sarcoma - mussa mensa

Mussa MensaCT2

The Welsh Centre for Burns & Plastic Surgery

Sarcoma

EpidemiologyHistopathologyClinical presentation InvestigationStaging and gradingManagementPrognosis

Overview

Sarcomas are a diverse group of rare tumours, accounting for less than 1% of all malignant tumours 1

Arise from the embryonic mesoderm

Introduction

Ectoderm nervous system, epidermis (muscle + connective tissue in the head)Mesoderm connective tissue, muscle (except head)Endoderm epithelial, glands

Sarcomas are a diverse group of rare tumours, accounting for less than 1% of all malignant tumours 1

Arise from the embryonic mesodermThey present most commonly as an asymptomatic mass

originating in an extremity, but can occur elsewhere in the body

Although rare, half of those diagnosed will die from the sarcoma 2

Introduction

Incidence varies 1.8 – 5 cases per 100,000 per year In the UK ≈1500-2000 cases diagnosed annually 1

Incidence increases with age – average age at diagnosis ≈57.4 years 3

Certain subtypes e.g. rhabdomyosarcoma more common in children

Men and women are equally affected 3,4

Epidemiology

The various sarcomas include: bone sarcomas (osteosarcomas and chondrosarcomas), Ewing's sarcomas, peripheral primitive neuroectodermal tumors, soft tissue sarcomas (STS) - most frequent

Sarcoma Types

The various sarcomas include: bone sarcomas (osteosarcomas and chondrosarcomas), Ewing's sarcomas, peripheral primitive neuroectodermal tumors, soft tissue sarcomas (STS) - most frequent

STS can occur anywhere in the body, but most originate in the following: lower extremity (thigh, buttock, groin) (46%) trunk (18%) upper extremity (13%) the retroperitoneum (13%), the head and neck (9%)

Usually differentiate towards one tissue typeThe WHO has defined more than 50 histological subtypes

Sarcoma Types

Table 1 – the main histological subtypes and line of differentiation

Sarcoma Types

Sarcoma Normal counterpart

Percentage of STS

Malignant fibrous histiocytoma

Fibroblast or myofibroblast

≈28%

Malignant fibrous histiocytoma (MFH):Formerly known as fibrosarcoma, and more recently classified as pleomorphic undifferentiated sarcoma (PUS)Most common type of STSAggressive biological behaviour and poor prognosis

Sarcoma Types

Malignant fibrous histiocytoma (MFH):Formerly known as fibrosarcoma, and more recently classified as pleomorphic undifferentiated sarcoma (PUS)Most common type of STSAggressive biological behaviour and poor prognosisTypically occur in the retroperitoneum and proximal extremities, and occasionally in boneMacroscopically - typically large (5-20 cm), well circumscribed but unencapsulated, with a grey firm heterogeneous cut surface, sometimes with areas of necrosis

Sarcoma Types


Sarcoma Types

Daigeler et al. BMC Surgery 2006 http://radiopaedia.org/

Microscopically - poorly differentiated fibroblasts, myofibroblasts, histiocyte-like cells with significant cellular pleomorphism, storiform architecture and also demonstrate bizarre multi-nucleated giant cells

Sarcoma Types


6


Sarcoma Types


Percentage of STS



≈28%

Liposarcoma Adipocyte ≈15%

Liposarcoma:Malignant tumours of fatty tissue and are the malignant counterpart to a benign lipomaThey are the second commonest type of soft-tissue sarcomaAge at diagnosis ≈40-60 yearsUsually occur at the extremities or in the retroperitoneum

Sarcoma Types

https://grosspathology-sites.uchicago.edu/lipoma http://radiopaedia.org/

Liposarcoma:Originate from mesenchymal cells, they are classified histologically into 5 types

I. well differentiated liposarcoma – commonest (≈50%); low gradeII. myxoid liposarcoma – 2nd commonest; intermediate gradeIII. round cell/de-differentiated liposarcomaIV. Pleomorphic liposarcoma – least commonV. mixed

Sarcoma Types

I - WDLS

III - DDLS

IV - PMLSII - MXOLS

7


Sarcoma Types


Percentage of STS



≈28%

Liposarcoma Adipocyte ≈15%Leiomyosarcoma Smooth muscle ≈12%

Leiomyosarcoma:Malignant neoplasms that originate from smooth muscle cellsMay be considered the malignant counterpart of a leiomyoma (most common = uterine leiomyoma/fibroid)Can potentially occur anywhere where there is smooth muscle. Commonly described sites include:

uterus: uterine leiomyosarcoma: most common retroperitoneum: retroperitoneal leiomyosarcoma; most common

non-uterine site stomach - gastric leiomyosarcoma (GIST) Other less common sites include the oesophagus, small intestine,

liver, bladder, nasopharynx, bone, venous structures (IVC/renal vein), spermatic cord

Sarcoma Types

Leiomyosarcoma:Macroscopic appearance - bulky, invasive masses which are often necrotic and hemorrhagic

Sarcoma Types

http://radiopaedia.org/

http://goo.gl/WF0les

Leiomyosarcoma:Macroscopic appearance - bulky, invasive masses which are often necrotic and hemorrhagicMicroscopically – well differentiated vs poorly differentiated

well differentiated = similar to leiomyomas/native smooth muscle tissue with little atypia

poorly differentiated = atypia, pleomorphism, increased mitotic rate +/- necrosis

Sarcoma Types

http://goo.gl/1hb7nO

normal myometrium

leiomyoma leiomyosarcoma

http://goo.gl/uk1Up9


Sarcoma Types


Percentage of STS 5



≈28%

Liposarcoma Adipocyte ≈15%Leiomyosarcoma Smooth muscle ≈12%Synovial sarcoma Unknown ≈10%Malignant peripheral nerve sheath tumour

Schwann cell ≈6%

Rhabdomyosarcoma

Skeletal muscle ≈5%

Angiosarcoma Endothelial cell ≈2%Ewing’s sarcoma Unknown ≈2%

Most sarcomas seem to arise de novo with no obvious causeCytogenetic analysis has identified several oncogenes and

chromosomal translocations associated with certain histologic subtypes

Mutations in tumour suppressor genes e.g. Rb gene or p53 gene can lead to the development of (retinoblastomas and) sarcomas of soft tissue and bone

P53 gene mutations observed in 30-60% of STS 5

Aetiology

High incidence of sarcomas in those with hereditary/germline mutations of p53 gene e.g. Li-Fraumeni syndrome

Radiation induced STS rare but has been associated with RTx for breast cancer and lymphoma

Exposure to chemical carcinogens e.g. vinyl chloride, associated with increased incidence 1

Aetiology

Soft tissue swellings are common, most are benignTypically present with a painless mass growing slowly for

months or yearsFunction and general health usually not affected, hence may

be found incidentallySize at presentation depends on location – extremities =

small when discovered; retroperitoneal = large before apparent

DDx includes - lipomas, lymphangiomas, leiomyomas, and neuromas; primary or metastatic carcinoma, melanoma, or lymphoma

History and presentation + rarity of sarcomas commonly leads to initial misdiagnosis

Clinical Presentation

O/E – important to ascertain the following: size, anatomical site + ?painful ?fixed to the skin ?beneath the skin but margins easily defined ?tethered + accentuated by muscle contraction i.e. beneath deep

fasciaDepth of tumour is a sensitive marker of malignancy 8

Table 2:

Clinical Presentation

Department of Health criteria for urgent (2WW) referral of a soft tissue lesionSoft tissue mass >5cm (golf ball size)Painful lumpA soft tissue lump that is increasing in sizeA lump of any size that is deep to muscle fasciaRecurrence of a lump after previous excision

NICE guidelines 9 recommend that patients with suspected soft tissue sarcoma are “urgently referred for rapid assessment at a one-stop diagnostic clinic” where triple assessment can be undertaken clinical history & examination ultrasound imaging + specific imaging tissue biopsy

Investigation

Plain radiography:lumps in the extremities; rule out mass arising from bonecertain subtypes e.g. synovial sarcoma show characteristic calcification

Ultrasound:rapid triage of benign vs supicious lesionsuseful when clinical suspicion exists but referral criteria not metshould not delay referral for lesions with a high degree of clinical suspicion for malignancyUS guided biopsy

investigation

http://goo.gl/oQ8FNI

http://goo.gl/zlm0wz

CT and MRI:MRI is preferred as the initial imaging modality for STS of the extremities, trunk and head & neckCT = gold standard for preoperative staging + used to assess intra-abdominal massesHRCT has a role in identification of bony involvement + exclusion of pulmonary metastasisNo difference in the two for efficacy of local staging of STS in the extremitiesAdvantage of MRI is multiplanar images with better spatial orientation

investigation

Biopsy:Core needle biopsy

advantages = sensitivity of 90-95%, quicker, cheaper and safer (0.4% vs 12-17% complication rate1) than open incision biopsy

disadvantages = several cores needed to improve accuracy; image guidance for deeper/necrotic tumours

FNAC – not recommended; lower accuracy than core biopsyNICE guidelines9 recommend that results should be interpreted by a specialist sarcoma pathologist

investigation

Tumour staging can help estimate prognosis and survival as well as plan management

Several systems are used to stage STSThe most widely accepted are the:

American Joint Comitte on Cancer grading system International Union Against Cancer staging system

Staging

American Joint Comitte on Cancer grading system - Table 3

Staging

Grade CharacteristicTumour (T)T0 No evidence of primary tumourT1 Primary tumour <5cm (T1a = superficial; T1b =

deep)T2 Primary tumour >5cm (T2a = superficial; T2b =

deep)Regional lymph nodes (N)N0 No regional lymph nodesN1 Regional lymph nodes involvedMetastases (M)M0 No metastasesM1 Distant metastases

International Union Against Cancer staging system – Table 4

Staging

Stage Tumour characteristics AJCC equivalent

1A Low grade, small, superficial or deep T1 a-b, N0, M0

1B Low grade, large, superficial T2a, N0, M0II A Low grade, large, deep T2b, N0, M0II B High grade, small, superficial or deep T1 a-b, N0.

M0II C High grade, large, superficial T2a, N0, M0III High grade, large, deep T2b, N0, M0IV Any metastasis Any T, N1 or

M1

Tumour grade is related to prognosis

A commonly adopted system in the UK is the Trojani grading system

High grade tumours are poorly differentiated or undifferentiated

They carry a high likelyhood of metastasis and poor patient survival

Tumour grade is the most important prognostic factor in metastatic recurrence

grading

Aims: Ensure long term survival Avoid local recurrence Maximise patient function whilst minimising morbidity

Requires an MDT approach with various combinations of surgery, radiotherapy and chemotherapy 9

Treatment decisions best made by an MDT consisting of surgeons, pathologists, radiologists, medical oncologists and clinical oncologists

Take into account the tumour’s site and stage plus the patient’s comorbidities and treatment preferences

Management

Surgery is the mainstay of treatment for patients with localised disease

Aims to excise the tumour completely along with a biological barrier of normal tissue

No international consensus exists on what constitutes an acceptable resection margin

UK consensus guidelines state that 1cm of normal soft tissue or equivalent (e.g. fascia) is an acceptable margin 10

Positive margins carry an increased risk of disease recurrence and reduced disease specific survival

Surgical management

The standard of care for most patients with STS of the extremities is ‘limb salvage surgery’

Aims to retain a functional limb to maintain a postop quality of life + acceptable resections margins to ensure low risk of recurrence

Improved adjuvant radiotherapy + reconstructive surgery have enabled more limited surgery to be performed and function to be preserved

Advances in reconstructive techniques have enabled limb preservation in complex cases

European Society of Medical Oncology guidance states that treatment by wide surgical excision if sufficient for low grade T1a/T1b + superficial high grade tumours

Surgical management

Surgical management

Early complications of surgery include haemorrhage, wound infection, VTE and flap failure

Postop rehab varies with patient and type of surgery – intensive specialist nursing, physiotherapy and occupational therapy often required

1

RTx has been shown to improve local control in surgically resectable disease

Candidates for Rtx include: intermediate or high grade STS large, deep low grade sarcomas incompletely resected tumours close to important structures

Optimal time for RTx unclear – in the UK postop RTx is the standard

Complications associated with postop RTx include joint stiffness, oedema and pathological fractures

Radiotherapy

UK consensus guidelines 10 do not advocate chemotherapy as standard management

There is conflicting evidence in the use of adjuvant chemotherapy in the management of STS of the extremities

Chemosensitivity varies with histological subtypes e.g.myxoid liposarcoma are more chemosensitive than some other types

In cases of advanced disease, use of palliative adjuvant chemotherapy may be appropriate e.g. in those with large and highgrade tumours (typically synovial

sarcoma and liposarcoma) aim to shrink the tumour prior to palliative surgery

Chemotherapy

Isolated limb perfusion

Widely used in Europe to treat STS of the extremities, but only in a few UK centres

High concentrations of chemotherapeutic agents are delivered under hyperthermic conditions

Via arterial and venous cannula to a limb isolated by pneumatic tourniquet compression

Can be used to reduce tumour size to enable limb salvage procedures or for palliative treatment

Limb salvage rates as high as 74-87% in selected patients with intermediate or high grade disease

40-50% of patients with soft tissue sarcoma develop metastatic disease

Common sites of metastases include: lung, local soft tissues, local and distant lymph nodes

≈20% of patients with STS of the extremities have isolated pulmonary metastases

The outlook for metastatic disease is poor (estimated 5 year survival of 8% with pulmonary metastases, 59% with lymph node metastases) 1

Restaging once mets discovered is important in planning subsequent management

Isolated/single organ mets may be managed surgically +/- adjuvant treatment

metastases

Rationale = early recognition and treatment of local or distant recurrence can prolong survival

Two thirds of recurrences develop within two years of initial surgery

Close surveillance, including regular history and clinical examination + periodic imaging (US or MRI and CXR), is important

In the UK there are varying practices and duration of follow-up

Follow up

Table 5 – Summary of European Society for Medical Oncology guidelines for follow-up in STS

Follow Up

Years since diagnosis Frequency of follow-up

High grade tumours1-3 3-4 months4-5 6 monthsMore than 5 Annually

Low grade tumours3-5 4-6 monthsMore than 5 Annually

Soft tissue lumps are common, but STS account for only 1% of adult cancers

Distinguishing between malignant and benign lumps is difficult but important because early diagnosis improves outcomes

A lump that is deep to fascia, increasing in size and/or painful and >5cm warrants urgent referral

Treatment options include wide surgical excision alone, excision with pre/post operative radiotherapy and adjuvant chemotherapy

Newer techniques of limb salvage surgery and adjuvant radiotherapy have reduced the need for amputation

summary

1. Sinha S, Peach AHS. Diagnosis and Management of soft tissue sarcoma. BMJ 2010; 341: c7170

2. Rydholm A. Improving the management of soft tissue sarcoma. BMJ 1998; 317: 93-933. Canter RJ et al. Interaction of histologic subtype and histological grade in predicting

survival for soft tissue sarcomas. J Am Coll Surg 2010; 210:191-84. Wibmer C et al. Increasing incidence rates of soft tissue sarcomas? A population-

based epidemiologic study and literature review. Ann Oncol 2010; 21:1106-115. Cormier, JN, Pollock, RE. Soft Tissue Sarcomas. CA: A Cancer Journal for Clinicians

2004; 54 (2): 94–1096. Bali A et al. Malignant Fibrous Histiocytoma - An Unusual Transformation from Benign

to Malignant. J Cancer Sci Ther 2010;2: 053-0577. Rekhi B, Navale P, Jambhekar N A. Critical histopathological analysis of 25

dedifferentiated liposarcomas, including uncommon variants, reviewed at a Tertiary Cancer Referral Center. Indian J Pathol Microbiol 2012;55:294-302

8. Lawrence W et al. Adult soft tissue sarcomas: A pattern of care survey of the American College of Surgeons. Ann Surg 1987; 205:349-59

9. National Institute for Health and Clinical Excellence. Improving outcomes for people with sarcoma. The manual. NICE 2006

10. Grimer R et al. Guidelines for the management of soft tissue sarcomas. Sarcoma 2010; 506182; online

References

sarcoma - mussa mensa

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