Fine Needle Aspiration Biopsy Cytology of Soft Tissue: A Diagnostic Approach Based on Pattern Recognition

Clinical Features

The most frequent soft tissue lesion encountered with a well-differentiated fat tissue fragment pattern is a lipoma. These lesions may occur in the subcutaneous tissue, deep soft tissues, and occasionally within or on the surface (parosteal) of bone. They are the most common soft tissue mesenchymal tumors in adults. Superficial lipomas are usually smaller (<5 cm) than deep-seated lipomas (>5 cm).

Intramuscular lipomas usually occur in mid to late adulthood and involve the trunk and head and neck regions, as well as the upper and lower extremities. Due to their frequently large size, a sarcomatous lesion may be clinically considered.

Subcutaneous lipomas are easily palpated and frequently undergo FNAB.

Cytopathology

Aspiration of a classic lipoma yields a slide with a grossly oily appearance. The fatty fragments sometimes slide off the slide when placed in alcohol; the tissue fragments may adhere better to air-dried slides.

Intramuscular lipomas have similar features to subcutaneous lipomas, although the fragments of adipose tissue may be closely associated with fragments of skeletal muscle. The skeletal muscle component may show atrophic changes.

Differential Diagnosis

The most important lesion in the DD is an atypical lipomatous tumor/ well-differentiated liposarcoma. The uniformity of the adipocytes and an absence of cytologic atypia usually distinguish lipomas from atypical lipomatous neoplasms/well-differentiated liposarcomas.

Ancillary Diagnostic Studies

Lipomas are positive for S100; the use of this stain is often not necessary to make a diagnosis. Lipomas lack amplification of abnormalities of the 12q13-15 chromosomal region found in liposarcomas and are therefore negative for ancillary IHC stains such as MDM2 and CDK4 and for CPM 12q15 FISH testing. These studies are useful in distinguishing well-differentiated liposarcoma from benign lipomas.

Clinical Features

Spindle cell lipomas most often occur in middle aged men in the posterior neck and shoulder region. They occur less frequently on the face, forehead, scalp, buccal-perioral area, and upper arm. Spindle cell lipomas are rare in the lower extremity.

Cytopathology

Differential Diagnosis

FNAB smears of spindle cell lipomas may resemble some other benign and malignant mesenchymal lesions due to the variable amounts of adipose tissue, including areas with cytologic atypia, myxoid change, and spindle cell component. Those with abundant myxoid change may resemble a myxoid liposarcoma or low-grade myxofibrosarcoma. However, spindle cell lipomas do not show the thin-walled chicken-wire vascular pattern of myxoid liposarcoma or the thick vascular fragments of myxofibrosarcoma.

Ancillary Diagnostic Studies

The spindle component in spindle cell lipomas shows positivity for CD34, and although nonspecific, this is unusual among fatty tumors.

Clinical Features

Liposarcoma is one of the most common soft tissue sarcomas with a peak incidence between the fifth and seventh decades. Almost all body sites are affected, especially the extremities and retroperitoneum. Liposarcomas are histologically divided into well-differentiated, myxoid, round cell, dedifferentiated, and pleomorphic subtypes. The myxoid type is the most common.

Atypical lipomatous tumor (ALT), also known as well-differentiated liposarcoma (WDL), comprises approximately 40% to 45% of all liposarcomas. Most ALT/WDL occur in middle-aged adults, and they are exceedingly rare in childhood.

Most ALT/WDL occur within the deep soft tissue of the extremities, especially the thigh, followed by the retroperitoneum, paratesticular area, and mediastinum. The diagnostic term used is dependent on the location of the tumor. Tumors with this pattern in the extremities and/or subcutaneous region are labeled “atypical lipoma” or “atypical lipomatous tumor” because the propensity of metastasis is low, while tumors with this morphology that are deep seated or retroperitoneal are diagnosed as “well-differentiated liposarcoma.” WDL of the retroperitoneum is often asymptomatic until the tumor has exceeded 20 cm in diameter. A substantial number of WDL are discovered incidentally.

Cytopathology

Deep-seated inflammatory variants of well-differentiated liposarcoma often show dispersed inflammatory cells, mainly reactive lymphocytes and plasma cells, admixed with tissue fragments with atypical adipocytes hyperlobated nuclei, coarse chromatin, and abundant ill-defined cytoplasm.

Differential Diagnosis

The main entities in the DD include lipoma and fat necrosis. Lipomas do not exhibit the complex chicken-wire vascular pattern that is typical of many well-differentiated liposarcomas. Fat necrosis may exhibit some degree of cytologic atypia; however, it does not show the same degree of hyperchromatic hyperlobated nuclei that are seen in WDLs.

Ancillary Diagnostic Studies

Most lipomatous tumors are positive for S100 that may highlight lipoblasts. Liposarcomas show nuclear positivity with MDM2 and CDK4 IHC stains and positive CPM 12q15 FISH testing, which is useful in distinguishing well-differentiated liposarcoma/atypical lipomatous tumors from benign lipomas.

Clinical Features

Nodular fasciitis is a reactive process that is characterized by a rapidly enlarging, often painful nodular subcutaneous growth and most commonly affects young patients. The most common sites of involvement are the upper extremities and head, neck, and trunk regions. Most lesions are less than 3 cm in diameter and regress spontaneously several weeks after presentation.

Cytopathology

Differential Diagnosis

The related pseudosarcomatous lesions including proliferative fasciitis and proliferative myositis have similar features. However, the myxoid background is less prominent, and the ganglion-like cells are more numerous and exhibit prominent nucleoli in these conditions. Proliferative myositis also often shows the presence of multinucleated regenerating muscle fibers.

Malignant conditions such as myxofibrosarcoma and myxoid leiomyosarcoma are also in the DD. Nodular fasciitis often shows a more mixed cell pattern than these two malignant conditions and is also characterized by cells with nuclei showing bland chromatin patterns. Strong diffuse reactivity with desmin may help demonstrate a leiomyosarcomatous lesion.

Clinical correlation is helpful when diagnosing cases of nodular fasciitis. These lesions often arise and regress rapidly. They can often be watched conservatively, although any suspected lesion that persists beyond 4 to 8 weeks should be considered for histologic examination.

Clinical Features

Intramuscular myxomas are benign soft tissue lesions that usually involve patients between 40 and 70 years of age. They are more common in women. The most frequent sites affected include muscles of the thigh, shoulder, buttocks, and upper arm. Most patients complain of a painless soft tissue mass.

Histologically, intramuscular myxomas are characterized by small numbers of bland, spindle-shaped cells within a hypovascular, myxoid stroma histologically. Focal areas of hypervascularity and hypercellularity may be present.

Cytopathology

FNAB grossly yields a gooey, clear, thick fluid.

Hypercellular variants may show more cellular tissue fragments composed of the spindle- and oval-shaped cells.

Differential Diagnosis

The DD of intramuscular myxomas includes other benign lesions with a myxoid matrix including ganglion cysts, benign nerve sheath tumors, and nodular fasciitis. Ganglion cysts occur more commonly near joints and are usually superficial, and they are characterized by a thick background of mucoid myxoid matrix with scant spindle- and oval-shaped mesenchymal cells. Nerve sheath tumors with myxoid degeneration may show a similar myxoid background to that seen in myxomas; however, the spindle cell component within nerve sheath tumors is typically present in sweeping, cellular fragments. In contrast to intramuscular myxomas that are slow growing, cases of nodular fasciitis arise rapidly and the smears are more heterogeneous and cellular compared with cases of intramuscular myxoma.

Malignant lesions in the DD include myxoid liposarcomas and myxofibrosarcomas. Although intramuscular myxomas may show small fragments of thin-walled blood vessels, they do not exhibit the complex chicken-wire vascular pattern and lipoblasts of liposarcomas. Myxofibrosarcomas show a vascular pattern composed of curvilinear vascular fragments and often demonstrate a component of pleomorphic stromal cells that identify these lesions as malignant.

Clinical Features

Myxoid liposarcoma usually occurs as a painless mass within deep soft tissues of the extremities. The peak incidence of this subtype of liposarcomas is within the fourth and fifth decades, and although rare, it is the most common form of liposarcoma in patients younger than 20 years of age. Myxoid liposarcomas often recur locally; however, high-grade tumors result in distant metastases in 40% of cases.

Myxoid liposarcoma histologically is characterized by a variable number of small signet ring lipoblasts and round to oval-shaped, primitive, nonlipomatous mesenchymal cells within a prominent myxoid background with a characteristic branching vascular pattern. The “round cell” subtype of liposarcomas is now included in this category and is associated with a poorer prognosis.

Cytopathology

Mitotic figures are often few in number.

Differential Diagnosis

The most common benign mimicker of myxoid liposarcomas based on the prominent myxoid background is an intramuscular myxoma. Intramuscular myxomas are usually considerably less cellular and lack the branched vascular pattern and atypical lipoblasts that characterize myxoid liposarcomas.

Myxofibrosarcomas are also associated with small blood vessels, similar to myxoid liposarcomas; however, their vessels are typically curvilinear and not as branched and complex as those seen in myxoid fibrosarcomas.

Ancillary Diagnostic Studies

Myxoid liposarcomas demonstrate a specific t(12;16) or t(12;22) translocation that shows a fusion of FUS:DDIT3 or EWS:DDIT3 genes, detectable by cytogenetics, PCR, or FISH studies.

Clinical Features

Myxofibrosarcomas, previously known as “myxoid malignant fibrous histiocytoma,” are one of the most common sarcomas, especially in elderly patients. There is a slight male predominance. The most common sites of involvement are the extremities, especially the lower limbs; they occur rarely in the trunk, head, and neck and on the hands and feet. Most cases are located in the subcutaneous tissues, with a minority in skeletal muscle and fascia. Retroperitoneal and abdominal cavity involvement is unusual, and lesions in these areas that resemble myxofibrosarcomas most likely represent dedifferentiated liposarcomas.

Patients with myxofibrosarcomas often present with a slow-growing mass. Local and repeated recurrences are relatively common. The risk of metastasis increases with tumor grade.

Histologically, these tumors demonstrate a spectrum of fibroblastic tumors with variable amounts of myxoid stroma, cellularity, cellular pleomorphism, mitotic activity, and the presence of curvilinear vascular pattern.

Cytopathology

There are relatively few reports of this lesion currently in the cytopathology literature.

Differential Diagnosis

The DD is essentially the same as myxoid liposarcomas and includes intramuscular myxomas, myxoid liposarcomas, and low-grade fibromyxoid sarcomas. The presence of a prominent curvilinear vascular pattern, increased cellularity, and cellular pleomorphism distinguishes myxofibrosarcomas from intramuscular myxomas.

Myxoid liposarcomas and myxofibrosarcomas may have similar features, but the vascular patterns of these lesions are characterized by a branching arborescent versus a curvilinear pattern, respectively.

Ancillary Diagnostic Studies

Myxoid liposarcomas demonstrate S-100 positivity, while myxofibrosarcomas show focal smooth muscle actin positivity, consistent with myofibroblastic differentiation, and can express smooth muscle actin (SMA) and vimentin while they are negative for CD34 and S100.

Clinical Features

Low-grade fibromyxoid sarcomas are a variant of fibrosarcoma, characterized by areas of myxoid and collagenized matrix with bland spindle cells and curvilinear blood vessels. These tumors are rare and occur most commonly in young adult men and women, but they can occur at any age. Most cases occur in the subfascial region of the upper extremities, although other unusual areas such as the head and retroperitoneum may be affected. There is often a history of a painless, deep soft tissue mass of several years’ duration.

Low-grade fibromyxoid sarcomas histologically reveal a mix of hypocellular collagenized areas and more cellular myxoid regions. Fascicular and whorling growth areas are present, the latter pattern most common at the interface between the collagenized and myxoid zones. The tumor cells are bland, with occasional hyperchromatic nuclei and, rarely, mitoses. Arteriole-sized sclerotic blood vessels and arcades of thin-walled vessels are present.

Cytopathology

Cytologic features of this tumor have recently been described.

Differential Diagnosis

This lesion shares some features with intramuscular myxomas. Occasionally, hyperchromatic, atypical nuclei help exclude myxoma. Distinction between a myxofibrosarcoma and low-grade fibromyxoid sarcoma may be virtually impossible because the vascular patterns of fibromyxoid sarcomas and low-grade myxofibrosarcomas are similar, but the distinction between these lesions and high-grade sarcomas should be possible.

Ancillary Diagnostic Studies

These tumors can focally express SMA and, rarely, CD34 or desmin. They are usually negative for S100 and EMA. Chimeric FUS/CREB3L2 fusion transcripts can be detected with reverse transcription (RT)-PCR or FISH studies.