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Neoplasms-4

• Osteosarcoma

• Osteoclastoma

• Ewing sarcoma

• Multiple myeloma

• Pigmented nevus

• Skin melanoma

Osteosarcoma

► Malignant mesenchymal tumor in which the neoplastic cells produce bone matrix

► The most common malignant neoplasm of the bone and accounts for approximately 20% of primary bone cancers

► It has a bimodal age distribution (2 peaks):

75% occur in patients younger than age 20.

The smaller second peak occurs in the elderly- who frequently suffer from conditions known to be associated with the development of osteosa.- Paget disease of the bone, prior irradiation, bone infarcts

Osteosarcoma

► The most common primary site is metaphyseal region of the long bones of the extremities (60% occur about the knee), but any bone may be involved

► Men are more commonly affected than women (1.6:1)

Major sites of origin of osteosarcomas

Osteosarcoma- genetic abnormalities

RB, TP53, CDKN2A (p16, p14), MDM2, CDK4

Osteosarcomas are grouped according to:

► The anatomic portion of the bone from which they arise(intramedullary, intracortical)

► Degree of differentiation

► Primary (underlying bone is unremarkable) or secondary(e.g associated with pre-existing disorders such as previous irradiation)

► Histologic variants (osteoblastic, chondroblastic, fibroblastic, teleangiectatic, small cell, giant cell)

Osteosarcoma- macroscopic picture

► Gray-white big tumor

► Foci of necrosis

► Foci of hemorrhage

► Cystic degeneration

► Tumor destroys the bone, infiltrates bone marrow and adjacent tissues

► Infrequently it invades the joint

Osteosarcoma of the upper end of the tibia. The tan-white tumor fills most of the medullary cavity of the metaphysis and proximal diaphysis. It has infiltrated through the cortex, lifted the periosteum, and formed

soft tissue masses on both sides of the bone.

Osteosarcoma- microscopic picture

► The tumor is formed by small, oval or spindle cells which synthetizeosteoid. We can see it as pale pink deposits surrounded by osteoblasts. The formation of immature bone is most characteristic for osteosarcoma.

► Sometimes islets of immature cartilage (chondroblastic osteosarcoma)

Osteosarcoma. Coarse, lacelike pattern of neoplastic bone produced by anaplastic malignant tumor cells. Note the mitotic figures.

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OsteoclastomaGiant cell tumor of the bone

► Majority of them exhibit local malignancy, in some cases, however, neoplasm may have malignant course with distant metastases

► Most commonly develops around the knee (but any bonemay be involved)

► Most frequently in women in 3rd and 4th decades of life

► Clinical signs: pain, tenderness, swelling, pathologicalfractures

Osteoclastoma (Giant cell tumor)

► Ma: Cut surface is brown, small cysts and small areas of necrosis. Bone is

destroyed but invasion of adjacent tissues is rare

► Mi: Small fusiform and oval cells with scanty cytoplasm. Numerous giant

cells (having more than 100 nuclei) which mimic osteoclasts. They

are postulated to arise from a monocyte-macrophage lineage and

form via fusion of mononuclear cells.

Fig. Giant cell tumor illustrating an abundance of multinucleated giant cells with background mononuclear stromal cells

Osteoclastoma - pathogenesis

Experimental evidence suggests that the neoplastic cells of the giant cell tumor are osteoblast precursors, which represent only a minority of the cells in the tumor.

The neoplastic cells express high levels of RANKL (Receptor Activator for Nuclear factor κ B Ligand) = ODF (osteoclast differentiation factor

RANKL promotes the proliferation and differentiation of normal osteoclast precursors into osteoclasts. The osteoclasts in turn cause localized but highly destructive resorption of bone.

Osteoclastoma – clinical course

They are typically treated with curettage, but 40% to 60% recur locally.

Up to 4% of tumors metastasize to the lungs, but these sometimes spontaneously regress and they are seldom fatal

The RANKL inhibitor, Denosumab, has shown promise in treating giant cell tumor.

Ewing sarcoma

► Ewing sarcoma is a malignant tumor composed of primitive smallround cells with varying degrees of neuroectodermal differentiation and a characteristic molecular signature

► Entities previously classified as primitive neuroectodermaltumor (PNET) and Askin tumor have been unified into the single category of Ewing sarcoma.

► ES accounts for approximately 6-10% of primary bone tumors (secondmost common group of bone sarcomas in children)

► Most commonly affects children and adolescents (most patients are 10-15 years old- 80% are younger than age 20)

► Boys are affected slighty more frequently than girls

► There is a striking predilection for whites; blacks are rarely afflicted

Ewing sarcoma

► In 85% there is a translocation between chromosomes 11 and 22; t(11;22)(q24;q12)

► In 5-10% - t(21;22)(q22;q12)

► In less than 1% - t(7;22)(q22;12)

► In all cases there is fusion of the EWS gene on 22q12 to a member of the ETS family transcription factor, mainly FLT1

► Evidence suggests that the most common fusion gene (EWS-FLI1) generated from the t(11;22) translocation acts as a dominant oncogene, and the resultant protein acts as a constitutively active transcription factor that stimulates cell proliferation

Ewing sarcoma

► Localization: ES arises in the diaphyses of long bones, especially the femur and the flat bones of pelvis

► Clinically: mimics acute osteomyelitis with pain and swelling of the bone and fever and leukocytosis

► Ma: grayish-white soft masses filling the marrow cavity. It frequently contains areas of hemorrhage and necrosis. The tumor may destroy the cortex and can infiltrate the adjacent soft tissues

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Ewing sarcoma- microscopic picture

► The tumor is composed of uniform small, round cells (slightlylarger than lymphocytes) whichhave almost no cytoplasm

► The presence of Homer-Wright rosettes (where the tumor cellsare arranged in a circle about a central fibrillary space) isindicative of neural differentiation

► Very little intracellular stroma

Ewing sarcoma composed of sheets of small round cells with small amounts of clear cytoplasm.

ES- Homer-Wright rosettes

Multiple Myeloma/Plasmacytoma

► Multiple myeloma is a plasma cell neoplasm characteristicallyinvolving the skeleton at multiple sites

► Although bone infiltration dominates, the neoplasm canspread to lymph nodes and extranodal sites.

► Multiple myeloma causes 1% of all cancer deaths in Western countries. Its incidence is higher in:* men, * people of African descent * older adults (the peak age: 50-60 years)

Multiple Myeloma/Plasmacytoma

Localization:

► Multiple myeloma presents most often as multifocal destructive bone tumors composed of plasma cells (plasmacytomas) throughout the skeletal system.

► Bones in the axial skeleton are affected most commonly. Sites of predilection:

vertebral column- 66%; ribs- 44%; skull- 41%; pelvis-28%; femur- 24%; clavicle- 10%; and scapula- 10%

Multiple Myeloma

The bone lesions appear radiographically as punched-out defects, usually 1 to 4 cm in diameter, and grossly consist of gelatinous, soft, red tumor masses.

Multiple myeloma: clinical course

The clinical features of myeloma stem from the effects of:

► Infiltration of organs, particulary bones, by neoplastic plasma cells

► The production of excessive Ig

► The suppression of normal humoral immunity

Multiple Myeloma- clinical course

CRAB –

► C = Calcium (elevated)

►

► R = Renal failure,

► A = Anemia,

► B = Bone lesions

Neurological symptoms: weakness, confusion and fatigue ; GI: nausea, vomiting, constipation

Due to hypercalcemia and tubular damage from excretion of light chains

usually normocytic and normochromic : fatigue, weakness etc

usually involves the spine and ribs. Persistent localized pain may indicate a pathological bone fracture (30%). Involvement of the vertebrae may lead to spinal cord compression (10-15%)

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HELLO!I’m a crab

Multiple myeloma

Light chains of immunoglobulins are filtered by glomeruli but renal tubular epithelium fails to reabsorb and catabolize their excess – they are found in urine as Bence-Jones protein.

The increased amount of light chains leads to tubular damage and amyloidosis. These events together with interstitial infiltrates of neoplastic cells, leads to renal failure

Multiple myeloma-prognosis

The prognosis for this condition is variable but generally poor.

Patients with multiple bony lesions, if untreated, rarely survive for more than 6 to 12 months.

Chemotherapy induces remission in 50% to 70% of patients, but the median survival is still a dismal 3 years.

A small subset of younger patients (less than age 50) receiving allogeneic bone marrow transplants have long-standing remissions

Multiple myeloma-microscopic picture

Malignant plasma cells resemble the normal ones. They constitute more than 30% of marrow cells. They have large, excentric nuclei with characteristic chromatin pattern and prominent nucleoli. Cytoplasm is eosinophilic (in H&E stain)

Nevocellular nevus -pigmented nevus

► This term refers to any congenital or acquired neoplasm of melanocytes

► In clinical appearance nevi are brown, uniformly pigmented, flat or elevated areas of the skin with defined borders

Nevocellular nevus, compound type.The compound nevus is raised and dome shaped. The symmetry and uniform pigment distribution suggest a benign process.

Pigmented nevi

► Melanocytes are normally found as single cells interspersed among basal keratinocytes within the epidermis

► Initially nevi are formed by melanocytes transformed into oval cells that grow in nests along the dermal-epidermal junction. These are junctional nevi and they represent an early developmental stage

► Most junctional nevi grow into the underlying dermis as nests or cords – compound nevi

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Pigmented nevi

Microscopic picture:

► Within the dermis nests of uniform cells with unclear nucleoli with litle or no mitotic activity

Nevocellular nevus, compound type. Histologically, compound nevi combine the features of junctional nevi (intraepidermal nevus cell nests) with nests and cords of nevus cells in the

underlying dermis.

Melanoma

► Relatively common neoplasm

► Most of them – on the skin. Other primary sites: oral and anogenital mucosal surface, oesophagus, meninges and eye

► Sunlight plays an important role in the development of skin melanoma. Lightly pigmented individuals are at higher risk for develop this neoplasm

► Malignant transformation of melanocytes is a multistep process (mainly caused by UV light–induced DNA damage) that leads to the stepwise acquisition of driver mutations (BRAF, RAS, p53, PTEN)

Melanoma

Clinical signs of melanoma:

► Enlargement of pre-existing nevi –A- asymmetry and D-diameter

► Irregular B-borders of nevi

► Change in C-colour within a pigmented nevus

► Pain of pre-existing nevi

Fig. Melanoma. A, In clinical appearance, lesions are irregular in contour and pigmentation.

Melanoma-microscopic picture

► Cells are usually considerable larger than nevus cells

► They contains large nuclei with irregular contours

► Chromatin characteristically clumped at the periphery

► Prominent, red nucleoli

► Cells proliferate as poorly formed nests or as individual

cells at all layers of the epidermis in the radial phase of

growth and in the dermis in the vertical phase of

growth

Melanoma- phases of growth

► Radial (horizontal) within the epidermal and superficialdermal layers. During this stage melanomas don’tmetastasize

► Vertical: melanoma grows downward into the deeperdermal layers. The extent of the vertical growth phasedetermines the biologic behavior of malignant melanoma

The probability of metastasis is predicted by measuring the depth of invasion in millimeters of the vertical growth phase nodule from the top of the granular cell layer of the overlying epidermis (Breslow thickness).Increasing thickness strongly correlates with worse biologic behavior of melanomas

Melanoma-microscopic picture

Malignant melanoma.B, Radial growth phase of malignant melanoma, showing irregular nested and single-cell growth of melanoma cells within the epidermis and an underlying inflammatory response within the dermis. C, Photomicrograph of lesion in the vertical phase of growth, demonstrating nodular aggregates of infiltrating cells. D, High-power view of malignant melanoma cells.