Fitzpatrick's Dermatology in General Medicine, 8e

Chapter 129. Neoplasms of Subcutaneous Fat

Thomas Brenn

Neoplasms of Subcutaneous Fat: Introduction

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Neoplasms of Subcutaneous Fat at a Glance

Adipocyte tumors are the most frequently encountered group of mesenchymal neoplasms. This is due to the high prevalence of lipoma and angiolipoma.
Tumors range from entirely benign neoplasms (e.g., lipomas) to those of intermediate malignant potential with risk for local recurrence (e.g., atypical lipomatous tumor) to high-grade pleomorphic sarcomas (e.g., pleomorphic liposarcoma).
Although liposarcoma is the single most frequently encountered sarcoma, the large majority of adipocyte tumors are benign.
The clinical presentation of adipocyte tumors is generally nonspecific.
Most adipocyte tumors show distinctive cytogenetic abnormalities that may be of diagnostic value.
Treatment is surgical excision. Adjuvant radiation therapy and/or chemotherapy may be of benefit for treatment of malignant tumors that are not amenable to complete excision or in cases of advanced disease.

Lipoma

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Lipoma at a Glance

Lipoma is the most common soft-tissue tumor.
It is benign and presents in adulthood as a small circumscribed mass. The anatomic distribution is wide with relative sparing of the head, hands, and feet.
Histologically, the tumors are circumscribed, encapsulated, and composed of mature white adipose tissue.

Epidemiology

Lipomas are the most common soft-tissue neoplasm. Although they affect individuals in a wide age range, they occur predominantly in adults between the ages of 40 and 60 years; presentation in childhood is rare. There is no gender predilection. Lipomas are multiple in approximately 5% of cases.1

Etiology and Pathogenesis

The majority of lipomas (approximately 75%) show karyotypic abnormalities. The cytogenetic findings are heterogeneous, but rearrangements of 12q13–15 are most common.2–4 Other affected loci are on chromosomes 6 and 13.2–4 Numerical abnormalities are scarce, and most tumors are diploid.

Clinical Findings

The most common presentation is as a painless, slowly enlarging mass involving the subcutaneous tissue of the trunk, neck, or proximal extremities. Involvement of the head, hands, and feet is uncommon. These superficial lipomas are typically small, measuring less than 5 cm.1 Lipomas may be multiple and familial and show a predilection for the arms and thighs in familial multiple lipomatosis (Fig. 129-1).5 The constellation of multiple lipomas, macrocephaly, lymphangiomas, and hemangiomas is known as Bannayan (Bannayan–Zonana) syndrome.6,7 This autosomal dominant disease shares features with other independently described entities and is currently also referred to as Bannayan–Riley–Ruvalcaba syndrome.8,9 Further clinical findings include intestinal polyposis, genital pigmented macules, and other hamartomas. The syndrome is caused by mutations in the PTEN gene and belongs to the larger family of PTEN hamartoma-tumor syndromes, including Cowden disease.10–15 Lipomas may also be seen as a manifestation of Gardner's syndrome. Gardner's syndrome is part of the spectrum of familial adenomatous polyposis and includes extracolonic manifestations such as desmoid fibromatosis, osteomas, cysts, and lipomas.

Figure 129-1

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Familial multiple lipomatosis: multiple lipomas of variable size show a symmetric distribution involving the forearms of this middle-aged man.

Less frequently, lipomas may be deep-seated and grow to sizes larger than 5 cm. They can affect a variety of anatomic locations, including the surface of bone (parosteal lipoma) and skeletal muscle (intramuscular and intermuscular lipoma). Intramuscular lipoma arises within skeletal muscle and may be circumscribed or infiltrative. It presents in adulthood and only rarely affects children. The range of anatomic sites is wide, but there appears to be a predilection for the trunk.16,17 In contrast, intermuscular lipoma develops between individual muscles and does not infiltrate skeletal muscle bundles. It is a rare lipomatous tumor with a predilection for the anterior abdominal wall.16,17 Lipomas of the forehead are frequently deep-seated, presenting in a submuscular or subgaleal location. They show a predilection for male adults.18,19 Lipoma arising in the orbit (orbital lipoma) is rare but may lead to exophthalmus and visual disturbances.20–22

Histologic Features

Conventional lipomas are circumscribed masses surrounded by a thin fibrous capsule. They are composed of lobules of mature white adipose tissue divided by delicate and inconspicuous fibrous septa containing thin-walled capillary-sized vessels (Fig. 129-2). The adipocytes are univacuolated and mature with eccentrically placed, compressed nuclei. There is only slight variation in adipocyte size, and nuclear atypia is not a feature. Morphologically, lipomas are indistinguishable from the surrounding adipose tissue and the identification of a distinct mass is necessary for the diagnosis. Lipomas may show changes of trauma with varying amounts of fat necrosis and inflammation. Extensive involvement of the dermis is known as dermal lipoma. These tumors are not encapsulated and are frequently less circumscribed than other forms of superficial lipoma (Fig. 129-3). Lipomas with increased fibrous tissue are referred to as fibrolipomas (Fig. 129-4). In contrast to atypical lipomatous tumors, cellularity is low within the fibrous strands, and no nuclear atypia is present. Myxolipomas are characterized by the presence of conspicuous myxoid stroma. Angiomyxolipoma or vascular myxolipoma is characterized by a myxoid stromal background in addition to a proliferation of vessels of variable sizes.23,24 A lipoma containing metaplastic bone or cartilage within the tumor is referred to as an osteolipoma or chondrolipoma, respectively. Cutaneous adenolipoma refers to the presence of intratumoral sweat ducts and sweat glands may be cystically dilated.25,26

Figure 129-2

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Lipoma: mature univacuolated adipocytes show only mild variation in size. Delicate intervening capillaries are present.

Figure 129-3

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Intradermal lipoma: mature adipocytes diffusely infiltrate preexisting dermal collagen bundles. Note the sparing of the papillary dermis.

Figure 129-4

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Fibrolipoma: this variant is characterized by the presence of increased fibrous tissue within a lipoma. The expanded fibrous bands contain bland appearing and uniform spindle cells. Cytological atypia is not a feature.

Intramuscular lipoma can either present as a circumscribed intramuscular mass or show an infiltrative growth of adipocytes in between skeletal muscle fibers (Fig. 129-5).

Figure 129-5

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Intramuscular lipoma: mature adipocytes show an infiltrative growth pattern within skeletal muscle splaying apart individual muscle fibers.

Clinical Course, Prognosis, and Treatment

Lipomas are entirely benign tumors and, with the exception of intramuscular lipomas, local recurrence is rare. The infiltrative variant of intramuscular lipoma is associated with an approximately 19% chance of local recurrence, but metastasis does not occur.16

Lipomatosis

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Lipomatosis at a Glance

Lipomatosis is characterized by diffuse overgrowth of adipose tissue infiltrating through preexisting structures.
Different clinical presentations are recognized.

Epidemiology and Clinical Findings

Diffuse lipomatosis 27,28 is characterized by overgrowth of adipose tissue involving subcutaneous tissue and skeletal muscle of the trunk and extremities. Osseous involvement may also be a feature. Young children are predominantly affected, but presentation may become apparent in adulthood. Tumors can grow to a large size, causing disfigurement and loss of function of the affected limb. Due to the diffuse growth of these tumors, complete excision may not be possible and recurrences are frequent.

Benign symmetric lipomatosis (Madelung's disease, multiple symmetric lipomatosis)29–36 is characterized by multiple symmetric masses composed of nonencapsulated adipose tissue with a predilection for the subcutaneous tissue and skeletal muscle of the neck, shoulder, and proximal upper limbs (Fig. 129-6). Presentation is in adulthood with a marked male predominance of 15:1. The estimated overall incidence is 1 in 25,000, with increased frequency in the Mediterranean region. The disease is associated with increased alcohol intake in the majority of cases. Two clinical variants are currently recognized. Type 1 disease is characterized by a symmetric distribution of adipose tissue, giving rise to a “pseudoathletic” appearance, whereas type 2 disease shows a more diffuse distribution, giving rise to a picture of more generalized obesity. An associated polyneuropathy affecting sensory, motor, and autonomic function is frequently present. The disease course is slowly progressive, and treatment is difficult due to infiltration of deep-seated structures and major nerves and vessels. There is significant disease-related mortality due to compression of vital structures as well as autonomic neuropathy with sudden cardiac death. Etiologically, the disease has been speculated to be a result of hypertrophy of brown fat due to a defect in adrenergic lipolysis.

Figure 129-6

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Symmetric lipomatosis: there is diffuse and symmetric overgrowth of adipose tissue affecting predominantly the upper trunk, neck, and proximal arms.

Pelvic lipomatosis37–40 is an unusual proliferation of adipose tissue involving the pelvis and retroperitoneal space. The disorder is most common among men in the third and fourth decades, and blacks account for about two-thirds of cases. Urinary symptoms are frequent presenting signs, and the disease is associated with cystitis in 75% of cases. Obstructive uropathy and renal failure may be complications of the disease.

Adiposis dolorosa (Dercum's disease)41–48 is rare and typically affects middle-aged women, although men may occasionally also be affected. The disease is typically sporadic, and familial cases are exceptional. There is an increased incidence with obesity. Patients present with multiple painful subcutaneous lipomatous lesions frequently associated with other symptoms such as weakness, depression, confusion, lethargy, or dementia. The disease predominantly involves the arms and trunk but may be progressive to involve large parts of the body. Treatment modalities include pain relief as well as surgical control with excision or liposuction. Weight reduction can be beneficial.

Human immunodeficiency virus lipodystrophy49–53 occurs in the setting of protease inhibitor treatment or other forms of antiretroviral therapy in patients with acquired immunodeficiency syndrome (see Chapter 198). There is a predilection for cervical fat pads, the breast, and visceral fat. Other associations include hyperlipidemia, insulin resistance, type 2 diabetes, and fat wasting affecting the face and limbs.

Histologic Features

The histologic features of all forms of lipomatosis are similar and show unencapsulated adipose tissue diffusely infiltrating preexisting structures such as skeletal muscle.

Lipomatosis of Nerve (Fibrolipomatous Hamartoma of Nerve)

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Lipomatosis of Nerve (Fibrolipomatous Hamartoma of Nerve) at a Glance

Lipomatosis of nerve is a rare tumor that affects infants and children and presents as a growing mass with a predilection for the hand.
Pathology shows a proliferation of adipose and fibrous tissue within the epineurium and perineurium. The median nerve is predominantly affected.

Epidemiology

Lipomatosis of nerve is rare and affects predominantly infants and young children. Presentation at birth is not uncommon.54 It is only rarely seen in young adults.

Clinical Findings

Clinical presentation is as a slowly growing mass that may be associated with pain and paresthesia due to compression of the affected nerve. There is a strong predilection for the hand, including the wrist, palm, and fingers, and, less frequently, the foot. The median nerve and its branches followed by the ulnar nerve are most commonly affected.54 Involvement of cranial nerves and the brachial plexus has been reported but is exceptional.55,56 In a subset of patients, there may be accompanying overgrowth of bone resulting in macrodactyly.

Histologic Features

The lesions are characterized by a proliferation of adipose and fibrous tissue within the epineurium infiltrating along and in between nerve bundles. There is marked concentric fibrosis affecting both epineurium and perineurium.54 Metaplastic bone formation may rarely occur.57

Clinical Course, Prognosis, and Treatment

The clinical behavior is entirely benign, but adequate treatment is difficult because of the anatomic location and involvement of major nerves.54

Nevus Lipomatosus Superficialis

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Nevus Lipomatosus Superficialis at a Glance

Nevus lipomatosus superficialis is a rare entity that affects children and young adults.
Papules and plaques show a predilection for the buttocks, lumbar back, and posterior thighs.
Bands of mature adipose tissue infiltrate dermal collagen.

Epidemiology

Nevus lipomatosus superficialis is a rare form of connective tissue-type nevus that affects children and young adults in the first two decades of life. There is an equal gender distribution.58–62

Clinical Findings

The classic presentation is as multiple papules and nodules that may coalesce to form larger plaques. There is a predilection for the buttocks, upper posterior thighs, and lumbar back. Occasionally, involvement may be extensive, and the lesions may form confluent linear plaques along the skinfolds. This phenomenon has been reported as the “Michelin tire man” appearance.63,64 Solitary lesions occur predominantly in adults and are more likely to represent a fibroepithelial polyp containing adipose tissue or an intradermal lipoma.

Histologic Features

The histologic features show mature adipose tissue in varying amounts within the superficial dermis (eFig. 129-6.1).

eFigure 129-6.1

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Nevus lipomatosus superficialis: infiltration of adipose tissue into the dermis with penetration of dermal collagen is a characteristic finding.

Piezogenic Pedal Papules

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Clinical Findings

Piezogenic pedal papules are relatively common. Patients present bilaterally with painful, small papules and nodules in the heel area of the foot. The lesions occur during periods of standing, but disappear when pressure is relieved.65–67 Piezogenic pedal papules have also been reported on the wrist and are present in about a third of patients with Ehlers–Danlos syndrome.68,69 Etiologically, they are thought to be due to herniation of subcutaneous fat into dermis presumably due to connective tissue defects.

Histological Features

Biopsy reveals a thickened dermis as well as loss of the normal compartmentalization of fat lobules in deep dermis and superficial subcutis. In addition, there is thinning or loss of subcutaneous fibrous septa.65

Precalcaneal Congenital Fibrolipomatous Hamartoma

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Epidemiology

Precalcaneal congenital fibrolipomatous hamartoma, also known as pedal papules in the newborn, is a poorly documented condition in the literature.70,71

Clinical Findings

Presentation is usually at birth or within the first few month of life as bilateral symmetrical papules on the medial plantar aspect of the foot in a precalcaneal location. The skin-colored nodules are painless, measure approximately 1 cm in diameter, and are slowly enlarging.70,71

Histologic Features

Histologically, lobules of mature fat are surrounded and separated by hypocellular fibrous sheaths. Prominent vessels are an additional finding.70,71

Angiolipoma

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Angiolipoma at a Glance

Angiolipoma is a relatively common lesion that presents as a small nodule with a predilection for the forearm.
Young adults are affected, and lesions are frequently multiple and painful.
Histologically, this circumscribed lesion shows an admixture of mature adipose tissue and a proliferation of capillary-sized vessels.

Epidemiology

Subcutaneous angiolipomas are relatively frequent and typically occur in young adults in their teens and 20s, with a strong male predilection.72–74 They are rare in children and in the elderly.

Etiology and Pathogenesis

Angiolipomas have traditionally been classified as adipocyte tumors. However, in contrast to most lipomas they appear to have a consistently normal karyotype, and it has been suggested that they may be reactive or hamartomatous rather than neoplastic.74 The fact that angiolipomas can occasionally be almost exclusively composed of blood vessels (cellular angiolipoma) has led to the speculation that they may in fact be hemangiomas rather than lipomas.74 There is an increased familial incidence, but no inheritance pattern has been elucidated as yet.75

Clinical Findings

A wide range of sites can be affected, but there is a predilection for the forearm followed by the trunk, upper arm, and legs.72–74 Angiolipomas are often multiple and present as subcutaneous nodules characteristically smaller than 2 cm. Tenderness and pain are frequently associated symptoms.

Histologic Features

Angiolipomas are circumscribed and encapsulated. They show an admixture of mature fat and capillary-sized small branching vessels in varying proportions (Fig. 129-7 and eFig. 129-7.1). The vascular density is often increased at the periphery in a subcapsular distribution. Fibrin thrombi are typically encountered. The term cellular angiolipoma is applied to those lesions that are almost exclusively composed of vascular elements (eFig. 129-7.2).76–78

Figure 129-7

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Angiolipoma: a proliferation of capillary-sized vessels is admixed with mature adipose tissue.

eFigure 129-7.1

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Angiolipoma: the adipocyte component can predominate.

eFigure 129-7.2

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Angiolipoma: lesions with a striking predominance of the vascular component are referred to as cellular angiolipoma.

Differential Diagnosis

The appearances of angiolipoma are quite characteristic. The differential diagnosis of cellular angiolipoma includes vascular tumors such as Kaposi sarcoma, spindle cell hemangioma, and angiosarcoma.

Clinical Course, Prognosis, and Treatment

The clinical behavior of angiolipomas is entirely benign. The tumors are frequently multiple as well as painful, however, and clinical management can be a challenge.

Spindle Cell and Pleomorphic Lipoma

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Spindle Cell and Pleomorphic Lipoma at a Glance

Spindle cell lipoma and pleomorphic lipoma are currently considered to represent a morphologic continuum.
They typically occur on the posterior neck, upper back, and shoulder of middle-aged men.
Morphologically characteristic is the admixture of mature fat with bland and uniform spindle cells in a myxoid stroma containing ropey collagen bundles and mast cells. Multinucleate (floret-type) giant cells are present in pleomorphic lipoma.

Epidemiology

Spindle cell lipoma and pleomorphic lipoma are believed to constitute a morphologic continuum. This view is based on the finding that there is significant clinical, histologic, and cytogenetic overlap and the fact that features of both can be present in a single lesion.79–87 These lipomas are rare; they represent only approximately 1.5% of all fatty tumors and are 60 times less frequent than conventional lipomas.80 They show a predilection for middle-aged to elderly adults (median age, 55 years) and a strong male predominance.79–87

Etiology and Pathogenesis

Spindle cell and pleomorphic lipomas show similar cytogenetic features. In comparison to conventional lipomas, their karyotype is more complex and frequently hypodiploid with frequent partial losses and few balanced rearrangements. Monosomy and partial losses involving chromosomes 13 and 16 are the most frequent findings.2,79,88–90

Clinical Findings

Spindle cell and pleomorphic lipoma present as circumscribed, mobile masses, often with a long-standing history. They are small, measuring around 5 cm, and almost exclusively present on the posterior neck, shoulder, and upper back.79–87 Other anatomic sites in the head and neck region, including the oral cavity, can occasionally be affected.91 Rarely, these tumors are multiple and familial.92,93

Histologic Features

Both tumors are circumscribed and are typically located within the subcutis. Spindle cell lipoma is characterized histologically by the presence of mature adipocytes admixed with bland-appearing and uniform, stubby spindle cells in a collagenous and myxoid stroma containing ropey collagen fibers and conspicuous mast cells (eFigs. 129-7.3, 129-7.4 and 129-7.5). Myxoid change can be prominent (eFig. 129-7.6), and occasionally slit-like spaces resembling vascular channels may be present (pseudoangiomatous variant).94 Mitotic activity is virtually absent. The characteristic feature of pleomorphic lipoma is the presence of bizarre multinucleate giant cells, termed floret cells. These cells show eosinophilic cytoplasm and multiple crowded and overlapping hyperchromatic nuclei arranged in a circle or semicircle resembling the petals of a flower (eFig. 129-7.7). As with spindle cell lipoma, there is a variably myxoid and collagenous matrix admixed with mature adipose tissue and containing spindled to rounded cells with hyperchromatic nuclei (eFig. 129-7.8). An inflammatory infiltrate may be present.

eFigure 129-7.3

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Spindle cell lipoma: mature adipocytes are admixed with short, loosely arranged spindle cells in a myxoid stroma. Mast cells are conspicuous.

eFigure 129-7.4

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Spindle cell lipoma: spindle cells predominate in this tumor. They are arranged in short fascicles.

eFigure 129-7.5

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Spindle cell lipoma: this field highlights the presence of spindle cells, ropey collagen fibers, as well as mast cells.

eFigure 129-7.6

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Myxoid spindle cell lipoma: extensive myxoid stromal change is seen in this tumor.

eFigure 129-7.7

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Pleomorphic lipoma: the characteristic floret-type giant cells contain overlapping hyperchromatic nuclei in a circular or semicircular arrangement.

eFigure 129-7.8

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Pleomorphic lipoma: floret-type giant cells are placed in a background of mature adipose tissue and myxoid stroma containing ropey collagen fibers.

Occasionally, spindle cell as well as pleomorphic lipomas arise within the dermis. These dermal tumors have features similar to those described earlier but are less circumscribed and show an infiltrative growth between dermal collagen bundles (eFigs. 129-7.9 and 129-7.10).95 In contrast to subcutaneous lesions, intradermal examples show a wide anatomic distribution.

eFigure 129-7.9

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Spindle cell lipoma: intradermal tumors are frequently less circumscribed and diffusely infiltrate preexisting dermal collagen bundles.

eFigure 129-7.10

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Spindle cell lipoma: this intradermal tumor shows an infiltrative growth through dermal collagen.

By immunohistochemical analysis, the spindle cells express CD34 and rarely S100 protein.

Differential Diagnosis

The differential diagnosis for spindle cell and pleomorphic lipomas includes the following:

Atypical lipomatous tumor
Solitary fibrous tumor
Cellular angiofibroma

Clinical Course, Prognosis, and Treatment

Spindle cell and pleomorphic lipomas are entirely benign adipocyte neoplasms and local recurrences are rare.

Chondroid Lipoma

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Chondroid lipoma is a rare and benign tumor that affects adults and shows a female predominance.
The anatomic distribution is wide, but there is a predilection for the proximal extremities and limb girdle.
The unique histologic features include the presence of mature adipose tissue, lipoblasts, and a chondroid matrix.

Epidemiology

Chondroid lipoma is a relatively recently recognized and exceedingly rare benign lipomatous tumor.96 It shows a predilection for adults and a wide age distribution with a median of 36 years. There appears to be a significant female predominance (estimated at 1:4).96

Etiology and Pathogenesis

Ultrastructural analysis confirms adipocyte rather than cartilaginous differentiation.97 Cytogenetically, a balanced translocation involving chromosomes 11 and 16, t(11;16)(q13;p12–13), has been shown in two separate tumors.98,99 The 11q13 locus has also been found to be involved in lipoma as well as hibernoma. However, rearrangements in these tumors are not associated with the 16p12–13 locus.

Clinical Findings

Chondroid lipoma is a relatively small tumor measuring approximately 5 cm. Larger examples of over 10 cm have also been reported. It presents as a painless circumscribed mass of variable duration and often comes to clinical attention because of a history of recent growth. The proximal extremities and limb girdles are the most frequently affected anatomic sites,96 but the trunk as well as the head and neck region, including intraoral sites, may also be affected.97,100–102 Tumors are typically deep-seated, involving deep subcutaneous tissue, fascia, and skeletal muscle.96 Imaging studies are rather nonspecific and show a multilobular and circumscribed mass containing fatty elements.102–104

Histologic Features

The characteristic feature of chondroid lipoma is the admixture of a mature adipocyte component and a chondroid matrix containing lipoblasts.96 This well-circumscribed tumor is frequently encapsulated and multilobulated. It is composed of univacuolated and multivacuolated cells, occasionally with eosinophilic cytoplasm, showing cytologic features reminiscent of those of lipoblasts or chondroblasts (eFig. 129-7.11).96 These cells contain small lipid droplets as well as periodic acid-Schiff-positive glycogen.96 They are arranged in cords, nests, and strands as well as more solid areas set in a background of a chondroid matrix typically containing chondroitin sulfates (eFig. 129-7.12).105 Intricately admixed are variable amounts of mature adipose tissue. Tumors can be highly vascularized and show areas of hemorrhage, fibrosis, and calcifications.

eFigure 129-7.11

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Chondroid lipoma: uni- and multivacuolated cells reminiscent of lipoblasts or chondroblasts are present adjacent to mature adipocytes. (Used with permission from Dr. S. Banerjee, Christie Hospital, Manchester, UK.)

eFigure 129-7.12

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Chondroid lipoma: the cells are arranged in cords and nests in a myxohyaline, chondroid matrix. (Used with permission from Dr. S. Banerjee, Christie Hospital, Manchester, UK.)

By immunohistochemical analysis, lipoblasts are positive for S100 protein. They are negative for epithelial membrane antigen and smooth muscle actin.105

Ultrastructural studies demonstrate intracytoplasmic lipid and glycogen as well as pinocytotic vesicles. These findings support adipocyte rather than cartilaginous differentiation.105

Differential Diagnosis

Differential diagnosis for chondroid lipoma includes the following:

Myxoid liposarcoma
Extraskeletal myxoid chondrosarcoma

Clinical Course, Prognosis, and Treatment

Chondroid lipoma is a benign lipomatous neoplasm, and neither recurrences nor metastases have been demonstrated so far. Excision is the treatment of choice.

Myolipoma of Soft Tissue

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Epidemiology

Myolipoma of soft tissue is also known as extrauterine lipoleiomyoma and is characterized by its admixture of mature adipocyte and smooth muscular components. It is an exceedingly rare tumor occurring in adulthood, with a female predominance of 2:1.106

Clinical Findings

Myolipomas can grow to a significant size and average 15 cm. They occur in deep soft tissue of the retroperitoneum, abdominal cavity, and inguinal area but can also arise within subcutaneous tissue of the trunk and extremities. Involvement of deep structures such as skeletal muscle and fascia is frequent. Myolipomas present as palpable masses but may be incidental findings when located at visceral sites.

Histologic Features

Myolipoma of soft tissue is a circumscribed and at least partially encapsulated neoplasm composed of mature adipose tissue with evenly distributed traversing fascicles of smooth muscle. It is important to note that there is no cytologic atypia or mitotic activity of either component, and thick-walled vessels as seen in angiomyolipoma are absent.

By immunohistochemical analysis, the smooth muscle component stains strongly and diffusely positive for smooth muscle actin and desmin.

Differential Diagnosis

The differential diagnosis for myolipoma of soft tissue includes the following:

Liposarcoma
Angiomyolipoma

Clinical Course, Prognosis, and Treatment

Myolipoma of soft tissue is a benign neoplasm, and recurrences have not been reported. Complete excision is curative.

Hibernoma

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Hibernoma at a Glance

Hibernoma is a benign neoplasm that resembles brown fat and typically presents in adulthood.
A wide range of anatomic locations may be affected.

Epidemiology

Hibernoma is a well recognized but rare benign adipocyte tumor that shows a wide age distribution. Young adults (mean age, 38 years) are predominantly affected, but presentation in the pediatric population as well as in the elderly is possible. Males appear to be affected only slightly more frequently than females.107

Etiology and Pathogenesis

The etiology of this rare tumor is unclear. Karyotypes can be slightly more complex than those observed in other benign lipomatous tumors, but structural rearrangements involving chromosome band 11q13 appear to be reproducible.108–111

Clinical Findings

Hibernoma is a painless, slowly enlarging tumor affecting a wide range of anatomic sites. There appears to be a predilection for areas in which brown fat can be found physiologically, and presentation on the trunk, especially the scapular area, the shoulder, and the head and neck is common. However, curiously the thigh appears to be the single most frequently affected site.107 Hibernomas are typically located in subcutaneous tissue or skeletal muscle but may occasionally affect the abdominal cavity, retroperitoneum, or intrathoracic location.112

Presentation as multiple separate lesions is exceptional.113 The average size is around 10 cm, but larger tumors up to 24 cm are not unusual.107 Imaging studies reveal a well-demarcated lobulated and septated mass showing contrast enhancement and tissue attenuation intermediate between those of fat and skeletal muscle.114–117

Histologic Features

Hibernoma is a well-demarcated and lobulated neoplasm. The hallmark feature is its morphologic resemblance to brown fat. The tumors are composed of variable numbers of multivacuolated adipocytes with small, centrally placed nuclei and pale to eosinophilic and granular cytoplasm (eFig. 129-7.13). On the basis of the appearance of these brown fat cells, the quality of intervening stroma, and the presence of a spindle cell component, six histologic variants are recognized.107

eFigure 129-7.13

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Hibernoma: the characteristic feature is the presence of multivacuolated adipocytes with centrally placed nuclei and clear to eosinophilic granular cytoplasm.

The typical variant is the most frequently encountered form and is characterized by large numbers of brown fat cells admixed with mature white fat (Fig. 129-8). Those tumors composed almost exclusively of brown fat cells with palely staining cytoplasm are further subclassified as the pale cell subtype. Tumors are labeled eosinophilic subtype when at least 50% of brown fat cells contain a deeply eosinophilic and granular cytoplasm. The mixed subtype is intermediate between the two and shows a roughly equal distribution of eosinophilic and pale-staining brown fat cells. Myxoid, lipoma-like, and spindle cell variants exist.

Figure 129-8

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Hibernoma: brown fat is admixed with mature adipose tissue.

Hibernomas showing acellular myxoid areas of the intervening stroma are recognized as the myxoid variant. This variant affects predominantly men and presents in the head and neck and shoulder area.

The lipoma-like variant shows large areas of white fat differentiation with only scattered hibernoma cells lying in between.

The least frequent is the spindle cell variant, showing overlapping features of spindle cell lipoma and hibernoma. Areas of brown fat are admixed with the short and bland spindle cells typical of spindle cell lipoma, and ropey collagen bundles, myxoid stroma, mast cells, and mature white fat are also present. As with spindle cell lipoma, this variant presents in the posterior neck and scalp.

By immunohistochemical analysis, hibernomas stain positively for S100. CD34 expression is seen in the spindle cells of the spindle cell variant of hibernoma.107

Differential Diagnosis

The differential diagnosis of hibernoma includes the following:

Granular cell tumor
Spindle cell lipoma
Atypical lipomatous tumor/well-differentiated liposarcoma

Clinical Course, Prognosis, and Treatment

The behavior of hibernoma is entirely benign without recurrence after local excision.

Lipoblastoma/Lipoblastomatosis

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Lipoblastoma/Lipoblastomatosis at a Glance

Morphologically, the benign adipocyte neoplasm lipoblastoma resembles fetal adipose tissue. It is most frequently found in individuals younger than 5 years of age.
Lipoblastoma has a multilobular and circumscribed appearance, whereas lipoblastomatosis shows an infiltrative growth.

Epidemiology

Lipoblastoma/lipoblastomatosis is an uncommon neoplasm affecting infants and young children. Its incidence decreases significantly in those older than 5 years of age, and presentation in adolescents is rare.118–125 Infrequently, tumors may be congenital.126–128 There is a male predominance, with a male–female ratio of approximately 2:1.118–124

Etiology and Pathogenesis

Cytogenetic analysis has identified a recurrent translocation involving chromosome band 8q11–13,129–131 leading to rearrangements of the transcription factor Plag1 (pleomorphic adenoma gene).132–135

Clinical Findings

Most tumors present as painless, slowly growing, solitary soft-tissue masses. Lipoblastomas are well circumscribed and located in subcutaneous tissue. In contrast, tumors with an infiltrative growth often extend into deeper structures such as skeletal muscle and are termed lipoblastomatosis.123 The extremities, trunk, and head and neck are predominantly affected sites.124 Visceral involvement of retroperitoneum, mediastinum, peritoneal cavity, or solid organs is rarely seen.118–123 Tumors are relatively small, measuring around 5 cm. However, larger tumors of more than 20 cm have been reported. In certain locations, tumors can become symptomatic due to compression of adjacent structures and organs.

Histologic Features

Lipoblastomas are well-circumscribed, lobulated tumors with fibrous septa (eFig. 129-8.1) composed of an admixture of mature and immature adipocytes in varying proportions (eFig. 129-8.2). Lipoblasts are present in different stages of development ranging from univacuolated forms with eccentrically placed and compressed nuclei to bivacuolated and multivacuolated forms (eFigs. 129-8.3 and 129-8.4). These lipoblasts show indented and scalloped nuclei, but cytologic atypia is not a feature (eFig. 129-8.3). Lipoblasts can be quite rare, and some tumors are predominantly composed of mature adipocytes. Varying amounts of a myxoid matrix containing uniform stellate spindle cells and a plexiform vascular pattern of capillary-sized vessels reminiscent of myxoid liposarcoma may be present (eFig. 129-8.4). Fibrous septa give rise to the tumor's lobulated appearance (eFig. 129-8.4). These septa may be quite cellular in areas. Lobulation is less pronounced in lipoblastomatosis, which has a more infiltrative growth pattern, and often preexisting structures such as skeletal muscle fibers are entrapped.

eFigure 129-8.1

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Lipoblastoma/lipoblatomatosis: lipoblastoma is a circumscribed tumor showing prominent multilobulation with dividing fibrous septa. (Used with permission from Dr. S. Banerjee, Christie Hospital, Manchester, UK.)

eFigure 129-8.2

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Lipoblastoma/lipoblastomatosis: mature and immature adipocytes are admixed in varying proportions. (Used with permission from Dr. S. Banerjee, Christie Hospital, Manchester, UK.)

eFigure 129-8.3

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Lipoblastoma/lipoblastomatosis: lipoblasts in different stages of development are present. (Used with permission from Dr. S. Banerjee, Christie Hospital, Manchester, UK.)

eFigure 129-8.4

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Lipoblastoma/lipoblastomatosis: areas with a prominent myxoid stroma containing delicate branching capillaries, lipoblasts, and primitive stellate cells closely resemble myxoid liposarcoma. (Used with permission from Dr. S. Banerjee, Christie Hospital, Manchester, UK.)

By immunohistochemistry, expression for S100 and CD34 is seen.124

Ultrastructurally, these tumors resemble maturing adipose tissue rather than brown fat.119,136

Differential Diagnosis

The differential diagnosis of lipoblastoma/lipoblastomatosis includes the following:

Myxoid liposarcoma
Atypical lipomatous tumor
Hibernoma
Lipofibromatosis

Clinical Course, Prognosis, and Treatment

Lipoblastoma/lipoblastomatosis is a benign tumor with a tendency to recurrence if inadequately excised. Complete surgical excision is curative and is the treatment of choice.

Hemosiderotic Fibrohistiocytic Lipomatous Lesion/Tumor

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Epidemiology

The exceedingly rare hemosiderotic fibrohistiocytic lipomatous lesion or tumor was first described by Marshall-Taylor and Fanburg-Smith 137 in 2000. Only 25 cases have been reported in the literature so far.137–139 Although the age range of occurrence is wide, the lesion typically presents in adulthood (median age, 50 years) and affects women more frequently than men.137,138

Etiology and Pathogenesis

The finding of antecedent trauma in a significant number of cases in the original description of hemosiderotic fibrohistiocytic lipomatous lesion initially suggested that this may be a reactive condition.137 There has been further speculation about the role of venous stasis in the pathogenesis of the lesion.139 However, a subsequent study did not detect a history of trauma or other predisposing conditions in most patients.138 At the moment, it is unclear whether this is a truly neoplastic or reactive condition. The proposal that hemosiderotic fibrohistiocytic lipomatous lesion is related to or even represents a precursor of pleomorphic hyalinizing angiectatic tumor is so far largely speculative and unsubstantiated.140

Clinical Findings

The presenting sign is a slowly growing, relatively circumscribed subcutaneous mass ranging from 1 to 17 cm with a median size of 5–6 cm.137,138 There is a strong predilection for the distal extremities, especially the dorsal aspect of the ankle/foot as well as less frequently the hand.137,138 Involvement of other anatomic sites is unusual. A history of antecedent trauma is observed in a subset of patients.137,138

Histologic Features

Hemosiderotic fibrohistiocytic lipomatous tumors show a slightly infiltrating architecture microscopically. They are composed of three main constituents demonstrating an adipocyte as well as a spindle cell component and hemosiderin deposition.137,138 The proportions of the individual components may vary, but the adipocyte element usually predominates. The fatty element appears mature and lobulated and is divided by variably cellular fibrous septa. No adipocyte hyperchromasia or atypia is observed. The variably cellular spindle cell component is arranged in fascicles percolating through the fatty elements to create a “honeycomb” appearance.137,138 Spindle cells are short and uniform, occasionally showing mild atypia. Mitotic activity is not a feature. Rarely, the formation of small nodular areas may be observed in the spindle cell areas, and occasionally there may be myxoid features. Hemosiderin deposition can be highlighted with Perls’ iron stain and is present within macrophages and spindle cells. The presence of osteoclast-like giant cells is a frequent finding, and calcifications may be present.

By immunohistochemical analysis, expression of CD34 is seen in spindle cells.

Differential Diagnosis

The differential diagnosis for hemosiderotic fibrohistiocytic lipomatous tumors includes the following:

Atypical lipomatous tumor
Plexiform fibrohistiocytic tumor

Clinical Course, Prognosis, and Treatment

There is an approximately 30% risk of nondestructive local recurrence after incomplete excision. So far, no metastasis or adverse outcome has been reported.137,138

Lipofibromatosis

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Epidemiology

Lipofibromatosis is an uncommon pediatric neoplasm that predominantly affects infants at a median age of 1 year.141–144 It can be congenital, but children and adolescents may also be affected. There appears to be a significant male predominance.

Clinical Findings

The clinical presentation of an ill-defined, slowly growing, painless mass ranging from 1 to 7 cm is typical.144 Tumors are located most frequently on the hands and feet, followed by the limbs and trunk. Appearance on the head and neck is rare.

Histologic Features

Tumors are composed of mature adipose tissue in addition to a bland cellular spindle cell component arranged in short fascicles. The spindle cell element follows the septa of the adipose tissue without architectural distortion of its lobulation (eFigs. 129-8.5 and 129-8.6). Cytologic atypia is minimal, and mitotic figures are rare. An additional finding is the presence of small univacuolated cells at the interface of the spindle cell and adipocyte components (eFig. 129-8.6).

eFigure 129-8.5

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Lipofibromatosis: this tumor shows expanded fibrous septa with preservation of the lobular architecture.

eFigure 129-8.6

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Lipofibromatosis: the fibrous septa contain uniform spindle cells. Also note the presence of small univacuolated adipocytes adjacent to the fibrous strands.

Immunohistochemical analysis may show the spindle cells to be focally positive for CD34, S100 protein, smooth muscle actin, and epithelial membrane antigen, but results are negative for desmin.144

Differential Diagnosis

The differential diagnosis for lipofibromatosis includes the following:

Fibromatosis
Fibrous hamartoma of infancy

Clinical Course, Prognosis, and Treatment

There is a significant rate of local nondestructive recurrence especially in congenital lesions and after incomplete excision. Further risk factors may include male gender and increased mitotic activity in the spindle cell areas.144 No metastases have been reported.

Atypical Lipomatous Tumor/Well-Differentiated Liposarcoma

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Atypical Lipomatous Tumor/Well-Differentiated Liposarcoma at a Glance

Atypical lipomatous tumor/well-differentiated liposarcoma is a tumor of adulthood that presents as an enlarging mass with a predilection for the extremities, retroperitoneum, and paratesticular tissue.
Best prognostic predictor is anatomic location:
- Recurrence, risk of dedifferentiation, and mortality negligible if excised.
- Retroperitoneum and paratesticular region, where complete excision is difficult, characterized by high long-term mortality.
- When excision is curative, tumors are called atypical lipomatous tumors; when clear margins cannot be obtained should be regarded as well-differentiated liposarcoma.

Epidemiology

Atypical lipomatous tumor/well-differentiated liposarcoma is a neoplasm of adulthood with a peak incidence in the sixth decade.145–153 It represents the largest subgroup of liposarcomas. There is no gender predilection.

Etiology and Pathogenesis

Cytogenetically, atypical lipomatous tumors are characterized by supernumerary circular “ring” chromosomes as well as giant long marker chromosomes derived from the 12q13–15 region and resulting in consistent amplification of the MDM2 gene along with adjacent genes such as CDK4.154–160

Clinical Findings

Tumors typically present in deep soft tissue. The subcutaneous tissue may occasionally also be involved. The predominantly affected site is the musculature of extremities with a predilection for the thigh, followed by the retroperitoneum, groin, and paratesticular area as well as the mediastinum.145–153 A wide range of other anatomic sites including the larynx, orbit, oral cavity, and vulva may be affected.161–164 An enlarging painless mass is the typical presenting sign, and especially in a retroperitoneal location, tumors can grow to a very large size before becoming symptomatic.

Histologic Features

Atypical lipomatous tumors are large, multilobulated, and most often circumscribed. The most frequently observed adipocytic (lipoma-like) morphologic variant closely resembles a lipoma. It is composed of relatively mature-appearing adipocytes with marked variation in cell size (Fig. 129-9). Additional findings include focal adipocyte atypia (eFig. 129-9.1) and the presence of hyperchromatic and often multinucleate bizarre stromal cells in cellular fibrous septa (eFigs. 129-9.2 and 129-9.3). Floret-type giant cells may also be a feature (eFig. 129-9.4). Lipoblasts may be monovacuolated or multivacuolated and vary in number (eFig. 129-9.5). They may be entirely absent and are not a prerequisite for the diagnosis. Sclerosing, inflammatory, and spindle cell variants exist.

Figure 129-9

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Atypical lipomatous tumor/well-differentiated liposarcoma: note the marked variation in adipocyte size.

eFigure 129-9.1

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Atypical lipomatous tumor/well-differentiated liposarcoma: adipocyte atypia with nuclear enlargement and hyperchromasia is a focal finding.

eFigure 129-9.2

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Atypical lipomatous tumor/well-differentiated liposarcoma: the typical fibrous strands with increased cellularity are present in this field.

eFigure 129-9.3

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Atypical lipomatous tumor/well-differentiated liposarcoma: the cellular fibrous strands contain bizarre and often multinucleate hyperchromatic cells.

eFigure 129-9.4

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Atypical lipomatous tumor/well-differentiated liposarcoma: floret-type giant cells may also be a feature.

eFigure 129-9.5

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Atypical lipomatous tumor/well-differentiated liposarcoma: multivacuolated lipoblasts showing hyperchromatic and indented nuclei are a focal finding.

The sclerosing variant occurs most commonly in a retroperitoneal or paratesticular location and is the second most frequently encountered histologic pattern (eFig. 129-9.6). It is characterized by a paucicellular fibrillary collagenous matrix containing scattered hyperchromatic and bizarre-appearing stromal cells as well as rare multivacuolated lipoblasts (eFig. 129-9.7). The adipocytic component may be inconspicuous, and often extensive sampling is required for the diagnosis.

eFigure 129-9.6

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Atypical lipomatous tumor/well-differentiated liposarcoma: the presence of a paucicellular stroma with admixed adipocytes characterizes the sclerosing variant.

eFigure 129-9.7

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Atypical lipomatous tumor/well-differentiated liposarcoma: bizarre appearing stromal cells in a fibrillary matrix are highlighted in this field of the sclerosing variant.

Rarely, there is a marked chronic inflammatory infiltrate potentially obscuring the underlying adipocytic component. Such tumors have been designated as the inflammatory subtype. This variant occurs in the same distribution as the adipocytic subtype and is characterized by a heavy lymphoplasmacytic infiltrate arranged in a multinodular pattern and separated by variably cellular stroma. The lipogenic areas show features of the adipocytic variant. However, they comprise only a small fraction of the tumor.165

The spindle cell variant has only recently been recognized. It is rare and shows a predilection for the subcutaneous tissue of the shoulder girdle and upper limb. The characteristic finding is the presence of a proliferation of bland-appearing spindle cells arranged in fascicles and whorls and set in a myxoid matrix (eFig. 129-9.8). This is accompanied by an atypical adipocytic component showing classic lipoblasts.166

eFigure 129-9.8

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Atypical lipomatous tumor/well-differentiated liposarcoma: bland appearing spindle cells are arranged in fascicles in this example of the spindle cell variant. A background myxoid matrix is characteristic finding.

Immunohistochemistry for MDM2 and CDK4 aided by fluorescence in situ hybridization to detect MDM2-CDK4 amplification is a useful ancillary diagnostic tool to distinguish well-differentiated as well as dedifferentiated liposarcoma from benign adipocyte tumors as well as other nonlipogenic tumors.160,167

Differential Diagnosis

The differential diagnosis of atypical lipomatous tumor/well-differentiated liposarcoma includes the following:

Lipoma
Spindle cell/pleomorphic lipoma
Dedifferentiated liposarcoma
Angiomyolipoma
Massive localized lymphedema

Clinical Course, Prognosis, and Treatment

The clinical behavior and prognosis are largely dependent on the anatomic site.168 Surgery is curative at anatomic locations where complete surgical excision with clear margins can be achieved (e.g., somatic soft tissue such as the limbs). The estimated rate of progressing to dedifferentiated liposarcoma is less than 2% with a mortality rate of virtually zero at these anatomic locations. In contrast, tumors arising at deep locations such as the retroperitoneum, mediastinum, or spermatic cord, where complete surgical clearance is not possible, are characterized by repeated local recurrence and ultimately may result in death from uncontrolled local disease or dedifferentiation with metastasis. The overall risk of development of dedifferentiated liposarcoma is estimated to be higher than 20% with an overall mortality rate of around 80% for tumors occurring in the retroperitoneum. The disease has a protracted course, and the median survival time ranges from 6 to 11 years.149,152,169 The primary approach to treatment is surgical excision. Adjunct chemotherapy and radiation treatment are reserved for advanced disease.

Dedifferentiated Liposarcoma

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Dedifferentiated Liposarcoma at a Glance

Tumors typically present as large masses in the retroperitoneum of adults.
The disease course is protracted, with a high rate of local recurrence and a significant risk for metastasis and associated mortality.
The morphologic characteristic is the presence of nonlipogenic areas adjacent to well-differentiated liposarcoma.

Epidemiology

The epidemiologic features of dedifferentiated liposarcoma are similar to those of well-differentiated liposarcoma, and it typically affects adults in the sixth decade.170–172 There is no gender predilection. De novo presentation is most commonly seen, occurring in approximately 90% of cases. Only around 10% of cases represent dedifferentiation of a previously well-differentiated liposarcoma.170,171

Etiology and Pathogenesis

The karyotypic findings are similar to those seen in well-differentiated liposarcoma and involve supernumerary ring and giant marker chromosomes.173

Clinical Findings

Tumors present as large painless masses with a predilection for the retroperitoneum followed by the limbs and paratesticular area and spermatic cord.170–172 Other sites, including the head, neck, and trunk, are rarely affected. Presentation in the subcutis is unusual.174

Histologic Features

The tumors are multilobulated and consist of yellow, fatty areas as well as discrete more solid areas representing dedifferentiation. The characteristic histologic finding is the presence of both atypical lipomatous tumor/well-differentiated liposarcoma and nonlipogenic sarcoma. The proportions may vary, and careful gross examination and adequate sampling may be necessary to identify the lipogenic areas. There is usually a very sharp demarcation between lipogenic and nonlipogenic areas (eFig. 129-9.9), but a more gradual transition or comingling may also be seen. The nonlipogenic component is most frequently morphologically high grade, showing a pleomorphic sarcoma-like (pleomorphic and storiform malignant fibrous histiocytoma-like) (eFigs. 129-9.10 and 129-9.11) or a myxofibrosarcoma-like appearance.170–172,175 Occasionally, the area of dedifferentiation may appear morphologically low grade and is then composed of bland-appearing spindle cells with a fascicular arrangement. Cellularity is significantly lower than in high-grade areas, cytologic atypia is mild, and mitotic figures are rare. A storiform growth reminiscent of dermatofibrosarcoma protuberans may be present.170,171

eFigure 129-9.9

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Dedifferentiated liposarcoma: frequently there is a sharp demarcation between dedifferentiated (right side) and well differentiated liposarcoma (left side).

eFigure 129-9.10

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Dedifferentiated liposarcoma: tumor cells are arranged in short fascicles and give rise to a storiform appearance.

eFigure 129-9.11

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Dedifferentiated liposarcoma: there is an admixture of spindle cells and large pleomorphic cells.

Heterologous elements are present in approximately 10% of cases and include predominantly osteosarcomatous or chondrosarcomatous as well as myogenic differentiation. A peculiar finding is the presence of meningothelial-like whorls often associated with metaplastic bone formation.176,177

Differential Diagnosis

The differential diagnosis of dedifferentiated liposarcoma includes the following:

Spindle cell liposarcoma
Pleomorphic liposarcoma
Other pleomorphic sarcomas

Clinical Course, Prognosis, and Treatment

Dedifferentiated liposarcoma is characterized by a protracted course with a high risk of local recurrence. Retroperitoneal tumors almost invariably recur if followed over a long period of time. The overall risk of distant spread is estimated at around 20%, with a disease-related mortality rate of approximately 30%.171 Although these rates are likely to be higher with long-term follow-up, the prognosis appears to be more favorable than that for other high-grade pleomorphic sarcomas, which are associated with a high mortality rate and shorter time to death. Anatomic location is the most important prognostic factor, and retroperitoneal tumors are associated with a poor prognosis. In contrast, neither the extent of dedifferentiation nor the morphologic features appear to be prognostically predictive. The mainstay of treatment is surgical removal with adjuvant chemotherapy and radiation in advanced disease.

Myxoid/Round Cell Liposarcoma

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Myxoid/Round Cell Liposarcoma at a Glance

Presentation is as a large mass involving the extremities and in particular the thigh of middle-aged adults.
There is a significant rate of local recurrence as well as metastasis.
Tumors are lobulated and circumscribed and are composed of a myxoid matrix containing primitive mesenchymal cells and lipoblasts in varying stages of differentiation. A prominent vascular pattern is a characteristic feature.
Round cell liposarcoma is currently regarded to represent the high-grade end of the morphologic spectrum.

Epidemiology

Myxoid liposarcomas represent approximately 10% of all soft-tissue sarcomas. They comprise more than one-third of all liposarcomas and are the second most frequent variant of liposarcoma.178 The tumor presents in young to middle-aged adults with a peak in the fourth to fifth decade and a slight male predominance.178–180

Etiology and Pathogenesis

Cytogenetically, myxoid liposarcoma is characterized by the translocation t(12;16)(q13;p11), present in approximately 95% of cases. The translocation involves the CHOP (DDIT3) gene on chromosome band 12q13 and the TLS (also known as FUS) gene located on 16p11 resulting in the generation of the TLS–CHOP hybrid gene.170,180–184 Rarely, the translocation t(12;22)(q13;q12), resulting in the EWS–CHOP hybrid gene, is observed.185–187 CHOP belongs to the family of leucine zipper transcription factors and is implicated in adipocyte differentiation and growth arrest, whereas TLS, similar to EWS, is a potent activator of transcription. In turn, the TLS–CHOP hybrid gene is speculated to interfere with normal adipocyte development and proliferation by aberrant transcriptional activation.

Clinical Findings

Presentation as a large, painless mass with a predilection for the extremities is characteristic. Tumors are located in deep soft tissue and involve the thigh in over two-thirds of cases.178–180 Presentation in subcutis or retroperitoneum is rare. Not infrequently, patients are found to have multifocal disease at initial presentation, which is generally regarded to represent metastases.185

Histologic Features

Tumors are large, well circumscribed, and multinodular with a gelatinous cut surface on gross examination. The appearance becomes fleshier in areas with increased cellularity, but large areas of tumor necrosis are not typically seen.

Microscopically, myxoid liposarcoma is a lobulated tumor composed of a mixture of bland-appearing oval mesenchymal cells without evidence of adipocyte differentiation and small univacuolated or bivacuolated lipoblasts, often with a signet-ring cell appearance (eFig. 129-9.12 and Fig. 129-10). The cellularity is low but increased toward the periphery of the tumor lobules (eFig. 129-9.12). The cells are placed in a myxoid matrix showing a characteristic pattern of delicate, branching capillary-sized vessels often referred to as chicken wire or crow's feet (eFig. 129-10.1). In the central areas, the extracellular mucin may become confluent to form mucin pools, giving rise to a pulmonary edema-like appearance (eFig. 129-10.2). In the well-differentiated areas, the tumors lack significant cytologic atypia, mitotic activity, or tumor necrosis. Poorly differentiated, high-grade tumors are characterized by increased cellularity with the formation of solid sheets of small-to-medium-sized round cells showing scant acidophilic cytoplasm (eFig. 129-10.3). Mitotic figures are more easily identified, but nuclear pleomorphism is not a feature.

eFigure 129-9.12

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Myxoid liposarcoma: these tumors are lobulated containing a myxoid matrix. Increased cellularity is frequently seen in the periphery of the tumor lobule.

Figure 129-10

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Myxoid liposarcoma: the presence of uni- to bivacuolated lipoblast and bland appearing oval shaped cells within a myxoid matrix is a characteristic feature.

eFigure 129-10.1

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Myxoid liposarcoma: delicate branching capillary sized resemble a chicken wire or crow's feet.

eFigure 129-10.2

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Myxoid liposarcoma: confluent areas of mucin pools give rise to a “pulmonary edema-like” appearance.

eFigure 129-10.3

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Myxoid liposarcoma/round cell liposarcoma: this high-grade tumor is characterized by increased cellularity. Pleomorphism is not a feature.

These cases have traditionally been classified as round cell liposarcoma and are associated with an adverse prognosis. However, the presence of classical myxoid and round cell areas within the same tumor with gradual transition from one to the other and the finding of identical cytogenetic alterations provide strong evidence that round cell liposarcoma represents the poorly differentiated, high-grade end of the spectrum of myxoid liposarcoma. Spindle cell differentiation may occasionally be seen in poorly differentiated tumors.

Differential Diagnosis

The differential diagnosis of myxoid liposarcoma includes the following:

Lipoblastoma
Myxofibrosarcoma
Low-grade fibromyxoid sarcoma
Chondroid lipoma
Myxoid melanoma

Clinical Course, Prognosis, and Treatment

The clinical course of myxoid liposarcoma is characterized by local recurrence with a rate of distant metastasis of 30%–40%.178–180 There is an unusually high incidence of soft-tissue and bone metastases in addition to metastases to the lung. Patients with multifocal disease at presentation have a poor prognosis, and adverse histologic features include the presence of round cell differentiation in more than 5% of the tumor, tumor necrosis, and p53 overexpression.179,180,188,189

Pleomorphic Liposarcoma

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Pleomorphic Liposarcoma at a Glance

Pleomorphic liposarcoma is an aggressive sarcoma that shows a predilection for the extremities of adults and is associated with a high rate of metastasis and mortality.
Histologic examination shows a pleomorphic high-grade sarcoma containing variable numbers of lipoblasts.

Epidemiology

Pleomorphic liposarcoma is a rare tumor representing only approximately 5% of all liposarcomas and up to 20% of pleomorphic sarcomas.190,191 It shows a slight male predominance and presents in adulthood (median age, 50–60 years). However, the age range is wide.192–194

Clinical Findings

Tumors present as enlarging firm masses, frequently with a short history. They are typically large, deep-seated, and subfascial sarcomas measuring 8–10 cm in median. Presentation in subcutaneous tissue is less frequent, and dermal location is unusual.192–195 The extremities are the most frequently affected sites, and there is a predilection for the lower limbs. The trunk, retroperitoneum, abdomen, mediastinum, head and neck, and pelvis may also be involved.

Histologic Features

Tumors can be well circumscribed but unencapsulated. However, more frequently they have infiltrative margins. In its classic appearance pleomorphic liposarcoma shows features of a high-grade pleomorphic (malignant fibrous histiocytoma-like) sarcoma containing pleomorphic spindle cells and multinucleate giant cells (eFig. 129-10.4). Admixed are lipoblasts in varying numbers. They may be scarce in areas or arranged in larger sheets (eFig. 129-10.5). Mitotic figures are frequent, including atypical forms, and areas of necrosis are often present. An additional finding is the presence of intracellular as well as extracellular eosinophilic hyaline droplets.

eFigure 129-10.4

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Pleomorphic liposarcoma: this tumor shows the classic appearances of a pleomorphic sarcoma.

eFigure 129-10.5

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Pleomorphic liposarcoma: admixed lipoblasts vary in number.

Two morphologic variants, a high-grade myxofibrosarcoma-like and an epithelioid variant, are recognized. One variant is characterized by the presence of areas resembling intermediate- to high-grade myxofibrosarcoma and containing large lipoblasts in varying amounts (eFig. 129-10.6). Another relatively recently recognized pattern is the epithelioid variant characterized by the presence of large, cohesive, and densely packed epithelioid cells containing abundant cytoplasm.196,197 The features are reminiscent of those of carcinomas, but scattered large lipoblasts can be identified.

eFigure 129-10.6

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Pleomorphic liposarcoma: lipoblasts can be identified in areas that are morphologically reminiscent of myxofibrosarcoma.

Immunohistochemically, tumor cells can focally express smooth muscle actin (approximately 50% of cases) and rarely desmin and cytokeratins (especially in the epithelioid variant). S100 highlights lipoblasts in about one-third of cases.

Cytogenetic analysis reveals complex karyotypes and high chromosome counts.198

Differential Diagnosis

The differential diagnosis of pleomorphic liposarcoma includes the following:

Dedifferentiated liposarcoma
Leiomyosarcoma
Pleomorphic rhabdomyosarcoma
Myxofibrosarcoma
Melanoma
Carcinoma

Clinical Course, Prognosis, and Treatment

Pleomorphic liposarcoma is characterized by a relatively aggressive clinical course with a more than 30% rate of local recurrence, a 30%–50% metastatic rate, and an estimated overall 5-year survival rate of 50%–60%. The lung is the preferred metastatic site. The treatment is surgical with adjuvant radiation and chemotherapy for advanced disease.

References

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Etiology and Pathogenesis

Clinical Findings

Histologic Features

eFigure 129-7.11

eFigure 129-7.12

Differential Diagnosis

Clinical Course, Prognosis, and Treatment

Epidemiology

Clinical Findings

Histologic Features

Differential Diagnosis

Clinical Course, Prognosis, and Treatment

Epidemiology

Etiology and Pathogenesis

Clinical Findings

Histologic Features

eFigure 129-7.13

Figure 129-8

Differential Diagnosis

Clinical Course, Prognosis, and Treatment

Epidemiology

Etiology and Pathogenesis

Clinical Findings

Histologic Features

eFigure 129-8.1

eFigure 129-8.2

eFigure 129-8.3

eFigure 129-8.4