L10. Malignant Tumors of the Musculoskeletal System

Soft tissue sarcomas (STS) are __________ and ___________ diseases.

rare and heterogenous


13k diagnoses; >5000 deaths

What is crucial in STS diagnosis?

tissue diagnosis

pathology should be reviewed by an experienced pathologist

STS account for ______% of adult malignancies and ____% of pediatric malignancies.

1%

15%

When is the peak incidence of STS and are males or females more likely to be affected?

15

males

What are the two most common STS?

Osteosarcoma (56%)

Ewing's Sarcomas (34%)

What STS is most common in children?

Rhabdomyosarcoma (RMS)

_____% of STS involve the limbs.

75%

although they can occur anywhere with connective tissues

Is there screening for STS?

no because very rare

What are 8 other differential diagnoses for STS? How can you differentiate?

1. endochonomas (tend to be benign)

2. osteoid osteoma (proximal femur & relieved with NSAIDs)

3. myositis ossificans (post-traumatic)

4. bone cysts

5. gout

6. brown tumors of hyperparathyroidism

7. osteomyelitis

8. paget's disease

What is the appearance of an enchondroma?

Left side is a radiograph

Right is a MRI

What secondary STS can occur from enchondromas?

secondary chondrosarcomas

What is the appearance of an osteoid osteoma?

these rarely have any malignant potential

Primary brown tumors of hyperparathyroidism are caused by what?

parathyroid adenoma

Secondary brown tumors of hyperparathyroidism are caused by what?

chronic renal disease

What is seen on imaging for osteomyelitis?

brodie's abscess

What is Paget's Disease and how can it be differentiated from STS?

Disorder of bone metabolism resulting in benign growths

May cause pain or nerve impingement & is often found incidentally on radiographs

Alkaline phosphatase is highly elevated

What is the treatment of Paget's Disease?

IV bisphosphonates

**Zoledronic acid**

If symptoms worsen in Paget's disease, you should reimage due to what concern?

secondary sarcoma (due to increased cell turnover)

STS: differential diagnosis

What are the risk factors for STS?

1. prior radiation therapy to the area affected

2. genetic cancer syndrome

- Li-Fraumeni syndrome

- Familial adenomatous polyposis (FAP)

- Carney-Stratakis Syndrome

- Hereditary retinoblastoma

- Neurofibromatosis

What mutation causes Li-Fraumeni Syndreom?

germline mutation in TP53 tumor suppressor gene

Li-Fraumeni syndrome increases your risk of developing multiple primary malignancies, such as?

STS, osteosarcomas, breast cancer, leukemia, brain cancers, and ACC before 45 years old

Familial adenomatous polyposis (FAP) is an inherited autosomal _____________ colorectal cancer syndrome.

dominant

What mutation causes FAP?

FAP?
germline mutations in the adenomatous polyposis coli (APC) gene on chromosome 5q21

What is FAP characterized by?

adenomatous colon polyps that progress to CRC by 35-40 year old

What is Gardner's syndrome?

Variant of FAP with extracolonic manifestations such as osteomas,

skin cysts, congenital hypertrophy of the retinal pigmented epithelium, and desmoid tumors (aggressive fibromatosis)

What is Carney-Stratakis Syndrome? What is the inheritence?

autosomal dominant

GISTs and paragangliomas

What is hereditary retinoblastoma caused by?

germline mutation in retinoblastoma tumor suppressor gene (RB1)

What causes neurofibromatosis?

mutations in the neurofibromin 1 gene (NF1) or neurofibromin 2 gene (NF2)

____% of patients with neurofibromatosis develop STS.

5%

What is the most common STS in neurofibromatosis?

malignant peripheral nerve sheath tumors

There are more than ______ different histologic subtypes of STS

50

Heterogenous

What are the two broad categories of STS?

1. soft tissue sarcomas (fat, muscle, nerve, nerve sheath, blood vessel, etc)

2. sarcomas of the bone

What are the most common anatomic sites of STS?

1. extremities (43%)

2. visceral (19%)

3. retroperitoneum (5%)

4. trunk (10%)

5. head & neck (9%)

What is the geography of osteosarcomas are _____________ while Ewing's sarcomas are _________________.

metaphyseal


diaphyseal

How do you diagnose STS (imaging)?

1. plain radiographs (AP and orthogonal views)

2. CT (small cortical lesions & lung windows for metastases)

3. angiogram (vascular structures & resectability)

4. Magnetic Resonance Imaging (MRI)
-Gold Standard!!!!!
-The most helpful test is an MRI!
-with contrast tells you more
-Collect x-ray first and if the x-ray is suspicious collect MRI

What is the preferred method for diagnosis and grading of STS?

pretreatment biopsy

Why is it important to have someone experienced performing and reading biopsies for STS?

track of needle matters in & out

"biopsy should be placed along the future resection axis with minimal dissection and careful attention to hemostasis"

grade can be underestimated

What type of needle should you use in STS biopsy?

core needle biopsy preferred (because you want more tissue)

do not perform fine needle aspiration

open excision may be required

What 8 things should the pathology report include in STS?

1. organ/site
2. depth
3. size
4. grade
5. margin status
6. lymph nodes
7. +/- necrosis
8. mitotic rate, vascular invasion, inflammatory infiltration

How do you stage STS?

T=size
N=# lymph nodes
M=metastasis
G=Grade (which is specific for STS and prostate cancer)

In sarcoma once the nodes are involved it's stage 4

Stage drives prognosis

How do you treat STS generally?

multidisciplinary and tertiary/university based team with surgeon, rad onc, med onc, & PT/OT

limb sparing is preferred, but need good margins

neoadjuvant chemo +/ XRT if primary resection difficult

What is the difference between allografting, prostheses, and rotationplasty?

allografting: bone from cadaver

prostheses: made of titanium

rotationplasty: makes fitting into prosthesis easier



The ankle is now the knee joint

Nerves can be re-taught

What are the options for radiation in the treatment of STS?

external beam radiation

axial lesions problematic to resect with good margins, so may use intraoperative RT or proton beam therapy

Can you treat osteosarcoma with chemo and radiation?

no --> radio-resistant & chemo-sensitive

**neoadjuvant chemotherapy is common

Can you treat Ewing's sarcoma with chemo and radiation?

yes --> radio- and chemo-sensitive

Can you treat chondrosarcoma with chemo and radiation?

no --> radio- and chemo-resistant typically

How does osteosarcoma typically present?

painful swelling around knee or humerus

night pain & limping

firm/soft mass fixed to underlying bone

serum alkaline phoshate elevated

What is the prognosis of osteosarcoma?

~20% survived 5 years before chemotherapy era

-60-70% 5-year survival currently

limb sparing in 80% currently

long term morbidity from chemo (heart disease, secondary cancers, infertility)

What is the Pathognomonic "appearance" of osteosarcoma?

Codman's Triangle

How does osteosarcoma appear on pathology?

derived from osteoblasts and will secrete osteoid (cotton candy appearance)

How do you treat osteosarcoma specifially?

chemo-sensitive with neoadjuvant chemotherapy --> crucial for limb preservation and tretament of "micro-metastatic" disease

surgery s/p chemo

"no viable cancer at resection is a good prognostic sign" --> but recurrence usually occurs in the lungs

How does Ewing's Sarcoma present?

similar to osteosarcoma, but is AGGRESSIVE (grows & spreads rapidly)

pain & constitutional symptoms present (mimics osteomyelitis)

metastatic disease in 25% at presentation (lungs, bone, bone marrow)

How does Ewing sarcoma appear on x-ray?

Onion skinning refers to the
concentric lines seen on plain
film. As this diaphyseal lesion
expands outward it has a this
characteristic appearance
radiographically.

How does Ewing Sarcoma appear on pathology slides?

cells are small, round, and blue of neuroendocrine origin without osteoid

What is the presentation of chondrosarcomas?

- pain related to location of mass lesion, typically in shoulder
- previous site of enchondroma
- suspect if tumor involves shoulder/sternum
- rapid expansion suggests higher grade or de-differentiation

How does chondrosarcoma appear on x-ray?

mass with matrix-like appearance


x-ray left; mri on right

How does chondrosarcoma appear on pathology?

derived from cartilage secreting cells and deposit a matrix material akin to osteoid

How does liposarcoma typically present?

- develop from well-differentiated tumors
- rapid growth suggests de-differentiated pathology
- develops in retroperitoneum preferentially and limbs next (rare)
- non-painful

How does liposarcoma appear on pathology?

develops from adipocytes and has fatty tissue surrounding the sarcomatous elements, which are spindle shaped

What is the typical presentation of angiosarcoma?

can appear years after
radiation therapy (anywhere)

are also associated with chronic lymphedema

What is the prognosis of angiosarcoma?

prognosis is good when caught early and poor if >5cm or metastatic

How do gastrointestinal stromal tumors present (GIST)?

can occur anywhere in the GI tract & typically metastasize to the liver

How can you treat GIST?

***Somatic tumors

c-KIT, PDGF and VEGF which can be inhibited by small molecule tyrosine kinases (Imatinib, Sunitinib, Regorafenib) --> aka tyrosine kinase inhibitors

Adjuvant therapy is generally employed with Imatinib for 3
years.

If you see a bone lesion in an adult, what is it most likely?

metastatic carcinoma


-in adults MC is the most common cancer to see in the bone and started somewhere else

How does metastatic carcinoma typically present? What do labs look like?

- Pain and pathologic fracture
- Lytic (myeloma/lung) or -blastic lesions (breast/prostate)
- Occasional mild hypercalcemia and elevated alkaline phosphatase
- Rare cytopenias

What cancers typically spread to bone?

breast, prostate, lung, thyroid, renal

What are the most common cases of metastatic carcinoma?

prostate & breast (the most common cancers)

How does metastatic carcinoma develop?

hematogenous spread to bone marrow

What is the prognosis of metastatic carcinoma?

prognosis better for bone only mets than visceral plus bone


***If you only have bone metasis they live a lot longer than breast cancer that has gone to the lungs and liver

What does a nuclear medicine bone scan look like in metastatic carcinoma?

look for asymmetry

Summary Slide