Lietuvos University of Health Sciences
Faculty of Medicine
Department of Pathological anatomy
Sara García Coronel
Final Master’s Thesis
MOST COMMON TYPES OF LIPOSARCOMA AND
INVESTIGATION OF PROGNOSTIC VALUES TO
DISEASE PROGRESSION
Thesis supervisor: dr. Lina Poškienė
TURINYS
SUMMARY ... 3
ACKNOWLEDGEMENTS ... 4
CONFLICT OF INTEREST ... 4
CLEARANCE BY ETHICS COMMITTEE ... 4
ABBREVIATIONS ... 5
INTRODUCTION ... 6
AIM AND OBJECTIVES OF RESEARCH ... 7
1.LITERATURE REVIEW ... 8
1.1.General characteristics of liposarcoma classification and its epidemiology ... 8
1.1.1.Atypical lipomatous tumor and its epidemiological patterns ... 9
1.1.2.Dedifferentiated liposarcoma (DDLPS) and its epidemiological patterns ... 10
1.1.3.Myxoid liposarcoma (MLS), or round cell liposarcoma, and its epidemiological patterns ... 10
1.1.4. Pleomorphic liposarcoma and its epidemiological patterns ... 11
1.2.Morphologic characteristics of different types of liposarcomas ... 12
1.2.1. Morphologic features of atypical lipomatous tumor ... 12
1.2.2. Morphologic features of dedifferentiated liposarcoma ... 13
1.2.3. Morphologic features of myxoid liposarcoma... 13
1.2.4. Morphologic features of pleomorphic high grade sarcoma ... 15
1.3.Prognosis factors and their impact on liposarcoma’s clinical course ... 16
2.RESEARCH METHODOLOGY AND METHODS ... 18
3.RESULTS OF RESEARCH ... 19
4.DISCUSSION OF RESEARCH RESULTS ... 26
CONCLUSIONS ... 29
SUMMARY
Author of master thesis: Sara García Coronel
Master thesis: “Most common types of liposarcoma and prognostic values to disease progression” Supervisor of master thesis: dr. Lina Poškienė, MD
Aim of research: to determine the characteristic features of the most common types of liposarcoma according to patient’s age, disease representation, liposarcoma’s anatomical localization and morphologic features.
Objectives of research: 1. To evaluate the clinical characteristics of patients diagnosed with liposarcoma between 2006 and 2016. 2. To determine the most common types of liposarcoma from biopsy and surgical material examined by histological examination between 2006 and 2016. 3. To evaluate anatomical localization, morphologic features of liposarcoma diagnosed for patients between 2006 and 2016. 4. To evaluate clinical and morphologic characteristics of different liposarcoma types in recurrence cases of patients diagnosed with liposarcoma between 2006 and 2016.
Methods: object of research – liposarcomas diagnosed for patients at the department of Pathological Anatomy of LUHSH Kaunas Clinics between 2006 and 2016. Retrospective investigation of pathology reports was performed evaluating patient’s clinical data, macroscopic and microscopic morphologic characteristics of different types of liposarcomas. Statistical analysis was performed by applying MS Excel and SPSS software. Statistical significance was p<0.05. Results: 65 patients with liposarcoma were evaluated by gender, age, anatomical localization, size and histological type of liposarcoma between 2006 and 2016. 52.3% of these patients were males and 47.7% were females. The average age of patients was 60±14 years old. The average size of liposarcoma was 15.018±10.79 cm. 16 (24.61%) of examined 65 patients were diagnosed with dedifferentiated liposarcoma, 23 (35.38%) cases – myxoid liposarcoma, 12 (18.46%) – pleomorphic liposarcoma and 14 (21.54%) cases of of overall examined patients were diagnosed with well-differentiated liposarcoma. According to anatomical localization, 6 (9.23%) cases were in the back, 26 (40%) cases were in the lower extremity, 4 (6.15%) cases were in the upper extremities, 1 (1.54%) case was in the mediastinum, 1 (1.54%) case was in the neck, 3 (4.2%) cases were not reported, 3 (4.62%) cases were in the pelvis, and 21 (29.2%) cases were retroperitoneal liposarcomas. There were no statistically significant differences by gender, age, anatomical localization, and liposarcoma type in tumor’s recurrence cases (p>0.05).
Conclusions: 1. Liposarcoma affects almost equally males and females mean age being about 60 years old. 2. The most common type of liposarcoma was myxoid, followed by dedifferentiated, well-differentiated and pleomorphic. 3. The average size of liposarcoma was 15.018±10.79 cm, most common localization being lower extremity followed by retroperitoneal are. The less common localizations of tumor were back, upper extremity, pelvis, neck and mediastinum. 4. Overall recurrence of liposarcomas was 26.4% (19 out of 65 patients). There were no statistically significant differences by gender, age, anatomical localization, and liposarcoma type in tumor’s recurrence cases (p>0.05).
ACKNOWLEDGEMENTS
This research is part of my integrated studies in the Lithuanian University of Health Sciences as a Final Master Thesis during my 6th year of medical studies.
CONFLICT OF INTEREST
The author of master thesis reports no conflict of interest.
CLEARANCE ISSUED BY ETHICS COMMITTEE
No. of approval by ethics committee: BEC-MF-85. Date of issue: 2017-11-24.
ABBREVIATIONS
% – percentage
ALT – atypical lipomatous tumour
CDK4 – cyclin-dependant kinase 4
CDKN2A – cyclinc-dependant kinase inhibitor 2A cm – centimeter
DDLPS – dedifferentiated liposarcoma EWS – Ewing sarcoma
EWSR1-CHOP – fusion of genes: EWS RNA-binding protein 1 and CCAAT/Enhancer-Binding
Protein Homologous Protein (CHOP), an activating protein of apoptosis FAP – fibroblast activating protein
Fig. – figure
FUS – gene encoding RNA-binding protein FUS/TLS (Fused in Sarcoma/Translocated
in Sarcoma)
HPF – hibernation promoting factor IHC – immunohistochemistry
MDM2 – gene encoding mouse double minute 2 homolog
MLS – myxoid liposarcoma STS – soft tissue sarcoma p16 – tumor suppressor protein RNA – ribonucleic acid
TP53 – gene that provides instructions for making a protein called tumor protein p53 (or p53)
WDL – well-differentiated liposarcoma WHO – World Health Organization
INTRODUCTION
Soft tissue as described by anatomical terms is the tissue that connects, supports or surrounds other tissues. Examples include muscles, tendons, fat, fibrous tissue, synovial tissue, vessels, and nerves. In other words, soft tissue is ¨non-epithelial, extra skeletal mesenchyme exclusive of the reticuloendothelial system and glia.
Soft tissue sarcoma (STS) is a cancer of these soft tissues that arise predominantly from the embryonic mesoderm(10) and can be classified according to the type of tissue they started in. They encompass a group of neoplasms of over 50 different types(31), that are anatomically and biologically diverse(9), a rare and heterogeneous group of malignant tumours of mesenchymal origin that comprise less than 1 percent of all adult malignancies with an estimated incidence of 4–5 neoplasms /100 000 per year in Europe and 12 percent of paediatric cancers.
Even though the skeletal and soft tissue are the most abundant tissue in the human body, STS consists of only 1%(29). As classified by the World Health Organization (WHO), the group of STS includes more than 100 different histological subtypes according to the presumptive tissue of origin. The natural behavior and outcome of STS are dependent of the age of the patient, anatomical site and depth, size, and resectability of the tumor, as well as of histology, grade, nodal disease, and distant metastasis. Some predisposing factors have been identified: genetic alterations (neurofibromatosis type 1, Li – Fraumeni syndrome, FAP/Gardner syndrome, Beckwith –
Wiedemann syndrome, hereditary retinoblastoma, Werner syndrome, Costello syndrome, Nijmegen
breakage syndrome)(3) and exposure to radiation or chemical substances.
Liposarcoma is the most common type of STS accounting to 80% of sarcomas and up to 20-35% of all STS (33), firstly described by Virschow in 1860, it resembles fat cells under a microscope and that can occur in almost any part of the body, being the most common accounting to more than 50% of the cases the thigh, followed by the retroperitoneum (1) and the inguinal region and less often in the head and neck area, and oral involvement is rare. Only a few studies reported some prognostic factors for liposarcoma, and optimal treatment strategies and prognoses have not been fully defined yet(22).
Therefore it is essential to investigate clinical and morphological characteristics of liposarcomas with a purpose to determine the factors that may define or assist in identifying risk factors for STS disease progress.
AIM AND OBJECTIVES OF RESEARCH
Aim:
To determine the characteristic features of the most common types of liposarcoma according to patient’s age, disease representation, liposarcoma’s anatomical localization and morphologic features for the patients between 2006 and 2016.
Objectives:
1. To evaluate the clinical characteristics of patients diagnosed with liposarcoma between 2006 and 2016.
2. To determine the most common types of liposarcoma according to WHO classification from biopsy and surgical material examined by pathology investigation between 2006 and 2016.
3. To evaluate anatomical localization, morphologic features of liposarcoma diagnosed for patients between 2006 and 2016.
4. To evaluate clinical and morphologic characteristics of different liposarcoma types in recurrence cases of patients diagnosed with liposarcoma between 2006 and 2016.
1.LITERATURE REVIEW
1.1.General characteristics of liposarcoma classification and its epidemiology
Liposarcoma is a lipogenic tumor of large deep-seated connective tissue spaces, a malignancy of fat cells that normally appears as a slowly enlarging, painless, nonulcerated mass, but some lesions grow rapidly and become ulcerated early.
Fusion proteins created by chromosomal abnormalities are key components of mesenchymal cancer development. An abnormality of band 12q13 has been associated with the development of liposarcomas. The most common chromosomal translocation is the
FUS-CHOP fusion gene, which encodes a transcription factor necessary for adipocyte differentiation.
These and other distinct genetic aberrations may aid in the diagnosis of particular liposarcoma subtypes, and they can potentially be targets that can be exploited therapeutically.
The development of a liposarcoma from a pre-existing benign lipoma is rare and most cases arise de novo; most frequently develops from the deep-seated stroma rather than the submucosal or subcutaneous fat, dermal lesions are rare and may resemble pleomorphic fibroma.
In the context of liposarcoma, the lipoblast is a neoplastic cell that to some extent recapitulates the differentiation cascade of normal fat cells. Useful criteria to identify diagnostic fibroblasts:
1. Hyperchromatic indented or sharply scalloped nucleus 2. Lipid-rich droplets in the cytoplasm
3. Appropriate histological background (2).
The anatomical distribution of liposarcoma appears to be partly related to the histological type. Well-differentiated liposarcoma (WDL) tends to occur in deep soft tissues of both the limbs and the retroperitoneum. Myxoid, round-cell and pleomorphic liposarcomas tend to occur on the limbs, and dedifferentiated liposarcoma occurs predominantly in the retroperitoneum. They occasionally arise in the subcutis but involvement of the dermis is extremely rare. According to other studies most cases originate in the neck (28%) followed by the head (scalp and face, 26%), larynx (20%), pharynx (18%), and mouth (8%).
According to other studies statistically talking atypical lypomatous tumor(ALT)/WDL comprises 40-45% of all liposarcomas, whereas myxoid and pleomorphic liposarcomas (MLS and PLS) represent 35-40% and 5%, respectively.
Correlated with the advent of metastases and with survival are tumor differentiation, cellularity, mitosis count, tumor necrosis, and vascular emboli(11) .
The most recent WHO(8) classification of soft tissue tumours recognizes 4 categories of liposarcomas(13), each with its own unique characteristics and behaviours:
1.Atypical lipomatous tumour (ALT), atypical lipoma or well-differentiated liposarcoma (4) (including the adipocytic or lipoma like, sclerosing and inflammatory subtypes);
2.Dedifferentiated liposarcoma (DDLPS);
3.Myxoid liposarcoma (MLS) or round cell liposarcoma; 4.Pleomorphic liposarcoma (PLS)(18,19).
1.1.1.Atypical lipomatous tumor and its epidemiological patterns
ALT arise most frequently in deep soft tissue at locations such as the limbs, specially the thigh, or the trunk, where complete excision is usually curative, however, in sites such as retroperitoneum and mediastinum, it is commonly impossible to obtain a wide excision margin and local recurrence is almost inevitable. Spindle cell liposarcoma is a variant of ALT with lesions which occur mostly in adults and show predilection to arise in somatic soft tissue and most often in subcutaneous or intramuscular soft tissue of the limbs with the majority of lesions measuring between 5–10 cm. These lesions have an ~15–20% rate of local recurrence but in contrast to atypical lipomatous tumor/well-differentiated liposarcoma of conventional type, dedifferentiation seems to be exceedingly rare.
It is the most common histological subtype accounting to 40-45% of all liposarcomas, occurring mostly in middle-aged adults with peak incidence in the sixth or seventh decade of life; extremely rare in childhood and usually associated with Li-Fraumeni syndrome. The disfribution within males and females is equal.
ALT most frequently arises in the extremities (60–75 % of cases). The most common localization is the thigh (51 %) with the second most common localization being the retroperitoneum (20 %)(23).
The risk of dedifferentiation is of about 10-15% in retroperitoneum and 5% for extremity lesions; it occurs after an average of 7-8 years but may be seen as long as 17-20 years after original diagnosis; once dedifferentiation occurs, the lesion can usually be considered fully malignant sarcomas.
1.1.2.Dedifferentiated liposarcoma (DDLPS) and its epidemiological patterns
The term "dedifferentiated" liposarcoma is used to describe a distinctive lesion in which a well-differentiated liposarcoma is juxtaposed with a high-grade nonlipogenic sarcoma. DDLPS is probably the most common of all the dedifferentiated sarcomas, occurring almost exclusively in the mediastinum, the retroperitoneum, and the inguinal/paratesticular regions(5).Retroperitoneum is the most common localization followed by spermatic cord and, more rarely, the head and neck and trunk. Usually presents as a large painless mass. Radiological imaging shows coexistence of both fatty and non-fatty solid components, which may be discontinuous in the retroperitoneum.
DDLPS occurs when a low-grade tumour changes, and the newer cells in the tumour are high grade and it is characterized by different areas of better-differentiated lipomatous cells, as well as well-differentiated liposarcoma, high-grade areas resembling fibrosarcoma, myxosarcoma and even osteosarcoma. Occasional cases of well-differentiated and dedifferentiated liposarcoma contain myxoid stroma, leading to confusion with other sarcomas(17).
Whereas most dedifferentiated liposarcomas display high-grade dedifferentiation, a small number contain exclusively low-grade areas or a combination of low and high-grade areas. DDLPS usually consists of large multinodular yellow masses containing discrete, solid, often tan-grey non-lipomatous areas that often show necrosis.
Dedifferentiation is found de novo in 90 % of cases, whereas 10 % occur in locally recurrent lesions and can develop within any deep-seated anatomic location and demonstrates a marked retroperitoneal predilection. The latent period for dedifferentiation in ALT can be up to 20 years. The risk of dedifferentiation depends on the location. The rate of dedifferentiation is 15 % for retroperitoneal tumors, 24 % in the lower extremity, and 4.5 % in the upper extremity. DDLPS affects the same patient population as liposarcoma and is equally frequent in males and females. Commonly affecting patients in their 6th and 7th decades of life.
1.1.3.Myxoid liposarcoma (MLS), or round cell liposarcoma, and its epidemiological patterns
MLS is the second most common type of liposarcoma, representing 30–40 % of all extremity liposarcomas. Grossly MLSs are well-circumscribed multinodular intramuscular tumours. Included in this category are more cellular lesions formerly known as round cell liposarcoma which are high grade radiosensitive sarcoma at the aggressive end of the liposarcoma spectrum and at the benign end of myxoid liposarcoma.
Myxoid/round cell liposarcoma is arguably the commonest type of liposarcoma occurring in the extremities and may show gradual progression from low-grade, pure myxoid liposarcoma to high-grade round cell liposarcoma, being more than 2/3 of the cases within the musculature of the thigh and rarely in the retroperitoneum or subcutaneous tissue. Rarely myxoid/round cell liposarcoma is associated with areas of well-differentiated or pleomorphic liposarcoma (mixed liposarcoma)(6). Independently of the histological grade 1/3 of the patients develop distant metastasis to unusual locations in soft tissue or bone even before spreading to the lungs.
MLPs accounts to 15-20% of liposarcomas and represents about 5% of all tissue sarcomas in adults with a peak incidence on the fourth and fifth decades. It is the commonest form of liposarcoma in children and adolescents and is equally common in males and females(34). They often occur in the intermuscular fascial planes and predominantly affect the lower extremities especially in the medial thigh and popliteal regions. The most common sites of metastatic disease for myxoid liposarcoma include the paraspinal and retroperitoneal soft tissues, bones, and opposite extremity. It is generally considered as a low-grade tumor with good prognosis.
1.1.4. Pleomorphic liposarcoma and its epidemiological patterns
PLS occurs in extremities in 2/3 of cases and most cases arise in deep soft tissue, but about 25% develop in subcutaneous fat. Most tumours are large with a median size of 8-10 cm. They are well demarcated but non-encapsulated or ill defined and infiltrative and sometimes multinodular. Colour is white or yellow, commonly with myxoid changes and foci of necrosis.
Pleomorphic liposarcoma is the least common subtype of liposarcoma, and accounts only about 5–15 % of all liposarcomas. Similar to other subtypes, the lower extremity is most commonly involved (56 % of cases). Both genders are almost equally affected with a slightly higher incidente in males than females and the majority of lesions arise in patients older than 50-70 years.
Lesions present with a firm, usually deep-seated, painless soft tissue mass, which rapidly increases in size. Imaging findings show a defined mass with areas of necrosis and hemorrhage, contributing to a heterogeneous appearance.
1.2.Morphologic characteristics of different types of liposarcomas
1.2.1. Morphologic features of atypical lipomatous tumor
Locally aggressive mesenchymal neoplasm composed either entirely or partly of a mature adipocytic proliferation showing significant variation in cell size and at least focal nuclear atypia in both adipocytes and stromal cells. Consists usually of a large, well-circumscribed, lobulated mass; rarely, an infiltrative growth pattern may be encountered; varying in colour from yellow to white, many be mistaken for a lipoma except for their extremely large size and tendency to have more fibrous bands, gelatinous zones, or punctuate haemorrhage.
It is the most common subtype and usually starts as a low-grade tumour, which cells look much like normal fat cells under the microscope and tend to grow and change slowly. Shows no potential for metastasis unless it undergoes dedifferentiation (fig. 1).
Fig. 1. A. Marked variation in adipocyte size; B. Presence of atypical, hyperchromatic stromal
cells; C. Varying number of lipoblasts
ALT is composed of a relatively mature adipocytic proliferation in which significant variation in cell size is easily appreciable. Focal adipocytic nuclear atypia as well as hyperchromasia is a consistent finding and scattered hyperchromatic as well as multinucleate stromal cells are often identified. Monovacuolated or multivacuolated lipoblast may be found on a varying number, in some cases these atypical spindle cells are numerous whereas in other cases these cells are so rare as to require extensive sampling of the tissue.
Genetic markers of liposarcoma include supernumerary chromosomes, which include amplified segments of chromosome arm 12q14-15. Well-/dedifferentiated liposarcoma is characterized by an amplification of the 12q13-15 region, including MDM2 and CDK4 genes which may play an important role in human tumorigenesis(20).
1.2.2. Morphologic features of dedifferentiated liposarcoma
Dedifferentiated liposarcoma results from the progression of a well-differentiated liposarcoma to a nonlipogenic sarcoma of variable histologic grades and morphologic patterns that acquires metastatic potential.
Dedifferentiated areas in DDLPS have the appearance of a high-grade sarcoma in approximately 90% of cases, and show a variety of growth patterns including, most frequently, nondistinct spindle cell and pleomorphic patterns, and less commonly, inflammatory, giant cell, round cell, or meningothelial-like patterns. Most frequently resemble undifferentiated pleomorphic sarcoma or intermediate to high-grade myxofibrosarcoma.
The remaining 10% of DDLPS have a morphologicall appearance of a low grade tumor, characterized by uniform spindle cells with mild nuclear atypia, often organized in a fascicular pattern and exhibiting lower cellularity, 5-10% may exhibit heterologus dedifferentiation, which does not affect the clinical outcome(30) (fig. 2).
Fig. 2. Morphologic features of homologous dedifferentiated liposarcoma
Transition from WDL to high grade non-lipogenic sarcoma occurs in most cases with a variable dedifferentiation extent and usually an abrupt transition, although in some cases there is a gradual transition between the two.
1.2.3. Morphologic features of myxoid liposarcoma
Myxoid liposarcoma is a malignant, intermediate to high grade tumour composed of uniform round to oval-shaped primitive non-lipogenic cells and a variable number of small
signet-ring cell lipoblasts in a prominent myxoid stroma with a characteristic branching vascular pattern (fig. 3). Morphologically, the severe degree of nuclear atypia may help to exclude MLS(26).
Fig. 3. Developing lipoblast from a myxoid liposarcoma with fine vacuoles and late stage
resembling mature white fat tissue cell (left and right)
Histologically, MLS(7) presents a mixture of uniform round to oval shaped nonlipogenic cells and a variable number of small signet ring lipoblasts in a prominent myxoid matrix, rich in a delicate plexiform capillary network.
Most cases of MLS tumors are relatively slow growing but 10–15% show a hyper cellular round cell morphology with less myxoid component that is associated with an unfavourable prognosis(23). Adipose tissue is sparse and hemorrhage can be present. Frequently the extracellular mucin forms large confluent pools creating a lymphangioma-like growth pattern. Grossly, the predominantly myxoid lesions are gelatinous, whereas lesions with round cells contain opaque white nodules.
A subset of MLS shows histological progression to hypercellular or round cell morphology associated with a significantly poorer prognosis and characterized by solid sheets of round cells with a high nuclear to cytoplasmic ratio without myxoid stroma. Round cell components are identified as solid sheets of uniform small round blue cells with infrequent lipoblasts and paucity of intercellular myxoid stroma. Tumors that exhibit greater than >5 % round cell component are considered high grade, and follow a more aggressive course with proportionally increased mortality rates.
Genetically, myxoid/round cell liposarcoma is characterized by a translocation causing
1.2.4. Morphologic features of pleomorphic high grade sarcoma
Pleomorphic high-grade sarcoma containing a variable number of pleomorphic lipoblasts and no other areas of differentiation present, it is a high-grade tumour with cells that look very different from normal cells (18,19). Pleomorphic liposarcomas include two related but clearly distinguishable histological forms that share a disorderly growth pattern and an extreme degree of cellular pleomorphism but differ in the content of intracellular lipid material (fig. 4).
Fig. 4. Pleomorphic liposarcoma showing sheets of epitheloid cells with scattered pleomorphic
lipoblasts
Most cases have infiltrative margins and all tumours contain a varying proportion of pleomorphic lipoblasts, which is necessary for diagnosis. Notable features: spindle and multinucleate giant cells arranged in short fascicles, extremely large tumour cells with clear or vacuolated cytoplasm, extracellular and occasionally intracellular eosinophilic hyaline droplets and necrosis present in more than half of cases. Most common histologic growth patterns are those which resemble undifferentiated pleomorphic sarcoma, myxofibrosarcoma, and, reflecting the epithelioid morphology that may be present, poorly differentiated carcinoma and melanoma.
1.3.Prognosis factors and their impact on liposarcoma’s clinical course
ALT requires complete excision due to the risk of local recurrence, lesions located in surgically amenable soft tissue do not recur after complete excision with a clear margin while tumours occurring in deep anatomical sites tend to recur repeatedly and may cause death or dedifferentiate and metastasize, lung is the most frequent site of metastases which is associated with decreased survival and risk of developing metastatic disease is statistically associated with tumor grade and local recurrence(27). Although histologically and karyotypically identical, ALT of the extremities has a better prognosis than retroperitoneal as it can usually be completely excised and lacks metastatic potential in the well-differentiated form.
Incomplete resection is more likely to occur in the case of the retroperitoneum, as differentiation of tumor from normal retroperitoneal fat can be difficult during surgery. In cases of incomplete resection, tumor may eventually dedifferentiate, resulting in metastatic capability and a worse prognosis. Studies reported approximately 10 % 5-year local recurrence rates for primary tumors; in contrast, local recurrence of retroperitoneal well-differentiated liposarcoma is approximately 60 % at 5 years. These tumors can undergo delayed dedifferentiation and therefore long-term surveillance of the operative site is recommended. Overall mortality ranges from 0% on extremities to over 80% for the retroperitoneum if patients are followed 10-20 years and median time to death ranges from 6 to 11 years.
DDLPS has a local recurrence of at least 40%, however almost all retroperitoneal cases tend to recur in 10-20 years. Distant metastases are observed in 15-20% of cases with an overall mortality rate is 28-30% at 5-year follow-up. Occurring relatively early in the course of disease and exhibiting a pulmonary predilection, these lesions are highly aggressive and commonly fatal. The most important prognostic factor is anatomical location, with retroperitoneal lesions exhibiting the worst clinical behaviour. Retroperitoneal masses with dedifferentiated components recur in almost 100 % of cases, and are almost uniformly fatal due to metastatic disease and local recurrence.
DDLPS exhibits a less aggressive clinical course than other types of high-grade pleomorphic sarcoma and an accelerated clinical course is observed in only a minority of patients but it results in worse patient outcomes than well-differentiated tumors despite shared molecular derangements, local recurrence rates of 40–80% are reported(28).
For MLP prognosis(25) is highly dependent on the proportion of round cell components, with higher proportions corresponding to increased rates of metastasis and mortality; 5 % is usually used as a cut-off for distinguishing higher-grade tumors and those patients who may benefit from more aggressive neoadjuvant therapy. High histological grade, presence of necrosis, and TP53 and
CDKN2A alterations are predictions of unfavourable outcome in localized MLS. Low grade MLS is
associated with a metastatic risk of <10%(12).
The 10-year mortality ranges from 30 % for patients with 5–25 % round cell component to 60 % for patients with greater than 25 % round cell component. Metastases developed in 23 % of patients with 0–5 % round cell component versus 56 % of patients with greater than 25 % round cell component.
Pleomorphic liposarcomas are aggressive and exhibit focal recurrence with metastatic rates of 30-50% and 60% over 5-year survival being the most common places for it the lungs and pleura. Factors associated with a poor prognosis include age greater than 60, deep-seated tumors, non-extremity lesions (central location), mitotic index and tumor size >5 cm. Recent reports demonstrate a 5-year survival rate of 63 % and a local recurrence-free, metastasis-free, and disease-free survival rates of 58-39 %.
2.RESEARCH METHODOLOGY AND METHODS
Retrospective research consisting on the collection of data of patients with liposarcoma treated in LHSUH Kaunas Clinics between 2006 and 2016 was performed. Investigation of the prognostic values as patients age, disease representation, tumor localization, morphological features and their relation with disease progression was accomplished by reviewing the reports of liposarcoma surgical or biopsy material pathology examination.
Statistical analysis was carried out using data acquisition and analysis program SPSS IBM to compare age and gender of the patients together with disease representation, localization and size. Quantitative variables were described as median and variable rank. Independence of the qualitative features was evaluated by the criterion of chi-square. Statistical significance was p<0.05.
65 patients were diagnosed with liposarcoma from which 31 were women and 34 were men, with ages ranging between 22 and 84. Patients age median at diagnosis was 63 years (range, 22 to 84). Of the patients, 47,7% (31) were female, 52,3% (34) were men.
The research methods were approved and the study was provided following the authorization of Kaunas Regional Biomedical Research Ethics Committee of Bioethics Committee of the Republic of Lithuania (No BE-2-8).
FEMALE 47.69% MALE
52.31%
3.RESULTS OF RESEARCH
In the study of 65 patients with liposarcoma are evaluated the age, type of liposarcoma, localization and size. From these patients 52.31% were males and 47.69% females. So this type of sarcoma is slighty more common (4,62%) in males than in females according to examined clinical cases (fig. 5).
Fig.5. Gender characteristics of patients diagnosed with liposarcoma between 2006 and 2016
The average of age was 60±14 years (min 22 max 84 years). Being in the female group the youngest at 22 years of life and the oldest at 82 years of life and in the male group the youngest at 36 years of life and the oldest at 84 years of life (fig. 6).
Fig. 6. Clinical characteristics of patients diagnosed with liposarcoma between 2006 and 2016
0 10 20 30 40 50 60 70 80 90 1 2 3 4 5 YEARS O F AG E Women (age) Men (age)
The average size of liposarcoma was 15.018±10.7931 cm (min 0.5 max 52.0 cm), and the size parameter of 14 tumors were not reported (biopsy material or tumor removed surgically in fragments) (table 1).
Table 1. Year, age and tumor size of patients diagnosed with liposarcoma between 2006 and 2016
Year Age Size (cm)
N Valid 65 65 51 Lost 7 7 21 Mean 2011,45 60,77 15,018 Median 2012,00 63,00 13,500 Deviation 3,580 14,892 10,7931 Range 11 62 51,5 Mínimum 2005 22 0,5 Máxiimum 2016 84 52,0
In 16 (24.61%) of 65 patients the type of liposarcoma was dedifferentiated liposarcoma, in 23 (35.38%) of 65 patients the type of liposarcoma was myxoid liposarcoma, in 12 (18.46%) of 65 patients the type of liposarcoma was pleomorphic liposarcoma and in 14 (21.54%) of our patients the type of liposarcoma was well-differentiated liposarcoma (fig. 7).
Fig 7. Ratio of the different types of liposarcoma according to WHO classification
According to localization 6 (9.23%) of the total 65 cases were in the back, 26 (40%) of the total 65 cases were in the lower extremity, 1 (1.54%) of the total 65 cases were in the mediastinum, 1 (1.54%) of the total 65 cases were in the neck, 3 (4.2%) of the total 65 cases were not reported, 3
24.61%
35.38% 21.54%
18.46%
(4.62%) of the total 65 cases were in the pelvis, 21 (29.2%) of the total 65 cases were retroperitoneal and 4 (6.15%) of the total 65 cases were in the upper extremities (fig. 8).
Fig. 8. Anatomical localization of tumor in patients diagnosed with liposarcoma between 2006 and
2016
On relation within type of liposarcoma and localization, regarding dedifferentiated liposarcomas the most common localization was retroperitoneal (5 cases) while the least common localizations reported were the pelvis and back (1 and 1 case respectively), regarding myxoid liposacroma the most common localization was the lower extremity (13 cases) while the least common localization reported was the upper extremity (1 case), regarding pleomorphic liposarcomas the most common localization was the lower extremity (5 cases) while the least common localizations reported were the neck and the back (1 and 1 case respectively), regarding well-differentiated liposarcomas the most common localization was retroperitoneal (6 cases) while the least common localization reported was the neck (1 case) (table 2).
Table 2. Liposarcoma’s characteristics by anatomical localization and type
Localization/type Dedifferentiated liposarcoma Myxoid liposarcoma Pleomorphic liposarcoma Well-differentiated liposarcoma Total by localization Back 1 2 1 2 6 Lower extremity 5 13 5 3 26 Mediastinum 0 0 1 0 1 Neck 0 0 0 1 1 Not reported 0 1 0 2 3 Pelvis 1 2 0 0 3 Retroperitoneal 9 4 2 6 21 Upper extremity 0 1 3 0 4 Total by type 16 23 12 14 65 Retroperitone al… Back 9.23% Upper extremity 6.15% Lower extremity 40% Neck 1.54% Pelvis 4.62% Mediastinum1.54%
Related to the type of procedure perfomed 19 (26.4%) of the total 65 patients underwent biopsy and 51 (70.8%) of the total 65 patients underwent operation. The total recurrence was 26.4% (19 out of 65 patients) (fig. 9).
Fig. 9. Ratio of procedure type and recurrence among patients diagnosed with liposarcoma
between 2006 and 2016
On a comparison of tumor size with different values of the study, such as gender, type, localization and age of the patients, we can compare a total of 51 cases out of 65 (78,5%) because in 14 of the cases (21,5%) size was not reported.
According to the data collected on the study the smallest-sized tumor (0,5 cm) corresponds to a male (differing on 1 cm from the smallest tumor studied corresponding to a female) and the largest sized tumor corresponds to a female (differing on 12 cm from the largest tumor studied corresponding to a male). Chi-square test was performed to look for association between size and gender categories and got this output: χ2=38,328, df=36, p=0.364. Since p is >0.05, there is not a significant correlation between tumor size among the different gender groups.
According to the data collected on the study the smallest-sized tumor (0,5 cm) corresponds to the dedifferentiated liposarcoma subtype (differing on 1 cm from the next smallest tumor studied corresponding to the pleomorphic subtype) and the largest sized tumor corresponds to the well-differentiated subtype (differing on 5 cm from the previous largest tumor studied corresponding to the dedifferentiated subtype). Chi-square test was performed to look for association between size and type of liposarcoma categories and got this output: χ2=110,302, df=108, p=0.420. Since p is
19 51 19 46 14 1.8 0 10 20 30 40 50 60 Biopsy Operation Recurrence No Yes
>0.05, there is not a significant correlation between tumor size among the different types of liposarcomas.
According to the data collected on the study the smallest sized tumor (0,5 cm) corresponds to the lower extremity (differing on 1 cm from the next smallest tumor studied corresponding to the upper extremity) and the largest sized tumor corresponds to the retroperitoneum (differing on 5 cm from the previous largest tumor studied corresponding to the retroperitoneum as well). Chi-square test was performed to look for association between size and localization categories and got this output: χ2=282,562, df=252, p=0.090. Since p is >0.05, there is not a significant correlation between tumor size among the different localizations.
According to the data collected on our study the smallest sized tumor (0,5) corresponds to an 82 years old patient (differing on 1 cm from the next smallest tumor studied corresponding to a 50 years old patient) and the largest sized tumor corresponds to a 58 years old patient (differing on 5 cm from the previous largest tumor studied corresponding to a 48 years old patient). Chi-square test was performed to look for association between size and age categories and got this output: χ2=1240,292, df=2, p=0.142. Since p is >0.05, there is not a significant correlation between tumor size among the different age groups.
Regarding recurrence, most of the cases were at the age of 40´s (6 out of a total of 19), being the youngest patient 30 years of age and the oldest 82 years of age. Chi-square test was performed to look for association between size and recurrence categories and got this output: χ2=38,815, df=41, p=0.568. Since p is >0.05, there is not a significant correlation between age and recurrence.
Regarding recurrence according to type of liposarcoma, dedifferentiated liposarcoma was the type with highest grade of recurrence (50%), followed by pleomorphic liposarcoma (25%), myxoid liposarcoma (21,7%) and well-differentiated liposarcoma (21,4%) (table 3).
Table 3. Reccurence rates of different types of liposarcoma between 2006 and 2016 Type of liposarcoma Total Dedifferentiated liposarcoma Myxoid liposarcoma Pleomorphic liposarcoma Well-differentiated liposarcoma Recu-rrence No 8 18 9 11 46 Yes 8 5 3 3 19 Total 16 23 12 14 65
Chi-square test was performed to look for association between type of liposarcoma and recurrence categories and got this output: χ2=4,476, df=3, p=0.214. Since p is >0.05, there is not a significant correlation between type of liposarcoma and recurrence.
Regarding recurrence according to the localization of the liposarcoma, only data from to places was reported, being the most common the retroperitoneal with 10 cases out of 21 cases (47,6%), followed by the lower extremity with 9 cases out of a total of 26 (34,6%) (table 4).
Table 4. Recurrence comparison within tumor localization among patients diagnosed with
liposarcoma between 2006 and 2016
Recurrence Total No Yes Localization Back 6 0 6 Lower extremity 17 9 26 Mediastinum 1 0 1 Neck 1 0 1 Not reported 3 0 3 Pelvis 3 0 3 Retroperitoneal 11 10 21 Upper extremity 4 0 4 Total 46 19 65
Chi-square test was performed to look for association between localization and recurrence categories and got this output: χ2=11,232, df=3, p=0.129. Since p is >0.05, there is not a significant correlation between localization and recurrence.
Regarding size, the smalest tumor to recur was at 0,5 cm while the biggest was at 40,0 cm, being the most common rate of recurrence at 13,0/13,5 cm. Chi-square test was performed to look for association between size and recurrence categories and got this output: χ2=37,134, df=36, p=0.417. Since p is >0.05, there is not a significant correlation between size and recurrence.
Regarding gender, recurrence was more frequent in woman with a total of 13 cases out of 21 (61,9%), than in men, with a total of 6 cases out of 25 (24%) (table 5). Regarding size, the smalest tumor to recur was at 0,5 cm while the biggest was at 40,0 cm, being the most common rate of recurrence at 13,0/13,5 cm.
Table 5. Recurrence comparison within gender among patients diagnosed with liposarcoma between 2006 and 2016 Gender Total Female Male Recurrence No 25 21 46 Yes 6 13 19 Total 31 34 65
Chi-square test was performed to look for association between gender and recurrence categories and got this output: χ2=2,794, df=1, p=0.095. Since p is >0.05, there is not a significant correlation between gender and recurrence.
4.DISCUSSION OF RESEARCH RESULTS
In contrast to benign lipomas, all four subtypes of liposarcoma are true adipocytic malignancies which can cause significant morbidity and mortality.
Liposarcomas comprise a histologically diverse group of soft tissue tumors that demonstrate a varied behavior patterns. Each subtype is characterized by distinct genetic and molecular aberrations and unique histologic appearance, suggesting separate pathways to malignant transformation. Accordingly, the initial presentation, pattern of disease progression and overall clinical outcome varies with each liposarcoma subtype. Understanding of these multi-level differences and distinguishing among liposarcoma subtypes has important therapeutic and prognostic implications since it is critical to select the appropriate management of the liposarcoma patient and select the appropriate treatment options.
Generally talking there is no association with race or geography know, liposarcomas are slightly more common in males than in females and the mean patient age at onset is 50 years. Although liposarcomas account for about 17% of all soft tissue sarcomas, they are involved in only 4% of childhood soft tissue sarcomas. Cases of liposarcoma are reported in young adults and teenagers, but cases in children are rare.
Prognosis relates to the type of liposarcoma present. In general, survival for extremity tumors is favorable been the histologic grade of localized liposarcomas of the extremities the most important prognostic factor.
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 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. Round-cell and poorly differentiated types have a poor prognosis.
Each type of liposarcoma has a 5-year survival rate of about 50% because they recur locally and tend to metastasize quickly and widely, especially in poorly differentiated liposarcomas. The lungs and the liver are the most common sites of metastasis.
Table 6. Comparative characteristics of different types of liposarcomas according to published
scientific research data
Histological subtype/ Comparative feature Atypical lipomatous tumor Dedifferentiated liposarcoma Myxoid liposarcoma Pleomorphic liposarcoma Histologic features Adipocytes of varying size, prominent fibrous stroma Highly-cellular portion (5 or more mitoses/10 HPF) next to WD portion Abundant extracellular myxoid material; sparse cellular portion w/mature adipocytes, immature lipoblasts, round cells (>5% of tumor) Highly cellular resembling MFH; pleomorphic lipoblasts; occassional multinucleated cells
Pathology (32) Low grade,
positive IHC for MDM2, CDK4, p16
High grade, positive IHC for MDM2, CDK4, p16 Low grade (percentage of round cells important for grading) High grade, pleomorphic, cellular sarcoma Anatomic site Retroperitoneum >extremities, paratesticular areas, trunk Retroperitoneum >extremities, paratesticular areas, trunk Proximal lower extremities Lower extremities >retroperitoneum; mediastinum Clinical behavior Locoregional recurrence Locoregional recurrence and distant metastases (10-15%) Distant metastases (10-20%) to visceral organs sites, bone and fat bearing areas
Distant metastases (30-50%)
According to master thesis research, after studying the collection of data of patients with liposarcoma treated in LHSUH Kaunas Clinics between 2006 and 2016, liposarcoma affects almost equally males and females being the mean age about 60 years of age. The most common type of liposarcoma was myxoid, followed by dedifferentiated, well-differentiated and pleomorphic. And the most common localization lower extremity followed by retroperitoneal, back, upper extremity, pelvis, neck and mediastinum.
On relation within type of liposarcoma and localization, regarding dedifferentiated liposarcomas the most common localization was retroperitoneal followed by lower extremity, back and neck, regarding myxoid liposacroma the most common localization was the lower extremity followed by retroperitoneum, back, pelvis and upper extremity, regarding pleomorphic liposarcomas the most common localization was the lower extremity followed by upper extremity, retroperitoneum, mediastinum and back, and regarding well-differentiated liposarcomas the most common localization was retroperitoneal followed by lower extremity, back and neck.
According to the data collected on our study the smallest sized tumor corresponds to a 82 years of age male and is a dedifferentiated liposarcoma while the largest sized tumor studied corresponds to a 58 years of age female and is a well-differentiated liposarcoma.
Regarding recurrence, most of the cases were at the age of 40´s, being the youngest patient 30 years of age and the oldest 82 years of age. Regarding recurrence according to type of liposarcoma, dedifferentiated liposarcoma was the type with highest grade of recurrence, followed by pleomorphic liposarcoma, myxoid liposarcoma and well-differentiated liposarcoma. Regarding recurrence according to the localization of the liposarcoma the most common was the retroperitoneal.
Regarding correlation of size with the different parameter studied, there is not a significant correlation between any of them since none of the times 2-tailed p was <0.05, but the closest one was localization (0.09). The same happened in correlation between recurrence and the different parameter of the study, none of the times 2-tailed p was <0.05, but the closest one was gender (0.095)
In this case, the most common localization for DDLPS was retroperitoneal and all of the patients with the exception of two underwent operation. This may lead to a conclusion that retroperitoneal is not only one of the most common localization, but also one with higher risks for recurrence, probably due to either late diagnosis or the difficulty of a total excision of the liposarcoma. It is also important to mention that none of the retroperitoneal tumors were under 10 cm in size (being the mean size 15 cm) and that the 3 biggest tumors reported were in fact retroperitoneal.
The other common localization of liposarcoma among ALT, DDLPS, MLS and pleomorphic together with retroperitoneal is lower extremity. Comparing one to another, the lower extremity liposarcoma recurrence rate was 9 out of 26 cases (34,62%) and the retroperitoneal recurrence rate was 10 out of 21 cases (47,62%).
In conclusion, liposarcoma, being one of the most common STS, usually manifests for >60 years old males as an average 15 cm tumor mostly in thigh or retroperitoneum and histologically identified as myxoid liposarcoma. Since no statistically significant differences were detected regarding examined cases, this research requires a further investigation including more clinical cases of clinically and pathologically diagnosed liposarcoma with a purpose to determine statistically significant patterns and identifying risk factors essential for determination of this neoplastic disease course and possible outcomes.
CONCLUSIONS
1. Both genders were affected by different types of liposarcoma at almost equal rates (47,7% were female, 52,3% were men, p>0.05), and the average of age of these patients was 60±14 years in the period of 2006 – 2016.
2. The most common type of liposarcomas according to WHO classification was myxoid liposarcoma (diagnosed in 23 cases, 35.38%), and pleomorphic liposarcoma was the rarest type of liposarcomas (diagnosed in 12 cases, 18.46%) in the period of 2006 – 2016.
3. The average size of liposarcoma was 15.018±10.79 cm, most common localization being lower extremity followed by retroperitoneal space. Less commone localizations were back, upper extremity, pelvis, neck and mediastinum
4. Overall recurrence of liposarcomas was 26.4% (19 out of 65 patients) in the period of 2006 – 2016. Dedifferentiated liposarcomas and liposarcomas that were localized in retroperitoneal area were mostly detected in recurrence cases. There were no statistically significant differences by gender, age, anatomical localization, and liposarcoma type according to WHO classification in tumor’s recurrence cases (p>0.05).
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