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Shrouq kraishan Pathology Sheet No( 7) 143/3/20

As in overview of bone tumors; the benign tumors of the bone are much more common than the malignant ones.

However, all the benign tumors are not necessary to be presented , some of them stay silent and cause no symptoms to discover it incidentally .

Benign tumors are greatly abnormal their malignant counterparts particularly before the age of 40 . now after the age of 40 elderly people -like any other tumor- the risk of malignancy increases .

Among the primary benign bone tumors :-- 2 prototypes

the most common primary benign tumor is ( Osteochondroma) العظم and there is , مسمارfibrous cortical defect -but we won’t discuss it -. These are the main 2 benign tumors .

Primary malignant Bone tumors :-- 3 prototypes

1- the most common primary malignant tumor is ( Osteosarcoma). Osteosarcoma is the most common primary bone cancer. Osteo means that tumor will produce bone so this tumor is Bone-Forming tumor.

The most common malignant bone tumor is Metastisis (bone is preferred site for other metastisis like other prostatic cancer , lung cancer, any cancer can metastasis to the bone ) , So matastisis tumor to the bone are the most common secondary malignant tumors .

But when I talk about primary malignant (arising from the bone itself ) , the osteosarcoma is the most common one .

2- followed by chondrosarcoma and Ewing sarcoma : chondrosarcoma will produce chondro(chondro=cartilage) so this tumor is Cartilage-Forming tumor . And Ewing sarcoma is also a primary malignant tumor .

*Most of bone tumors especially the malignant ones , they arise De novo ( no predisposing factor for the tumor ) , they arise without any predisposing condition .

However some conditions that are associated with increased risk of malignancy in the bone, what are the conditions ?

1- familiar conditions (like familiar inherited syndromes ) that increases the risk of bone tumors and other tumors , first example of familiar inherited syndrome is Li-Fraumeni syndrome .

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Shrouq kraishan Pathology Sheet No( 7) 143/3/20Li-Fraumeni : this syndrome is linked to a mutation of TP53 tumor suppressor gene which normally help to control the cell growth , this mutation will cause so many tumors one of them is osteosarcoma . The second example of familiar inherited syndrome is retinoblastoma syndrome, it increases the risk of osteosarcoma of bone and the retinoblastoma of the eye ( malignant tumor in eye and one of the primitive tumors ) . So these are the genetic predisposing syndromes or conditions that predispose to malignancy , li-fraumeni syndrome ( mutation in TP53 gene ) and retinoblastoma syndrome ( mutation in RB gene or retinoblastoma gene ) . Most commonly osteosarcoma arises De novo but rarely it can in the setting of other diseases . Note: chronic osteomylitis rarely it can predispose or increase the risk of osteosarcoma after a long period of time

2- Other rare predisposing condition is bone infarct ( cut of blood supply to the bone so it is dead bone or necrotic bone ) , with the time it increases the risk of development of secondary malignancy .

3- Chronic osteomylitis that we discussed it last lecture 4- Paget disease of the bone

Paget disease : occur in the cycles growth of bone and envolution of bone resulted in abnormal bone which increases the risk of malignant . From Wikipedia : is a chronic disorder that can result in enlarged and misshapen bones. Paget's is caused by the excessive breakdown and formation of bone, followed

by disorganized bone remodeling. This causes affected bone to weaken, resulting in pain, misshapen bones, fractures, and arthritis in the joints near the affected bones. Often Paget's disease is localized to only a few bones in the body. The pelvis, femur, and lower lumbar vertebrae are the most commonly affected bones.

5- Irradiation : patients who are exposed to radiotherapy as a treatment for certain cancers ,they will the result of secondary cancers like secondary malignant bone tumor .

6- Use of metal orthopedic devices : Means that the patients who have implanted screws and plates to fix their fractures and joints for a long time . These screws and plates are considered as foreign objects within patient’s bone underground to initiate and increase the risk for development of secondary osteosarcomas . Note: so all of these previous ones ( 6 causes ) are secondary causes leading to osteosarcoma but remember always that osteosarcoma most of the time they occur primarily.

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-------1 - Bone-Forming tumors Osteoma

Osteoid osteoma and osteoblastoma Osteosarcoma

2 - Cartilage-Forming tumors Chondroma

Osteochondroma Chondrosarcoma

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Primary Bone Tumors

3- Miscellaneous tumors: which cannot be categorized to the previous types

Ewing’s sarcomaPrimitive

Neuroectodermal Tumor


BONE-FORMING TUMORSPrototypes:A- Osteoma :

Bone Forming – tumor Benign tumor most common location of this tumor is encountered in the head and neck area ,

mostly in the paranasal sinuses, The main presentation for this tumor , it can obstruct the paranasal sinuses and

provide the symptoms of nasal obstruction or recurrent sinusitis or recurrent infections . this is the most presenting characteristic for osteoma .

Usually it is a middle-age lesion ( 30s-40s) Most of the time , they are solitary ( single osteoma ) . slowly growing lesion hard because the main component of osteoid is the bone exophytic masses on a bone surface :mean; protruded masses at above of bone however, in certain cases , osteoid can occur in a multiple pattern ( not solitary

pattern) as multiple osteomas like that occurred in a syndrome called Gardner syndrome (Multiple lesions).

Gardner syndrome : we will discuss it in GI system , it is one of the familial polyposis syndrome that includes multiple colonic polyps with multiple osteoma in the head and neck region or in the maxilla-facial region

Microscopy: Osteomas recapitulate the cortical type bone( like the normal cortical bone but as a tumor or outgrowth ) and they are composed of a mixture of woven and lamellar bone.

Woven bone : 1- the newly formed bone ,2- it didn’t get the lamellated structure which must be in the normal bone . normal bone contains haversian system , canals and normal structure component of the bone , 3- woven bone is laid down haphazardly (randomly ) as a weak bone . 4- abnormal mineralization .

So because woven bone is weak bone , the osteoid will present within it easily ; the firs presentation is a fracture of the effected bone

Osteoid can cause compressive symptoms . obstructive symptoms especially in paranasal sinuses .

All of osteoid causes cosmetic deformity, because as we said that most of the time it occur in maxilla-facial area , this cosmetic deformity will desiccate osteoid removal.

Treatment choice of osteoid is surgical removal because They are not locally aggressive even that some benign tumors could be locally aggressive , but these tumors are well circumscribed and there is no risk of malignant transformation

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Shrouq kraishan Pathology Sheet No( 7) 143/3/20( osteoma will not transform to osteosarcoma ) --_So osteomas are completely benign condition .

B- Osteoid Osteoma and Osteoblastoma : Second Bone-Forming tumor These 2 tumors differ in the site , development and size of a lesion Histological: they look same Osteoid osteoma :- bone production and osteoid production

Osteiod is the newly formed bone which is not mineralized yet , you can imagin that osteoid is soft material not hard like the normal mature bone .

Osteoblastoma : - is larger one of the bone-forming tumors . They are benign tumors Histological: as we said they are similar and no differentiating features between

them Typically they appear during teenage years and 20s . male predilection/predominance : males are affected more than females. Distinguished from each other primarily by their site of occurrence , size of lesion

and clinical presentation.

According to the size of lesion :-

* Osteoblastoma is being the larger ones

*osteoid osteoma is the smallest (less than or equal 2 cm in diameter ) .

Any lesion that will be similar to ostoid osteoma’s appearance but its size above 2 cm so it will be Osteoblastoma because osteoblastoma is larger than osteoid osteoma .

Malignant transformation in osteoid osteoma and osteoblastoma is very Rare , unless the lesion is treated with the radiation therapy because the radiation is one of secondary causes of osteosarcomas .

Ostoid osteomas Osteoblastomas 1- Most of the time ,they occur in the cortex of bone

Note : long bones have epiphysis , metaphysisi , diaphysis ,periosteum then under it we’ll find cortex then medulla which has bone morrow .

So these osteoid osteomas arise most often beneath the periosteum as cortical lesions ( sub-periosteum : under the periosteum , in cortex ) .

2- Most common location is Long bones : proximal femur and proximal tibia ,however, they can also occur in Vertebra in the posterior spinal elements .

Don’t occur in long bone .Main location for them is Vertebral column by vertebral lesions

3- by definition less than 2 cm in diameter Larger , more than 2 cm in diameter 4- The MOST characteristic feature of osteoid osteomas is

the PAIN which is the main clinical presentation . because o.osteomas produce prostaglandins E2 which stimulate pain so it is related to the production of PGE2 .

Cause Non typical pain The pain is like discomfort ,not sharpNot relieved by aspirin

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Shrouq kraishan Pathology Sheet No( 7) 143/3/20The pain of prostaglandin is typical that it will occur at night and will wake the patient from sleep ,also this typical pain can be relieved by aspirin so it is like an inflammatory pain .Also it is localized pain so the patient can pinpoint the site of sharp pain by his finger . Not easily- localized pain

But by radiology and histology ; osteoid osteoma and osteoblastoma look the same

Morphologically

Osteoid osteoma produce osteoid and osteoid is unmeneralized bone which is laid primarily with

osteoblast the main thing that we see in this tumor :- randomly - haphazardly- distribution

trabeculae of woven osteoid bone rimmed by osteoblasts

C- Main malignant tumor of bone is Osteosarcoma :- Malignant mesenchymal tumor :- most of the times ,it is sarcoma and when it will be in the

bone we called osteosarcoma . If it will be in cartilage it’s called chondrosarcoma . in muscles it will be called leiomyosarcoma.

Bone-Producing malignant mesenchymal tumor is osteosarcoma After myeloma and lymphoma ( they are not a primary bone tumors ) , the bone can

be involved by lymphoma as a secondary pattern cause primary bone lymphoma is rare but Multiple Myeloma ( tumor of plazma cells ) and lymphomas ( tumor of lymphocytes) .

Most common primary malignant bone tumor is osteosrcoma Osteosarcoma , accounting approximately 20% of primary bone cancers. The peak age of osteosarcomas : osteosarcoma is the tumor in children , adolescence ,

teenagers so 75% of osteosarcomas .they occur below the age of 20 years There is also a second peak of osteosarcoma in elderly patients (70s-80s) , most of the

time it occur with underlying predisposing factors like Paget disease(will increase in elderly) , osteomylitis , using of prosthesis mechanical , radiation therapy for other cancers , all of these can cause osteosarcoma in the elderly .

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Pinkish material is : osteoid

These cells which provide rim/barrier that surround the pinkish osteoid material

they are called osteoblast

The spaces In between the osteoid elements , and the spaces in between the woven bone trabeculae will be filled by fibro-vascular stroma rich in vessels and fibrous loose connective

tissue and collagen

Typical Histological Appearance Of Osteoid Osteoma and Osteoblastoma

Shrouq kraishan Pathology Sheet No( 7) 143/3/20 So there are 2 peaks of osteosarcoma : 75% in the first peak under the age of 20 and

another peak in late age Main location of osteosarcoma is the long bones in the metaphysis of them , especially

the long bones around the knee , the distal femur and proximal tibia . this is the most common location of osteosarcoma

60% occurring around the knee joint 15% around the hip joint 10% at the shoulder and proximal humerus and 8% can occur in the jaw-not most common type- .

the most common type of osteosarcoma is primary (not preceded by predisposing factors ) , solitary(one lesion ) , intramedullary(osteosarcoma starts in medulla of bone then they spread to cortex then periosteum then surrounding soft tissue and this is typical periosteo-osteosarcoma ) , and poorly differentiated(highly grade and aggressive) , producing a predominantly bony matrix because some osteosarcomas can produce cartilage- cartilaginous osteosarcomas –or produce fibrous tissue – fibrous

osteosarcoma. Morphology of osteosarcoma :

Typical feature is the production of unmineralized bone (osteoid) by malignant cells and this is essential feature for diagnosis of osteosarcoma , if we don’t find osteoid directly laid down by malignant osteoblast cells I can’t diagnose osteosarcoma , this is the main histological feature for diagnosis of osteosarcoma .

As we said that the tumor is able to produce bone , cartilage , fibrous tissue but we must find the osteoid because the complete malignant tumor that contains cartilage without osteoid ,called (chondrosarcoma)

If we find malignant cartilage containing osteoid rimmed by malignant cells , is called chondroblastic osteosarcoma so osteoid is the main characteristic feature of osteosarcoma

Vascular invasion is common in osteosarcomas main way of metastisis of osteosarcoma is hematogenous metastisis by blood and

most of the time they go to lung

Pathogenesis : o familiar genetic osteosarcoma is associated with retinoblastoma syndrome ( mutation in RB

gene ) the gene that involved is same to Von Hippel-Lindau in renal cell carcinoma . o RB gene(tumor suppressor gene ) mutations occur in 60% to 70% of sporadic tumors, and

persons with hereditary retinoblastomaso Person with hereditary retinoblastoma also they have this mutation but not as acquired

mutation , it is mutation presented in the germline o Retinoblastoma patients they have a thousand thousand-fold increased risk of osteosarcoma

and other tumors like retionoblastoma of eye

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Shrouq kraishan Pathology Sheet No( 7) 143/3/20Clinical presentation and radiology of osteosarcoma :-

Clinical

Most of time, it is like osteomylitis (pain, swelling , constitutional symptoms, fever ) so sometime the clinicians think that it is osteomylitis not osteosarcoma

Then by radiology , imaging , histological examination of lesion , the clinicians decided if it is oseteomylitis or osteosarcoma

Painful enlarging masses and swelling is the typical presentation Sometimes the first presentation could be the pathological fracture ( caused by tumor

because the underlined abnormality weakness of bone

Radiology of the lesion

Ill-defined lesion , filling the medulla and cortex of bone cortical destruction & extension to the marrow or soft tissue & the periosteum of bone is

elevated also the lesion destructs the marrow of bone and can extend to surrounding soft tissue to

form soft tissue masses this soft tissue mass help us to diagnose this tumor because it will arise clearly from the bone (from cortex and invade surrounding tissue) in x-ray image .

the main feature which is seen in x-ray and considered to be a characteristic for osteosarcoma is Codman triangle , A triangular shadow on the x-ray film between the cortex and raised periosteum and accumulation of tumor between cortex and periosteum

because the invasion of cortex and soft tissue the periosteum will elevate like in children we said the periosteum is loosely attached to bone so most of the time osteosarcoma will be in children , the periosteum is slept over cortex so the tumor accumulates between bone and periosteum to form triangular shape on x ray

(Codman triangle) is characteristic of osteosarcomas. Hematogenous spread 10% to 20% of patients have demonstrable pulmonary metastases at time of diagnosis ,

this will be too late Aggressive behavior Standard treatment for osteosarcomas is limb salvage plus and minus pre and post

surgical adjuvant therapy and usually they treated by chemotherapy The long-term survival after these treatments (surgical and chemotherapy ) is 60% to

70% and it is good . However it is aggressive tumor but can be treated

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Cartilage – forming Tumors

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osteochondroma

*osteo:bone / chonro:cartilage* so this tumor produses both elements

bone and cartilage *it's common tumor * benign tumor

*cartilagecapped tumor ( like mashroom shape; its stalk from bone and its cap

from cartilage ) *attached by a bony stalk to the

underlying skeleton,Arising in the metaphysis of bone near the growth

plate ( commonly at younger age due to the active growth plate at young age )

* most common location in long tubular bones, especially most common around the knee.

note : its distribution is similar to osteosarcoma common location

*Rarely it may affect the short tubular bones of hands and feet

*no increase in risk of malignancy except they are multiple and associated with syndrome , malignat type of tumor here will be called

multiple osteochondramitosi .*appearance : outgrowth of bone in metaphysis near of growth plate(like the osteophytes is osteoarthritis) , attached by a stalk to the bone origin and covered by a cartilagnous cap

it is continous with bone even the bone morrow of original bone is also present in the

osteochondroma

Solitary osteochondromas rarely progress to chondrosarcoma or other sarcomas, but malignant

transformation it occurs when the lesions are multiple and associated

with a hereditery syndrome like multiple hereditary osteochondromas.

chondrosarcoma

* osteosarcoma : is a tumor of young * chondrosarcoa : is a tumor of elderly

*unlikely to occur in child or teenage*it's malignant connective tissue tumor which manufacture and

secrete cartiligenous matrix *no osteoid production

*Chondrosarcomas commonly arise in the pelvis, shoulder, and ribs . not like the

distribution of osteosarcoma ehich is usually in long bones and about knee

joint

* there are primary chondrosarcoma and secondary ones

* secondary chondrosarcoma : assocaited with underlying

predisposing factor like hereditry osteochondroma syndrome .

Types and behavior : depending on the appearance of lesion on microscope

1- conventional chondrosarcoma : low grade , the most common type ,most variant , arises with the medullary cavity of bone form an expansile glistening mass that

often erodes the superfacial cortex and sometime it may extend to the

surrounding soft tissue . it is just tumor that produses cartilagenous matrix

2- Myxoid chondrosarcoma : viscous and gelatinous morphology by histologic

examination under the light microscope , it showed myxoid matrix ,grossly it's

gelatenous and fliudy

3-Dedifferentaited chondrosarcoma : presence of high grade component in a typical conventional low grade . dedifferentiad means loss of differentiation and loss of low grade converting to high grade

Shrouq kraishan Pathology Sheet No( 7) 143/3/20 The most important feature to determine the outlook of chondrosarcoma is Tumor grade ,

conventional they do better than dedifferentiated .

How do we grade chondrosarcoma ? it depend on the cellularity of lesion ( more cellular more mitosis more atypia high grade ) .

In normal cartilage less cellularity , less mitosis , less nuclear atypia .

Atypia : is nuclear feature occurs in cell ; larger nucleus , more hyperchromatic ,more N/C ( nuleus to cytoplasm ratio will increase ) ,atypical mitosis , irregular nuclear membrane so abnormal malignant cell .

Abnormal and ugly shape of cell forms high grade tumor ( more atypia more high grade tumors ).

Chondsarcomas also they can metastasize hematogenously through blood stream like osteosarcomas and the preferred sites for metastisis are the lung and bone , the lung is always the preferred site of metastisis in tumors which spread through the hematogenous way .

Ewing Sarcoma & Primitive Neuroectodermal tumor (PNET)

Ewing and PNET are tumors in the same family If it occurs in the bone, it is called Ewing sarcoma If it occurs in soft tissue and shows neural differentiation, it is called PNET Both tumors are primitive tumors ( t the cells are primitive cells ,are not producing bone or cartilage like the previous tumors )

they don’t have the capacity to differentiate to bone or cartilage in specific way . they are primary malignant small round cell tumors because the morphology of cells look like

this

you can see that these malignant cells are similar to lymphocytes so by diagnosis we can define it as lymphoma and you can see that cells are primitive ( not cartilaginous , not bony , not epithelial , not mesenchymal , not fibrous , ..etc) ,

they are primitive small round blue cells with the very small rim of cytoplasm around cells .

PNET : has some neural differentiation like ganglion cells whereas Ewing sarcoma are completely undifferentiated . After osteosarcoma( first common primary tumor in young age ) , Ewing sarcoma is the

second most common primary tumor of the bone in young age .

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There are a lot of tumors have this morphology of malignant cells like :

Ewing sarcoma

PNET

william tumors

Shrouq kraishan Pathology Sheet No( 7) 143/3/20 Most patients are 10 to 15 years of age, and 80% are younger than 20 years like

osteosarcoma which is a tumor of young age . Boys are affected slightly more frequently than girls The specific feature in Ewing sarcoma and PNET is : the most of the time , they are

associated with translocation means part of a chromosome will move to another one , it is translocation (11;22) or translocation (21;22) This Translocation characteristic is important to diagnostic process, because recently we

have used a lot of cytogenetic studies, lab investigation, histological studies in addition to the traditional clinical diagnosis . cytogenetic studies detect the translocation feature in Ewing sarcoma and PNET cases EWS gene will move from chromosome to another CLINICAL FEATURES of Ewing sarcoma 1- Painful large masses , most of time they occur in diaphyses not in metaphyses , but with time

when the metaphysial lesion will grow, enlarge ,extend to diaphyses 2- The Initiation of enlargement will start at the diaphyses level of long tubular bones primarily the

femur so it’s the same distribution as osteosarcoma , also Ewing sarcoma can occur around knee joint and pelvic flat bone

3- Systemic signs and symptoms are suggestive of infection like fever ,malasia,nausea .Also the clinician will think about them as osteomylitis

4- Imaging studies : the same as osteosarcoma but osteosarcoma codman triangle is not seen here in Ewing.S and PNET .

5- The imaging studies will show the destructive lytic ( lyses the bone العظم tumor with ( يحلَلinfiltrative margins and extension into surrounding soft tissuesز

6- There is characteristic periosteal reaction with deposition of bone which is different from what be seen in osteosarcoma

7- We see in osteosarcoma the :elevation of periosteum and bone accumulation between cortex and elevated periosteum using the codman triangle )

8- Here in Ewing .S and PNET , the surrounding bone around tumor will proliferate to form onion-skin pattern OR sun pattern that is typical on X-ray .

TREATMENTTreatment includes chemotherapy and surgery without radiotherapy .Somehow , they are similar to osteosarcoma treatment .The 5-year survival rate also is high in the presence of these treatment modalities .

HISTOLOGICAL appearance : they are sheets of primitive small round cells that resemble lymphocytes + the cell is mainly compose of nucleus + scanty cytoplasm + PAS stain shows intracytoplasmic glycogen deposition

PAS stain : Perioidic Acid-schiff stain , it stains the glycogen positive .

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