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Histology of soft tissue sarcoma in extremities and trunk wall

There are many different histological types of malignant soft tissue tumors (sarcomas).

The most frequent are:

  • Liposarcoma
  • Pleomorphic and spindle cell sarcoma/malignant fibrous histiocytoma (MFH)
  • Leiomyosarcoma
  • Synovial sarcoma
  • Angiosarcoma
  • Small round cell sarcoma
  • Ewing's sarcoma/PNET
  • Rhabdomyosarcoma

Liposarcoma

Photomicrograph demonstrating a well differentiated liposarcoma. Click to enlarge.

Liposarcoma is one of the most frequent sarcomas. There are several subtypes of liposarcoma with different prognoses, such as:

Well-differentiated liposarcoma  

Well-differentiated liposarcoma closely resembles benign lipoma. The diagnosis is based on the variation in cell size, atypical lipoblasts, or atypical spindle cells in fibrous areas. These tumors can be lipoma-like, sclerosing, inflammatory, or spindle celled in appearance. The important differential diagnosis is benign lipoma.

Cytogenetic analysis is useful since the demonstration of ring or giant cell marker chromosome derived from chromosome 12q indicates well-differentiated liposarcoma. The occurrence of ring or giant cell marker chromosome derived from chromosome 12q indicate a well-differentiated liposarcoma. MDM2 or CDK4 on chromosome 12 is amplified in these tumors. Most well-differentiated liposarcomas have no metastatic potential, but tumors in the retroperitoneal space have a higher recurrence rate. Well differentiated liposarcoma is very seldom seen in the subcutaneous fat, but appear more frequently in striated muscle or in the abdomen.

Dedifferentiated liposarcoma

Photomicrograph of a dedifferentiated liposarcoma. Click to enlarge.

Dedifferentiated liposarcoma consists of two separate, distinct growth patterns: partly well differentiated liposarcoma and a sarcoma component similar to malignant fibrous histiocytoma or fibrosarcoma. The dedifferentiated component is usually high-grade. Dedifferentiation can either be demonstrated in the primary tumor or in the later occuring recurrence. This tumortype is more common in the abdomen than in the extremities. Cytogenetic findings are the same as in well differentiated liposarcomas.

Myxoid liposarcoma/round cell liposarcoma

At myxoid liposarcoma consists of relatively small round/oval cells and in addition lipoblasts and in the background a richly vascularized myxoid stroma is seen. This tumor is by definition a low-grade malignant tumor.

Cytogenetically, a patogonomic translocation t(12;16)(q13;p11) can be detected in 90% of the cases. This translocation produces a gene fusion between DDIT3 gene on chromosome 12 and FUS(TLS) gene on chromosome 16. This can be demonstrated by a RT-PCR test.

In poorly differentiated tumors, areas with small round primitive cells appear in addition to the typical myxoid liposarcoma features. This is designated as a round cell component in myxoid liposarcoma or transition to a round cell liposarcoma. This is a more aggressive tumor where the percentage of round cell components correlates with the prognosis. These tumors has less vessels and lipoblasts compared to pure myxoid liposarcoma. The cytogenetic findings are the same as typical myxoid liposarcomas.

Pleomorphic liposarcoma

Pleomorphic liposarcoma is a liposarcoma with pleomorphic, spindle, and round cells with varing numbers of pleomorphic lipoblasts.

Pleomorphic and spindle cell sarcoma/malignant fibrous histiocytoma (MFH)

These tumors can be divided into pleomorphic, giant cell, or inflammatory subtypes. When myxoid areas are detected, they are often designated as myxofibrosarcomas.

Pleomorphic and spindle cell sarcoma/malignant fibrous histiocytoma (MFH)  account for a considerable number of sarcomas in adults. Microscopical findings are characterized by pleomorphic and spindle cells with severe nuclear atypia, often necrosis and a high number of mitotic figures. These tumors are poorly differentiated and are therefore difficult to separate from other poorly differentiated malignant tumors. The subclassification is useful in order to differentiate them from other tumors such as metastases, malignant melanoma, and malignant lymphomas. Other differential diagnosis is pleomorphic liposarcoma or pleomorphic leiomyosarcoma.

Cytogenetic analysis demonstrates complex chromosomal abberations, none of diagnostic significance.

Specimen from the hip region with malignant fibrous histiocytoma (MFH). Click to enlarge. Photomicrograph showing a malignant fibrous histiocytoma (MFH). Click to enlarge. Photomicrograph demonstrating a cytological specimen from a malignant fibrous histiocytoma (MFH). Click to enlarge.

Synovial sarcoma

Photomicrograph showing a synovial sarcoma. Click to enlarge.

Synovial sarcoma is a tumor that can appear in almost any location in soft tissue. It occurs very seldom in bone tissue. Microscopically, two cell types in varying amounts are seen: spindle cells or epithelial-like cells. There can be cases with dominating spindle cell appearance (monophasic synovial sarcoma) or a mixed appearance with epithelial and spindle cell areas (biphasic). In a seldom variant the epithelial component. Bone metaplasia or calcifications is observed in about 30% of these tumors. Immunhistochemistry demonstrates positivity for cytokeratin (90%), EMA (>90%) and CD99 (60%)

Cytogenetic investigations often demonstrate a specific translocation t(X;18)(p11;q11) producing the fusion gene SS18-SSX. This translocation on the SS18 gene in chromosome 18 with three close homolog genes SSX1, SSX2 or SSX4 in the X chromosome.

Leiomyosarcoma

Leiomyosarcoma is a sarcoma consisting of fascicles with spindlecells or cells with eosinophilic cytoplasm and typically cigar-shaped nuclei. Immunhistochemistry demonstrates positivity for smooth muscle actin (SMA), actin, and desmine. Cytogenetically, there are complex abberations and no specific findings.

Operation specimen from the thigh with a leiomyosarcoma. Click to enlarge. Photomiograph showing a leiomyosarcoma. Click to enlarge. Photomiograph: immunohistochemistry demonstrating desmine positively in a leiomyosarcoma. Click to enlarge.

Angiosarkoma

In angiosarkoma differentiation into vessels of different maturation can be detected. Immunohistochemistry is helpful demonstrating endothelial cell markers such as CD31, CD34 og faktor VIII.

Skin specimen with an angiosarcoma. Click to enlarge. Photomigraph with an angiosarcoma. Click to enlarge. Photmicrograph demonstrating immunhistochemical CD31 positively (brown staining) in an angiosarcoma. Click to enlarge.

Small round cell sarcoma

Small round cell sarcomas consist of a group av aggressive sarcomas characterized by small round cells with sparse cytoplasm. The diagnoses in the group are: Ewing/PNET, rhabdomyosarcoma of embryonal and alveolar type, round cell desmoplastic sarcoma, mesencymal chondrosarcoma and, sometimes, neuroblastoma is also included in this group.

Synovial sarcoma can sometimes look very much like a small round cell tumor. The subtyping of these tumors is difficult and often not possible with light microscopy alone. Immunhistochemistry, genetic analysis and/or electron microscopy is often necessary to confirm the specific diagnosis.

Ewing's sarcoma/PNET 

Ewings sarkom, PNET (primitive neuroectodermal tumor) and Askin's tumor belongs to a family of small cell tumors (”the Ewing family of tumors”) which demonstrate varying degree of neuroectodermal differentiation. These tumors can appear in soft tissue or bone.

Histologically, they consists of small round cells with sparse cytoplasm containing glycogen (glycogen can be demonstrated by histochemical PAS staining). A few cases show more pleomorphic cells. There is no matrix production and rosettes can sometimes be seen and is related to neuroectodermal differentiation. This tumor is, by definition, highly malignant and grading meaningless.

There are several differential diagnosis such as malignant lymphoma, mesenchymal chondrosarcoma, small cell carcinoma, and neuroblastoma. A number of special analysis are performed to exclude other diagnoses such as immunhistochemistry, cytogenetic or molecular methods (RT-PCR and FISH) and sometimes electron microscopy.

Immunhistochemical analysis demonstrates positivity for vimentine, CD99 (sensitive, but not specific) and FLI-1. It is importnat to include an extensive panel to exclude the differential diagnosis. Ewings sarcoma/PNET has positive findings for some neuroectodermal markers, such as synaptophysin, S-100 protein and chromogranin.

Ewings sarcoma/PNET has diagnostic genetic findings. The most common translocation is t(11;22)(q24;q12) with an EWSR1-FLI1 gene fusion (more than 90 %). There are several variants of translocations in Ewing's sarcoma/PNET where the EWSR1 gene is involved. EWSR1 rearranging (gene fusions) can appear in other malignant tumors such myxoid liposarcoma, extraskeletal myxoid chondrosarcoma and clear cell sarcoma, but then with other fusion partners. This can be determined by cytogenetic analysis, RT-PCR and FISH.

 

Chromosome changes related to EWSR1

Chromosome arrangement

Gene fusion

Tumor type

t(2;22)(q35;q12)

EWSR1-FEW

Ewing sarcoma

t(7;22)(p21;q12)

EWSR1-ETV1

Ewing sarcoma

t(11;22)(q24;q12)

EWSR1-FLI1

Ewing sarcoma

t(17;22)(q21;q12)

EWSR1-ETV4

Ewing sarcoma

inv(22)(q12;q12)

EWSR1-PATZ1

Ewing sarcoma

t(2;22)(q33;q12)

EWSR1-CREB1

Angiomatoid fibrous histiocytoma/Clearcell sarcoma in soft tissue

t(12;22)(q13;q12)

EWSR1-ATF1

Angiomatoid fibrous histiocytoma/Clearcell sarcoma in soft tissue

t(9;22)(q22;q12)

EWSR1-NR4A3

Exstraskeletal myxoid chondrosarcoma

t(11;22)(p13;q12)

EWSR1-WT1

Desmoplastisc small cell roundcell tumor

t(12;22)(q13;q12)

EWSR1-DDIT3

Myxoid liposarcoma

 

Rhabdomyosarcoma

Rhabdomyosarcoma is tumor differentiated towards skeletal muscle. Rhabdomyosarcoma can be divided into three subtypes: alveolar, embryonal, or pleomorphic rhabdomyosarcoma. All three exhibit vary degrees of positivity for muscle markers such as: desmine, MyoD1, and Myf-4. The last two are good markers for differentiation towards skeletal muscle.

Alveolar rhabdomyosarcoma comprise 30 % of all rhabdomyosarcomas. This is a tumor composed of small round cell with centrally localized nuclei. Sometimes striated cytoplasm can be detected. In alveolar rhabomyosarcoma, alveolar or compact growth pattern can be seen. In a few cases a mixture of alveolar and embryonal type can occur. This tumor is characterized by diagnostic chromosome translocations such t(2;13)(q35;q14) (about 80%) og t(1;13)(p26;q14)(about 20%). This produce fusion genes PAX3-FOXO1 and PAX7-FOXO1. This differentiate the tumor from other variants of rhabdomyosarcoma.

 

Photomicrograph demonstrating an alveolar rhabomyosarcoma. Click to enlarge. Photomicrograph with a lymph node with metastasis from a rhabomyosarcoma -immunhistochemistry demonstrating desmin positivity (brown color). Click to enlarge. Photomicrograph demonstrating a rhabomyosarcoma in a cytological specimen. Click to enlarge.

 

Embryonal rhabdomyosarcoma comprise about 50% of rhabdomyosarcomas and is more frequent in childhood.

The tumor is characterized by varying cellularity partly with myxoid areas. Tumor cell demonstrate differentiation towards varying stages of unmature striated muscle with a mixture of small round cells, spindle shaped cells and cells with eosinophilic cytoplasm typical for rhabdomyoblasts. Striated cytoplasm can be detected in about 50% of these tumors.

The diagnosis can be established by microscopy, but additional methods such as immunohistochemistry is often necessary to confirm the diagnosis. A variant of embryonal rhabdomyosarcoma is called botryoid, because it is typically polypous.

Pleomorphic rhabdomyosarcoma is often seen in adults and demonstrate pleomorphic tumor cells with differentiation towards striated muscle. Immunhistochemistry is positive for desmin, MyoD1 and Myf-4.

Evaluation of operation specimens

When a soft tissue sarcoma is diagnosed the following information should be included in the pathology report:

  • Histological diagnosis
  • Malignancy grade/mitotic count
  • Tumor size (three dimensions or largest diameter)
  • Vessel invasion
  • Necrosis (percentage area with necrosis)
  • Growth pattern (infiltrative growth or not)
  • Tumor localization and infiltration of surrounding tissue
  • Resection borders
  • Result of additional special investigations (immunohistochemical or molecular, genetical analysis)

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