Normal Adipose Tissue Histology

Adipose tissue can be divided in to white fat and brown fat. White fat consists of spherical adipocytes containing a single lipid vacuole that compresses a crescent-shaped nucleus at the periphery of the cell (Figure 18-1A). White fat provides several key functions such as thermal insulation, mechanical protection, and storage and release of lipid/free fatty acids in response to physiologic stimuli. Brown fat has the primary function of heat production and is typically found during the neonatal period in areas such as the axilla, perirenal region, and posterior neck. The abundant mitochondria in brown fat cells along with tissue vascularity are responsible for the red-brown coloration of this tissue. Microscopically, brown fat consists of a mixture of multivaculoated, granular cells with centrally placed nuclei and univacuolated cells that appear similar to cells of white fat (Figure 18-1B).

Lipoblasts are embryonic mesenchymal cells that are the center of much controversy in the topic of lipomatous neoplasms. Morphologically, these cells have a hyperchromatic-scalloped nucleus that is multiply indented by numerous fat vacuoles or indented by a single large fat vacuole. It is critical to appreciate that lipoblasts can be seen in both benign and malignant fatty tumors and the identification of lipoblasts is not always requisite for the diagnosis of liposarcoma (Figure 18-2).

The most common soft tissue tumors are of lipomatous differentiation. Lipomatous tumors occur in both superficial and deep soft tissue. Location (subcutaneous, intramuscular, retroperitoneal) is often helpful in making the correct diagnosis. While immunohistochemistry is frequently used to elucidate a line of differentiation in other soft tissue tumors, the use of immunohistochemistry is limited in fatty neoplasms. Instead, ancillary studies such as cytogenetics and molecular techniques are invaluable in the categorization and diagnosis of some of these lesions. Distinct cytogenetic aberrations have been described in almost all fatty tumors.

Lipomas are the most common soft tissue tumor and rarely are clinically significant. They typically present as a slowly growing painless subcutaneous mass in anatomic locations such as the back, shoulder, neck, abdomen, or proximal extremities. They may become large but average 3 cm in size. When superficial they are generally well circumscribed, but lipomas can have a diffuse pattern of growth if deep seated. Morphologically, lipomas consist of mature adipose tissue and have the gross yellow appearance of fat. Although these lesions are well vascularized, the blood vessels are usually compressed by the adipocytes and relatively inconspicuous. While thin fibrous bands may be identified, these septae are hypocellular without atypical cells. Up to two-thirds of lipomatous tumors show cytogenetic abnormalities, with aberrations involving 12q13-15 being most common. Lipomas only rarely recur after excision.

Variant forms of benign lipomas include angiolipomas, spindle cell/pleomorphic lipoma, and intramuscular lipomas. Angiolipomas are benign lipomatous neoplasms with unique clinical and morphologic features. The classic clinical presentation is a young adult male with multiple tender subcutaneous nodules. Morphologically, these tumors are composed of mature adipose tissue and clusters of capillary-sized vessels most easily recognized at the periphery of the lesion. Thrombi are seen in the lumens of the intralesional vessels (Figure 18-5). This type of lipomatous tumor is unusual because although familial cases have been reported, no distinct cytogenetic aberration has been characterized to date.

Spindle cell/pleomorphic lipoma is another benign lesion with a characteristic clinical history: an older male with posterior neck/back mass. In fact, with that clinical history, spindle cell lipoma should always be the first thing on the differential diagnosis. These tumors are well-circumscribed subcutaneous lesions that are composed of three elements: mature adipose tissue, bland spindle cells, and ropey collagen. Occasionally, multinucleated floret-like giant cells may be a component of these tumors (Figure 18-6). The spindled cells of spindle cell/pleomorphic lipoma are strongly CD34 positive, the one exception to the teaching that immunohistochemistry is not useful in fatty tumors.

Intramuscular lipomas are benign fatty tumors that occur within skeletal muscle of the extremities. Therefore, these tumors are deep-seated and are of clinical concern. Intramuscular lipomas rarely recur, and complete resection is usually curative (see Case 18-1).

In clinical practice, when a pathologist examines a deep (intramuscular, retroperitoneal) well-differentiated lipomatous tumor, the key differential diagnosis is lipoma (a benign lesion) versus ALT/WDL (Table 18-1). The terms “atypical lipomatous tumor” and “well-differentiated liposarcoma” are best thought of as synonyms describing the same entity. The term ALT was introduced to describe lesions occurring in the extremities since those tumors almost always have a favorable prognosis. In contrast, those tumors located in the retroperitoneum have a worse clinical course with frequent recurrences and even death. There are several gross, microscopic, and cytogenetic/molecular features that can be helpful in making the distinction between lipoma and ALT/WDL. First, lipomas are typically grossly homogeneous, whereas examination of ALT/WDL may reveal fibrous bands. Second, ALT/WDL is characterized histologically by atypical hyperchromatic stromal cells that exhibit large, hyperchromatic smudgy nuclei. Such cells are often found in fibrous septae and vessel walls (Figure 18-7). It is the identification of these cells, not lipoblasts, which solidify the diagnosis of ALT/WDL. As alluded to earlier, ALT/WDL can recur and cause death. Those tumors located on the extremity recur in approximately 40% of cases, while retroperitoneal lesions have a recurrence rate of over 90%. ALT/WDL can recur but do not metastasize. However, with time, these tumors are at risk of dedifferentiation, and dedifferentiation occurs more frequently with retroperitoneal lesions than with those tumors involving the extremities. Morphologically, dedifferentiated liposarcoma is characterized by well-differentiated liposarcoma immediately adjacent to a high-grade nonlipogenic sarcoma, usually with an abrupt transition (Figure 18-8) Cytogenetic analysis has shown that these tumors contain the same abnormalities as well-differentiated liposarcoma (giant marker and ring chromosomes) but also usually have additional abnormalities.

Myxoid liposarcoma is another malignant lipomatous neoplasm. This tumor commonly presents in young to middle-aged adults in deep soft tissue of the extremities. Histologically, myxoid liposarcoma is characterized by round to stellate-shaped cells in a myxoid background with a prominent plexiform capillary network. Signet ring and less commonly multi-vacuolated lipoblasts can be identified in these tumors. Additionally, foci of “round cell differentiation” can be seen. These areas are composed of sheets of virtually back-to-back round cells with vascularity that is obscured by cellularity (Figure 18-9).

Normal Histology

The vascular system consists of a series of vessels through which blood flows and can be divided into arterial (arteries, arterioles) and venous (veins, venules) systems. The arterial system is responsible for delivering blood pumped from the heart to capillary beds that are the site of gas exchange. Blood is returned to the heart via the venous system. Most vessels in the vascular system have the same basic structure: tunica intima, tunica media, and tunica adventitia. The tunica intima consists of a flattened endothelial layer surrounded by a basement membrane. The tunica media is an intermediate muscular layer and exhibits the most variation in arterial and venous components. The outer supporting layer is called the tunica adventitia. Capillaries consist only of a single layer of endothelial cells without muscular or advential components. Besides serving as a conduit for blood delivery, blood vessels play a role in coagulation and immune function (Figure 18-10).

The lymphatics are a unidirectional system of vessels and transport excess fluid from the interstitium to regional lymph nodes and finally to the venous system. Lymphatic vessels are found in almost all tissues, and the structures of lymphatics are similar to that of vessels of the venous system. In fact, it is often not possible to distinguish between veins and lymphatics on hematoxylin and eosin (H&E) sections.

Hemangiomas are benign neoplasms of endothelial cells. These lesions are relatively common and occur most frequently in the head and neck region of infants and children. It is often difficult if not impossible to distinguish hemangiomas from arteriovenous malformation. Some regress over time, and others reach a relative stable size. Hemangiomas do not undergo malignant transformation.

Variants: There are several types of hemangioma including lobular capillary hemangioma, pyogenic granuloma, and cherry angioma. While these lesions have varying clinical presentations, they share a common morphologic appearance.

Lobular capillary hemangiomas (see Case 18-2) are characterized by a circumscribed nodular arrangement of small capillary size vessels with a larger feeder-type vessel.

Pyogenic granulomas are polypoid hemangiomas that occur on mucosal surfaces and skin with a granulation tissue appearance. Some are associated with trauma or pregnancy.

Cherry angiomas typically present in adults, usually occur on the trunk or extremities, and have a ruby red appearance.

Some vascular lesions occur in deep soft tissue. Although most of these are benign and do not metastasize, they may recur and even be locally aggressive. Intramuscular hemangioma usually presents as a deep soft tissue mass in the lower extremity of young adults. They many contain small capillary-sized vessels, larger cavernous-sized vessels, or a mix of the two. Some contain a significant amount of adipose tissue and may be mistaken for a lipomatous tumor. Intramuscular hemangiomas may be difficult to excise. Up to 20% recur; they may be challenging to manage clinically.

Papillary endothelial hyperplasia is not a true neoplasm; rather it is a reactive process that usually involves the wall of a preexisting blood vessel or even a vascular neoplasm like a hemangioma. Even though this is a reactive condition, it still follows the rules outlined earlier: circumscribed, bland nuclear features. Complete excision is curative.

Angiosarcoma is a malignant tumor of vascular differentiation. These tumors are uncommon lesions that usually affect adults. The classic clinical presentation is a skin lesion on head/neck of an elderly person. These tumors are very infiltrative (poorly circumscribed) and gross examination often underestimates the true extent of the lesion. For this reason, surgeons may have difficulty completely excising the lesion, and the surgical margins may be positive. Microscopically, these tumors are composed of an intricate network of poorly defined vascular structures diffusely infiltrating the dermis or other tissue. In some cases, primitive vessels may be identified, but in other lesions the neoplastic cells show no evidence of endothelial differentiation (Figure 18-12). The neoplastic cells have hyperchromatic and pleomorphic nuclei and nuclear stratification. Even though mitotic figures should not be used to distinguish between reactive/benign and malignant vascular lesions since reactive/benign lesions can have brisk mitotic activity, the mitotic rate in angiosarcomas is usually high. In cases where the pathologist cannot be confident of endothelial differentiation by H&E morphology, immunohistochemical stains such as CD31 and CD34 can be used. Angiosarcoma is an aggressive tumor, and the overall long-term survival is poor.

Angiosarcoma can occur in several clinical scenarios. Although the most common clinical scenario involves the head/neck of the elderly, angiosarcoma may also arise with chronic lymphedema, following radiation treatment or with exposure to certain chemicals like Thorotrast or vinyl chloride. Despite the clinical differences, the morphologic features are similar, and prognosis is dismal in all types.

Normal Histology

Fibroblasts are slender spindled cells with pale cytoplasm, indistinct cell borders, uniform nuclei, and pinpoint nucleoli. They are responsible for the production of extracellular matrix of fibrous connective tissue including collagen, elastin, and glycosaminoglycans. Myofibroblasts are the most important cell type in tissue repair, and they have overlapping features of fibroblasts and smooth muscle. Microscopically, they are also spindled cells with lightly eosinophilic cytoplasm and bland nuclei, but unlike fibroblasts they contain bundles of intracytoplasmic microfilaments that provide a mechanism of cell contraction.

Nodular fasciitis is a self-limited fibroblastic and myofibroblastic proliferation that is often clinically concerning because patients present with a rapidly growing mass. These lesions most commonly affect young adults, in areas such as upper extremity. In children, nodular fasciitis has a predilection for the head and neck. Histologic examination shows bland spindle cells without significant cytologic atypia. Mitotic figures are usually easily found, but no atypical mitotic figures are present (Figure 18-14). These lesions are benign, and they should not recur after excision. Nodular fasciitis is an important entity to be aware of because it is the most common reactive/benign lesion that is misdiagnosed as a sarcoma. Recent work has shown most cases of nodular fasciitis harbor rearrangements of the USP6 gene, supporting the notion that this entity ia a “transient neoplasia”.

Fibromatoses are a group of locally aggressive but nonmetastasizing tumors composed of fibroblasts and myofibroblasts. There are two main types of fibromatosis: superficial and deep. Both superficial and deep groups share are characterized by a bland but infiltrative spindle cell proliferation of fibroblasts and myofibroblasts in long sweeping fascicles with a regular distribution of thin-walled blood vessels. Although these superficial and deep fibromatosis are impossible to distinguish by microscopic examination, they differ in clinical presentation and behavior.

Superficial fibromatosis includes plantar and palmar subtypes. Palmar fibromatosis, also known as Dupuytren contracture, affects up to 20% of people over 65 and presents as a single nodule or multiple small nodules. Plantar fibromatosis also occur in adults but occasionally occur in children and young adults. Although superficial fibromatosis has the same morphologic features as the deep type, they have a much better clinical outcome with surgery reserved for symptomatic cases.

Deep fibromatosis can be divided into abdominal, intra-abdominal, and extra-abdominal subtypes. The abdominal type arises from the musculoaponeurotic structures of the abdominal wall and usually occurs in women of childbearing age. Intra-abdominal fibromatosis includes mesenteric and pelvic fibromatosis. Extra-abdominal fibromatosis mainly affects muscles and overlying fascia of the pelvic and shoulder girdle of young adults. Even though the clinical features of these subtypes are variable, all forms of deep fibromatosis have similar morphologic features. While deep fibromatoses do not metastasize, they can cause significant morbidity and mortality from aggressive local behavior. Recurrence rates following excision vary, but reach almost 80% in some series.

Myxofibrosarcoma is a malignant fibroblastic lesion that classically presents as a superficial mass in the lower extremity of the elderly. Grossly these tumors are lobular and have a gelatinous cut surface. Microscopically, the amount of myxoid stroma varies by case and correlates with less aggressive course (see Figure 18-13). Conversely, those tumors with increased cellularity are high grade and are at risk of more aggressive behavior including more frequent local recurrence and potential for distant metastasis (see Case 18-13).

Lesional Histology

Fibrohistiocytic lesions are a group of entities that contain a mixture of histiocytes and fibroblasts. Histiocytes are cells derived from monocyte–macrophage lineage. They have eosinophilic cytoplasm containing lysosomes that are enzyme-containing organelles used to break down cellular waste material.

Benign fibrous histiocytoma is a benign lesion that usually present as a solitary slowly growing nodule in adults in the dermis. Microscopically, this lesion consists of a mixed cellular population including spindle cells, xanthoma cells, multinucleated giant cells, inflammatory cells, and hemosiderin-laden macrophages. Epidermal hyperplasia and peripheral collagen trapping are helpful clues to the diagnosis (Figure 18-15). Simple excision is curative as these lesions rarely recur.

Numerous variants of fibrous histiocytoma are recognized and vary in morphology and clinical behavior. For example, atypical fibrous histiocytoma exhibits cytologic atypia and mitotic activity in a background that resembles classic benign fibrous histiocytoma. These variants have a higher recurrence rate than benign fibrous histiocytoma.

Normal Histology

Smooth muscle is found throughout the body in organs such as the genitourinary tract, gastrointestinal tract, and respiratory tract and provides relatively continuous contractions of low force in a rhythmic or wavelike pattern. The activity of smooth muscle is influenced by the autonomic nervous system, hormones, and local metabolites.

Smooth muscle cells have distinct histologic features and usually can be identified by H&E morphology. One of the characteristic properties of a smooth muscle cell is its brightly eosinophilic cytoplasm. The cells are elongated and spindled, and the nuclei have blunt ends that give them a “cigar-like” appearance. Smooth muscle cells are bound together into fascicles (Figure 18-16). Ultrastructurally, smooth muscle cells have three types of filaments: myosin, actin, and intermediate. Oftentimes when the lineage of spindle cells is in question, immunohistochemistry can help to prove muscle origin by positive staining for actin, desmin, or H-caldesmon.

Benign Smooth Muscle Tumors

Superficial or cutaneous leiomyoma can be divided into two types: those arising from pilar arrector muscles and the genital form. Leiomyoma of pilar arrector origin may be solitary or multiple and present as small 1–2 cm brown-red papules that may coalesce. These lesions typically arise during early adulthood and, like angiomyomas, may be painful. Genital leiomyomas are usually solitary and affect sites such as the scrotum, vulva, and areola of the nipple. Microscopically these tumors are composed of bundles of smooth muscle. Genital leiomyomas are usually more circumscribed than the pilar arrector type. Close examination is necessary to make sure that the lesion does not contain worrisome features such as nondegenerative atypia, necrosis, or increased mitotic activity.

Angiomyoma is a benign smooth muscle tumor that classically affects middle-aged women. Patients usually present with a slowly enlarging and painful mass that may be worsened by pressure or change in temperature. Grossly, the mass is circumscribed with a white-gray cut surface. Microscopically, these lesions are composed of smooth muscle concentrically arranged around thick-walled blood vessels. Myxoid change, calcification, and hyalinization may be seen. While degenerative atypia may be seen, these lesions should not have mitotic activity or necrosis. Simple excision is curative.