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Muscoloskeletal Diseases #8

Infections and Tumors Professor Scotti 21 January 2014 Author Francesca Rossetti Reviewer Luigi Bonini

INFECTIONS Infections in orthopedics are osteomyelitis, arthritis and infected arthroplasty.

OSTEOMYELITIS Osteomyelitis is an infection of bone and bone marrow; it may be caused by

direct inoculation of bacteria through an open fracture or via the hematogenous route by blood-borne organisms. Osteomyelitis is typically caused by bacteria, very rarely by fungi. It may be acute or chronic.

ACUTE HEMATOGENOUS OSTEOMYELITIS is typical of children and is diagnosed within 2 weeks from the onset of symptoms; typically patients seek for medical advice within 48 hrs since symptoms are very severe. It shows me-ta-epiphyseal localization (lower extremity more frequent) and it is typically monosthotic, i.e. it affects only one bone.

The metaphysis is the typical localization in children because it is highly vascularized. This area is very metabolically active because of the presence of the growth plate allowing for limb lengthening during childhood and adoles-cence; this area is extremely vascularized and that's why typically hematog-enous bacteria stop here. Moreover, the growth plate, which is avascular and cartilaginous, is a natural barrier to the diffusion of the abscess to the epiphy-sis (you can appreciate it also in the MRI below). So, generally the onset of acute hematogenous osteomyelitis is located here in the metaphysis with no spread to the epiphysis; this may, however, occur in more advanced cases.

As you can see here in this drawing (left), the ab-scess diffuses prevalently through the bone and tends to elevate the periosteum. This causes abnormal ossifi-cation around the bone: the cambial layer of the perios-teum in fact is rich in mesenchymal progenitor cells which typically participate in bone healing; in this case these cells are stimulated by the inflammatory microen-vironment rich in cytokines, so the periosteum tends to ossify during osteomyelitis.

Here (below) you can see how the infectious pro-cess may also erode the periosteum and go through the soft tissue and the skin, forming a draining sinus.

Q: How long does this take to develop? A: It's variable, but this doesn't happen in the first days. Typically it's difficult

to see this nowadays. If it's superficial e.g. in the distal metaphysis of the tibia, it may take a few days. The progression of osteomyelitis is quite fast also because the immune system of children is not completely mature so these kinds of infec-tion tend to be more aggressive in kids.

Symptoms include pain, loss of limb function, limp (they cannot walk), swell-ing (can be very important), tenderness, soft tissue abscess (in case of diffusion of the infection to the soft tissues), and fever (up to 39-40 C). Typical presenta-tion is within 48 hrs.

The most sensitive monitor for diagnosis and follow-up is C-reactive protein, while MRI is the most sensitive and specific imaging technique for diagnosis and differential diagnosis. Differential diagnosis is crucial in children presenting with typical symptoms; acute hematogenous osteomyelitis' symptoms are in fact very similar to those of sarcoma (Ewing Sarcoma), that's why it's vital to perform an adequate diagnosis in both cases. Bone scan may also be very useful when diagnosis is unclear.

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The two following imaging features are characteris-tic of osteomyelitis and may help you in the DD with e.g. sarcoma: the sequestrum (ita: sequestro) and the involucrum (ita: sarcofago). Sequestra are areas of dead bone with surrounding granulation (see on the MRI on the left) while the involucrum is the periosteal new bone formation (appears later wrt sequestra) (in the MRI the periosteal membrane appears enhanced and detached by the infection and ossified because of the activation of cells).

Clinical case: 9 yo female after 7 days of pain; so quite a delayed diagnosis. Look at the X-ray pictures and this patchy bone resorption, there is not a clear ar-ea of resorption, but it's rather patchy. You can see here how the growth plate has been interrupted and, since the diagnosis has been delayed, also the epiphy-sis has been involved. So these are the consequences of a delayed diagnosis and that's why it's crucial to do it ASAP. What could be the consequences of diffusion to the epiphysis? Possible complications can be osteoar-thritis and infection to the joint with very severe conse-quences, e.g. disruption of the cartilage, necrosis, and early osteoarthritis. Since this was a young child, this pathology may affect the normal growth pattern. You may have both necrosis, so a growth arrest, or you may have a stimulation of cells, so excessive growth compared to the controlateral side. But this is difficult to predict and it also depends on how soon you treat the osteomyelitis.

Treatment is based on identification of pathogen involved, by performing blood culture and with local aspiration if possible. Often also surgical debridement is required, especially in case of massive infection. However, while you're waiting for cultures (typically you wait 5 days) you can establish an empirical therapy with the most common antibiotics vs common bacteria, as you know that most of these infections in children are due to S. Aureus (most important), but also gram-bacilli and group B Streptococci in the newborn, while in children >4yo group A strepto-cocci. In adults there is a wide variety of bacteria, but still S.Aureus is the one most commonly involved.

ACUTE POST TRAUMATIC OSTEOMYELITIS is typical of adults. Usually it is secondary to open fractures,

that's why prevention, adequate prophylaxis of open fractures is very important and its usually done with a com-mon antibiotic; open fractures with wide soft tissue damage (e.g. type III of Gustilo Anderson class.) require a mul-tiple antibiotic therapy in order to cover gram-, gram+ and anaerobes. Clinical findings are very similar to those of the hematogenous, as this is again an acute osteomyelitis. The most common infecting pathogens are S. Aureus (because it resides on the skin), P. Aeruginosa (quite aggressive, infections can be quite troublesome), and gram- bacteria. Empirical therapy again should be started immediately while waiting for cultures.

In case of fractures which became infected after implantation of any kind of hardware (plates or nails), you have to remove the hardware because this may be a site where bacteria attach and in which it is difficult to kill them with the antibiotic. So we always have to use an external fixator to minimize the implants at the site of infection.

This drawing shows the osteomyelitis with all the bacteria growing across the bone; you perform surgical deb-ridement to clean it up, remove the necrotic bone and use an external fixator as a stabilization device: as you can see, it does not include any kind of implant through the infection site. Finally, you properly cover with soft tissue, so you have to perform a muscle flap if needed. This should be accompanied by a proper use of antibiotics, i.e. intravenous antibiotics at high doses.

CHRONIC OSTEOMYELITIS is typically the re-

sult of a poorly treated acute osteomyelitis, usually post-traumatic. We don't see chronic osteomyelitis in children, because symptoms are so severe that they have diagnosis soon and you can establish a proper and effective therapy in time. In adults this is different: especially after a trauma, onset of os-

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teomyelitis may be very subtle, not as severe as in children and that's why it may become chronic.

Risk factors include local/mild systemic deficiency, smoke, major nutritional systemic disorders (e.g. diabetes), diabetic foot (skin ulcers if not treated may involve the bone). Typical patients are old, diabetic or immunosup-pressed for any reason (e.g. systemic disease, age...) or IV drug abusers (because they have a continuous source of bacteria from the skin).

Typical infecting organisms are S.Aureus and P.Aeruginosa, but now you have to be very careful to the methicillin-resistant S.Aureus (MRSA): this is an emerging clinical problem because it can be treated with only very few antibiotics, vancomycin for example.

This is the Cyernys Anatomic classification of chronic osteomyelitis, very academic:

Medullary Superficial Localized Diffuse The natural history is quite typical: periods of quiescence (with no big symp-

toms) and periods of exacerbation. This is why they seek medical advice quite late, because they have long periods of quiescence, they may take some NSAIDs dur-ing the exacerbation periods, so they can only get worse.

There is no rationale for empirical therapy in chronic osteomyelitis: they are of-ten not given any antibiotic at all for months, so it doesn't make any sense to estab-lish an empirical antibiotic therapy. Therapy is only based on deep cultures; even blood cultures are not often diagnostic in these patients. You have to go in the infection site, perform a biopsy, do a debridement of the lesion and ask for cultures.

ARTHRITIS This is another very important topic which can have terrible consequences if not treated.

Here you can see the typical presentation: a knee like this should always warn you: here there is some-thing wrong and whatever it is, it must be serious.

CHILDREN: causes are hematogenous spread from metaphyseal osteomyelitis or from other infection sites, or it can be a complication of therapeutic/diagnostic procedures. So, every time you perform an intraarticu-lar procedure (like steroid injections) you have to be very careful with abscesses. Even arthroscopy, a very minimally invasive surgical procedure, may have arthri-tis as a consequence.

An important organism you have to consider is haemophilus influenzae (30% of < 5 yo patients), plus S.Aureus and type A streptococci. The most common site is the hip; then proximal humerus, distant fibula, radial neck. Usually it involves one single joint.

Treatment: surgical decompression and drainage: you have to decompress the intraarticular swelling, because it may result in necrosis. Also, you have to immediately establish an empirical therapy while waiting for definitive cultures.

Terrible consequences can ensue if not treated properly. Here you can see an intraarticular abscess which can cause damage to the vascular supply especially at sites like the hip where vascularization is not particularly well represented: the femoral epiphysis has been completely disrupted because of the intraarticular pressure. In these cases antibiotic treatment alone is not enough and surgery to decompress the joint is mandatory.

In ADULTS arthritis is more commonly a complication of therapeutic/diagnostic procedures (iatrogenic), or less commonly form hematogenous spread. The most common infecting organisms are S.Aureus, N. Gonorrhoeae and streptococci.

Treatment is the same: first empirical therapy plus definitive cultures. It is im-

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portant to perform decompression which can be arthroscopic: basically you do an arthroscopy, wash the joint (you do arthroscopy under fluid, so you can wash it) you can also leave one tube going into the joint, one tube going out in order to continuously wash the joint even in the ward for a couple of days and decompress.

What I want you to know is that the sequelae may be terrible. An arthritic joint may develop, rapidly evolving to osteoarthritis and also muscle contraction complicates the situation. So every time you see a knee like this in an adult or in a child, it's crucial to start treatment ASAP, even when you are in the ER: give immediately an antibiotic after performing an ar-throcentesis, a synovial fluid aspiration, not to have false negatives. If you are seeking for the bacteria responsible for the infection you want to harvest the fluid or the tissue when the patient is not taking any an-tibiotic, otherwise the bacterial count would be too low.

These are the consequences of an improper or of a proper but late treatment. Look at the disruption: the patient had to receive prosthesis of the good hip because of arthritis.

INFECTED ARTHROPLASTY As I said we are implanting every year more and more arthroplasties. Metallic implants, as in the case of heart

valves, are very prone to infection, and when they get infected, this is really a devastating complication for the patient. It causes severe disability requiring long term IV antibiotic therapy and a two stage surgical procedure: you have to first remove the implant (which is infected, it is impossible to clean it from the bacteria with antibiotics), im-plant a cemented spacer (a kind of prosthesis made of cement capable of releasing locally antibiotics in order to sterilize the area), and then after months during which the patient cannot walk on his limb (the cement spacer doesn't work like a prosthesis), you can implant a new prosthesis.

Infection to an arthroplasty can occur at any time after surgery. That's why, even if the risk is higher in close proximity to surgery (1st six weeks), sometimes infections in the mouth, teeth, lungs, urinary tract, or skin, or just after regular dental procedures that involve gum bleeding can force bacteria in the bloodstream, causing infected arthroplasty. Therefore you always have to recommend antibiotic prophylaxis to any patient carrying a pros-thesis before any (even dental) surgery. Every time we operate a patient, in case we do a medium/demanding surgery, we always establish a prophylactic therapy, which is very effective in minimizing the risk. However, 1-1.2% of patients receiving an arthroplasty get infected, despite the prophylaxis. This is a complication you are going to see if you are attending an orthopedic department. In our department we do maybe 120 prostheses per year, so we see at least one infection in these patients, whatever we do to prevent it. These are part of the complications which are not caused by malpractice, but by the procedure itself. What you can do is to recommend to patient to establish prophylaxis and of course never operate on patients who have an ongoing UTI or dental infection.

The most frequent pathogens are Staphylococcus Epidermidis and S.Aureus, which are on the skin, group B streptococci and of course MRSA; MRSA infection to an arthroplasty is a really severe condition because it requires long-term therapy with multiple antibiotics with frequently lots of complications.

This is the early presentation of an infected total knee (here in a recently operated patient). The joint is typically swollen, red and warm. The joint is typically flexed in a po-sition as motion is usually very painful, so we have loss of function, and also drainage may be present.

CRP is typically very elevated before starting the antibiotic therapy and is the best monitor to assess the effectiveness of your therapy. If your antibiotic is the right one and it is effective, CRP decreases fast once you have started the treatment.

Q: How do you distinguish if CRP is elevated due to surgery or due to infection? A: CRP is increased after surgery, but not that much compared to how it can be increased in such cases; so

with such infections CRP is much more increased. Also, it generally decreases in the first days after surgery, so within the first six weeks you have time to establish the proper diagnosis based on CRP elevation, fever and symp-toms. Moreover patients usually have fever after surgery, because surgery is a trauma, patients are reabsorbing the hematoma which is rich in cytokines and this causes fever. Fever in the first days after surgery is a very unspe-cific sign, it is not a sign of infection. It has to be correlated with elevated CRP and it has to be prolonged for days after surgery. The value depends on the unit used by the lab: in our lab, after surgery we may have a value of CRP of 10/20/50 while with an infection is really much higher like 100.

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Infection of prosthesis causes its mobilization. There are some very specific radiological signs that can help you in performing diagnosis (image on the right). Look at this tibial plate that has been mobilized. All the bone around here has been resorbed because infection activates macrophages and osteoclasts which resorb the bone around the prosthesis; it is very painful because this is moving, it is not stable anymore. This pa-tient had to be treated with revision implant, bone grafting...a very long treatment.

Q: What is the resolution rate of these infec-tions?

A: I don't really have statistical values, but in the normal population it is close to 100%. Chronic infections are rare. Typically they occur in immun-ocompromised patients.

TUMORS

Musculoskeletal oncology is a very complex topic which is 100% managed by orthopedic surgeons specialized in musculoskeletal oncology.

Tumors to the bones are very rare and account for ~2% of all malignant tumors, while metastatic bone dis-eases are probably the most common form of metastasis. Bone metastases are an emerging clinical problem which requires proper treatment.

Grading means "how bad is the tumor". Grading is based on histopathological features, so it's only given on the basis of biopsy, not on imaging. Sarcoma is the general name for mesenchymal tumors. Grade 1: very well differentiated tumors resembling the original tissue, with very low risk of metastasis Grade 2 Grade 3: poorly differentiated, very high risk of metastasis. However, grading of sarcomas is typically very difficult for the pathologist. So, they tend to classify them into

high grade and low grade, i.e. poorly vs highly differentiated.

The TNM classification of tumors is a bit different here. The tumor size is not calculated in cm, but is instead based on the diffusion of the tumor through a compartment; the T of sarcomas is defined as intracompartmental (T1) vs extracompartmental (T2), i.e. wheth-er the primary tumor of the bone extends out of the bone or a soft tissue sarcoma extends out of the fascia. This is based on imaging studies not on biopsy like the M, so whether it is metastatic or not. That's why every time you suspect a malignant tumor, always ask for a total body CT scan and a bone CT scan. Enneking's staging system is based on grade (G), tumor site (T) and metastatic status (M). It identifies three stages, 1, 2 and 3, which correspond to low grade, high grade without metastasis and high grade with metastasis. Also, stages 1 and 2 are further divided into a and b according to their site, whether they are compartmental or not. Typically a low grade sarcoma does not determine metastasis at dis-tant sites but it may.

Q: What about the N staging? A: Lymph node involvement is extremely UNfrequent in sar-

comas. Only some subtypes, e.g. synovial sarcomas, give metas-tasis to lymphnodes.

Localization is crucial and follows typical patterns according

to age of patient and tumor type. You don't have to memorize this, but it's to give you an idea. Of course you have to memorize the sites of tumors, but we'll talk about it later; I want you to un-derstand how difficult it may be to perform diagnosis on the basis of an X-ray when most of them look the same on the X-ray. But if you know the features, then diagnosis is easier. Here you can see the localization 30 yo. Metastasis and myeloma or lymphoma typically can involve the diaphysis, myeloma being a tumor of adults, while Edwing sarcoma is a tumor of children,

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but still localized in the diaphysis. Epiphysis is typically spared by tumors because of the barrier represented by the growth plate; however, chondroblastoma, for example, or infections can affect it; the growth plate is also typically disrupted by malignant tumors, like osteosarcomas. The metaphyseal area can be a site of many tumors. Giant cell tumor is typically epiphyseal, while cartilage tumors, chondrosarcomas, are metaphyseal.

Benign tumors of bone are also very common but we don't know the epidemiology because, being asymp-tomatic, their diagnosis is typically incidental. So anyone may have a bone cyst. Lots of patients are diagnosed when they fall down and they may have fractures for a minimal trauma because the bone was weakened by the cyst or the enchondroma for example; this is typical of enchondromas of finger. Benign tumors are innocuous, but have this feature, they cause pathologic fractures.

Typical symptoms of malignant tumors are persistent pain and progressive swelling, so the symptoms typi-cally should drive the patient to seek medical advice immediately because they are quite scaring, but especially soft tissue sarcomas tend to grow very slowly and especially old patients don't really care about it. They affect mainly young patients.

Surgical resection is the mainstay of treatment; you always have to remove the tumor. These tumors are never treated with CT/RT only, you have to perform resection. Neoadjuvant/adjuvant CT and/or RT depending on the tumor type and grade have to be performed.

Resection can be performed in different fashions:

Intralesional resection: improper treatment for a malignant tumor. Marginal resection: you only enucleate the tumor. This is not a proper treatment for a malignant tumor while

it is a proper treatment for benign tumors. Wide resection: with wide margins in healthy tissue around the tumor. It is a proper treatment for some ma-

lignant tumors Compartmental/radical resection: we take out the entire compartment surrounding the tumor. It is a proper

treatment for high grade malignant tumors. Compartmental resection is very important be-cause you often have skip-metastases: these are metastases to the same tissue, but distant-ly from the primary tumor. Skip metastases may be microscopic and that's why you should perform a wide resection. Also, these tumors diffuse through the vessels, not through the lymphatics, that's why diffusion is typically lo-cally, or to the lungs or to the bone. Now we start our overview of tumors, starting form conditions which are not tumors.

TUMOR-LIKE CONDITIONS NON-OSSIFYING FIBROMA: it is not a tumor. This is the typi-

cal presentation in the metaphysis. Typically you see a radiolucent lesion like a cyst surrounded by a sclerotic rim. The sclerotic rim is always a sign of a benign lesion; malignant tumors do not show this sclerotic rim.

They often resolve spontaneously; so often no treatment is re-quired when the risk of pathological fracture is low, whereas it is required if the lesion is big and there's risk of pathologic fracture. In this case the patient needs no treatment, as it is not that big.

Fibroma typically does not disrupt the corti-ces of bone, so they make the bone weaker compared to other kinds of lesion. This is the typical incidental finding of patients that may come to the ER: they will be very scared, but you can reassure them because it is not serious, nothing really pathologic.

Another tumor-like condition is the SIMPLE

BONE CYST. The difference with fibroma is that, as you can see here in the MRI (central), cysts are filled with fluid.

Simple bone cysts are characterized by symmetric expansion with thinning of the cortices. So, pathologic frac-

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tures may occur more frequently in cysts wrt fibromas.

Very common presentation with a fracture, otherwise they are totally asymptomatic. They show metaphyseal localization (proximal femur, humerus and distant fibula): it may extend to the epiphysis or the diaphysis, but it starts in the metaphysis.

Treatment is mandatory, since the risk of pathologic fractures is very high. Treatment is curettage (i.e. intrale-sional resection) and bone grafting (not always performed, only for big cysts). Bone grafting may be autologous from the iliac crest, or you can use synthetic bone substitutes hydroxyapatite or allografts from multiorgan donors.

Musculoskeletal transplants are the most frequently preformed transplants. We very often use allografts taken from multiorgan donors for ligament reconstruction, bone grafting procedures. And we have no rejection, since the-se allografts are decellularized, so there are no allogeneic cells, it is exclusively extra cellular matrix.

ANEURYSMAL BONE CYST (ABC): this is not a tumor, but it is typically really disrupting. Patients are typically

young (

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affecting also the cartilage.

It is uncommon in children and adolescents, it is more typical of adults 30 - 50 yo. It involves typically epiphysis and metaphysis of long bones (50% around the knee and 10% distal radius).

Treatment is very difficult and has to be planned cor-rectly. Treatment is curettage (removal of all the tissue inside which is brownish and soft) in combination with lo-cal adjuvants (cement, phenol), to kill all the possible remaining cells. However, depending on the patient, you may also decide to do a bone grafting or even a massive allograft, i.e. implanting a whole piece of bone from a ca-daver or to implant a prosthesis. So treatment is very challenging and depends on the site. I remember a patient with giant cell tumor to the distal tibia with the involvement of the ankle joint with subchondral bone, so all the carti-lage. Even if we were very conservative with the treatment, he developed late osteoarthritis. There was no func-tional cartilage in the joint anymore.

Q: Is it fast or slowly progressing? A: This is very difficult to say, because, since it is asymptomatic patients come to you only when pain and dis-

ruption come up, so you never know when it started, you only know when it's like this.

ENCHONDROMA: this is a very common cartilaginous bone tumor. They are persisting islands of cartilage in bone developed through endochondral ossification, like the tibia. Hyaline cartilage has some degree of calcification. This is only cartilage not completely calci-fied and this is a pathological fracture; typical fracture of the proximal phalanx after a minimal trauma. They're seen at any age especially because they are totally asymptomatic, so diagnosis is typically inci-dental because of pathologic fractures mostly or dur-ing routine X-rays maybe for minor trauma.

Treatment is curettage, so you just take it out.

OSTEOCHONDROMA (EXOSTOSIS): it is another typical cartilaginous tumor. They are small overgrowth of cartilage at the edge of a growth plate that develops into a bony protuber-ance with a cartilaginous cap. This was the growth plate and because of an anomaly, there is an overgrowth. They can have a pedicle-like appearance or the can be sessile, so with a very wide basis. Of course at this site it may have some complications, like compression of the neuromuscular bundle. Here is a patient with brachial artery pseudoaneurysm because of an osteochondroma. Here the bony protuberance has a cartilaginous cap: this is calcified cartilage and this grew like a continuation of the growth plate.

There is a small risk of malignant transformation, especially when it's isolated. However, with multiple lesions the risk of malignant transformation increases up to 6-fold: in those cases you always have to perform strict follow up to check for malignant transformation and to possibly remove these lesions even if they are not symptomatic. They may be symptomatic when they compress neurovascular structures or muscles, when they create swelling.

They affect typically teenagers. They grow together with the growth plate, so they stop growing together with the bone: if the growth continues after the closure of the growth plate, it is a sign of malignancy. So when there is no growth plate like here, if the osteochondroma continues to grow, that is a sign of malignancy. Treatment is marginal resection. It is quite common in the distal phalanges.

MALIGNANT BONE TUMORS CHONDROSARCOMA: this is a malignant tumor of cartilaginous origin. Low grade chondrosarcoma may re-

semble an enchondroma, that's why you have to perform proper imaging when you see something like this. In gen-eral, if you don't have an orthopedic oncology background you always consider them enchondromas; indeed most of them are just enchondromas but still in some cases, especially when the borders are not well defined like here, these lesions may be malignant. And that's why you always have to be very careful.

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Chondrosarcoma is the most common primary ma-lignant tumor of the bone. They are typically low-grade, so not particularly aggressive. It affects the proximal long bones (proximal humerus, proximal fe-mur) and it's frequently found around the knee (distal femur, proximal tibia), pelvis and shoulder. Localization is typically central and metaphyseal. It is painful and it can present as an enlarging mass, like this one. This is a high grade osteosarcoma: massive destruction of normal anatomy, huge mass requiring wide/radical re-section.

Surgical treatment of this tumor may be difficult sometimes because they are in close proximity with vascular structures: you want to remove them properly, but preserving motion. We'll see afterwards that most malignant tu-mors were once treated with amputation. Of course this is not true anymore; we always try to perform limb-saving procedures by using allografts and prostheses. Since chondrosarcomas are mainly or typically low grade, they do not require neoadjuvant or adjuvant chemotherapy, only surgery or radiation therapy, in case you did not have clean margins. If you did not an adequate surgery, you have to perform a radiation therapy.

OSTEOSARCOMA: it is the second most common primary malignancy of bone. There are many subtypes (that

you don't need to know); teleangectatic was one, the DD with bone cyst.

Differently from chondrosarcoma, osteosarcoma is mainly high-grade; so this is an extremely aggressive condi-tion. It is typical of children, that's why you have to perform an adequate, ASAP diagnosis. Usually localized about the knee (=distal femur or proximal tib-ia) (50%) in children with a second peak in late adulthood.

This (right) is the typical appear-ance of osteosarcoma: patchy osteolyt-ic lesions, very wide alterations to nor-mal anatomy. It can be barely visible, but one sign that may help you in the diagnosis is the Codman triangle: it is a periosteal reaction to the tumor. It is typically a sign of malignant bone tu-mor. Always perform an MRI, since it is usually diagnostic (above you see that the MRI could detect the edema and bone involvement that was not visible on x-ray, in same patient). Also adults may be affected but much less frequently.

These tumors are treated with neoadjuvant CT + wide/radical resection and reconstructive procedure + adjuvant CT, a very aggressive treatment. Chemo is not required in low grade, but low grade osteosarcomas are rather rare. This is one of the most important successes of polytherapy with 70% of long term survival. All of these patients used to undergo amputation decades ago. Now 70% of these patients are long term cured with a limb sparing procedure. Metastases are typically to the lung and to the bone.

EWING SARCOMA: this is a terrible

condition, typically affecting young chil-dren >5 yo. Its origin is unknown, we don't know from which cells it originates. It's mainly located around the knee, proximal humerus, femoral diaphysis and symp-toms are pain, mass, swelling, fever, ele-vated erythrocytes sedimentation rate, anemia, leukocytosis; the differential diag-nosis is with osteomyelitis, and since this is an extremely aggressive malignant tu-mor, DD has to be performed immediately, because the consequences of a delayed diagnosis both of osteomyelitis or of Ewing sarcoma may really compromise the success of treatment.

You often see a large disrupting mass. Disruption can be enormous or minimal, but in a patient with these symptoms always ask for an X-ray and full blood count. Treatment is the same of osteosarcoma, plus radiation. So treatment is even more aggressive.

Limb sparing surgery: standard of care. One of the most relevant advances in surgery in the last decades, which has a strong impact on the quality of life. We do not perform primary amputation anymore in bone tumors,

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especially in children (like picture on the right, left image). Nowadays we do use mod-ular prostheses (also taken from cadavers); this is a total femur prosthesis (picture on the right, right image). Function will not be optimal, but it is better than the loss of a limb.

Allograft-prosthesis composite is a type of salvage surgery: plastic surgeons can reproduce the extensor mechanism of the knee, the quadriceps, by using a latis-simus dorsi flap. It can be performed both in children and in adults.

I'll show you some examples. This (left) was a malignant tumor we treated with a wide resection implanting a modular reversed prosthesis; after this procedure the functionality of the limb was not iden-tical to a normal limb, he won't play vol-leyball, but still perfectly compatible with normal life.

This is another example of limb-sparing surgery, tumor to the proximal tib-ial metaphysis: what we did was an allo-

graft prosthesis composite. So we implanted a prosthesis but since we had to resect all the proximal tibia, we cut the tibia in the diaphysis, we put here a massive allograft from a cadaver and then put the prosthesis on the allograft. The benefit here of having an allograft was that we had the possibility to at-tach the patellar tendon to the tendon of the allograft allowing for some func-tion. Without this allograft we would have to attach the patellar tendon to the prosthesis which is metallic and does not allow for the integration of the ten-don. So, no extension is possible without an allograft. Again function here was very good: patient could walk without crutches after wide resection.

SOFT TISSUE SARCOMA: sarcomas may arise also from soft tissues. This is the typical presentation, a huge

mass growing within thigh. They don't feel it, especially because the patients are usually old, with poor care of themselves.

Soft tissue sarcomas may arise from fibrous, fatty, neural, muscular, synovial, vascular tissues. Typical presen-tation is a painful, or even painless, frequently enlarging mass.

By definition, every mass >5cm deep to fascia has to be considered a sarcomas; even lipomas which are benign tumors of fat may be larger than 5 cm. They have to be removed properly.

In children the most common is rhabdomyosar-coma, which is an extremely aggressive tumor; oth-erwise they are typical of adults.

Metastases are to the lungs or lymphatics in 5% of cases (only in synovial sarcoma and rhabdomyo-sarcoma); so lymphatic metastases are really uncommon in sarcomas.

Treatment is wide/radical resection in combination with adjuvant therapy depending on the grade. Typically the very large masses are low grade, because they develop slowly and they are painless.

METASTASES They are more common in adults. Metastases typically

come from breast, lung, prostate, kidney, thyroid carci-nomas. Common localizations are to the pelvis and to the spine, ribs and proximal limbs (proximal femur, proximal humerus). The most important problem with metastases is the risk of pathologic fractures because they impair qual-ity of life. I don't want to go into the details of metastatic mechanism of osteolysis; however I want you to know that osteolysis is not caused by the cancer cells directly. In-stead, tumor cells release PTH-related peptide that stimu-

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lates cells towards an osteolytic phenotype; also, osteoclasts are activated and secrete TGF- and IGF1, which fur-ther enhance the release of PTH-rp. So this is basically a vicious circle of metastatic bone disease and osteolysis continues and can only get worse without treatment.

PATHOLOGIC FRACTURES These are a very important clinical entity for you, since they will be more and more common because cancer is

becoming a chronic disease. Most treatments of cancer result not in a cure, but they make cancer chronic, increas-ing the risk of bone metastasis.

The best treatment is prevention, so you have to be able to evaluate impending fractures to understand whether a bone metastasis may determine a fracture with minimal trauma. Typically we perform a prophylactic in-ternal fixation of prosthetic replacement when more than 50% of cortical destruction occurs or 50-75% of metaph-yseal destruction. The goal of this treatment is not to cure the patient from cancer, but to maintain independence, avoid fractures and control pain. Treatment has to be as definitive as possible.

Commonly we use cement (PMMA) as an adjuvant. Here (first image of the picture on the right) the metasta-sis was treated with resection, cement and plate; we want this humerus to be strong to allow the patient to live nor-mally. Here (second image) the metastasis was in the femoral neck with disruption of structures, so very high risk of pathologic fractures with implantation of prosthesis.

Look at this (right) pathologic fracture: there is no bone here. And look at this skip metastasis, very prob-lematic to treat: we have to perform a resection, implanta-tion of a modular prosthesis with a long stem and cement in order to allow for immediate weight bearing and avoid relapse. This was an improper treatment: you cannot use a plate without cement for a metastasis, otherwise the metastasis continues to grow. What they should have done was to resect the whole piece and implantation of a modular prosthesis.

I want to show you another important concept that is very up to date: isolated lesions 2 years after diagnosis of primary (possibly with a good prognosis) disease have to be treated radically with wide resection. You have to consider this kind of metastases like a new primary to be treated radically because these patients have a very long life expectancy. We made a massive allograft from a cadaver donor so that we could attach the glutei here to the greater trochanter and this was synthe-sized with a plate to the normal bone. These patients live usu-ally 7-8 yrs after such a treatment so a long survival after the metastasis. *hip reconstruction video*