Case 69 - Discussion

Uploaded: 2007-07-22, Updated: 2007-07-22

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MICROSCOPIC INTERPRETATION (Dr. PS)

Entire tumor is submitted for microscopic examination. Sections show a multilobular tumor with a pseudocapsule. The tumor lobules are composed of spindle shaped cells that are arranged in short and long interlacing fascicles. The tumor exhibits hypocellular and hypercellular areas with prominent fine vasculature. The cells are relatively bland with elongated nuclei in hypocellular areas. Hypercellular areas show cells with moderate atypia and pleomorphic multinucleated giant cells. Mitotic count ranges from 2-6 per 10 high power fields. Foci of mature bone and calcifications are identified within the tumor. Tumor necrosis is not identified. Lymphovascular invasion is identified. Upon extensive sampling, a well differentiated intramuscular lipomatous component is seen adjacent to the tumor.

 

IMMUNOHISTOCHEMISTRY
Vimentin - positive.
Smooth muscle actin - weakly positive.
p16 - positive
GFAP - weakly positive.
BCL2 - weak focal positivity.
Desmin - negative.
Myogenin - negative.
CD68 - negative.
AE1/AE3 - negative.
EMA - negative.
S100 - negative.
MART-1 - negative.
CD57 - negative.
Neuron specific enolase - negative.
CD31 - negative.
CD34 - negative.
CD117 - negative.
Ki-67 immunostain reveals proliferation index of approximately 8-15 %.
 

ELECTRON MICROSCOPY (Dr. WJH)
Ultrastructurally, the neoplasm consists of sheets of roughly spindle shaped cells embedded in a patently granular matrix with abundant long space collagen. The neoplastic cells contain irregular and angulated nuclei with prominent chromatin clumping and occasional prominent nucleoli. No mitotic figures are noted. The nuclei are quite large relatively to the cytoplasm. The cytoplasm of many of these cells contain areas of abundant rough endoplasmic reticulum. Many of the cells appear to contain long thin cytoplasmic processes. There are focal collections of intermediate filaments and in an occasional cell, appear to condense at the plasma membrane. Many of these cells appear to be classic myelofibroblasts. Pinocyto-vesicles at the plasma membrane are occasionally seen but are a prominent feature. In several areas, there is some intertwining of the thin cellular processes. The neoplastic cells do not appear to be producing significant basal lamina like material. No lipid material is noted. No osteoid is noted

CYTOGENETICS (MMI, UNMC)
Molecular cytogenetic (FISH and M-FISH) studies revealed the ring chromosomes observed in the G-band from chromosome 12. Additional studies were negative for a t(17;22)(q21.3;q13.1)(COL1A1-PDGFB fusion) and for a disruption of the FUS gene region at 16p11.2.

DIAGNOSIS

Dedifferentiated liposarcoma, grade 3/3 (FNCLCC system).

   
 

Liposarcoma

General Futures of Liposarcoma

 
  • Account for about 10-16% of all soft tissue sarcomas, 4% of childhood soft tissue sarcomas, most common soft tissue sarcoma in adults. The mean age 50 years. Most cases arise de novo. Liposarcomas most frequently arise from the deep-seated stroma rather than the submucosal or subcutaneous fat.

  • The most recent WHO classification of soft tissue tumors recognizes 5 categories of liposarcomas: (1) well differentiated, which includes the adipocytic, sclerosing, and inflammatory subtypes; (2) dedifferentiated; (3) myxoid; (4) round cell; and (5) pleomorphic. Well differentiated liposarcoma and dedifferentiated liposarcoma may comprise on subgroup since they are closely related. Round cell liposarcoma is a poorly differentiated myxoid liposarcoma.

  • The anatomical distribution of liposarcoma appears to be partly related to the histologic type. Well-differentiated liposarcoma tends to occur in deep soft tissues of both the limbs (75%) and the retroperitoneum. Myxoid and/or round-cell liposarcomas and pleomorphic liposarcomas have a striking predilection for the limbs (75%), and dedifferentiated liposarcoma occurs predominantly in the retroperitoneum (75%). Although any liposarcoma subtype occasionally arises in the subcutis, involvement of the dermis appears to be exceedingly rare, and despite high-grade morphology, cutaneous liposarcomas have a favorable clinical prognosis

  • The recognition of lipoblasts is the key finding in the diagnosis of liposarcoma. The earliest cells arise as pericapillary spindle adventitial cells resembling fibroblasts. As fat accumulates in the cytoplasm, the cells lose ER and assume round shape. Gradually, the nuclei become indented and pushed to aside. Criteria for identifying lipoblasts: (1), hyperchromatic indented or sharply scalloped nuclei; (2), well-demarcated cytoplasmic lipid (neutral) droplet; and (3), an appropriate histological background since lipoblasts or lipoblast-like cells are present in other conditions. Presence of lipoblasts is not diagnostic of liposarcoma. Lipoblasts are noted in benign adipocytic tumors, including chondroid lipoma, lipoblastoma,  pleomorphic lipoma.

Well-differentiated liposarcoma

 
  • General: Also named atypical lipoma and  atypical lipomatous tumor. Represents 40-45% of all liposarcoma, most common liposarcoma in late adult life. Tends to occur in deep soft tissues of both the limbs and the retroperitoneum. and rarely in the spermatic cord and the mediastinum. Grossly, large multilobular, deep yellow to ivory.

  • Four histopathological subtypes: 

     

     

     

    1. Adipocytic (Lipoma like ): the most common form. Grossly, large well circumscribed and coarsely lobulated tumour. Microscopically, the tumor predominantly consists of mature adipocytes with a variable number of spindle lipoblasts with hyperchromatic nuclei and multivacuolated cytoplasm. Lipoma-like liposarcomas rarely recur, and they do not metastasize.

    2. Sclerosing: These are relatively pale and firm lesions occur most frequently in the retroperitoneum and the paratesticular region. Microscopically, tumor contains dense fibrotic zones alternating with mature adipocytes. The fibrotic areas contain collagen fibrils of variable thickness and scattered hyperchromatic spindle or multipolar stromal cells. Multivacuolated lipoblasts are rarely present. Therefore, the diagnosis of this subtype more depends on the identification of the atypical stromal cells than on the identification of the diagnostic lipoblasts.

    3. Inflammatory: There is a dense chronic inflammatory infiltrate almost obscuring the lipogenic areas. Prominent aggregates of lymphoid cells and plasma cells are noted simulating inflammatory pseudotumor.

    4. Spindle cell: There  is proliferation of bland spindle cells in a fibrous or myxoid background together with atypical lipomatous component  including lipoblasts. The differential diagnosis include: malignant peripheral nerve sheath tumour, spindle cell lipoma , neurofibroma (S100 positive), dermatofibrosarcoma protuberans (diffuse CD34 positive) ,  well differentiated sclerosing liposarcoma and low grade fibromyxoid sarcoma.

  • Differential diagnosis:

     

     

     

    1. Fat necrosis: foamy macrophages;

    2. Lipoma with lochkern;

    3. Fatty atrophy: lobular pattern, uniform size of lipocytes, lipofuscin;

    4. Lymphoedema;

    5. Spindle cell lipoma/pleomorhpic lipoma;

    6. Atypical lipoma: only diagnosed in skin;

    7. Myolipoma;

    8. Angiomyolipoma/Myolipoma;

    9. Silicone reaction.

  • Cytogenetics: Ring or giant marker chromosome (RGC) derived from 12(q13-q15). Several tumor-associated genes, localized to 12q13-q21, are amplified, in particular MDM2, but also SAS, CDK4, and HMGI-C. Another characteristic feature, seen in the majority of these tumors, is the high frequency of telomeric associations, showing a non-random pattern with a preferential involvement of the 11p telomere.

  • Prognosis: The well-differentiated type and most myxoid types have favorable prognoses, with 100% and 88% 5-year survival rates, respectively. However, these tumors are poorly circumscribed and oftn locally recur after incomplete excision. Although they rarely metastasize, repeated local recurrences may cause the tumor to evolve into a higher grade of sarcoma or to dedifferentiate, in which case metastasis is possible.

Myxoid liposarcoma

 
  • General: Myxoid liposarcoma is the most common form of liposarcomas, constituting about half of the cases,  and the much less common and more aggressive round cell liposarcoma is regarded as a poorly differentiated variant of myxoid liposarcoma. Myxoid and round cell liposarcomas commonly occur in the limbs (75%) usually between third and fifth decade. grossly, multinodular, gelatinous masses devoid of necrosis. Areas with round cell predominance reveal opaque white nodules in the myxoid mass.

  • Microscopic appearances: Multilobular with central hypocellarity and enhanced cellularity peripherally. Each lobule consists of bland fusiform or round cells in myxoid background composed of hyaluronic acid. A delicate plexiform capillary network is present throughout the tumor that is distinguish from the myxoma. Purely myxoid liposarcoma (low grade tumour) is characterised  by  hypocellular  bland spindle cells  in a myxoid  background. Univacuolated lipoblasts are noted around the vessels. Multivacuolated lipoblasts are present in the peripheral subcapsular zone.  There are thin walled branching vessels arranged in a plexiform pattern ('crow's feet' or 'chicken wire pattern' ). Mitotic figures are rare. Transition to hypercellular (round cell) areas are noted in myxoid liposarcoma. Myxoid/round cell liposarcoma is characterised by hypercellular areas with undifferentiated round cells. These cells are larger with hyperchromatic and more rounded configuration, in contrast to the spindle cells in the myxoid variant . Mitotic figures are more frequent in these areas.

  • Differential diagnosis:

     

     

     

    1. Myxofibrosarcoma (myxoid MFH): marked nuclear atypia and a coarser vasculature;

    2. Myxoid chondrosarcoma: small, distinctive eosinophilic cells in small clusters, cords or pseudoacini in a pale-blue background;

    3. Intramuscular or cutaneous myxoma;

    4. Angiomyxoma;

    5. Myxoid dermatofibrosarcoma protuberans

    6. Myxolipoma

  • Immunohistochemistry and electron microscopy: Electron microscopy: non-membrane bound lipid droplets. Undifferentiated round cells and bland spindle cells in myxoid and round cells display cytoplasmic and nuclear positivity with S100 protein. The lipoblasts stain positively with S100 protein. Plexiform vascular areas may be demonstrated by CD31 and CD34 stains.  Antibody to aP2 protein (adipocyte lipid-binding protein).

  • Cytogenetics:  t(12;16)(q13;p11) is found in about 90% of myxoid/round cell liposarcomas, involving FUS (TLS) in 16p11 and CHOP in 12q13, encoding a chimerical protein. The CHOP protein belongs to the C/EBP family of basic leucin zipper group of transcription factors. The most common secondary aberration, in 6-7% of the cases, is trisomy 8. The alternative t(12;22)(q13;q12) has been identified in about 5% of the cases. The t(12;22)(q13;q12) results in CHOP and EWS genes. Thus, the two closely related genes FUS and EWS seem to be interchangeable when fused to CHOP; both FUS and EWS carry a central RNA-binding RNP-1 motif.

  • Prognosis:  Pure round cell liposarcoma is rare (more than 80% round cells and with a relatively favorable prognosis;). More than 10% round cell areas - increased potential for metastasis. More than 25% round cell areas - High grade tumour.

 Round-cell liposarcoma

 
  • General: Pure round cell liposarcomas are very rare, and more often the tumors represent mixed liposarcomas with both myxoid and round cell components at different proportions. In recurrences the round cell component may increase. In the round-cell type, lipoblasts are interspersed among sheets of poorly differentiated round cells.

  • Differential diagnosis: Metastatic carcinoma, lymphoma, melanoma, Ewing's sarcoma.

  • Cytogenetics: Among the few reported cases as pure round cell liposarcoma , t(12;16) is rare and the majority of cases have had fairly complex, unspecific aberrations

  • Prognosis: Round-cell and poorly differentiated types have a poor prognosis. Each has a 5-year survival rate of about 50% because they recur locally and tend to metastasize quickly and widely. The lungs are particularly affected

Pleomorphic liposarcoma

 
  • General: Least common form of liposarcoma (5% of liposarcomas), equally located in the limbs and retroperitoneum of older adults.

  • Microscopic appearances: Two subtypes. A high grade pleomorphic MFH-like form:  disorderly growth pattern and extensive cellular pleomorphism, containing a mixture of scattered bizarre and often multivacuolated lipoblasts and atypical stromal cells, many of which contain highly abnormal mitotic figures. Hemorrhagic and necrotic areas are common. Numerous intracytoplasmic eosinophilic globules may be present. Sometimes a heavy neutrophilic infiltrate is present, which may be confused with well differentiated inflammatory liposarcoma. Another form is less common and mainly consists of sheets of large pleomorphic giant cells associated with smaller mononuclear cells. A new variant of pleomorphic liposarcoma characterised by sheets of epithelioid cells and focal adipocytic differentiation.

  • Cytogenetics: Few cases have been cytogenetically characterized; they invariably show complex karyotypic changes, with no characteristic changes identified.

  • Prognosis: Aggressive tumors showing distant metastasis and about 40% mortality rate.

Dedifferentiated liposarcoma

 
  • General: Characterised by abrupt transition from low grade to high grade non lipogenic morphology within a well differentiated liposarcoma. 90% cases occur  in primary tumour and 10% cases occur in recurrent tumour.
  • Microscopic appearances: Tumor consists of well-differentiated areas and non-lipogenic (dedifferentiated) areas. Dedifferentiated areas are characterised by spindle and pleomorphic cells exhibiting various patterns, including storiform-pleomorphic MFH, myxofibrosarcoma, osteochondrosarcomatous and angiosarcomatous features. New variant has been described exhibiting neural-like, meningothelial-like whorls of spindle cells, or rarely paraganglioma-like histologic pattern. Sometimes the tumour exhibits fascicles of bland spindle cells these are described as low-grade areas.
  • Differential diagnosis:

     

     

     

    1. Spindle cell liposarcoma (lipogenic lesion) must be distinguished from low grade dedifferentiated liposarcoma  which is non lipogenic in nature and has a relatively better prognosis;

    2. Pleomorphic liposarcoma must be differentiated from high grade dedifferentiated liposarcoma (non lipogenic);

    3. Sarcoma infiltrating fat.

  • There is no difference in biological  behavior of low and high grade dedifferentiated liposarcomas. These are associated with 20-25% metastasis. Recurrence rate is usually high.

Reference