Soft tissue sarcoma (STS)tsh.or.th/file_upload/files/13 Thirachit... · 2019. 7. 30. · Soft...

Soft tissue sarcoma (STS)

Assoc. Prof. Thirachit Chotsampancharoen Division of Hematology/Oncology Department of Pediatrics Prince of Songkla University Hat-Yai, Songkhla Thailand 90110

4 August 2019

Soft tissue sarcoma

Sarcoma is a malignant tumor of mesenchymal cell origin

Mesenchymal cells normally mature into skeletal muscle, smooth muscle,

fat, connective tissue, vascular tissue, fibrous tissue, bone, and cartilage

Soft tissue sarcomas are a heterogeneous family of tumors comprised of >50

histological subtypes arising in nearly any site in the body and representing

the full spectrum of malignant behavior

Major soft-tissue sarcomas in children: rhabdomyosarcoma

Lanzkowsky’s manual of pediatric hematology and oncology 2016 Callegaro D, Cancer 2017

The ASR from 1990 to 2011 for all cancer groups was 98.5 per

million person‐years

Leukemias, brain neoplasms, and lymphomas were the

third most prevalent cancer groups overall, with ASRs of 36.1, 12.0,

and 10.3 cases per million person‐years, respectively.

STS were fourth common in childhood

Childhood cancer incidence and survival in Thailand: A comprehensive population based registry analysis 1990-2011

Pediatr Blood Cancer 2019 Asian Pacific J Cancer Prev, 2011

Pediatric soft tissue sarcoma

Rhabdomyosarcoma

Non rhabdomyosarcoma

Osteosarcoma

Ewing’s sarcoma

Surg Clin N Am 2016

Rhabdomyosarcoma (RMS)

Rhabdomyosarcoma (RMS) is the fourth most common soft tissue

sarcoma in children and adolescents

Most cases occur in age younger than 10 years

Histologic subtypes: embryonal, alveolar, pleomorphic

Different in age of onset, primary tumor sites, metastases,

long-term outcome

Event-free survival rate depend on low, intermediate,

high risk classification

Pediatr Blood Cancer 2013

Clinical manifestations

Usually present with anatomical mass

Clinical characteristics

Dagher R, The Oncologist 1999

Metastasis: Lung (40-50%), bone marrow(20-30%), bone(10-15%), lymph node depend on site (non-orbit, parameningeal, paratesticular boy>10yrs, retroperitoneum)

PresenterPresentation Notesประมาณง่ายๆว่าของ ERMS เป็น 75%, ส่วน ARMS คิดเป็น 25% Presentation มาด้วย 2 clinical 1. mass ที่อวัยวะร่างกายโดยที่ไม่มีอุบัติเหตุอะไรมากอ่น 2. disturbance of function พบได้ 50% head and neck GU: vagina จะเป็นพวก young children มากกว่าจะมาด้วยมี vaginal กรหแฟพเ แต่ถ้าโตขึ้น older child with ado : cervical and uterine มากกว่า Diff diag พวก benign เช่น inflame, hematoma, lipoma, neurofibroma, malignancy: nonHod, ewing , neuroblastoma พวก proptosis, และ langerhand cell การส่งตรวจทางรังสีนิวเคลียพบว่าการใช้ PET positron emission tomoghraphy จะทำให้สามารถบอกได้ดีว่ามีกระดูกหรือว่า BM metastasis ตรงไหนบ้าง และยังสามารถใช้ในการวางแผนทางรังสีรักษาได้อีกด้วย

Histological subtype RMS is a small round blue cell tumor with two main histologic subtypes

a: Embryonal RMS (ERMS): dense spindle areas, loose myxoid stroma (60%)

b: Alveolar RMS (ARMS): nests with dense stroma, pseudoalveolar spaces (20-25%)

a b

Most cases of RMS appear to be sporadic in nature, but

the disease has been associated with familial syndromes such

as Li-Fraumeni syndrome (LFS)

RMS has also been observed in association with Beckwith-Wiedemann syndrome, a fetal overgrowth syndrome associated with abnormalities on chromosome 11p15, where the gene for insulin-like growth factor II (IGF-II)

RMS diagnosed at or below the age of three years should undergo screening for germline p53 mutations


Risk factor

Risk factor • Ionizing radiation

• Neurofibromatosis (NF1): 15% risk of developing MPNST;

chromosome 17 deletions

• Costello syndrome

(delayed development, MR, hyperflexible joints, hypertrophic

cardiomyopathy, short stature)

• Maternal and paternal use of marijuana, cocaine, prenatal X-ray exposure

Associated syndrome Cancer syndrome Locus Gene Nonneoplastic finding Characteristic tumor

Frequency

of RMS

Costello syndrome 11p15.5 HRAS Facial anormaly, cardiac

hypertrophy, cognitive defect,

developmental delay

Benign: skin papillomas

Malignant: RMS, neuroblastoma, bladder cancer

7%

Li-Fraumeni syndrome 17p13.1

22q12.1

TP53

CHEK2

None Sarcoma, breast cancer, brain tumor, adenocortical cancer, leukemia

6%

Hereditary retinoblastoma 13q14 RB1

None Retinoblastoma, osteosarcoma 2%

Neurofibromatosis type 1 17q11.2 NF1 Café au lait spots, skinfold

freckling, Lisch nodules

Benign: neurofibroma

Malignant: MPNST, AML

1%

Beckwith-Wiedemann

syndrome

11p15.5 Unknown Macrosomia, macroglossia,

hemihypertrophy,

visceromegaly

Wilms tumor, hepablastoma

The two histologic subtypes of RMS, embryonal and

alveolar, have distinct genetic alterations (pathogenesis of these tumors)

Alveolar RMS demonstrated characteristic translocation between the long arm

of chromosome 2 (PAX3 gene) and the long arm of chromosome 13, referred

to as t(2;13)(q35;q14) (PAX3-FKHR fusion)

The variant t(1;13)(p36;q14) fuses the PAX7 gene located on chromosome 1

with FKHR (PAX7-FKHR fusion)

PAX7-FKHR fusion tend to be younger and present with an extremity lesion

Genetic aspects


This translocation fuses the PAX3 gene

(regulate transcription during early neuromuscular development)

with the FKHR gene: transcription factor - forkhead box (FOX) family

(a member of the forkhead family of transcription factors)

It is hypothesized that this fusion transcription factor inappropriately

activates transcription of genes that contribute to a transformed

phenotype

Genetic aspects


Genetic study

The characteristic translocation in alveolar RMS: the structure of the PAX3gene on chromosome 2, the FKHR gene on chromosome 13, and the fusion product of the t(2;13)(q35;q14) translocation (PB = paired box; HD = homeodomain; FKHR = forkhead)

Arch Dis Child 2003

Genetic study

Outcome of reciprocal balanced translocation is worse than in RMS cases without a

translocation (including embryonal RMS and translocation-negative ARMS)

Patients with localized t(2;13) and t(1;13)-positive ARMS had comparable

outcomes whereas a recent study with small numbers suggested that localized

t(1;13) had a better outcome than those with localized t(2;13) tumors

Among patients presenting with metastatic disease, those with t(2;13)-positive had

significantly poorer outcome than those with t(1;13)-positive tumors

Effect of genetic aspects

Embryonal RMS is known to have loss of heterozygosity (LOH) at the 11p15 locus with loss of maternal genetic information and duplication of paternal genetic information

Genetic study

Genetics of RMS 1. Alveolar RMS: translocation of FOXO1-PAX3; t(2;13)

or FOXO1-PAX7; t(1;13) >> activates abnormal growth, differentiation

2. Embryonal RMS: loss of heterozygosity (LOH) at 11p15.5 locus, loss of tumor suppressor >> overproduction of IGF-II, stimulates growth of RMS

- Both subtypes: deregulations of p53, RAS, and MYC pathways

J Clin Oncol 2010

Age onset and overall outcome

Sultan I, J Clin Oncol 2009

Sultan I, J Clin Oncol 2009

Comparing adult and pediatric RMS: An Analysis of 2,600 Patients

J Assoc Pediatr Surg 2006

Histological distribution

Embryonal Alveolar

Age Younger Older

Location Central Peripheral

Invasion Low-moderate High

Metastases Lungs Other

Prognosis 40-90% 30-60%

Nathan and Oski’s Hematology and Oncology of Infancy and Childhood 8th ed, 2015

Histological subtypes of RMS

Diagnostic Evaluation • CBC, metabolic panel, LFT, urinalysis, LDH • Coagulation profile in advanced ARMS, tumor-induced DIC • Primary tumor imaging: MRI, USG paratesticular, bladder/prostate or biliary tree

• Metastatic workup: CT chest, MRI/CT of draining lymph nodes, FDG-PET scan, bone scan, BMA

• Tissue biopsy: histologic examination: desmin, myogenin, MyoD1, muscle-specific actin

• Brain MRI is recommended in patients with widespread metastatic disease in NRSTS

Metastatic workup

Breneman JC, J Clin Oncol 2003

Prognostic factor

Favorable

Embryonal

Botryoid

Spindle cell

Unfavorable

Alveolar

Anaplastic

Favorable

Orbit

Head/ Neck

GU system

Biliary tract

Unfavorable

Bladder

Prostate

Parameningeal

Extremities

Perineal, perianal

Primary site Histopathology

Pretreatment: TNM staging system

Postoperative: clinical grouping system


Risk classification Pretreatment: TNM staging system

Postoperative: clinical grouping system


FAV

- Confined - Extension 5 cm

Regional node

involved

Un FAV

Risk stratification

Risk classification and outcome


Breneman JC, J Clin Oncol 2003

Treatment for RMS Local Control:

◦ Surgery, local control is accomplished using radiotherapy

Systemic Control: ◦ Chemotherapy; localized disease require systemic therapy to

eradicate micrometastatic disease typically present at diagnosis

Vincristine (V), Actinomycin D (A), Cyclophosphamide (C)

The Oncologist 2009

Guideline

Surgery Total tumor removal is key aspects

(main prognostic factor in treatment of RMS)

Quality of resection is defined by worst pathological margin (microscopic complete, microscopic incomplete, and macroscopic complete resection)

Predominant site of treatment failure: local recurrence

Both surgery and RT contribute to local control

but each has risks and benefits

Semin Pediatr Surg 2016

Chemotherapy - COG studies: standard chemotherapy consists of backbone of vincristine, actinomycin-D, cyclophosphamide (VAC)

- Low risk: duration of chemotherapy, dosing of cyclophosphamide both can be decreased while maintaining good outcomes, limiting toxicity

- Intermediate risk: VAC/VI (irinotecan) equally effective to VAC while decrease dose of cyclophosphamide

- European Soft tissue Sarcoma (EpSSG): ifosfamide, vincristine, actinomycin-d is standard treatment for RMS, due to lower gonadal toxicity


Low risk, subset 1

Low risk, subset 2 Intermediate risk

Chemotherapy regimens

High risk

Chemotherapy regimens

Radiotherapy - RT is used in almost all RMS patients to improve local control and outcome (except Clinical Group I ERMS)

- Candidates for RT: Group I ARMS (36Gy), Group II (41.4Gy) or Group III (50.4Gy) disease

- Dose adjustment of RT: depend on completeness of resection prior to chemotherapy (Clinical Group) or completeness of a delayed primary excision after adjuvant chemotherapy

- European studies: radiation dosage is determined according tumor histology, tumor response and clinical group


Radiotherapy - STS are only moderately radiation-sensitive

- NRSTS require higher radiation doses than do RMS to achieve local control

- Recommendation is fractionated daily doses of 180 cGy for most sites

- Preoperative radiotherapy is recommended in NRSTS when tumor shrinkage will enable the surgeon to achieve negative margins

- All metastatic lesions should be radiated


Outcome of RMS

Current Opinion Oncol 2000

Prognostic factor of metastatic RMS at diagnosis

J Clin Oncol 2008

Conclusion Prognosis for RMS: age, site of primary tumor, tumor size, resectability, metastases, regional lymph node involvement, histopathology (fusion status)

Favorable prognostic factors:

Embryonal histology fusion-negative tumor sites in orbit (non-parameningeal), head/neck, GU exclude bladder/prostate no distant metastases, complete resection tumor size

New treatment strategies

Molecular targeted therapy • Insulin-like growth factor 1 receptor (IGF-1R): transcription control of IGF-1R expression by PAX-FOXO1 in ARMS; promotes cell growth, inhibits apoptosis

• Mammalian target of rapamycin (mTOR): Activation of mTOR-signaling pathway is common in RMS, mTOR inhibitor (temsirolimus): 6% response rate in recurrent RMS

• Angiogenesis pathways: Inhibition of angiogenesis via VEGF blockade; Clinical trial Bevacizumab monoclonal antibody against VEGF with advanced solid tumors


Post-treatment evaluation First Year after Completion of Therapy

1. Physical examination including complete blood count every 3 months.

2. Chest radiograph every 3 months.

3. Appropriate imaging studies (i.e., CT or MRI of the involved region) every 3-6 months.

Second and Third Years after Completion of Therapy

1. Physical examination including complete blood count every 4 months.

2. Chest radiograph every 4 months.

3. Appropriate imaging studies every 4-6 months

Post-treatment evaluation

Fourth year after completion of therapy: every 6-12 months.

Fifth to tenth years after completion of therapy: annual visit for physical examination, imaging

Tenth years after completion of therapy

1. maintain yearly visit or phone contact

2. record attainment of puberty and pregnancy

Non-RMS Soft tissue sarcoma

Heterogeneous group of rare mesenchymal tumors

Wide variety of histopathologies, biologies

Surgery has a primary role in treatment of resectable NRSTSs,

Adjuvant treatment relies on Children’s Oncology Group risk stratification guideline

Radiation therapy is administered to patients whose resection margins are close to the tumor

World J Clin Pediatr 2015


Extraosseous Ewing’s sarcoma family of tumors Malignant peripheral nerve sheet tumor (MPNST) Synovial sarcoma Congenital infantile fibrosarcoma Desmoplastic small round cell tumors



Surg Clin N Am 2016

Surg Clin N Am 2016


Several studies have demonstrated common themes with regard to prognosis of patients with NRSTS: 1. extent of disease (local vs metastatic) 2. extent of tumor resection (resectable vs unresectable),

maximal tumor diameter (5 cm) 3. tumor grade (low vs high) Using these factors, 3 distinct risk groups were proposed


Williams RF, Surg Clin N Am 2016

Risk classification for NRMS

Low risk group

Comprise about 50% of the population of NRSTS

Patients with grossly resected nonmetastatic tumors except those patients with high grade and greater than 5 cm in maximal diameter tumors

A 5-year survival estimate of 90%

Intermediate risk

Comprise approximately 35% of NRSTS patients

Patients with both high-grade and greater than 5-cm tumors

Patients with initially unresectable nonmetastatic tumors, regardless of grade or size


High risk group

Comprise 15% of NRSTS tumors

Patients with metastatic tumors, including those with regional lymph node metastasis


The Oncologist 2009


Chemotherapy: poorer response than pediatric RMS, advocated in select types of NRSTS

Backbones chemotherapy: Ifosfamide and doxorubicin

Systematic review: autologous hematopoietic stem cell transplantation following high dose chemotherapy in locally advanced or metastatic NRSTS did not result in better OS than standard-dose chemotherapy



Regimens

MPNSTs - Malignant schwannomas, neurofibrosarcomas, neurogenic sarcomas (6% of all NRSTSs)

- 50% of cases associated with neurofibromatosis type 1

- NF1 mutation

- 80% of cases diagnosed at age 10 years or older

- The worst prognosis in pediatric NRSTSs: 5-year OS of 43-59%

- Complete surgical removal is only chance for cure

- Radiation therapy: recommend in cases with residual tumor after surgery; no evidence indicates that this improves survival, adjuvant chemotherapy have minimal benefit


Synovial sarcoma - Aggressive spindle cell tumor, 10% of all STSs

- Common located in lower extremities, other sites (including the head/ neck, hands, retroperitoneum, digestive system, mediastinum)

- Histology: spindle cells with varying degree of epithelial differentiation

- IHC study: marked with both mesenchymal and epithelial markers

- Cytogenetic signature: reciprocal translocation t(X;18) that leads to a chimeric fusion between SS18-SSX (SSX1, SSX2 or SSX4) from ch.X


Synovial sarcoma - Management of SS: based on risk categorization, risk determinants include clinical group (as in RMS), size (5 cm) and sites

- Low risk: tumors include group I,

Synovial sarcoma - Survival in intermediate-risk SSs (group I, size > 5 cm and group II) after surgery followed by chemotherapy (ifosfamide and doxorubicin) with or without radiation

- Chemotherapy is mainstay treatment in high risk (group III or axial SS) patients with response rate in group III SS was 55%, and OS was 74%


Congenital infantile fibrosarcoma During first month of life, often misdiagnosed as hemangioma or vascular malformation

Rapid growth rate, ulceration are clinical clues necessitating biopsy

Histology: densely packed with spindle cells arranged in bundles

IHC study: Positive with mesenchymal marker vimentin, negative for desmin, S100 protein

- Chromosomal translocation t(12;15)(p13;q25), fusion ETV6-NTRK3

- Tumor is locally aggressive:bony destruction

distant metastasis is rarely reported


Congenital infantile fibrosarcoma

Surgical removal is recommended primary treatment

Adjuvant treatment is generally unnecessary except very large mass, involves vital structures

- neoadjuvant chemotherapy may help down-size tumor

- Prognostic factors: site, extent of lesion

- Extremity: more favorable outcome than axial tumors


Desmoplastic small round cell tumors

Rare, highly aggressive mesenchymal tumor originating on peritoneal surface

Typically in adolescent

Tumor can also be found at other sites, such as head/neck, pleura, kidneys, ovaries, testes

Histology: small round cells arranged in nests with desmoplastic stroma, central necrosis, trabecular or indian fire arrangements

Tumor expresses polyphenotypic differentiation with coexpression of epithelial, mesenchymal and neuronal markers

Desmoplastic small round cell tumors

Tumor is highly aggressive, 60% of cases die within 2 years

Complete resection is not possible in majority of cases

Surgical debulking of tumor followed by radiation therapy is recommended

Tumor appears to respond to multiagent chemotherapy: cyclophosphamide,doxorubicin, vincristine, ifosfamide, etoposide

Recurrent disease is common

Molecular targeting therapy: 3-year OS was reported at 44%,

with a 5-year OS of 15%

The Oncologist 2009

Thank you

Soft tissue sarcoma (STS)Soft tissue sarcomaChildhood cancer incidence and survival in Thailand:�A comprehensive population based registry analysis�1990-2011Pediatric soft tissue sarcoma�Rhabdomyosarcoma (RMS)Slide Number 6Clinical characteristicsHistological subtypeRisk factorRisk factorAssociated syndromeGenetic aspectsGenetic aspectsGenetic studyGenetic studyEffect of genetic aspects Genetic studyGenetics of RMSSlide Number 19Comparing adult and pediatric RMS:�An Analysis of 2,600 PatientsComparing adult and pediatric RMS:�An Analysis of 2,600 PatientsSlide Number 22Slide Number 23Slide Number 24Diagnostic Evaluation Metastatic workupPrognostic factor��Pretreatment: TNM staging system �Postoperative: clinical grouping system �Risk classificationRisk stratificationRisk classification and outcomeTreatment for RMSSlide Number 34SurgeryChemotherapyChemotherapy regimensChemotherapy regimensRadiotherapyRadiotherapyOutcome of RMSSlide Number 42ConclusionNew treatment strategiesSlide Number 45Molecular targeted therapyPost-treatment evaluationPost-treatment evaluationNon-RMS �Soft tissue sarcomaNon-RMS �Soft tissue sarcomaNon-RMS �Soft tissue sarcomaNon-RMS �Soft tissue sarcomaNon-RMS �Soft tissue sarcomaNon-RMS �Soft tissue sarcomaRisk classification for NRMS Low risk group�Intermediate risk�High risk group�Non-RMS �Soft tissue sarcomaNon-RMS �Soft tissue sarcomaNon-RMS �Soft tissue sarcomaSlide Number 62RegimensMPNSTsSynovial sarcomaSynovial sarcomaSynovial sarcomaCongenital infantile fibrosarcomaCongenital infantile fibrosarcomaDesmoplastic small round cell tumorsDesmoplastic small round cell tumorsSlide Number 72Slide Number 73

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