Introduction: Tumor Classification and Immunohistochemistry

Tumor Classification

Soft tissue tumors have traditionally been classified according to line of differentiation—that is, which normal cell type the neoplastic cells most closely resemble. Such a “lineage” can often be assigned based on a combination of histologic appearances, patterns of protein expression (assessed by immunohistochemistry), and ultrastructural findings (identified by electron microscopy). Although electron microscopy once played an important role in the evolution of soft tissue tumor classification, it is now rarely used in clinical practice and has largely been supplanted by immunohistochemistry and molecular genetics. The majority of soft tissue tumors shows mesenchymal or neuroectodermal differentiation. However, a small subset of soft tissue tumors shows unusual lines of differentiation generally reserved for cell types that are usually not found in soft tissues (e.g., epithelial, myoepithelial, or melanocytic). For still other soft tissue tumors, it is not possible to assign a specific line of differentiation even after extensive immunohistochemical (and ultrastructural) evaluation (“undifferentiated” sarcomas). Finally, there exist distinct subtypes of soft tissue sarcomas (most often associated with chromosomal translocations) whose line of differentiation is uncertain.

Assigning a line of differentiation (when appropriate) can be very helpful for the classification of soft tissue tumors. However, tumors within such groups may show highly varied clinical presentations, histologic appearances, and behavior. One such example of this diversity is the group of tumors classified as “rhabdomyosarcomas.” The pediatric rhabdomyosarcomas (namely, embryonal and alveolar rhabdomyosarcomas; see Chapter 8 ) share little, if anything, in common with pleomorphic rhabdomyosarcoma of adults (see Chapter 7 ). Another such example is the group of tumors designated “liposarcomas.” Although well-differentiated/dedifferentiated liposarcoma, myxoid liposarcoma, and pleomorphic liposarcoma are often considered to be “subtypes” of liposarcoma, their clinical presentations, histologic appearances, genetic features, and behavior are entirely different (see Chapter 12 ). Furthermore, the differential diagnosis of any particular type of soft tissue tumor often does not include other tumors with a shared lineage but instead tumors with similar histologic appearances. As such, although it is conceptually useful to consider groups of tumors with similar lines of differentiation together as a general classification system (as is the case for the World Health Organization classification ), for the practicing pathologist, a pattern-based approach to soft tissue tumors is very helpful for arriving at a specific diagnosis. This is the organizational scheme for this textbook.

Some of the chapters approach tumors based on the shape of the tumor cells (spindle cell, epithelioid, round cell, pleomorphic, biphasic or mixed) or the presence of other distinguishing features (myxoid stroma, inflammatory cells, giant cells), whereas separate chapters are dedicated to vascular, adipocytic, and cartilaginous and osseous tumors because the lineage is usually clear for these latter tumor types. Many soft tissue tumors exhibit several such distinguishing features (e.g., spindle cells and inflammatory cells, or epithelioid cells and myxoid stroma); thus some soft tissue tumors are covered in more than one chapter to emphasize approaches to differential diagnosis. Cutaneous, gastrointestinal, and lower genital tract tumors are considered separately, because many distinctive soft tissue tumors are exclusive (or nearly exclusive) to such sites. Although each chapter in the book includes molecular genetic findings of diagnostic relevance to individual tumor types, the final chapter, which is devoted to molecular testing, provides a discussion of methodology and specific examples for which molecular testing is particularly useful in differential diagnosis and serves as a quick reference for the distinguishing genetic features of many tumor types.

Immunohistochemistry

Immunohistochemistry plays a central role in the diagnosis of soft tissue tumors. Although many mesenchymal tumors are characterized by particular patterns of protein expression, for some tumors, the histologic features are sufficiently distinctive such that immunohistochemistry is unnecessary to make a confident diagnosis. In contrast, other types of soft tissue tumors show considerable morphologic overlap, and immunohistochemistry is an invaluable aid in distinguishing among them. In this latter category, there are often (sometimes subtle) histologic clues that might allow for a specific diagnosis; however, application of a narrow panel of markers can provide reassurance for a more confident diagnosis. For rare tumor types as well as examples arising either at unusual anatomic locations or in patients of uncharacteristic ages—even when the histologic diagnosis is relatively straightforward—immunohistochemical support for the diagnosis can be very helpful ( Box 1.1 ). As mentioned previously, traditional immunohistochemical markers are used to identify specific proteins within tumor cells that indicate a line of differentiation. Unfortunately, with rare exceptions, these markers are not particularly lineage specific: there is considerable overlap in the patterns of protein expression shared by various cell types and soft tissue tumors. Over the past decade, markers directed against protein correlates of more specific molecular genetic signatures have become available. Most recently, gene expression profiling has led to the identification of novel, highly specific markers that are proving to be powerful means of confirming the diagnosis of soft tissue tumors, particularly in cases for which specific markers were previously lacking. Although the immunohistochemical markers helpful for diagnosing specific tumor types are covered in the appropriate sections of the other chapters in this book, this chapter discusses these various categories of diagnostic markers in some detail. This is intended to be an introduction to the application of the most commonly used markers, rather than a comprehensive discussion of sensitivity and specificity.