SOFT TISSUE TUMOURS By Dr Fahd AlMulla Understand

SOFT TISSUE TUMOURS By Dr. Fahd Al-Mulla • Understand the classification and types of soft tissue tumours • Understand the necessity for a team-approach • Correlate Pathological findings with clinical presentation (Clinico-pathological correlation) • Know the most relevant information and know it well • ALL INFORMATION IS ON WEBSIT: http: //www. tumours. com

Soft Tissue Tumours: Definition Mesenchymal proliferations that occur in the extraskeletal, nonepithelial tissues of the body, excluding the viscera, coverings of the brain, and lymphoreticular system.

Histologic type Benign Malignant Adipose Tissue Lipoma Liposarcoma Fibrous tissue Fibromatosis Nodular fasciitis Fibrosarcoma Fibrohistiocytic tumours Fibrous histiocytoma Dermatofibroma Malignant Fibrous Histiocytoma? ? ? Skeletal Muscle Rhabdomyoma Rhabdomyosarcoma Smooth Muscle Leiomyoma Leiomyosarcoma Vascular Haemangioma Lymphangioma Angiosarcoma Peripheral nerve Neurofibroma Schwannoma Malignant peripheral nerve sheath tumour Uncertain histogenesis Granular cell tumour Synovial Sarcoma Alveolar soft part sarcoma Epithelioid sarcoma

The cause of most soft tissue tumors is unknown. There are documented associations, however, between radiation therapy and rare instances in which chemical burns, heat burns, or trauma were associated with subsequent development of a sarcoma. Exposure to phenoxyherbicides and chlorophenols has also been implicated in some cases. Kaposi sarcoma in patients with AIDS and in immunosuppressed patients is related to viruses and defective immunocompetence. Most soft tissue tumors occur sporadically, but a small minority are associated with genetic syndromes, the most notable of which are neurofibromatosis type 1 (neurofibroma, malignant schwannoma), Gardner syndrome (fibromatosis), Li-Fraumeni syndrome (soft tissue sarcoma), and Osler-Weber-Rendu syndrome (telangiectasia).

More recently, Enzinger and Weiss proposed a classification system based on histogenic origin. Problems: 1) It is very difficult for competent pathologists to agree on the histogenesis of these tumors. Some sarcomas have multiple cell types present in different areas of the tumor. 2) Many tumors are so undifferentiated that to subclassify them into their histogenic type is close to impossible, even with specialized techniques such as electron microscopy and immunohistochemistry However, the major drawback of this classification system is that it does not really take into account the grade of the tumor and its implications for prognosis.

After the histologic type of soft-tissue sarcoma has been determined, the tumor is graded 1 to 4, depending on its degree of differentiation (How similar it is to the original tissue) The majority of histologic types can be low-, intermediate-, or highgrade (grade 1, 2, or 3, respectively). However, some soft-tissue sarcomas such as well-differentiated liposarcomas and myxoid liposarcomas are always low-grade, whereas others such as rhabdomyosarcoma, synovial sarcoma, mesenchymal chondrosarcoma, and extraskeletal Ewing’s and osteosarcomas are always high-grade The American Joint Committee on Cancer (AJCC) has developed a clinicopathologic staging system that depends primarily on the grade and size of soft-tissue sarcomas

Primary tumor (T) T 0 T 1 T 2 No evidence of primary tumor Tumor <5 cm Tumor >5 cm Lymph nodes (N) N 0 N 1 No regional metastasis Regional node metastasis Distant metastasis (M) M 0 M 1 No distinct metastasis Distant metastasis Histopathalogic grading (G) G 1 G 2 G 3 G 4 Well differentiated (low grade) Moderately differentiated (intermediate grade) Poorly differentiated (high grade) Undifferentiated American Joint Committee on Cancer AJCC of soft tissue sarcomas classification Stage IA IB IIA IIB IIIA IIIB IVA IVB G 1 G 2 G 3 G 4 Any G T 1 T 2 Any T N 0 N 0 N 1 Any N M 0 M 0 M 0 M 1

FATTY TUMOURS Benign tumors of fat, known as lipomas, are the most common soft tissue tumor of adulthood. MORPHOLOGY. The conventional lipoma, the most common subtype, is a wellencapsulated mass of mature adipocytes that varies considerably in size. It arises in the subcutis of the proximal extremities and trunk, most frequently during mid-adulthood. Infrequently, lipomas are large, intramuscular, and circumscribed. Histologically, they consist of mature fat cells with no evidence of pleomorphism or abnormal growth. Lipomas are soft, mobile, and painless (except angiolipoma) and are usually cured by simple excision. conventional lipomas often show rearrangements of 12 q 14 -15, 6 p, and 13 q, and spindle cell and pleomorphic lipomas have rearrangements of 16 q and 13 q.

Liposarcomas are one of the most common sarcomas of adulthood and appear in the forties to sixties; they are uncommon in children. They usually arise in the deep soft tissues of the proximal extremities and retroperitoneum and are notorious for developing into large tumors. MORPHOLOGY. Histologically, liposarcomas can be divided into well-differentiated, myxoid, round cell, and pleomorphic variants. The cells liposarcomas are readily recognized as lipoblasts, which mimic fetal fat cells

Fibrous tumours and Fibrohistiocytic tumours Fibromatoses SUPERFICIAL FIBROMATOSIS (PALMAR, PLANTAR, AND PENILE FIBROMATOSES) Palmar, plantar, and penile fibromatoses, more bothersome than serious lesions, constitute a small group of superficial fibromatoses. They are characterized by nodular or poorly defined fascicles of mature-appearing fibroblasts surrounded by abundant dense collagen. Immunohistochemical and ultrastructural studies indicate that many of these cells are myofibroblasts Examples: Dupuytren contracture, plantar fibromatosis DEEP-SEATED FIBROMATOSIS (DESMOID TUMORS) Biologically, deep-seated fibromatoses lie in the interface between exuberant fibrous proliferations and low-grade fibrosarcomas. On the one hand, they present frequently as large, infiltrative masses that may recur after incomplete excision, and on the other, they are composed of banal well-differentiated fibroblasts that do not metastasize.

Fibrosarcomas are rare but may occur anywhere in the body, most commonly in the retroperitoneum, the thigh, the knee, and the distal extremities. MORPHOLOGY. Typically, these neoplasms are unencapsulated, infiltrative, soft, fishflesh masses often having areas of hemorrhage and necrosis. Betterdifferentiated lesions may appear deceptively encapsulated. Histologic examination discloses all degrees of differentiation, from slowly growing tumors that closely resemble cellular fibromas sometimes having spindled cells growing in a herringbone fashion to highly cellular neoplasms dominated by architectural disarray, pleomorphism, frequent mitoses, and areas of necrosis.

TUMORS OF SKELETAL MUSCLE Skeletal muscle neoplasms, in contrast to other groups of tumors, are almost all malignant. The benign variant, rhabdomyoma, is distinctly rare. Rhabdomyosarcomas, the most common soft tissue sarcomas of childhood and adolescence, usually appear before age 20. They may arise in any anatomic location, but most occur in the head and neck or genitourinary tract. MORPHOLOGY. Rhabdomyosarcoma is histologically subclassified into the embryonal, alveolar, and pleomorphic variants. The rhabdomyoblast--the diagnostic cell in all types--contains eccentric eosinophilic granular cytoplasm rich in thick and thin filaments. The rhabdomyoblasts may be round or elongate; the latter are known as tadpole or strap cells

Cytogenetics play an important role in confirming the diagnosis rhabdomyosarcoma. Alveolar rhabdomyosarcoma is associated with a specific translocation, t)(13; 2)q 37; q 14) or its variant t(1; 13)(p 36; q 14). Embryonal rhabdomyosarcoma often shows loss of heterozygosity for 11 p, but there is no specific cytogenetic or molecular marker comparable to those for alveolar RMS.

TUMORS OF SMOOTH MUSCLE Leiomyomas, the benign smooth muscle tumors, often arise in the uterus where they represent the most common neoplasm in women. Leiomyomas may also arise in the skin and subcutis from the arrector pili muscles found in the skin, nipples, scrotum, and labia (genital leiomyomas) and less frequently develop in the deep soft tissues. They are usually not larger than 1 to 2 cm in greatest dimension and are composed of fascicles of spindle cells that tend to intersect each other at right angles. The tumor cells have blunt-ended elongated nuclei and show minimal atypia and few mitotic figures. Leiomyosarcomas account for 10% to 20% of soft tissue sarcomas. Most develop in the skin and deep soft tissues of the extremities and retroperitoneum. Microscopically, the lesion is composed of interlacing fascicles of mildly pleomorphic, spindle cells with blunt-ended nuclei and eosinophilic cytoplasm. Average mitotic rate was 3 per 10 hpf. Geographic areas of necrosis is present

SYNOVIAL SARCOMA Synovial sarcoma is so named because it was once believed to recapitulate synovium, but the cell of origin is still unclear. In addition, although the term synovial sarcoma implies an origin from the joint linings, less than 10% are intra-articular. Synovial sarcomas account for approximately 10% of all soft tissue sarcomas and rank as the fourth most common sarcoma. MORPHOLOGY. The histologic hallmark of synovial sarcoma is the biphasic morphology of the tumor cells (i. e. , epithelial-like and spindle cells). Immunohistochemistry is helpful in identifying these tumors, since the epithelioid and spindle cell portions yield positive reactions for keratin and epithelial membrane antigen, differentiating these tumors from most other sarcomas.

In Summary: -Soft tissue benign tumours outnumber malignant Tumours 100: 1 -They are aggressive if malignant -Be a good clinician and always correlate clinical with pathological findings. -Work together as a multi-disciplinary team Any Questions? ?

Bone Tumours WHAT SHOULD YOU KNOW • Understand the clinical algorithm • Correlate clinical presentation with radiological features • Understand the classification and types of bone tumours • Comprehend the management of bone tumours • Understand the necessity for a team-approach • Correlate Pathological findings with clinical presentation (Clinico-pathological correlation)

CLASSIFICATIONS OF PRIMARY TUMOURS INVOLVING BONES Metastatic cancers are the most frequent malignant tumors found in bone Histological Types Benign Hematopoietic (40%) Malignant Myeloma Malignant lymphoma Chondrogenic (22%) Osteochondroma Chondroblastoma Chondromyxoid fibroma Chondrosarcoma Dedifferentiated chondrosarcoma Osteogenic (19%) Osteoid osteoma Osteoblastoma Osteosarcoma Unknown origin (10%) Giant cell tumour Ewing tumour Giant cell tumour Adamantinoma Histiocytic origin Fibrogenic Notochordal Vascular, Cystic, lipogenic neurogenic Fibrous histiocytoma Fibroma MFH Fibrosarcoma Chordoma

AGE(probably the most important clinical clue). Age group Most common benign lesions Most common malignant tumors 0 - 10 simple bone cyst eosinophilic granuloma Ewing's sarcoma leukemic involvement metastatic neuroblastoma 10 - 20 non-ossifying fibroma fibrous dysplasia simple bone cyst aneurysmal bone cyst osteochondroma (exostosis) osteoid osteoma osteoblastoma chondromyxoid fibroma osteosarcoma, Ewing's sarcoma, adamantinoma 20 - 40 enchondroma giant cell tumor chondrosarcoma osteoma metastatic tumors myeloma leukemic involvement chondrosarcoma osteosarcoma (Paget's associated) MFH chordoma 40 & above

SITE OF LONG BONE INVOLVEMENT (most primary bone tumors have favored sites within long bones; this may provide a clue to diagnosis). Diaphyseal lesions centered in the cortex: Adamantinoma, osteoid osteoma Metaphyseal intramedullary lesions: Osteosarcoma is usually centered in the metaphysis. Chondrosarcoma and fibrosarcoma often present as metaphyseal lesions. Osteoblastoma, enchondroma, fibrous dysplasia, simple bone cyst, and aneurysmal bone cyst are common in this location. Metaphyseal exostosis: Osteochondroma Diaphyseal intramedullary lesions: Favored location for Ewing's sarcoma, lymphoma, myeloma. Common for fibrous dysplasia and enchondroma Metaphyseal lesions centered in the cortex: Classic location for a non-ossifying fibroma (NOF). Also, a common site for osteoid osteoma. Epiphyseal lesions: Chondroblastoma (Ch) and Giant Cell Tumor (GCT) are almost invariably centered in the epiphysis. Chondroblastoma is a rare tumor seen in children and adolescents with open growth plates. GCT is the most common tumor of epiphyses in skeletally mature individuals with closed growth plates. GCT often shows metaphyseal extension.

General Histologic Assessment of the Lesion The following are the most important histologic features to consider: • Pattern of growth (eg. , sheets of cells vs. lobular architecture) • Cytologic characteristics of the cells • Presence of necrosis and/or hemorrhage and/or cystic change • Matrix production • Relationship between the lesional tissue and the surrounding bone (eg. , sharp border vs. infiltrative growth) But remember: 1. Listen to your patients (Is the lesion painful, What is the age of the patient) 2. Listen to the Radiologist (patterns of growth and ask to see the films) 3. Listen to the surgeons (rapid growth, involve the periosteum, soft tissue)

An 11 -year-old male was seen in consultation for an increasingly painful distal femoral lesion associated with a soft tissue mass. Plain radiograph shows an ill-defined destructive tumor in the distal femur. Fluffy radiodense infiltrates represent malignant tumor osteoid. Biopsy material shows two major components of this neoplasm: highly pleomorphic cells and haphazard deposits of osteoid. Note that the malignant cells fill the spaces between osteoid deposits. Lace-like osteoid deposition is very characteristic of this neoplasm.

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.

A 17 -year-old male presented with increasing pain in the left upper arm of approximately 3 months' duration and a recent onset of low-grade fever. On physical examination, there was some local tenderness and soft tissue swelling over the proximal and mid thirds of the left humerus. Most important here is the patient's age and short duration of symptoms. Plain radiograph shows a large ill-defined, destructive, diaphyseal intramedullary lesion with permeative pattern of bone destruction and periosteal reaction of a "hair-on-end" type. The lesion is associated with a soft tissue mass. Biopsy material showed a highly cellular, infiltrative neoplasm consisting of sheets of tightly packed, round cells with very scant cytoplasm ("round blue cell tumor"). Occasional Homer-Wright rosettes were identified. Other fields showed extensive necrosis. The cell population consisted of two distinct cell types: the larger round cells with a high N/C ratio, fine chromatin pattern and occasional small, inconspicuous nucleoli, and the smaller and darker cells with eosinophilic cytoplasm and hyperchromatic, "shrunken" nuclei (degenerated cells, a typical finding in this entity). Mitotic rate averaged 2 per 10 hpf.

The following studies are required to support the diagnosis of ES and PNET: Demonstration of t(11; 22) or EWS-FLI-1 fusion transcript (present in both ES and PNET) Immunostains(both ES and PNET are positive for CD 99/O 13. In addition, PNET shows positive staining with neural markers) EM (ES cells are undifferentiated and show prominent glycogen deposits; PNET shows neural differentiation)

A 16 -year-old boy was seen in consultation for increasing pain in the mid upper arm. Characteristically, the pain intensified at night and subsided with aspirin. Plain film shows a small, intracortical, radiolucent focus (nidus), surrounded by dense reactive periosteal bone. The lesion is located in the mid portion of the humeral shaft. If the nidus is removed intact, it appears as a circumscribed portion of red, trabecular bone, usually less than 1 cm in size. Low-power view shows the lesional tissue ("nidus"), well demarcated from the surrounding sclerotic bone. The lesion is composed of thin, often interconnected spicules of osteoid and woven bone rimmed by osteoblasts. Osteoclast-like giant cells can be seen. Intervening fibrous stroma shows prominent vascularity.

A 39 -year-old female gave a 2 -month history of increasing pain in her knee. There was no evidence of joint effusion. Laboratory work-up showed normal serum levels of calcium, phosphate and alkaline phosphatase Plain radiograph demonstrated a well defined, lytic lesion eccentrically located in the distal femoral epiphysis with subchondral and metaphyseal extension. There was associated focal thinning of the cortex Curettage specimen consisted of fragments of soft, hemorrhagic, tan-brown tissue with some firm areas and yellowish speckles. Microscopic examination showed a cellular lesion composed of numerous multinucleated giant cells in a background of small, ovoid, mononuclear stromal cells Stromal cells had poorly defined cytoplasmic borders and bland nuclei resembling those of giant cells. Mitoses were easily found averaging 4 per 10 hpf. However, no atypical mitoses were identified.

A 45 -year old female presented with increasing pain and swelling around the knee. She mentioned that the symptoms had progressed over a 4 month period. Age of the patient is an important diagnostic clue. If a pathologic fracture is excluded, pain and swelling imply active growth of the lesion. Plain film demonstrates a large, lobulated, illdefined lesion centered in the distal femoral metaphysis. There is endosteal scalloping and periosteal thickening. Central stippled and "ring and arc" calcifications are apparent and are typical of cartilaginous matrix. Small radiolucent areas are seen at the periphery of the lesion. Low magnification shows a moderately cellular, lobulated cartilaginous tumor. High-power view shows scattered plump, moderately pleomorphic chondrocytes. Binucleated cells are present. Mitotic rate averaged 1 per 10 hpf.

The aggressiveness of chondrosarcomas can be predicted by their histologic grade. Grading system is based on three parameters: cellularity, degree of nuclear atypia and mitotic activity. Grade 1 (low-grade) Very similar to enchondroma. However, the cellularity is higher, and there is mild cellular pleomorphism. The nuclei are small but often show open chromatin pattern and small nucleoli. Binucleated cells are frequent. Mitoses are very rare. Grade 1 chondrosarcomas are locally aggressive and prone to recurrences, but usually do not metastasize. Grade 2 (low-grade) The cellularity is higher than in Grade 1 tumors. Characteristic findings are moderate cellular pleomorphism, plump nuclei, frequent bi-nucleated cells, and occasional bizarre cells. Mitoses are rare. Foci of myxoid change may be seen. Unlike Grade 1 tumors, about 10% to 15% of Grade 2 chondrosarcomas produce metastases. Grade 3 (high-grade) Characteristic findings are high cellularity, marked cellular pleomorphism, high N/C ratio, many bizarre cells and frequent mitoses (more than 1 per hpf). These are high grade tumors with significant metastatic potential.

A 14 -year-old female was seen in consultation for an increasingly painful left humeral lesion associated with mild joint effusion. Pay attention to the patient's age, skeletal location, and the presence of joint effusion, which may complicate epiphyseal lesions. Plain radiograph showed an irregular, but circumscribed, lytic epiphyseal lesion surrounded by reactive bone sclerosis. There was no evidence of bone expansion, and the cortex was intact. The growth plates were open. The cytoplasmic borders were very distinct with multiple foci of "chicken-wire" calcification (calcified reticulin network around individual tumor cells).

A 20 -year-old male presented with a painless, hard subcutaneous mass in the popliteal fossa. He stated that the mass had been present for several years and did not change in size. Two words, "painless" and "non-growing" (or very slow growing), suggest that the lesion described here is probably benign. Plain radiograph demonstrated a pedunculated bony outgrowth at the proximal tibial metaphysis. The lesion had a uniform, cartilagenous cap with stippled calcifications. The tibial cortex and medulla were continuous with those of the lesion. The specimen consisted of a pedunculated lesion, 3 x 2 cm, with a lobulated cartilage cap measuring up to 0. 9 cm in thickness Osteochondroma, the most common benign bone tumor, is not a neoplasm but a hamartoma. It is thought to arise from a portion of growth plate cartilage entrapped beneath the periosteum during skeletal growth. These entrapped pieces continue to grow and ossify at the same rate as the adjacent bone. When skeletal maturity is reached, osteochondromas usually stop growing.

An incidental finding of a bone lesion in the distal femur of a 38 -year old female. The lesion was completely asymptomatic. Plain radiograph showed an intarmedullary zone of stippled and ring-shaped calcifications in the distal femoral metaphysis. This mineralization pattern with radiodense stipples and rings is characteristic of mature hyaline cartilage. Low-power microscopic examination of the biopsy specimen shows three characteristic features of this lesion: a) vague lobularity; b) abundant cartilaginous matrix, which can be focally calcified; c) low cellularity. High-power view shows clustered and scattered chondrocytes with small, uniform, darkly stained nuclei. Occasional bi-nucleated chondrocytes are present. Importantly, there were no mitotic figures.

A 17 -year-old male presented with a slowly enlarging, painful lesion of the right clavicle. Plain radiograph reveals a circumscribed, loculated, radiolucent lesion producing blowout expansion of the bone. Gross photograph shows a spongy, expansile lesion containing multiple, blood-filled cavities of varying sizes. Low-power view demonstrates blood-filled cystic spaces without recognizable epithelial lining.

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