5/10. Pathology Soft tissue tumors. Farah Bhani. Mohammed Alorjani
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1 5/10 Pathology Soft tissue tumors Mohammed Alorjani Farah Bhani
2 Slides are included in this sheet. Objectives: Soft tissue tumors 1. Describe soft tissue tumors. 2. Understand the classification of soft tissue tumors 3. Understand the importance of cytologic and histologic features of soft tissue tumors in identifying type and behavior 4. Discuss the commonest benign and malignant soft tissue tumors. General Characteristics: Soft tissue tumors are classified according to the tissue of origin, (Some examples of soft tissue tumors do not have a definite tissue or cell of origin ' an example will be mentioned later in this lecture.) Any age; some prefer to occur in young people whereas others prefer to occur in young adults/adults or in the elderly. Present as an enlarging mass May be part of inherited syndromes, like: Neurofibromatosis, type I Li-Fraumeni Syndrome: (Inherited; p53 mutation, associated with osteosarcoma) Some have specific gene lesions Malignant tumors arise de novo or after recurrent Benign tumors SARCOMA Usually benign tumors stay benign, this is the ideal scenario but every rule has an exception, an example is the Tubular adenoma that grows in the colon, also known as the "Tubulovillous adenoma" whether it was sporadic or familial, these adenomas can show low grade dysplasia or high grade dysplasia but they are considered benign lesions that can transform into malignant lesions.
3 Classification of Soft tissue tumors: This is a simplified list of soft tumors, derived from the WHO list of tumors. Notes: -oma is benign and sarcoma is the malignant counterpart. Sarcoma: Malignancy in soft tissue, connective tissue and bones. Adipose tissue: Lipoma - Liposarcoma Fibrous tissue: Fibroma - Fibrosarcoma Fibrohistiocytic tumors: Distinctive tumors in which we find both fibroblasts and macrophage like cells in a part of the lesion. Smooth muscle: Leiomyoma - Leiomyosarcoma Skeletal muscle: Rhabdomyoma - Rhabdomyosarcoma Benign skeletal muscles are rarely encountered, the majority are malignant. Rhabdomyoma: may affect the tongue, heart and rarely the skeletal muscles, so generally speaking it is rare. Vascular tumors: Hemangioma Angiosarcoma (blood vessels) Lymphangioma Angiosarcoma (lymphatic vessels) There are many examples of benign, borderline malignant and malignant vascular tumors, but they won't be covered in this lecture. Peripheral nerve sheath tumors: derived from the sheath of peripheral nerves
4 Ex: Schwannoma: benign peripheral nerve sheath tumor arising from Schwann cells. Ex: Neurofibroma: consists of a collection of Schwann cells, fibroblasts and perineurial cells forming a benign mass. The malignant counterpart is known as: 'Malignant peripheral nerve sheath tumor' 'MPNST'. The last group in this classification are: Tumors of unknown exact cell of origin, these are difficult and have not yet been thoroughly understood and discovered. Malignant soft tissue tumors are graded according to differentiation, mitoses and necrosis into grade I III In the pathology practice there are two systems for grading soft tissue tumors: -American system 'NCI' -French system ' FNCLCC' which is more generally accepted according to the WHO in grading soft tissue tumors. As mentioned above they grade it according to three parameters: Differentiation: which is the degree of resemblance of the tumor cells to the cells of origin The number of Mitoses The presence/absence of Necrosis or the portion of the tumor that is necrotic. You score the patient according to these parameters, sum up the score then grade the patient's case from I-III I being low grade, II being intermediate, III being high. Grade I (Low grade) may recur but rarely metastasizes. Grade III (High grade) high risk or recurrence after excision, and a high risk of spreading away from the area or origin.
5 *The importance of grading malignant tumors lies in the fact that it helps in predicting the behavior and estimating the prognosis of the tumor, if it were Grade I I'd expect it to be locally acting and rarely metastatic, however if it was Grade III I'd expect it to expand from the area it originated. The prognosis depends on: Type; skeletal, fat etc... Grade Stage: whether the tumor had spread locally to adjacent structures or spread distally like to the lymph nodes. One of the most important parameters when it comes to the stage is the size; Tumors <=5cm are more favorable than tumors that are larger in size because smaller tumors are associated with lower metastatic rates generally speaking. Tumors <=5cm Mets rate: 30%. 'Smaller=lower mets rate' Location: superficial better. **If I am talking about tumors in the extremities or subcutaneous fat 'above the fascia' those are considered superficial. Below the fascia into the muscles and deeper soft tissues those are classified as deep. Generally speaking superficial soft tissue tumors are usually benign and have better prognosis, on the other hand deep tumors could be either benign or malignant, but in the case of a large, deep soft tissue tumor, it is more likely to be malignant and I need to do further investigation to confirm this finding. Tumors of Adipose tissue Lipoma: Commonest of soft tissue tumors Most in subcutaneous tissue meaning it is a superficial disease Usually small in size 'Lipoma could be large and deep but statistically speaking it is usually small and superficial' Single or multiple, may be familial No malignant transformation 'generally speaking'
6 Grossly: Circumscribed yellow mass Histologically: Mature fatty tissue Many histological variants: Pathologist must keep this in mind while diagnosing a tumor as it may lead to other possibilities or an erroneous diagnosis. Liposarcoma: Ex: Myxoid Lipomas, Chondroid Lipomas and Pleomorphic Lipomas **Pleomorphic Lipomas contain large Pleomorphic cells and have certain characteristics in terms of their location and their size, but they can be misdiagnosed as Liposarcomas, that is why pathologists should always consider the histological variants. *In some cases the physician may face challenges in which the tumor was identified as a Lipoma but after excision it recurred and was later re-identified into a Liposarcoma, in this case it was found after investigation that this tumor was originally a Liposarcoma but was misdiagnosed. Adults: years Usually occurs in the deep soft tissue of the extremities & retroperitoneum Grossly: Large >5cm, yellow glistening mass Histologically: According to the grade: Low grade 'I': Well differentiated (Amp. 12q, MDM2 gene) **Alteration In the shape of chromosome 12 'giant shape' also Amplification of the MDM2 gene that stimulates proliferation and is controlled by the P53 gene. Intermediate grade 'II': Myxoid type (t(12;16)) **Translocation of chromosome 12, this genetic abnormality involves two genes, forming a fusion gene that ends in the development of this tumor. High grade: Round cell Liposarcoma & Pleomorphic cell liposarcoma.
7 (The Round cell liposarcoma is the end of the spectrum of the myxoid liposarcoma, it shows many round cells and is given a high grade classification because its behavior shows aggressive tendencies in comparison with the myxoid, although both are them are considered the same disease in terms of genetics (t(12;16))and biology but the difference is in the aggressive nature of the Round cell Liposarcoma.) Diagnosis depends on identification of lipoblasts, because liposarcomas are tumors of immature cells unlike lipomas, which consist of mature fatty tissue. In some cases other findings are searched for to make a Liposarcoma diagnosis. Prognosis depends on type and sight: Well differentiated Liposarcoma likes to occur in two sights: 1. Deep parts of the extremities such as the deep soft tissue of the thigh 2. Peritoneum **It behaves similarly in both sights but since the peritoneum is somewhat hidden and spacious, the tumor reaches a large size up to 20 cm before it gets discovered, that is why I expect it to have a worse prognosis in the peritoneum, although they only differ in the terms of location. **Well differentiated liposarcomas in the peritoneum could be dedifferentiated at the time of discovery or after excision and recurrence.
8 Lipoma: Mature fat cells. These fat cells seem mature, but if we take a second look we will notice the presence of occasional lipoblasts, hyalinized fibrous stroma and atypical spindle cells indicating that this is a diseased lipoma sight.
9 **Myxoid liposarcoma: background is myxoid, there are some lipoblast, and you can also notice chicken wire vascular spaces. **Pleomorphic Liposarcoma, Pleomorphic lipoblasts are abundant
10 Fibrous Tumors & Reactive Proliferations: 1- Nodular fasciitis: reactive lesion Fasciitis: inflammation of the fascia, although it is a proliferative lesion. Morphology: Reactive fibroblastic proliferation frequently misdiagnosed as sarcoma, because it is rapid in proliferation and can show numerous mitoses Mostly affects young adults and presents as rapidly enlarging sometimes painful mass. Location: subcutaneous fat, dermis, in or below the fascia in the muscle Many have history of local trauma. Self-limiting. Whether you choose to excise it or not it causes no harm. Similar reactive lesion in muscle is Myositis Ossificans, contains bone. ** Myositis Ossificans: a form of nodular fasciitis that happens in the muscles and involves ossification 'bone formation'. Grossly: Unencapsulated < 3 cm mass in subcutaneous tissue, fascia or muscle. Micro: immature appearing fibroblasts with numerous mitoses, but no pleomorphism, with a myxoid background. Myxoid background, spindle and stellate fibroblasts, numerous mitosis (doesn't always indicate malignancy).
11 2- Fibromatosis: A group of fibroblastic proliferations Grow in an infiltrative fashion, but in superficial cases it is well circumscribed ** (nodular fasciitis: well circumscribed but not necessarily encapsulated) Recur after surgical excision but do not metastasize (deep cases) Various age groups Various types Two types: Superficial: Palmar (Dupuytren s contracture) in which it fixes one or more of the finger forward by developing a fibrous connection between the tendon and the skin. It can also occur in the plantar aspect of foot or on the penis. Deep: called Desmoid tumors: Arise in the abdominal wall Inside the abdomen Muscles of trunk and extremities Tend to be more aggressive Could be single or multiple Could happen as part of Gardner syndrome; APC/B-Catenin pathway abnormality. Dupuytren s contracture: patient can't extend finger well
12 Desmoid tumor: infiltrative; you can see spindle cells infiltrating the muscle and the fat. Fibromatosis is locally aggressive especially if it was deep seated, but it does not metastasize. 3-Fibrosarcoma: Malignant form of fibrous lesions. Mostly affects adults Sites: Deep soft tissues (thighs), knees and retroperitoneum. They tend to grow slowly. Gross: solitary, infiltrative or well-circumscribed. Micro: Fasicles of fibroblasts arranged in herringbone pattern Recurrence and metastatic rates depend on the grade. **as the grade goes higher the risk of metastasis goes up**
13 Its pattern resembles the way bones of fish are assembled. Fibrosarcoma / Herringbone pattern: Histological pattern.
14 Fibrohistiocytic Tumors: Several types Benign, borderline & malignant Mostly occurs in adults Usually benign in superficial lesions. Deep lesions are often malignant, larger, highly pleomorphic and can metastasize. Treatment is by excision Examples: Benign Fibrous Histiocytoma (Dermatofibroma): Common tumor Occurs in the dermis hence its name. Circumscribed tumor in the dermis or in subcutaneous tissue usually < 1 cm. Histology: lesion composed of Spindle cells & histiocytes Dermatofibrosarcoma Protruberance: (DFSP) Borderline malignant lesion As the above, it also occurs in the dermis and subcutaneous fat, but is larger and deeper. Infiltrative in nature, Mitoses is present and the tumor cells (fibrospindle cells) are CD34 positive. (CD34: vascular endothelial marker) Testing for this marker helps us to differentiate between the benign and malignant lesions of fibrohistiocytic origin. Recurs after excision Pleomorphic undifferentiated sarcoma Tumors of Smooth Muscle: Benign: Leiomyoma, mainly occurs in the uterus but could arise from vascular smooth muscles also. Malignant: Leiomyosarcoma (10-20% of STS) Also arises from the uterus or soft tissue. Better prognosis when superficial (easier to detect than deep) Large and deep lesions found in extremities or in retroperitoneum.
15 Tumors of Skeletal Muscle Almost all are malignant Rhabdomyosarcoma: Most common sarcoma of children, adolescents & young adults. (Important) Associated with chromosomal translocation t (2; 13) that produces a fusion gene PAX3-FKHR controlling muscle differentiation (alveolar type) Sites: Soft tissue, head & neck, genito-urinary tract Aggressive tumor Types: Embryonal: most common type mainly in head & neck, genitourinary & retroperitoneum. Alveolar: in extremities of adolescent Pleomorphic: usually in the deep soft tissues of adults. All three types are +ve for: Desmin, Myogenin & MYOD-1. Diagnostic cell is the Rhabdomyoblast which is Tadpole or Strap cell Prognosis worsens in this order: Embryonal pleomorphic alveolar **Desmin: intermediate fibers seen within the cytoplasm, aid in the differentiation of muscles regardless of their type (not specific for skeletal muscles) Myogenin & MYOD-1 (specific markers for skeletal muscles) so they will stain the nuclei of skeletal muscle fibers but will come back negative for smooth muscles.
16 You can notice Spindle cells in loose myxoid stroma, microphages and more primitive cells which are small round blue cells in this example. In the examples below you can notice an abundance of Rhabdomyoblasts (strap cells) in which some show cross striation 'maturation' Distinctive pink cytoplasms Round blue cells that are an indicative of: Ewing's Sarcoma, in this case if you suspect Rhabdomyosarcoma, test for Desmin, Myogenin & MYOD-1, if possitive then rhabdomyo. If for any reason you couldn't make a verdict after testing, you should test for genes associated in translocation.
17
18 SYNOVIAL SARCOMA Cell of origin is unknown Occurs in ages yrs. 10% of STS. Most are in deep soft tissue, adjacent to joints (Knee commonest) Rarely intra-articular (<10%) Specific translocation: t(x;18) fusion gene involved in transcription and the proliferation of tumor cells The name of this Sarcoma indicates that it occurs inside joints, but it actually doesn't except in rare cases. Morphology: Produces a mass, usually in the deep soft tissue Histologic findings: Biphasic (can show dual cell population which are spindle and epithelial structures) or monophasic (only spindle) it rarely only consists of epithelial structures. +ve for CK (cytokeratin epithelial marker) EMA (epithelial membrane antigen marker) ** It is a sarcoma but it is positive for epithelial markers which helps us to differentiate it from other sarcomas** Aggressively treated with limb-sparing surgery and chemotherapy Metastasizes through the blood to the lungs and bone, through lymphatic to the lymph nodes (sarcomas usually only metastasize through blood, but here it takes both routes of metastasis, blood and lymph) 5 year survival rate: 25-62%. But only 10-30% live > 10 yrs.
19 Biphasic synovial Sarcoma: You can see spindle stromal cells and epithelial elements forming gland like structures.
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