thymus, Waldeyer's ring, pelvic organs, liver and spleen. Extralymphoid involvement can be seen in the skin, testis, bone and central nervous system (CNS). Nearly 75% of children with lymphoblastic lymphoma present with a large, bulky, anterior mediastinal mass which may compress the trachea or create superior vena caval obstruction. Most common presenting symptoms include dyspnea, wheezing, stridor, swelling of the head and neck and sometimes dysphagia. Pleural effusions (often bilateral) are frequently present; cytologic examination of the fluid can be diagnostic. Up to 80% of children will present with cervical or axillary lymphadenopathy. NB: Similar to HL, NHL must be considered in any child with lymphadenopathy. In patients with generalized lymphadenopathy and/or hepatosplenomegaly, bone marrow and CNS involvement should be suspected. Bone marrow involvement may cause diagnostic confusion in determining whether the child has NHL with bone marrow involvement or leukemia. Although somewhat arbitrary, patients with greater than 25% bone marrow blasts are considered to have leukemia and children with less than 25% bone marrow blasts are considered to have lymphoma. Small, noncleaved cell lymphomas most often (up to 90%) present in the abdomen as a fast growing tumor. Other sites of involvement include Waldeyer's ring, testis, nasal sinuses, bone, bone marrow, the CNS, peripheral lymph nodes and skin. More than half of abdominal cases involve the small bowel and probably originate in the Peyer's patches. The presenting symptoms are usually abdominal pain, anorexia, or tenderness. Rarely the presentation is intestinal obstruction caused by intussusception with the lymphoma as the lead point. Large-cell lymphoma usually occurs at extranodal sites and is frequently widely disseminated at the time of presentation. It seldom involves the gastrointestinal tract. Primary sites include the skin, testis, eye, tonsils, soft tissues and sometimes the mediastinum. The peak incidence of the large-cell lymphoma is at puberty. Patients may also present with B symptoms.

38 Common Childhood Tumors 38 The heterogeneity of this disease makes it essential to perform diagnostic biopsy to identify the histopathology. Immuno-phenotyping and cytogenic studies are essential to establish the diagnosis [11, 26, 28]. Since approximately 20% of these children have bone marrow involvement at the time of presentation, bone marrow biopsy and aspiration are required. Lumbar puncture is used to identify cerebrospinal involvement [14, 26]. Laboratory studies including complete blood cell count, liver function tests (LFTs) and serum levels of uric acid, electrolytes, lactate dehydrogenase, creatinine, calcium and phosphorus are required for appropriate staging and treatment. Radiographic imaging is the principal means of evaluating the extent of the primary tumor. The following tests and procedures may be used: - Blood tests. - Imaging tests. These may include a chest x-ray, MRI, CT scan, and PET scan. - Biopsy: One of the following types of biopsies may be done: * Excisional biopsy: The removal of an entire lymph node or lump of tissue. * Incisional biopsy: The removal of part of a lump, lymph node, or sample of tissue. * Core biopsy: The removal of tissue or part of a lymph node using a wide needle. * Fine-needle aspiration (FNA) biopsy: The removal of tissue or part of a lymph node using a thin needle. * Bone marrow aspiration and biopsy: The removal of bone marrow, blood, and a small piece of bone by inserting a hollow needle into the hipbone or breastbone (Image 9.24). - Lumbar puncture. - Thoracentesis. Image 9.24 Bone marrow aspiration and biopsy of NHL is based upon histology, immunophenotype and clinical stage [11, 26, 28]. Unlike HL, NHL in children is considered to be widely disseminated from the beginning, even when the disease appears localized. Combination chemotherapy is recommended for all patients [28, 43, 45]. Radiation therapy is sometimes added for children with: primary NHL of the bone, CNS involvement (sometimes emergency therapy), testicular involvement, or severe mass effect (i.e., superior vena caval compression or airway obstruction). Children with localized disease do not benefit from radiation therapy, which, in this setting, only increases toxicity. Initial surgical management includes incisional biopsy for diagnosis, followed by intense, multiagent chemotherapy, except for small, easily resectable lesions [28]. Complete surgical resection of well-localized tumors, particularly if confined to the bowel, may be beneficial to overall survival and reduces complications such as tumor lysis syndrome or bowel perforation following chemotherapy [26, 43].

39 Common Childhood Tumors 39 Outcomes Children with Stage I disease have a 90-95% long-term survival on multiple drug chemotherapy with or without radiation therapy. Stage II patients have a 75% survival rate. In advanced cases, a multiple drug program offers about 70% relapse-free survivals [14, 43]. A major complication of therapy is tumor lysis syndrome that results from rapid breakdown of malignant cells. Gastrointestinal problems of bleeding, obstruction and rare perforation are also part of this syndrome. MEDIASTINAL MASSES Mediastinal masses are varied and present at all ages, from newborn to adolescence (Table 9.7). Anatomy of mediastinum The mediastinum is the area in the chest between the lungs. It extends from the sternum in front to the vertebral column behind and may be divided for purposes of description into two parts: - a n upper portion, above the upper level of the pericardium, which is named the superior mediastinum (contains the thymus, lymphatics and vascular structures) with its superior limit at the superior thoracic aperture and its inferior limit at the plane from the sternal angle to the disc of T4-T5; - and a lower portion, below the upper level of the pericardium. This lower portion is subdivided into three parts: The anterior mediastinum is the space below the superior compartment, bounded by the pericardium and diaphragm. The middle mediastinum contains the pericardium, heart, origins of the great vessels, trachea, mainstem bronchi and lymphatics. The posterior mediastinum is bounded by the great vessels anteriorly and the vertebral bodies posteriorly. The normal structures in this space include the esophagus, sympathetic ganglia, thoracic duct, vessels and lymphatics Table 9.7 Mediastinal masses in the pediatric population [14] Mediastinum Pathology Incidence - Lymphomas Hodgkin s Lymphomas Non-Hodgkin s Lymphomas - Germ cell tumors Superior & Anterior Middle Posterior Teratoma Seminoma - Thymic lesions Hyperplasia Thymic cyst Thymoma - Cystic Hygroma Lymphomas Bronchogenic cyst Granuloma Pericardial cyst Hamartoma - Neurogenic Neuroblastoma Ganglioneuroblastoma Ganglioneuroma Neurofibroma - Enteric (Duplication) Cyst 54% 26% 20%

40 Common Childhood Tumors 40 As in adults, mediastinal masses in pediatric patients are placed in one of three mediastinal compartments (anterior, middle, posterior) on the basis of the lateral chest radiograph (Image 9.25). Anterior mediastinal compartment is area surrounded by sternum anteriorly and anterior margin of pericardium posteriorly. Middle mediastinal compartment is bordered by anterior margin of pericardium and imaginary line drawn approximately 1-cm posterior to anterior margin of thoracic vertebral bodies. Posterior mediastinal compartment is area surrounded anteriorly by imaginary line drawn 1-cm posterior to anterior border of thoracic vertebral bodies and posteriorly by paravertebral gutters. Pathology Approximately one half of the masses are malignant, and of neurogenic or lymphomatous origin. According to different reports, neurogenic tumors predominate before the age of 4 years, while lymphomas are most common beyond age 4 and germ cell tumors are seen in adolescence [14]. The mediastinal masses can also be categorized as developmental, neoplastic, or inflammatory. Developmental: Foregut duplication, bronchogenic and pericardial cysts, cystic or ectopic thymus. Neoplastic: The most common neoplasm of the anterior mediastinum in children is lymphoma, accounting for up to 45% of pediatric mediastinal masses. Other neoplasms in the anterior mediastinum include germ cell tumors (25%), mesenchymal tumors Image 9.25 Lateral chest X-ray (15%) and thymic tumors (17%). The majority of these tumors are malignant [14]. Neurogenic lesions (neuroblastoma, ganglioneuroblastoma, ganglioneuroma and schwanoma), which comprise approximately 20% of mediastinal tumors, are usually located in the posterior mediastinum [14, 43]. Inflammatory: Acute infection of the mediastinum is most often seen following esophageal perforation, as well as after cardiac operation or penetrating chest trauma. However, infection may be the first presentation in developmental conditions, such as thymic cyst, enteric and bronchogenic cysts and cystic hygroma. That is why elective resection is performed for these lesions when they are diagnosed [14, 45]. Clinical Presentation Many mediastinal masses are asymptomatic (50%). Because of the limited space and confined geometry of the region, masses can interfere with both the respiratory and cardiovascular systems, sometimes with grave results [14]. The most common symptoms are chest pain and weight loss. Lymphomas may manifest with fever and weight loss. Symptoms and signs also depend on location. Large anterior mediastinal masses may cause dyspnea when patients are lying supine. Lesions in the middle mediastinum may compress blood vessels or airways, causing the superior vena cava syndrome or airway obstruction. Lesions in the posterior mediastinum may encroach on the esophagus, causing dysphagia or odynophagia. o Chest X-ray o CT scan o MRI (depending on location) o Pulmonary function tests for anterior mediastinal mass o Appropriate tumor markers as indicated by clinical suspicion (AFP; β-hcg; urine for catecholamines and metanephrines) o Ultrasound or CT-guided percutaneous needle biopsy of solid mediastinal mass can be performed to establish tissue diagnosis. Tissue diagnosis may also be obtained from sites alternative to the tumor itself, such as lymph node or bone marrow [11, 14, 26].