Department of Pathology, Sinai Hospital of Baltimore Pathology, Baltimore, MD, USA
Tumors of soft tissue are among the most challenging in surgical pathology. There are several reasons for this: they are rare, so you see few in training; they are overlapping in morphology; they do not always obey the principles that help you to identify malignant potential in carcinomas; and each entity has at least three names, four variants, and seven mimickers. However, this chapter covers some of the names you will hear most commonly. The tumors are broken down into lines of differentiation, with the caveats that there are some tumors that do not differentiate along any known lineage (grouped separately) and that many soft tissue tumors dedifferentiate into the same final common malignant pathway, undifferentiated pleomorphic sarcoma (the entity formerly known as malignant fibrous histiocytoma or MFH ). The good news is, once it is that high grade, the origin becomes sort of academic.
One overarching principle is that there are roughly three categories of sarcomas. The first is the well-differentiated or low-grade sarcoma, which closely resembles its tissue of origin and is sometimes difficult to identify as malignant. The second large category is the high-grade sarcoma with an unstable karyotype, of which undifferentiated pleomorphic sarcoma (UPS ) is the textbook example (Figure 29.1). The unstable karyotype leads to a marked nuclear irregularity and pleomorphism that is readily identifiable as malignant. These are usually tumors of older adults or postradiation. The third category is the translocation sarcoma, of which most are high grade. These tumors, usually found in children to young adults, are not histologically linked to any particular normal tissue, as they represent a uniquely transformed stem cell (presumably). In addition, because they actually have a homogeneous genome, they tend to have monomorphic nuclei which are quite distinct from the pleomorphic sarcomas .
Undifferentiated pleomorphic sarcoma (UPS ). There are scattered large dark nuclei with bizarre shapes (such as those at arrows) in a background of hyperchromatic spindle cells and a fibrous pink stroma. The most striking feature of the UPS is the nuclear pleomorphism. The nuclei lack nucleoli or distinct nuclear membranes, however.
Another general principle is that sarcomas are often very well circumscribed (angiosarcoma being an exception). They tend to grow in an expansile and pushing fashion, sometimes with a surrounding pseudocapsule. Therefore, you cannot rely on infiltrative growth at the periphery to identify malignancy.
A third principle is that mitotic figures are sometimes relevant and sometimes not. Nodular fasciitis , for example, a benign neoplasm, can have a rip-roaring mitotic rate. In a soft tissue leiomyoma, however, you really don’t want to see any mitoses at all. Therefore, a high mitotic rate, in isolation, is not significant until you have identified the tumor and know the tolerance for mitoses in that tumor.
When diagnosing a soft tissue lesion, especially in its initial presentation, you must always walk yourself through the mental game of “what else could this be?” It is a good habit for any organ system but especially in the field of sarcomas and spindle-cell lesions. For lesions that are cellular and spindled, you must always consider a sarcoma mimicker, such as nodular fasciitis. For lesions with bizarre and huge nuclei, despite the malignant look, you must rule out benign entities with degenerative atypia, such as ancient schwannoma or pleomorphic lipoma. For lesions in or near an organ, such as in visceral sites, you must always ask if it could be a carcinoma masquerading as a sarcoma. For spindle-cell lesions anywhere, you must prove it is not melanoma. Some of these questions require immunostains to answer, some just a skeptical eye.
The second question to ask, once you have ordered the cytokeratins and melanoma markers, is “what family of soft tissue does it belong to?” Table 29.1 lists some stereotypical features of different tumor families, seen best in low-grade (well-differentiated) lesions. If there is a well-differentiated tumor component adjacent to a high-grade sarcoma, the high-grade component is often referred to as dedifferentiated. The well-differentiated areas may not be obviously tumor, so you need to ensure the tumor is well sampled and search for the well-differentiated areas at the periphery.
Characteristics of tumor families.
Fat cells intermixed with other elements; fat cells are identified by their crescent-shaped nuclei hugging large clear vacuoles
Fibroblasts and myofibroblasts are typically fusiform or stellate cells with pale nuclei in a collagenous (pink) matrix
Smooth muscle (“leiomyo”)
Smooth muscle cells are elongated cells that run in parallel bundles, intersecting at right angles. The nuclei may be cigar or corkscrew shaped and often have paranuclear vacuoles
Skeletal muscle (“rhabdomyo”)
Skeletal muscle may show either rhabdoid cells, which are plump round cells with eccentric nuclei and pink cytoplasm, or strap cells, like individual elongated myocytes with cytoplasmic cross-striations
Nerve sheath (neurofibroma , schwannoma )
Nerve sheath tumors may show delicate spindle cells with wavy nuclei in a myxoid background with thin curly tendrils of collagen, as in a neurofibroma . They may also show the dense nuclear palisading and fibrillar background of a schwannoma
Vascular (“hemangio,” “angio”)
Vascular tumors are characterized by a network of irregular vascular spaces, often with admixed blood. Malignant endothelial cells tend to protrude into the lumens with a hobnail appearance
Once sarcomas become high grade, they may take on any number of appearances, regardless of line of differentiation. Some classic visual patterns are described in Table 29.2. The herringbone pattern is classically ascribed to fibrosarcoma, but in truth, fibrosarcoma is exceedingly rare, and most things that look like fibrosarcoma are not. A similar pattern is the leiomyosarcomatous pattern, which also has long bundles of tumor cells. A high-grade tumor with a myxoid stroma is usually a myxofibrosarcoma (once called “myxoid MFH ”). A tumor with large pink cells with eccentric nuclei may be called rhabdoid (when used as an adjective, this means resembling a rhabdomyosarcoma), and in fact sarcomas of all types may develop foci of true rhabdomyosarcoma. If, however, the sarcoma has none of these patterns, and no differentiation can be identified through immunostains, history, or the low-grade remnants of another tumor found at the periphery, the diagnosis of exclusion is an undifferentiated pleomorphic sarcoma (UPS ).
Features of high-grade sarcoma patterns.
A hypercellular, fascicular tumor with a “herringbone” pattern (see Chapter 2). Atypia may not be significant. May be seen in fibrosarcoma, malignant peripheral nerve sheath tumor, synovial sarcoma, and others
A fascicular tumor with bundles of cells intersecting at right angles, a high mitotic rate, and significant cytologic atypia, although not as pleomorphic as the UPS . Non-smooth muscle tumors may occasionally show this pattern
A tumor with a myxoid or edematous background containing highly pleomorphic cells, frequent mitoses, and characteristic arcing vessels
A tumor with large eosinophilic cells with eccentric nuclei. May occur as a component of other high-grade sarcomas
Undifferentiated pleomorphic sarcoma (UPS )
A cellular tumor with bizarre nuclear atypia, including giant cells and highly pleomorphic and hyperchromatic nuclei. Very mitotically active, often with necrosis. A common tumor that is occasionally still referred to as “MFH ”
A reliable clue to a high-grade sarcoma is the presence of malignant nuclei. A pleomorphic sarcoma nucleus has some reproducible features across many tumor types. The nucleus has an irregularly shaped border and has dark, dense, granular chromatin that is fairly evenly distributed throughout the nucleus (Figure 29.2). Unlike carcinoma nuclei, prominent nucleoli and nuclear membranes are not a usual feature. Learning to recognize this sort of atypia is critical in identifying some of the sarcomas.
The sarcoma cell vs. the benign cell. (a) Malignant cells in a UPS or other high-grade sarcoma show large nuclei with irregular shapes and very dark chromatin with a coarse texture (arrowheads). It is as though (in fact, it is likely) the nucleus has way too many chromosomes, and the nucleus is swollen and dark with the extra chromatin (truly hyperchromatic). Nucleoli are not usually prominent. (b) Tumor cells in nodular fasciitis have large nuclei and prominent nucleoli that stand out against a pale nucleus (arrow). The nuclear membrane is smooth and oval.
Tumors of Fat
Throughout this chapter, you will find tables listing some of the more common entities, grouped by clinical behavior. Table 29.3 lists some of the common tumors of fat. There are no specific immunostains for fatty tumors, although MDM2 is a marker that is often expressed in well-differentiated liposarcomas (and negative in lipomas).
Common neoplasms of fat.
Malignant but indolent
Malignant and aggressive
Well-differentiated liposarcoma/atypical lipomatous tumor
Myxoid liposarcoma with round cell morphology
Pleomorphic liposarcoma (no relation to pleomorphic lipoma)
Spindle-cell/pleomorphic lip oma
The most common soft tissue tumor is the lipoma. A lipoma is defined as a neoplasm of mature fat. It is histologically indistinguishable from ordinary fat; to tell the difference, you must know it appeared clinically as a discrete lobular mass. There are many histologic variants of lipoma, classified based on what additional soft tissue component is present, such as angiolipoma, myolipoma, myelolipoma, etc. A hibernoma is a lipoma of brown fat, in which the fat cells are full of innumerable tiny vacuoles. The lipoblastoma, despite the alarming name, is a benign pediatric tumor of mature fat and benign lipoblasts.
There is a lot of fuss about lipoblasts. They are immature fat cells in which the nucleus is star shaped or scalloped, due to being indented on multiple sides by small bubbles of fat (Figure 29.3). They are often associated with liposarcomas, but they can also appear in the benign lipoblastoma, and they are not necessary for a diagnosis of liposarcoma. Note that normal adipocytes are not mitotically active cells, so mitoses are generally seen only in high-grade liposarcomas.
Lipoblast. Small fat vacuoles indent the nucleus of this lipoblast (arrow), seen in a well-differentiated liposarcoma. Other cells within the fibrous septa (arrowhead) have the look of sarcoma cells, with irregular, large, dark nuclei.
One type of lipoma is notable for unusual cytologic features. Spindle-cell/pleomorphic lipom a is usually found on the back or neck of elderly men and may be fibrous and nonfatty on low power. Pleomorphic lipoma and spindle-cell lipoma represent two ends of a morphologic spectrum . Spindle-cell lipoma has areas of nondescript spindle cells and collagen and may remind you of a nerve sheath tumor if there is not much fat in the lesion. Pleomorphic lipoma is similar but with the addition of giant cells and floret cells (hyperchromatic wreath-shaped nuclei). These giant cells (Figure 29.4) are an example of a benign lesion simulating malignant atypia; clinical information is helpful in not mistaking these for liposarcomas.
Pleomorphic lipoma. This type of benign lipoma is known for having very bizarre stromal cells that mimic sarcoma. The classic cell is the floret cell, with a circular wreath of nuclear lobes (arrows). Their presence suggests the diagnosis of pleomorphic lipoma.
Well-differentiated liposarcoma (WDLS ) is a tumor of adults. It looks similar to a lipoma on low power except for an increase in fibrous “interstitium” between fat cells and fibrous bands (Figure 29.5). A close examination of the fibrous areas reveals hyperchromatic, irregularly shaped nuclei; these are usually large and dark enough to be visible at 4×. Finding a lipoblast is a bonus. A softer feature is an assortment of differently sized fat cells, unlike the monomorphic benign lipoma, but this feature can be unreliable as it is seen in benign entities as well. WDLS is so named when it occurs in a nonresectable location, such as the retroperitoneum. By definition, when it occurs on an extremity, it is called an atypical lipomatous tumor (ALT), as the prognosis in these sites is excellent with simple resection.
Well-differentiated liposarcoma. There is an increased amount of fibrous interstitium between fat cells, and atypical cells stand out at low power (arrowheads).
When WDLS has been around for a while, especially in a recurrent or occult retroperitoneal lesion, there is a risk of the tumor transforming into a high-grade pleomorphic sarcoma. When this happens, you will see a tumor with WDLS areas and an abrupt transition to a high-grade tumor (storiform, spindled, pleomorphic, or even rhabdoid or leiomyosarcomatous). Regardless of morphology, this is called a dedifferentiated liposarcoma, and the key to diagnosis is recognizing adjacent WDLS . Because a retroperitoneal sarcoma is a dedifferentiated liposarcoma until proven otherwise, if you are grossing such a tumor, be sure to sample anything near the tumor that looks like normal fat: it may be the well-differentiated component.
Myxoid liposarcoma is unrelated to the WDLS ; it is actually a translocation tumor. It is not clearly fatty on gross examination, but may have a myxoid or gelatinous cut surface. The low-power impression is that of a gelatinous tumor with scattered fat cells and a stereotypical capillary network that has been compared to chicken wire (Figure 29.6). These vessels are very delicate , and, unlike normal capillaries, they have little substance to their walls; they appear as a naked sleeve of endothelium stretched through the tumor. The vessels are arborizing or branching and often take on Y-shapes. The tumor cells themselves are small regular rounded cells and single-vacuole lipoblasts, without the large atypical cells of WDLS . (This, remember, is in keeping with the translocation tumors.) Correct identification of myxoid liposarcoma on biopsy is essential, as it can be treated presurgically with radiation.
Myxoid liposarcoma . The fatty component may be very subtle in myxoid liposarcoma; the vessels are more often the tip-off. The vasculature is composed of a delicate network of very thin capillaries with three- and four-way branch points, similar to chicken wire (arrow). The cell population is composed of small cells, which may have fat vacuoles in them, and a myxoid background. Large atypical cells should not be present. Inset: areas of closely packed small cells are indicative of round cell differentiation.
Myxoid liposarcoma can also transform into a higher-grade lesion. When the small uniform cells become very densely packed and obscure the vascular pattern, it is indicative of round cell morphology, a poor prognostic sign. Remember to always give the estimated round cell component when signing out this type of tumor.
The rare pleomorphic liposarcoma describes a high-grade tumor with extremely bizarre pleomorphic lipoblasts. It does not arise from WDLS or from a pleomorphic lipoma; conceptually you may think of it as a high-grade sarcoma that happens to have lipoblastic differentiation .
Fibrous Tumors and Myxoid Tumors
The fibroblast and the myofibroblast are ubiquitous cells in charge of the reparative changes that take place in every part of the body. In resting state, they are fusiform-to-stellate cells with oblong pale nuclei, and they lay down a collagen matrix. Their job is to proliferate, and therefore mitotic activity is not unusual in fibroblastic tumors. Although myofibroblasts may stain for actin (and are occasionally mistaken for smooth muscle), in general immunostains are not helpful in this tumor family (Table 29.4).
Fibrous and myxoid neoplasms.
Malignant but indolent
Malignant and aggressive
Low-grade fibromyxoid sarcoma
Malignant solitary fibrous tumor
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