CASE ANALYSIS

Wilms tumor is the most common abdominal cancer in childhood

and typically presents between ages 3 to 5 years 1,3-5. There are
approximately 650 new cases in the United States every year. Girls are
slightly more likely to have Wilms than boys.6
Wilms is more common in Africans and African Americans while
it is least common in East Asians.  Asian patients also had fewer
unfavorable histology tumors, tend to have lower-stage disease, and
enjoy better survival outcomes. Ninety percent of Wilms tumors are
diagnosed before six years of age with the median age of diagnosis
being 3.5 years.2
The age-specific incidence of WT peaks at 1 year of age in boys
at 17.9 per million person-years. However, in girls, a similar peak
remains almost constant at 1, 2 and 3 years of age, with the respective
incidences of 17.8, 18.0 and 18.1 per million person-years. 5 The age
distribution at diagnosis varies by region and ethnicity, with affected
individuals in East Asia being younger at diagnosis than those in the
rest of the world, and this observation may be mainly due to earlier
onset of the disease.5,7
Most children with Wilms tumor present with an abdominal mass
or swelling, without other signs or symptoms. 8 Other symptoms can
include abdominal pain (30 to 40 percent of patients), hematuria (12 to
25 percent), fever, and hypertension (25 percent). 8,9 A subset of
patients with subcapsular hemorrhage can present with rapid
abdominal enlargement, anemia, hypertension, and, sometimes,
fever.11 Although the lung is the most common metastatic site, children
rarely present with respiratory symptoms. 10 Physical examination
reveals a firm, nontender, smooth mass that is eccentrically located
and rarely crosses the midline. Once a Wilms’ tumor is suspected,
subsequent abdominal examinations should be performed carefully.
Vigorous palpation may rupture the renal capsule, resulting in tumor
spillage, which increases the tumor stage and the need for more
intensive therapy. As noted above, Wilms tumor may be associated
with congenital anomalies and syndromes. Thus, the examination
should include assessment for associated anomalies, such as aniridia,
hemihypertrophy, and genitourinary anomalies.
There are two subclassifications in Wilms’ tumor [25,26,27,28]:
(1) Classical nephroblastoma: Classical nephroblastoma includes
blastemal, epithelial, and stromal components. Sometimes one or two
components are predominant, and sometimes they are equally
apportioned. The latter type of tumor is classified as a mixed-type or
triphasic Wilms’ tumor.
(2) Anaplastic Wilms’ tumor: If the tumor cells contain multipolar
mitotic figures, hyperchromasia with enlarged cells, or nuclei that are
three times larger than in adjacent cells, it is classified as an anaplastic
Wilms’ tumor. This type of tumor constitutes 4–8% of all cases. It may
have a diffuse or focal form; this classification has prognostic
importance, as patients with focal anaplasia should be treated with less
intensive protocols than those with diffuse anaplasia. 13
Table x. Risk classification according to SIOP Renal Tumour Study
Group20

Tumour type For pretreated patients For patients undergoing

primary nephrectomy
Low-risk Congenital mesoblastic Congenital mesoblastic
tumours nephroma nephroma
Cystic partially Cystic partially
differentiated WT differentiated WT
Completely necrotic WT
Intermediate- WT epithelial type Non-anaplastic WT and its
risk tumours WT stromal type variants
WT mixed type WT focal anaplasia
WT regressive type
 WT focal anaplasia
High-risk WT blastemal type
tumours WT diffuse anaplasia
Clear cell sarcoma of the
kidney
Rhabdoid tumour of the
kidney
Renal cell carcinoma
WT diffuse anaplasia
Clear cell sarcoma of the
kidney
Rhabdoid tumour of the
kidney
Renal cell carcinoma

Previously, a tumor was classified as focal anaplasia if anaplastic

cells were encountered in fewer than 10% of microscopic fields. This
description was revised by Faria et al. 12 in 1996, as follows: In focal
anaplasia, anaplastic changes are confined to circumscribed regions
within the primary tumor and are surrounded by non-anaplastic tissue.
Diffuse anaplasia has the following characteristics: it is found in an
extrarenal site, the random biopsy specimen reveals unequivocal
anaplasia, the tumor is coupled with extreme nuclear unrest, and there
is nuclear atypia elsewhere in the tumor.
This classification of focal and diffuse anaplasia has been used
in the NWTS (from North America); the other large-scale collaborative
group, the SIOP (from Europe), stratifies risk groups according to
histopathologic structures. SIOP has analyzed risk for two groups:
those patients who have been pretreated and those receiving primary
nephrectomy. For pretreated patients, those in the low-risk group had
complete necrosis and cystic nephroblastoma; focal anaplasia and
other classic nephroblastoma except blastemal type characterized the
intermediate-risk group. The high-risk group had blastemal-type,
diffuse anaplasia and other variants of Wilms’ tumor, such as clear cell
sarcoma and rhabdoid tumor. Low-risk patients with primary
nephrectomy had the same characteristics as low-risk pretreated
patients. Intermediate-risk patients had all variants of classic Wilms’
tumor, including the blastemal type, as well as focal anaplasia. High-
risk group patients with primary nephrectomy had diffuse anaplasia,
rhabdoid tumor of the kidney, and clear cell sarcoma of the kidney.
Table 1 shows SIOP risk groups according to histopathology [30].

The definitive diagnosis of Wilms’ tumor is made by histologic

confirmation at the time of either surgical excision or biopsy. Children
who are suspected of having Wilms’ tumor should be referred to a
pediatric cancer center for evaluation and diagnosis. Abdominal
imaging is useful to differentiate Wilms tumor from other causes of
abdominal masses.14 The first goal of imaging is to establish the
presence of a renal tumor. Imaging studies also guide management
decisions prior to confirmation of a histologic diagnosis, such as
surgical approach and need for preoperative chemotherapy. Important
information includes confirming the presence and function of the
contralateral kidney as well as determining whether there is also tumor
in the contralateral kidney, the size and extent of the tumor, and the
presence of lung metastases. Abdominal ultrasonography is typically
the initial study performed for evaluation of abdominal mass.
Ultrasonography detects hydronephrosis and multicystic kidney
disease, which may present as abdominal masses or swelling. In
patients with a suspected renal tumor, Doppler ultrasonography can be
performed to detect tumor infiltration of the renal vein and inferior vena
cava and to assess patency of blood flow. Ultrasonography provides
information about the organ of origin, extension into the renal and
inferior cava veins or urinary collecting system, the contralateral kidney
and associated urogenital abnormalities, and may identify liver or
lymph node metastases. In resource-limited regions, ultrasonography
is sufficient for abdominal staging and can be complemented by chest
plain radiography, recognizing that plain radiography may miss smaller
pulmonary lesions (typically <1 cm).14,15
This information can also be clarified with computed tomography
(CT).16 Contrast-enhanced CT or magnetic resonance imaging (MRI) is
recommended to further evaluate the nature and extent of the mass,
including evidence of preoperative rupture or ascites. 16 CT or MRI also
may detect small lesions of tumor or nephrogenic rests in the opposite
kidney that were not detected by ultrasonography. The Children's
Oncology Group (COG) evaluated the diagnostic performance of CT
and MRI for local staging of pediatric renal tumors and found that they
have similar abilities to detect lymph node metastasis and capsular
penetration. MRI detected more contralateral synchronous lesions;
however, these were rare. The investigators concluded that either
modality can be used for initial locoregional staging of pediatric renal
tumors based on institutional expertise, need for anesthesia, risks of
radiation exposure, and cost concerns. At the authors' institution, we
typically use CT at the time of initial diagnosis; MRI or CT may be used
for follow-up imaging depending on the patient's specific
circumstances. In a separate study, the COG investigated the role of
preoperative CT scans in detecting tumor rupture and found that
ascites beyond the cul-de-sac was the best indicator of rupture;
however, the sensitivity of CT to detect tumor rupture was poor (54 to
70 percent).16 Preoperative imaging helps the surgeon determine
whether the tumor is operable at diagnosis. Patients with any of the
following findings or circumstances generally undergo an upfront
biopsy and receive prenephrectomy chemotherapy rather than initial
primary nephrectomy:17,18
- Tumor thrombus above the level of the hepatic veins
- Pulmonary compromise from massive tumor or extensive
pulmonary metastases
- Resection requiring removal of contiguous structures (other than
adrenal gland)
- Surgeon judges that attempting nephrectomy would result in
significant morbidity, tumor spill, or residual tumor
Imaging of the chest is needed to determine whether there are lung
metastases. It is noteworthy that COG and SIOP incorporate centrally
reviewed CT identification and response to therapy of lung nodules into
current risk stratification treatment algorithms.17,18 If there is a
suspicious nodule, a biopsy is performed at diagnosis or after six
weeks of therapy to determine whether it represents metastatic
disease. An alternate approach (used by the International Society of
Paediatric Oncology [SIOP]) is to perform the initial evaluation for
pulmonary metastases with chest radiography in two planes. A patient
with normal chest radiographs is considered to be free of metastatic
lung disease. CT is performed in cases of suspicious or positive chest
radiography. In addition, chest CT is used to assess the response of
the pulmonary nodules to chemotherapy. 17,18 Laboratory studies include
tests for renal function including urinalysis, liver function, serum
calcium, complete blood count, and coagulation studies. When
neuroblastoma is suspected, levels of the catecholamines homovanillic
acid (HVA) and vanillylmandelic acid (VMA) should be analyzed to
facilitate diagnosis.Neuroblastoma (NB) is the fourth most common
malignancy of childhood, preceded by leukemias, CNS tumors, and
lymphomas. NB is the most common intra-abdominal malignancy of
infancy and the most common extracranial solid tumor of childhood. In
about 90% of cases of NB, elevated levels of catecholamines or its
metabolites are found in the urine or blood which includes
Vanillylmandelic Acid (VMA). The parameters studied VMA showed
highest sensitivity (91%), specificity (94.4%) positive predictive value
(97.8%) and 85% negative predictive value at the cut off levels of 7mg/
ml of creatinine as compared to other studied parameters. 19
 The differential diagnosis of Wilms tumor includes neuroblastoma
and other renal tumors. Imaging studies and tissue histology
differentiate Wilms tumor from these other disorders. Neuroblastoma
can be differentiated from Wilms tumor by contrast-enhanced
computed tomography (CT), magnetic resonance imaging (MRI),
and/or ultrasonography, which distinguish renal and nonrenal tissue.
Final diagnostic confirmation is based upon tissue histology at the time
of either biopsy or surgical excision. In children, other renal cell tumors
are rare. They are differentiated from Wilms tumor by tissue histology:
- Clear cell sarcoma is the second most common pediatric renal
tumor. It has a less favorable prognosis than Wilms tumor, with
increased rate of relapse and mortality. Bone is a common
metastatic site, giving this tumor the alternate name of bone-
metastasizing renal tumor of childhood. 21 The histologic appearance
is generally distinctive, with cords and nests of pale-stained tumor
cells with abundant extracellular matrix separated by a network of
fine capillary arcades. However, in some cases, histologic variation
can make it difficult to distinguish this tumor from Wilms tumor. As a
result, clear cell sarcoma is the most frequently misdiagnosed
pediatric renal tumor.22
- Rhabdoid tumor of the kidney is a highly malignant renal tumor that
occurs most frequently in children less than two years of age and
almost never in those older than five years of age. At presentation,
the tumor is often metastatic and involving the lungs, abdomen,
lymph nodes, liver, bone, and brain. The prognosis is poor, with a
reported mortality rate of greater than 80 percent within the first
year of diagnosis.23
- Congenital mesoblastic nephroma is usually detected within the first
year of life or by prenatal ultrasonography and can be divided into
the classic and cellular subtypes. It has been associated with
hypertension and elevated concentrations of calcium and renin. 24
 - Renal cell carcinoma is rare in childhood. Children and adolescents
with RCC present with more advanced disease than do adults. 25,26
There is a subset of affected adolescent males with a unique
chromosomal translocation at Xp11.2, which appears to have a
poorer prognosis than non-Xp11.2 translocation RCC. 27,28 In
addition, survivors of neuroblastoma who received renal-directed
radiation therapy and platinum-based chemotherapy appear to be
at risk of developing RCC. Factors associated with increased risk of
mortality in children with RCC include advanced disease (ie, stage
4), histologic subtype (ie, non-chromophobe), and nonsurgical
treatment as first-line therapy.
- Renal medullary carcinoma is a highly lethal tumor that is virtually
restricted to patients with sickle cell hemoglobinopathy, most
commonly sickle cell trait. It is a highly invasive tumor with early
metastases.
Two principle WT staging systems are utilized. 31 Children’s
Oncology Group (COG) staging is based on pretreatment findings prior to
administration of chemo- or radiotherapy. The local stage defines the
extent of abdominal disease while the disease stage considers both the
local extent of disease and distant metastasis. Both factors determine the
treatment protocol with the use of radiation therapy to the tumor bed
based on the local stage and the chemotherapeutic regimen based on the
disease stage. Size alone is not a determinant of local stage and complete
removal of a resectable WT may preclude the need for abdominal
radiation even in the presence of Stage IV disease. A child may have a
local stage I tumor and pulmonary metastasis for a disease IV stage.
Treatment will be different than for a patient with a local stage III tumor
and pulmonary metastasis.
International Society of Paediatric Oncology (SIOP) protocols
recommend chemotherapy followed by nephrectomy with
surgicopathologic staging occurring at the time of nephrectomy. Tumors
are classified on SIOP protocols as completely necrotic (low risk tumor),
blastemal (high risk tumor) or other histology (intermediate risk
tumors).30,31

The SIOP staging system30

Stages Description
Stage 1 (a) Tumor is limited to kidney and is completely resected (resection
margins “clear”)
(b) The tumor may be protruding into the pelvic system and “dipping”
into the ureter (but it is not infiltrating their walls)
(c) The vessels of the renal sinus are not involved
(d) Intrarenal vessel involvement may be present
Stage 2 (a) The tumor extends beyond kidney or penetrates through the renal
capsule and/or fibrous pseudocapsule into perirenal fat but is
completely resected (resection margins “clear”)
(b) The tumor infiltrates the renal sinus and/or invades blood and
lymphatic vessels outside the renal parenchyma but is
completely resected
(c) The tumor infiltrates adjacent organs or vena cava but is
completely resected
Stage 3 (a) Incomplete excision of the tumor, which extends beyond the
resection margins
(b) Any abdominal lymph nodes are involved
(c) Tumor rupture before or intraoperatively (regardless of other
criteria for staging)
(d) The tumor has penetrated through the peritoneal surface
(e) Tumor thrombi present at resection margins of vessels or ureter,
transected or removed piecemeal by surgeon
(f) The tumor has been surgically biopsied (wedge biopsy) prior to
preoperative chemotherapy or surgery
 Stages Description
Stage 4 Hematogenous metastases (lung, liver, bone, brain, etc.) or lymph
node metastases outside the abdominopelvic region
Stage 5 Bilateral renal tumors at diagnosis

Wilms’ tumor is derived from primitive metanephric blastema and is

characterized by histopathologic diversity. The classic Wilms’ tumor is
composed of persistent blastema, dysplastic tubules (epithelial), and
supporting mesenchyme or stroma. The coexistence of epithelial,
blastemal, and stromal cells has led to the term triphasic to characterize
the classic Wilms’ tumor. Each of the cell types may exhibit a spectrum of
differ- entiation, generally replicating various stages of renal
embryogenesis. The proportion of each cell type may also vary
significantly from tumor to tumor. Some Wilms’ tumors may be biphasic or
even monomorphous in appearance. The absence of anaplastic features
identifies Wilms’ tumors as having favorable histology (FH). Clear cell
sarcoma of the kidney, rhabdoid tumor of the kidney and RCCs have
unique histologies and are not Wilms’ tumor variants. 32
The main objective in the treatment of bilateral Wilms’ tumor is
eradicating the tumor with maximum preservation of renal tissue. The goal
is for patients to undergo unilateral or bilateral partial nephrectomies, if
feasible.35 Current therapy recommendations for bilateral Wilms’ tumor
include: Open or percutaneous biopsy of each lesion to determine that the
tumor is indeed Wilms’ tumor. Some physicians advocate not doing a
biopsy because the overwhelming majority of bilateral renal tumors are
Wilms’ tumor. Moreover, biopsies are insensitive in the detection of
anaplasia.
Surgery, chemotherapy, and radiotherapy comprise the treatment
modalities for Wilms’ tumor. COG and SIOP guidelines provide two
different strategies for the initial treatment of Wilms’ tumor in children. 33,34
COG recommends patients undergo surgery before chemotherapy. 36 North
America commonly adopts NWTSG/COG guideline. However, most
children in European countries are treated with preoperative
chemotherapy based on the SIOP guideline. Different treatment strategies
are based on different staging systems. The COG staging system relies on
pathology analysis from a primary nephrectomy in most cases. The SIOP
staging is based on the results after preoperative chemotherapy. 38 Though
with so remarkable differences, the overall survival rate for the patients
treated by the two guidelines is similar over 90%.39
The COG recommends primary surgery before chemotherapy. 36 For
resectable tumors, preoperative biopsy or intraoperative biopsy is also not
performed.36 Radical nephrectomy and lymph node sampling are done
through a transabdominal incision. En bloc resection can be done to avoid
tumor spill.37 Resection of the primary renal tumor should be considered
even if in a stage IV disease (usually pulmonary metastases); renal-
sparing surgery is not recommended by COG guideline, except when
children having a solitary kidney, with predisposition to bilateral tumors,
horseshoe kidney or in infants with Denys-Drash or Frasier syndrome (to
delay the need for dialysis). The SIOP recommends radical tumor
nephrectomy performed after preoperative chemotherapy. Lymph node
sampling is important for staging, and sampling seven locoregional lymph
nodes is necessary for accurate staging. 40 Nephron-sparing surgery is
used for non-syndromic unilateral WTs under following conditions such as
with small tumor volume (<300mL) and the expectation of a substantial
remnant kidney function in patients who never had lymph node
involvement.
The SIOP guideline recommends preoperative chemotherapy for all
patients after diagnosis.40 For patients with unilateral localized tumor, 4-
week pretreatment with vincristine (weekly) and dactinomycin (biweekly) is
given; for patients with bilateral tumors, vincristine– dactinomycin for no
longer than 9–12 weeks is recommended (doxorubicin is added for
reinforcement in some patients); for patients with metastasis, a regimen
including 6 weeks of vincristine–dactinomycin (like above) and
doxorubicine on weeks 1 and 5 is given. 40 The SIOP guideline also
recommends postoperative chemotherapy in all patients with WT except
those with stage I low risk tumor. The SIOP recommends whole-
abdominal radiotherapy for patients with intermediate-risk or high-risk
histology tumors with major preoperative or intraoperative tumor rupture,
or macroscopic peritoneal deposits; pulmonary radiotherapy is indicated
for lung metastases lacking complete response until postoperative week
10. Patients with a complete response after induction chemotherapy with
or without surgery do not need pulmonary radiotherapy. Patients with
viable metastases at surgery or high-risk histology require pulmonary
radiotherapy. Whole-lung irradiation is recommended for patients who did
not receive lung irradiation during the first-line treatment, irrespective of
histology.40

The American Society of Clinical Oncology defines cancer cachexia

as a multifactorial syndrome characterized by loss of appetite, weight, and
skeletal muscle, leading to fatigue, functional impairment, increased
toxicity, poor quality-of-life (QoL), and reduced survival. 41,47,48 In pediatric
cancer, nutrition-related care and research focus on failure to thrive,
malnutrition, or weight loss but lack comprehensive conceptualization of
adult cancer cachexia.42 Brain myelination and ongoing growth in children
necessitate better characterization of cachexia due to the potential
irreversible developmental consequences. More importantly, when
children with cancer experience malnutrition during treatment, they
experience more treatment-related toxicity. 43 Quality of life is diminished
due to increased fatigue with effects during treatment, after treatment, and
even after the patient is in remission. The effects of poor nutrition are
further magnified by potentially delaying or decreasing curative
delivery.44,45 Patients with malnutrition have been identified to tolerate
treatment less than patient’s without malnutrition causing dose reductions
and treatment delays due to decreased health.

All children with cancer should receive nutrition screening, including

diet history, anthropometric measurements (age- and sex-normalized z-
scores for weight, height, and/or body mass index). 42 Ideal screening
should include body composition assessment beyond height and weight,
such as mid upper arm circumference, triceps skin fold thickness, or
growth velocity.42 Cancer treatment is associated with treatment-related
anorexia, nausea, vomiting, and other symptoms, but little disease-
specific, pediatric cachexia data exist. 44 Chemotherapy, radiation, surgery,
and immunotherapy directly result in nausea, vomiting, and anorexia or
other metabolic changes such as weight or muscle loss which are further
exacerbated by malnutrition. Malnutrition during cancer treatment can lead
to increased deleterious side effects due to compromised immunity
leading to higher infection rates, worse physical function, more
neuropathy, and overall detrimental effects on quality of life. Survival
impact of malnutrition alone is challenging to quantify, but individual
studies suggest lower survival for patients with poor nutrition. 46 While
therapy modification recommendations exist for mucositis and some
toxicities, no guidance exists for body composition changes nor lack of
expected growth. The relationship between nutrition, muscle wasting, and
inflammation has been described, but these same principles should be
applied to pediatric cachexia clinical evaluations, treatments, and drug
development.

Adequate nutritional care is pivotal to provide the essential building

blocks to maintain and rebuild tissue in cachectic patients. Furthermore,
nutrition is also crucial to supply energy and micronutrients that are vital to
fuel and catalyze metabolic processes. 49 In addition to the nourishing of
the cachectic patients, various nutrients have been implied in the
regulation and normalization of metabolic processes underlying the
wasting in cachectic patients. From European Society for Clinical Nutrition
and Metabolism (ESPEN) guidelines on nutrition in cancer patients the
recommend that the total energy expenditure (TEE) of cancer patients, if
not measured individually, be assumed to be similar to healthy subjects
and generally ranging between 25 and 30 kcal/kg/day. 49 Nutritional therapy
should preferably be initiated when patients are not yet severely
malnourished. The first form of nutritional support should be nutrition
counseling to help manage symptoms and encourage the intake of
protein- and energy-rich foods and fluids that are well tolerated; a diet
enriched in energy and protein is the preferred way to maintain or improve
nutritional status. The additional use of ONS is advised when an enriched
diet is not effective in reaching nutritional goals. Medical nutrition is
indicated if patients are unable to eat adequately (e.g. less than 50% of
the requirement for more than one week or only 50-75% of the
requirement for more than two weeks). If a decision has been made to
feed a patient, recommend enteral nutrition (EN) if oral nutrition remains
inadequate despite nutritional interventions (counseling, ONS), and PN if
EN is not sufficient or feasible. 49,50 Nutritional therapy in cancer patients
who are malnourished or at risk of malnutrition has been shown to improve
body weight and energy intake but not survival. If oral food intake has
been decreased severely for a prolonged period, we recommend to
increase (oral, enteral or parenteral) nutrition only slowly over several days
and to take additional precautions to prevent a refeeding syndrome. The
following electrolytes should be monitored and substituted, if necessary,
by the oral, enteral, or parenteral route: potassium (requirement
approximately 24 mmol/kg/day), phosphate (requirement approximately
0.3-0.6 mmol/kg/day) and magnesium (requirement approximately 0.2
mmol/kg/day if supplied intravenously or 0.4 mmol/kg/day if supplied
orally). Dietary Protein Adequate supply of dietary protein is a prerequisite
for maintenance or gain of skeletal muscle mass. A positive protein
balance is required to increase skeletal muscle mass, and elevated
plasma levels of essential amino acids from dietary protein are considered
an effective anabolic stimulus. However, fundamental evidence on the
sufficient and optimal quantity and quality of protein intake for treating low
muscle mass is lacking. The European Society for Clinical Nutrition and
Metabolism (ESPEN) guidelines on nutrition in cancer patients suggest a
protein intake in the range of 1.0–1.5 g/kg/day. 49 Dietary fat is an
important source of energy and contributes a significant caloric value to
our diet. In Western diets, dietary fat may constitute 40–45% of the total
caloric intake. Dietary fat is not just a source of energy, it also functions as
structural component of cell membranes, carries fat soluble vitamins, plays
an important role in signal transduction and is a precursor for inflammatory
mediators.51 Physical activity is well-tolerated and safe at different stages
of cancer and also patients with advanced stages of the disease are able
and willing to engage in physical activity. 49 This consists of supervised or
home-based moderate-intensity training (50-75% of baseline maximum
heart rate or aerobic capacity), three sessions per week, for 10-60 min per
exercise session. Physical activity in cancer patients is associated with
maintenance or significant improvements in aerobic capacity, muscle
strength, health-related quality of life, self-esteem, and a reduction in
fatigue and anxiety. For some patients, recommendations for physical
activity should consist of motivating patients to take a daily walk in order to
reduce risks of atrophy due to inactivity.49

Anemia is a clinical status distinguished by a decreased erythrocyte

mass with subsequent low hemoglobin (Hb) and hematocrit counts. The
World Health Organization (WHO) and National Cancer Institute (NCI)
have devised a scale to define anemia grade based on Hb values. 52 As
stated by WHO, normal Hb values are ≥12 g/dL in women, and ≥13 g/dL in
men. The NCI grading of anemia is defined as follows: “mild (Grade 1), Hb
from 10 g/dL to the lower normal limit; moderate (Grade 2), Hb 8.0–9.9
g/dL; severe (Grade 3), Hb <8 g/dL to 6.5 g/dl; life-threatening (Grade 4),
Hb <6.5 g/dL”.53 Cancer-related anemia (CRA) is a sign that may
accompany the evolution of cancer disease and is more commonly
diagnosed in patients at advanced disease stages. It can occur
independently from concurrent antineoplastic regimen, typically as a
consequence of chronic inflammation associated to cancer disease. In
fact, CRA biological and hematologic features resemble those described in
anemia associated to chronic inflammatory disease. At this regard it
should be specified that cancer patients with anemia should be sorted into
two main categories: those with normal Hb values before starting medical
treatment (often patients with limited, locally advanced resectable disease
and candidate to undergo adjuvant cancer therapy) for whom anemia must
be interpreted as a specific treatment-related toxicity (chemotherapy-
induced anemia); and those with diagnosis of anemia preceding
antineoplastic treatment (often receiving chemotherapy for advanced
cancers).54 For the latter group, anemia is a mostly a result of the chronic
inflammatory status existing in advanced neoplastic patients; this is the
real CRA. Cancer-related anemia is most often normochromic (MCH≥27
pg), normocytic (MCV between 80–100 fl). Usually it is a hypoproliferative
anemia with a reticulocyte count below normal (<25,000/microL) and a low
value of reticulocyte index (normal range between 1 and 2), which is a
more accurate measure of the reticulocyte count corrected against the
severity of anemia on the basis of hematocrit. Additional features include
normal/low serum iron concentrations (normal range 55–160 μg/dl for men
and 40–155 μg/dl for women) and reduced total iron binding capacity
(transferrin saturation <50%), whilst ferritin values may be normal (30–500
ng/ml) or more often increased (≥500 ng/mL), with increased iron storage.
Hence, a defect in iron handling instead of a lack of iron, termed
“functional iron deficiency,” has been hypothesized to underlie CRA.
Patients with CRA (Hb range, 8–10 g/dL) exhibit fatigue, lethargy,
dyspnea, anorexia, and have difficulty concentrating, which can
compromise their overall functional status and significantly reduce
adherence to anticancer regimens. In particularly, CRA-related fatigue
may negatively influence patient QL and as a consequence the patient
tolerance and motivation to sustain the antineoplastic regimen, thus not
allowing patients to receive full and timely doses and potentially impairing
the therapeutic response. CRA is associated with the decreasing efficacy
of chemotherapy, radiotherapy, and chemoradiotherapy regimens, with a
subsequent detrimental effect on patient prognosis. 55 The relationship
between CRA and reduced efficacy of chemo- and radiotherapy could be
also a result of the increased aggressiveness of advanced neoplasia and
the associated inflammation, which is known to affect prognosis and cause
CRA. However, experimental and clinical studies have shown that low
oxygen (O2) levels (hypoxia) had a specific negative effect on the efficacy
of antineoplastic treatment. Cancer-related anemia could worsen tumor
hypoxia, which in turn favors disease progression and metastases, and
reduces tumor sensitivity to antiblastic treatments via various mechanisms
including tissue acidosis, production of ROS, immunodepression, and
alterations in tumor cells apoptosis. Cancer related anemia (CRA) refers to
a condition occuring without bleeding, hemolysis, neoplastic bone marrow
infiltration, kidney and/or hepatic failure. It principally results from the
chronic inflammation associated with advanced stage cancer and the
synthesis of proinflammatory cytokines by both immune and cancer cells. 54

The main pathogenetic mechanisms by which inflammation may

cause anemia include shortened erythrocyte survival in conjunction with
increased erythrocyte destruction, suppressed erythropoiesis in bone
marrow, effects of inflammation on erythropoietin production. Alterations in
iron metabolism that result in iron-restricted erythropoiesis induced by
hepcidin increase. The increased destruction of erythrocytes is mainly due
to macrophage activation by different proinflammatory stimuli. The
inhibition of erythropoiesis is related to two main mechanisms; iron
restriction and direct inhibitory cytokine action on erythropoietic
progenitors. Therefore, erythropoiesis is insufficient to compensate for the
increased destruction of erythrocytes. Moreover, in patients with chronic
inflammatory disease (as cancer) EPO shows a decreased synthesis in
reply to hypoxic stimuli and its circulating concentrations are inadequately
low for Hb levels, irrespective of intrinsic renal pathologies. A direct effect
of proinflammatory cytokines on kidney cells that produce EPO may
contribute to the defective synthesis of this hormone. A lot of evidence in
the literature demonstrate that inflammation mediators exert a major
contribution in the etiopathogenesis of CRA. In particular, proinflammatory
cytokines (e.g., TNF-α, IL-1, IL-6), released by the cancer and activated
immune cells in response to malignancy, may result in anemia by inducing
changes to iron balance, inhibition of erythropoiesis, impairment of EPO
synthesis and activity, reduction of erythrocytes lifespan and changes of
energy metabolism. Moreover, IL- 1 and TNFα acts by activating the
transcription factors GATA2 and nuclear factor-κB, both of which are
negative regulators of the hypoxia-inducible factor 1 (HIF1) expression.
Among cytokines, in particular IL-6 is able to induce hepatic synthesis of
hepcidin, which regulates iron homeostasis by mediating the degradation
of the iron export protein ferroportin 1, thereby inhibiting iron absorption
from the small intestine and release of iron from macrophages. As a
consequence iron is withdrawn from erythropoiesis. Additionally, in
advanced cancer patients, other triggering factors may contribute to
anemia through a multifactorial pathogenesis; among them, the following
mechanisms can be highlighted are poor nutritional status, antineoplastic
therapies (chemo- and radiotherapy) that may cause overt and/or
aggravate CRA. Of high relevance are in particular the metabolic and
nutritional issues typical of advanced cancer patients and the defect of
specific components (such as iron, vitamins, folic acid etc.) essential for
erythropoiesis. Notably, the availability of these nutrients (e.g., glucose,
iron) influence the synthesis of heme, which also depends on the
efficiency of glucose metabolism via the Krebs cycle, and is essential, in
combination with iron, for the synthesis of Hb. During the evolution of the
cancer disease, patient nutritional status is severely compromised by
symptoms and signs including weight loss associated with significant
reduction of muscle mass, increased resting energy expenditure, anorexia,
nausea and vomiting. A recent large observational study supported the
central role of weight loss, together with the body mass index (BMI), as a
negative prognostic factor in cancer patients at diagnosis independently of
other more standardized parameters such as tumor site, stage, and PS.
Even cancer patients who exhibit at diagnosis a slight decrease of body
weight >2.4% have an increased risk of morbidity and mortality. Loss of
body weight represents the main measure for the diagnosis of cancer
cachexia, which is a complex inflammatory-driven syndrome often
accompanying the advanced stages of the neoplastic disease. The weight
loss observed in cachectic cancer patients cannot be justified only by the
reduction of the supply of nutrients, caused by anorexia and consequent
reduced food intake. Energy metabolism changes, which account for a
significant increase in resting metabolic expenditure, significantly
contribute to loss of body weight. Notably, cancer- associated chronic
inflammation concurs to the derangements of energy metabolic pathways
inflammatory by modulating glucose metabolism, regulating the
functioning lipoprotein lipase, which controls the uptake of circulating
triglycerides into adipocytes, and changing protein synthesis and
degradation, with subsequent depletion in lean body mass. 57 In fact, in
cancer patient muscle protein production is decreased while proteolysis is
increased, following the raised activity of proteolytic enzymes. Such
metabolic behavior is completely different in the liver, where, despite a
stable or reduced albumin synthesis, the synthesis of other proteins,
especially those of acute phase inflammation (PCR, fibrinogen and
hepcidin), is significantly increased. In fact, anemia associated with
chronic inflammation in advanced cancer patients is not an isolated
symptom, but it is more typically associated with weight loss and
remodeling of energy metabolism caused by cancer itself. 57

Cancer-related anemia, not associated with concomitant

antineoplastic treatment, is underestimated and undertreated. The
approach to treating CRA must begin with an exhaustive assessment of its
defining parameters and identifying its multiple potentially treatable
causes: because CRA is mostly multifactorial it should be effectively
treated with multitargeted therapies. It should be underlined that CRA
reflects the progressive growth of the underlying disease, thus the
eradication of cancer should be the only definitive treatment of this
particular form of anemia. However, as the neoplastic disease, in many
cases, is not curable, the therapeutic strategies against CRA should target
the multiple causes that trigger the disease and should include
erythropoietic agents, iron supplementation or blood transfusions,
nutritional supplementation, and anti-inflammatory therapies. Future
strategies could include chelate-iron therapy, use of hepcidin antagonists
and cytokines or hormones that can modulate erythropoiesis under severe
inflammatory conditions. Red blood cells (RBC) transfusions are almost
universally successful in raising Hb levels and the oxygen transport
capacity of the blood. Therefore, they represent a fast and effective
therapeutic intervention useful to ameliorate rapidly the patient’s
symptoms, e.g., breathlessness, and improve health-related QL. 56 The
major benefit, not provided by any alternative therapy for anemia, is the
fast Hb and Hct value rise. Notably, the last published NCCN guidelines
indicate that RBC transfusions should be considered not on the basis of a
specific threshold value of Hb but in patients with symptomatic anemia, in
high risk patients (e.g., those undergoing high-dose chemo-or
radiotherapy with cumulative decrease of Hb levels) or asymptomatic
patients with comorbidities.56
 Diakité, FLF et al,58 conducted retrospective study to determine the
prevalence and prognosis of Wilms’ Tumor in pediatric population. They
found the average time to relapse was 10 months after nephrectomy; 16%
of patients had recurred before the end of postoperative chemotherapy
and 84% of relapses after this treatment. The relapse was local (53%),
pulmonary (32%), hepatic (21%) and cerebral (5%). The treatment
consisted of high-risk chemotherapy with four molecules
(cyclophosphamide, Doxorubicin, Carboplatin, Etoposide) in 37% of cases
and palliative treatment in 63% of cases. The evolution was marked by
death in 58% of cases; 21% were lost to follow-up and 21% had survived
the relapse of which 5% were in continuous remission. They concluded
the difficulties in the management of nephroblastoma relapses with poor
prognosis. (Level of Evidence 2B, Recommendation B).

A prospective observational study from Sigh59 analyze the clinical

profile along with the response and outcome to neoadjuvant
chemotherapy according to the SIOP protocol in India. Gender distribution
showed male preponderance with a median age at diagnosis was 31
months. The abdominal lump was the dominant clinical presentation. The
median volume of tumor at diagnosis was 359.48 mL (52.67–1805.76).
Radiological staging workup shows that stage I, II, III, IV, and V were
7.1%, 39.3%, 39.3%, 10.7%, and 3.6% respectively. There was 71.4% of
patients showed >50% of tumor volume reduction, while 28.6% of patients
showed < 50% of tumor mass reduction. There was a statistically
significant decrease in the tumor volume reduction following neoadjuvant
chemotherapy (p < 0.001). There was a statistically significant stage down
of the disease (p = 0.018). Bivariate correlation studies showed recurrence
was correlating statistically significantly with age < 24 months (p = 0.049),
locoregional lymph nodes (p = 0.008), histopathological subtypes (p <
0.001), stage of the disease (p = 0.003), and risk groups (p < 0.001). In
addition, 25% of patients developed recurrence during the median follow-
up of 25 months. The median disease-free survival (DFS) and overall
survival (OS) were not reached. The mean DFS and OS were 48 and
59.13 months, respectively. One and 3-year DFS were 100% and 64.1%,
respectively. One and 3-year OS were 100% and 75% respectively. (Level
of Evidence 2A, Recommendation B).
A retrospective study from Zekri evaluate the outcome of relapsed
Wilms’ tumor pediatric patients treated at the National Cancer Institute
(NCI), Egypt, between January 2008 and December 2015. One hundred
thirty patients diagnosed with Wilms’ tumor during the study period, thirty
(23%) patients had relapsed. The median follow up period was 22.3
months (range 3.6–140 months). The Overall Survival (OS) was 30.9%
while the event-free survival (EFS) was 29.8% at a 5-year follow up
period. Median time from diagnosis to relapse was 14.4 months. A second
complete remission was attained in 18/30 patients (60%). The outcome of
the 30 patients; 11 are alive and 19 had died. Three factors in our
univariate analysis were prognostically significant for survival after relapse.
The first was radiotherapy given after relapse (p = 0.012). The 5-year EFS
and OS for the group that received radiotherapy were 41.9% versus
16.7% and 11.1% respectively for those that did not. The second was the
state of lymph nodes among patients with local stage III (p = 0.004).
Lastly, when risk stratification has been applied retrospectively on our
study group, it proved to be statistically significant (p = 0.029). (Level of
Evidence 2B, Recommendation B).
Larasanti et al analyze the risk factors of mortality in children with
Wilm’s tumor at Soetomo Hospital Surabaya during 2006-2011. There
were 32 Wilm’s tumor children, 5/32 children in stage I, 7/32 children in
stage II, 8/32 children in stage III, 11/32 children in stage IV, and 1/32
children relapsed. There were 20/32 children died, associated with anemia
(P=0.033, OR=6.111, 95% CI = 1.056-35.352) and advanced stage
(P=0.021, OR=8.000, 95% CI=1.575-40.632). The risk of mortality
increased 3.284 folds with every increased stage (P=0.007, 95%
CI=1.338-7.775). (Level of Evidence 2B, Recommendation B).

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