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Staging and Therapeutic Regimen

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1 Staging and Therapeutic Regimen
Wilm’s Tumor Neuroblastoma Hydronephrosis Sacrococcygeal teratoma

2 TNM Staging T ((0),1–4): size or direct extent of the primary tumor
N (0–3): degree of spread to regional lymph nodes N0: tumor cells absent from regional lymph nodes N1: tumor cells spread to closest or small number of regional lymph nodes N2: tumor cells spread to an extent between N1 and N3. N3: tumor cells spread to most distant or numerous regional lymph nodes M (0/1): presence of metastasis M0: no distant metastasis M1: metastasis to distant organs (beyond regional lymph nodes) Just in case i-ask yung general staging method =)

3 Wilm’s Tumor: Staging

4 Staging of Wilm’s Tumor
Stage I 43% Tumor limited to the kidney and completely excised without rupture or biopsy. Surface of the renal capsule is intact. Stage II 20% Tumor extends through the renal capsule but is completely removed with no microscopic involvement of the margins. Vessels outside the kidney contain tumor. Also placed in stage II are cases in which the kidney has undergone biopsy before removal or where there is “local” spillage of tumor (during resection) limited to the tumor bed. Stage III 21% Residual tumor is confined to the abdomen and of nonhematogenous spread. Also included in stage III are cases with tumor involvement of the abdominal lymph nodes, “diffuse” peritoneal contamination by rupture of the tumor extending beyond the tumor bed, peritoneal implants, and microscopic or grossly positive resection margins. Stage IV 11% Hematogenous metastases at any site. Stage V 5% Bilateral renal involvement. Stage I (43% of patients) Tumor is limited to the kidney and is completely resected. The renal capsule is intact. The tumor is not ruptured or biopsied prior to removal. No involvement of renal sinus vessels. No evidence of the tumor at or beyond the margins of resection. Stage II (20% of patients) The tumor extends beyond the kidney as evidenced by any one of the following criteria: There is regional extension of the tumor (i.e., penetration of the renal sinus capsule, or extensive invasion of the soft tissue of the renal sinus) Blood vessels within the nephrectomy specimen outside the renal parenchyma, including those of the renal sinus, contain tumor. Stage III (21% of patients) Lymph nodes within the abdomen or pelvis are involved by tumor. The tumor has penetrated through the peritoneal surface and tumor implants are found here. Gross or microscopic tumor remains postoperatively (e.g., tumor cells are found at the margin of surgical resection on microscopic examination). The tumor is not completely resectable because of local infiltration into vital structures. Tumor spillage occurs either before or during surgery. The tumor is treated with preoperative chemotherapy and was biopsied before removal. The tumor is removed in more than one piece (e.g., tumor cells are found in a separately excised adrenal gland; a tumor thrombus within the renal vein is removed separately from the nephrectomy specimen). Extension of the primary tumor within vena cava into thoracic vena cava and heart is considered stage III, rather than stage IV, even though outside the abdomen. US National Cancer Institute. Townsend: Sabiston Textbook of Surgery, 18th ed. Copyright © 2007 Saunders, An Imprint of Elsevier

5 Staging of Wilm’s Tumor
Stage I or Stage II The 4-year survival is 94% Stage III The 4-year survival is 76% US National Cancer Institute.

6 Wilm’s Tumor: Therapeutic Regimen

7 Treatment of Wilm’s Tumor
NWTS-5 Treatment Recommendations for Wilms' Tumor Stage I (FH) Surgery, no radiotherapy, dactinomycin + vincristine for 18 wk Stage I focal anaplasia Stage II (FH) Stage II focal anaplasia Surgery, 1080 cGy to tumor bed, dactinomycin +vincristine + doxorubicin for 24 wk Stage III (FH) Stage III focal anaplasia Stage I (FH), stage I focal anaplasia and stage II (FH) are all managed with surgery, no radiotherapy, dactinomycin + vincristine for 18 wk Stage II focal aaplasia, stage III (FH) and stage III focal anaplasia are all managed with surgery, 1080 cGy to tumor bed, dactinomycin +vincristine + doxorubicin for 24 wk Dactinomycin – an antitumor antibiotic isolated from a Streptomyces organism. It binds tightly to double stranded DNA through intercalation between adjacent cytosine-guanine base pairs and inhibits all forms of DNA-dependent RNA synthesis, with rRNA formation being most sensitive to drug action. Doxorubicin – one of the anthracycline antibiotics derived from Streptomyces peuctius var caesius. It has a broad spectrum of clinical activity against hematologic malignancies and a wide range of solid tumors. Mechanisms of cytotoxic action: (1) inhibition of topoisomerase II; (2) high-affinity binding to DNA through intercalation, with consequent blockade of the synthesis of DNA and RNA, and DNA strand scission; (3) binding to cellular membranes to alter fluidity and ion transport; (4) generation of semiquinone free radicals and oxygen free radicals through an Fe-dependent, enzyme-mediated reductive process. Administered IV, metabolized in the liver. Vincristine – an alkaloid derivative of Vinca rosea and is closely related in structure to vinblastine. Mechanism of action: functions as a mitotic spindle poison leading to arrest of cells in the M phase of the cell cycle. Main dose-limiting toxicity: neurotoxicity (peripheral sensory neuropathy) Surgery: nephrectomy with lymph node sampling Radiotherapy: 1080 cGy * Infants <11 mo are given half the recommended dose of all drugs. Full doses lead to prohibitive hematologic toxicity in this age group. Full doses of chemotherapeutic agents should be administered to those >12 mo. National Wilms Tumor Study (NWTS) Group US National Cancer Institute. Townsend: Sabiston Textbook of Surgery, 18th ed. Copyright © 2007 Saunders, An Imprint of Elsevier

8 Treatment of Wilm’s Tumor
NWTS-5 Treatment Recommendations for Wilms' Tumor Stage IV (FH) focal anaplasia Surgery, 1080 cGy to tumor bed according to local tumor stage, 1200 cGy to lung and/or other metastatic sites, dactinomycin +vincristine + doxorubicin for 24 wk Stage II-IV diffuse anaplasia Surgery, radiotherapy (whole lung; abdominal 1080 cGy), cyclophosphamide + etoposide +vincristine +doxorubicin + mesna for 24 wk Stage I-IV (clear cell sarcoma) Surgery, radiotherapy (abdominal 1080 cGy; whole lung, stage IV only), cyclophosphamide +etoposide +vincristine + doxorubicin +mesna for 24 wk Stage I-IV (rhabdoid tumor): Surgery, radiotherapy, carboplatin +etoposide +cyclophosphamide +mesna for 24 wk * Infants <11 mo are given half the recommended dose of all drugs. Full doses lead to prohibitive hematologic toxicity in this age group. Full doses of chemotherapeutic agents should be administered to those >12 mo. Surgery: nephrectomy with lymph node sampling Radiotherapy: 1080 cGy Mesna - 2-MercaptoEthane Sulfonate sodium(NA). National Wilms Tumor Study (NWTS) Group US National Cancer Institute. Townsend: Sabiston Textbook of Surgery, 18th ed. Copyright © 2007 Saunders, An Imprint of Elsevier

9 Resectable Tumors Procedure of choice: Radical nephrectomy and lymph node sampling via a transabdominal incision Preoperative biopsy should not be performed Most important role of the surgeon to ensure complete tumor removal without rupture and perform an assessment of the extent of disease National Wilms Tumor Study (NWTS) Group US National Cancer Institute.

10 Surgery: Nephrectomy Radical
Removal of the kidney, the ipsilateral adrenal gland, and all the fat contained within Gerota's fascia. If there is no evidence of adrenal involvement by the tumor on the CT scan, the adrenal gland can be spared Partial Controversial; not recommended except for bilateral tumors National Wilms Tumor Study (NWTS) Group US National Cancer Institute.

11 Routine exploration of the contralateral kidney is not necessary if technically adequate imaging studies do not suggest a bilateral process. If the initial imaging studies are suggestive of regional and contralateral kidney involvement, the contralateral kidney should be formally explored to rule out bilateral involvement. This should be done prior to nephrectomy since the diagnosis of bilateral disease would dramatically alter the approach.

12 Massive, Nonresectable Unilateral Tumors, Bilateral Tumors
Candidates for preoperative chemotherapy because of the risk of initial surgical resection. National Wilms Tumor Study (NWTS) Group US National Cancer Institute.

13 Major Treatment Conclusions of the National Wilms Tumor Studies (NWTS 1—5)
Routine, postoperative radiation therapy of the flank is not necessary for children with stage I tumors or stage II tumors with favorable histology (FH) when postnephrectomy combination chemotherapy consisting of vincristine and dactinomycin is administered. The prognosis for patients with stage III FH is best when treatment includes: (a) dactinomycin, vincristine, doxorubicin, and 10.8 Gy of radiation therapy to the flank; or (b) dactinomycin, vincristine, and 20 Gy of radiation therapy to the flank. The addition of cyclophosphamide to the combination of vincristine, dactinomycin, and doxorubicin does not improve prognosis for patients with stage IV FH tumors. Just in case slide

14 Major Treatment Conclusions of the National Wilms Tumor Studies (NWTS 1—5)
A single-dose of dactinomycin per course (stages I–II FH, stage I anaplastic, stage III FH, stages III–IV, or stages I–IV clear cell sarcoma of the kidney) is equivalent to the divided-dose courses, and results in the same event-free survival, greater dose intensity, and is associated with less toxicity and expense. Eighteen weeks of therapy is adequate for patients with stage I FH whereas other patients can be treated with 6 months of therapy instead of 15 months. Tumor-specific loss of heterozygosity for combined 1p and 16q predicts recurrence of FH Wilms tumor and may be used to select patients for more aggressive treatment. Just in case slide

15 Neuroblastoma: Staging

16 “International Neuroblastoma Staging System" (INSS) established in 1986 and revised in 1988 stratifies neuroblastoma according to its anatomical presence at diagnosis: Stage 1 Localized tumor confined to the area of origin 2A Unilateral tumor with incomplete gross resection; identifiable ipsilateral and contralateral lymph node negative for tumor 2B Unilateral tumor with complete or incomplete gross resection; with ipsilateral lymph node positive for tumor; identifiable contralateral lymph node negative for tumor 3 Tumor infiltrating across midline with or without regional lymph node involvement; or unilateral tumor with contralateral lymph node involvement; or midline tumor with bilateral lymph node involvement 4 Dissemination of tumor to distant lymph nodes, bone marrow, bone, liver, or other organs except as defined by Stage 4S 4S Age <1 year old with localized primary tumor as defined in Stage 1 or 2, with dissemination limited to liver, skin, or bone marrow (less than 10 percent of nucleated bone marrow cells are tumors)

17 International Neuroblastoma Risk Group Staging System (INRGSS)
Stage L1 Localized disease without image-defined risk factors L2 Localized disease with image-defined risk factors M Metastatic disease MS Metastatic disease "special" where MS is equivalent to stage 4S

18 Shimada Histopathologic Classification System
Describes tumors as either favorable or unfavorable histology based on the degree of differentiation, mitosis-karyorrhexis index, schawannian stroma In general, children of any age with localized neuroblastoma and infants <1yr with advanced disease and favorable disease characteristics have a high likelihood of disease free survival By contrast, older children with advanced stage disease have significantly decreased chance for cure despite intensive therapy

19 Shimada Histopathologic Classification System
Favorable histology group Patients of any age with stroma-rich tumors without a nodular pattern Patients younger than 18 months with stroma-poor tumors, an MKI of less than 200/5000 (200 karyorrhectic cells per 5000 cells scanned), and differentiated or undifferentiated neuroblasts Patients younger than 60 months with stroma-poor tumors, an MKI of less than 100/5000, and well-differentiated tumor cells

20 Shimada Histopathologic Classification System
Unfavorable histology group Patients of any age with stroma-rich tumors and a nodular pattern Patients of any age with stroma-poor tumors, undifferentiated or differentiated neuroblasts, and an MKI more than 200/5000 Patients older than 18 months with stroma-poor tumors, undifferentiated neuroblasts, and an MKI more than 100/5000 Patients older than 18 months with stroma-poor tumors, differentiated neuroblasts, and an MKI of /5000 Patients older than 60 months stroma-poor, differentiated neuroblasts, and an MKI less than 100

21 Neuroblastoma: Therapeutic Regimen

22 Stage of the cancer Child's age Prognostic markers  (hyperdiploid tumor DNA, N-myc, H-ras) Chemotherapy Surgery Radiation therapy Retinod therapy

23 Intermediate Risk Group
Low Risk Group Intermediate Risk Group High Risk Group Children at low risk often require surgery as their only treatment Chemotherapy is typically given after surgery if less than half the tumor can be removed (carboplatin, cyclophosphamide, doxorubicinetoposide) Infants with 4S disease and no symptoms can often be watched carefully with no treatment, because these cancers often mature or go away on their own Surgery with chemotherapy before or after the procedure, or radiation therapy if chemotherapy is not effective “Second look surgery" More aggressive treatment Combination of chemotherapy, surgery, and radiation High-dose chemotherapy followed by a stem cell transplant  Retinoid drug 13- cis-retinoic acid (isotretinoin) is often given for 6 months after other treatments are completed.

24 Recurrent Neuroblastoma
For low- and intermediate-risk neuroblastomas that recur in the same area where they started, surgery with or without chemotherapy may be appropriate 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 intensive treatment with high-dose chemotherapy/radiation therapy, followed by a donor stem cell transplant

25 Chemotherapy Anti-neoplastic agents Side effects
cyclophosphamide or ifosfamide cisplatin or carboplatin vincristine doxorubicin (Adriamycin) etoposide teniposide topotecan hair loss mouth sores loss of appetite nausea and vomiting increased chance of infections (due to low white blood cell counts) easy bruising or bleeding (due to low blood platelet counts) fatigue

26 Surgery Diagnosis and treatment Complete resection
Use of adjuvant therapies

27 Radiation Therapy Uses high-energy rays or particles to kill cancer cells External beam radiation therapy MIBG radiotherapy

28 External beam radiation therapy
uses radiation focused on the cancer from a source outside the body to destroy neuroblastoma cells that remain behind after surgery and chemotherapy to try to shrink tumors before surgery, making them easier to remove at the time of surgery to treat larger tumors that are causing serious problems (such as trouble breathing) and do not respond quickly to chemotherapy as part of the treatment regimen (along with high-dose chemotherapy) before a stem cell transplant in children with high-risk neuroblastoma to help relieve pain caused by advanced neuroblastoma mild skin reactions, nausea, diarrhea, or fatigue

29 MIBG radiotherapy chemical similar to norepinephrine
Once injected into the bloodstream, the MIBG goes to the sites of tumors anywhere in the body, where it delivers its radiation child will need to stay in a special room for a few days nausea and vomiting, lower blood cell counts

30 Retinoid Therapy chemically related to vitamin A
“differentiating agents” 13-cis-retinoic acid (isotretinoin) reduces the risk of recurrence after high-dose chemotherapy and stem cell transplant 6 month therapy drying and cracking of the lips, dry skin or eyes, nosebleeds and changes in the nails

31 Hydronephrosis: Grading

32 Hydronephrosis (Grading)
Society of Fetal Urology (SFU)Grading System Mild hydronephrosis (Grade I or II) Moderate hydronephrosis (Grade III) Severe hydronephrosis ( Grade IV) Grade No splitting of the central renal echo complex I Slight splitting of the central renal echo complex II Dilated renal pelvis and some fluid in calyces III Pelvis dilated beyond sinus, calyces uniformly dilated IV Pelvis and calyces dilated, parenchyma thin Wala daw staging accdg to dino Fernbach SK, Maizels M, Conway JJ. Ultrasound grading of hydronephrosis: introduction to the system used by the Society for Fetal Urology. Pediatr Radiol. 1993;23:478-80

33 Hydronephrosis: Therapeutic Regimen

34 Treatment (Medical) The role of medical treatment is limited to pain control and treatment or prevention of infection Most conditions require either minimally invasive or open surgical treatment. Two notable exceptions are (1) oral alkalinization therapy for uric acid stones and (2) steroid therapy for retroperitoneal fibrosis Vourganti, S. (2008). Hydronephrosis and Hydroureter: Treatment & Medication

35 Treatment (Medical) Neonates with hydronephrosis are at high risk for pyelonephrosis Therefore, all neonates diagnosed with unilateral or bilateral hydronephrosis should be started on antibiotic prophylaxis Example: Amoxicillin 10 mg/kg per 24 h Schwartz’s Manual of Surgery 8th Ed.

36 Treatment (Surgical) The specific treatment of a patient with hydronephrosis depends on the etiology of the process Any signs of infection within the obstructed system warrant urgent intervention because infection with hydronephrosis may progress rapidly to sepsis The potential for loss of renal function also adds to the urgency Vourganti, S. (2008). Hydronephrosis and Hydroureter: Treatment & Medication

37 Treatment (Surgical) Urethral catheterization to help rule out a lower tract cause for hydronephrosis and hydroureter Difficulty in placing a Foley catheter may suggest urethral stricture or bladder neck contracture Ureteral stent placement in cases of intrinsic and extrinsic causes of hydronephrosis. Stents can bypass an obstruction and dilate the ureter for subsequent endoscopic treatment Vourganti, S. (2008). Hydronephrosis and Hydroureter: Treatment & Medication

38 Treatment (Surgical) Nephrostomy tube
Using the Seldinger technique, a tube ranging from 8-12F can be placed Placed when a retrograde stent cannot be passed because of anatomic changes in the bladder or high-grade obstruction in the ureter Seldinger technique: Vourganti, S. (2008). Hydronephrosis and Hydroureter: Treatment & Medication

39 Treatment (Surgical) Advances in endoscopic and percutaneous instrumentation have decreased the role of open or laparoscopic surgery for hydronephrosis. However, extrinsic causes of hydropnephrosis (retroperitoneal fibrosis, retroperitoneal tumors, and aortic aneurysms) still require treatment with open surgery. Some stones that cannot be treated endoscopically or with extracorporeal shockwave lithotripsy require open removal Vourganti, S. (2008). Hydronephrosis and Hydroureter: Treatment & Medication

40 Sacrococcygeal Teratoma: Staging

41 Sacroccocygeal Teratoma
SCTs are classified morphologically according to their relative extent outside and inside the body: Altman type I — entirely outside, sometimes attached to the body only by a narrow stalk Altman type II — mostly outside Altman type III — mostly inside Altman type IV — entirely inside; this is also known as a presacral teratoma or retrorectal teratoma

42 AAPSS Staging Classification of Sacrococcygeal Teratomas
Type Description I Completely external, no presacral component II External component and internal pelvic component III External component and internal component extending into abdomen IV Completely internal and no external component Fetology: diagnosis & management of the fetal patient  By Diana W. Bianchi, Timothy M. Crombleholme, Mary E. D'Alton

43 Sacrococcygeal Teratoma: Therapeutic Regimen

44 Treatment Chemotherapy Cisplastin Bleomycin
If serum AFP levels remain elevated, chemotherapy containing cisplastin for four cycles is recommended Carboplatin Etoposide Avery's diseases of the newborn  By H. William Taeusch, Roberta A. Ballard, Christine A. Gleason, Mary Ellen Avery

45 Treatment JEB Regimen Etoposide 120 mg/m2i.v. over 1 hour
Carboplatin i.v. over one hour on day 2 in a dose calculated as 600 mg/m2 Bleomycin 15 mg/m2 i.v. over 15 minutes S.N. Huddart Æ J.R. Mann Æ K. Robinson Æ F. Raafat J. Imeson Æ P. Gornall Æ M. Sokal Æ E. GrayP. McKeever Æ A. Oakhill Sacrococcygeal teratomas: the UK Children’s Cancer Study Group’s experience. I. Neonatal

46 Treatment Surgery complete surgical excision through a chevron-shaped buttock incision most tumors can be completely removed using a sacral approach If preoperative imaging demonstrates significant intra-abdominal extension of the tumor combined abdominal-sacral approach Townsend: Sabiston Textbook of Surgery, 18th ed.

47 Care must be taken to individually ligate the vessels supplying the tumor, including the middle sacral artery and branches of the hypogastric arteries After the tumor is excised, the levator muscle complex is secured to the presacral fascia, and the remaining wound is closed in layers Townsend: Sabiston Textbook of Surgery, 18th ed. Mature sacrococcygeal teratoma: case report JN Legbo, WEk Opara, and JF Legbo Department of Surgery, Usmanu Danfodiyo University Teaching Hospital, Sokoto, Nigeria


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