Vascular Tumors Case 1: Papillary endothelial hyperplasia Papillary endothelial hyperplasia (PEH) essentially represents a stage in the recanalization of a thrombosed blood vessel. It may occur in any location, but most commonly presents in the superficial soft tissues of the extremities, head, and neck, as a small, firm, red to blue mass. The thumb is a particularly common location for this process. A history of trauma is occasionally present. Most cases are intravascular, and the lesion may be surrounded by the remnants of a vessel wall or by a fibrous pseudocapsule. PEH may also be superimposed on a pre-existing benign vascular lesion, such as a hemangioma. PEH is a reactive process that requires only simple excision. PEH usually begins within a thrombosed blood vessel, and abundant thrombotic material is usually present. On occasion the process may extend beyond the vessel wall into the adjacent soft tissues. Early lesions show ingrowth of endothelial cells into the thrombus, with the formation of pseudopapillae, lined by plump, normochromatic endothelial cells, which grow in a single, non-stratified layer. Mitotic activity may rarely be focally present. In more fully developed lesions, the endothelial proliferation may produce interanastomosing vascular channels, simulating angiosarcoma. The most important differential diagnostic consideration is angiosarcoma. The bland appearance of the endothelial cells, the overall circumscription of the lesion, and recognition of the typical features of PEH are the keys to avoiding this serious misdiagnosis. The great majority of angiosarcomas will present as larger masses, with clear-cut nuclear atypism, frequent mitotic figures and necrosis. Unlike PEH, which shows overall low-power circumscription, angiosarcomas are diffusely infiltrating lesions. Many cases of PEH arise within blood vessels, a distinctly unusual feature in 1
angiosarcoma. PEH may also occur within essentially any vascular tumor, as well as onto areas of hemorrhage and thrombosis within other types of tumors. Cavernous hemangiomas showing extensive PEH may show a distinctly sinusoidal pattern, and have been referred to as sinusoidal hemangiomas. Case 2: Glomeruloid Hemangioma Glomeruloid hemangioma is an unusual intradermal vascular proliferation seen in patients with POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M- protein, skin lesions). Glomeruloid hemangiomas are cutaneous tumors, showing an unusual intravascular proliferation closely resembling the renal glomerulus, and containing epithelioid cells with intracytoplasmic immunoglobulin droplets. Conceivably the glomeruloid nests of capillaries within ectatic capillaries seen in this lesion could be mistaken for the intraluminal papillations of Dabska-type hemangioendothelioma. Case 3: Extensive myxoid and hyalinized sinonasal capillary hemangioma Capillary hemangiomas are the most common vascular tumors of the sinonasal region, and most show an easily recognized lobular pattern. Some sinonasal capillary hemangiomas may show atypical features, such as high cellularity or mitotic activity. We recently reported a series of 16 sinonasal capillary hemangiomas displaying very striking stromal myxoid change and hyalinization, almost all of which were submitted in consultation with various other benign and malignant diagnoses, in particular angiosarcoma. Microscopically, these tumors showed striking stromal myxoid change and/or hyalinization, which largely obscured the underlying lobular capillary arrangement. Within this myxohyaline matrix, a florid capillary proliferation was present, frequently with non-atypical mitotic activity. In some instances a branching, "hemangiopericytoma-like" vascular pattern was present in areas. The overall cellularity was low to moderate, and endothelial atypia or hyperchromatism was absent. Ulceration and thrombosis were frequently present. Immunostains to CD31, CD34 and SMA highlighted areas of lobular growth pattern inapparent on the routinely stained slides. Four tested cases were negative for androgen receptors and beta-catenin. Follow-up for 2
these patients was uniformly benign. Awareness of these unusual sinonasal capillary hemangiomas should allow their confident distinction from more aggressive endothelial tumors (e.g., angiosarcoma) and from non-endothelial tumors, including nasopharyngeal angiofibroma, solitary fibrous tumor and sinonasal hemangiopericytoma-like tumor. Case 4: Epithelioid hemangioma (angiolymphoid hyperplasia with eosinophilia) Epithelioid hemangiomas usually present as small, superficial masses, most often in the head and neck region, in young to middle aged adults. The tumors are more common in women than in men. Multiple lesions may be present. Although most epithelioid hemangiomas arise in the dermis or subcutis, deeply seated and intravascular cases may rarely occur. In over 60% of cases, epithelioid hemangiomas will show a damaged, centrally located blood vessel, often lined in part by epithelioid endothelial cells. Typically these epithelioid endothelial cells emanate through the wall of this vessel, forming numerous capillary-sized vessels in the surrounding soft tissues. A vaguely lobular growth pattern may be appreciated at low-power magnification, but is often to a degree obscured by the overall cellularity of the lesion, and by the accompanying eosinophil and lymphocyte-rich inflammatory infiltrate. The endothelial cells lining the proliferating vessels have abundant eosinophilic cytoplasm, reminiscent of epithelial cells, which may protrude into the lumen in a tombstone pattern. Intracytoplasmic vacuoles are frequently present. The nuclei of these epithelioid endothelial cells are typically enlarged but normochromatic, with finely dispersed chromatin and small nucleoli. Mitotic figures may be present, but atypical mitoses are not seen. Epithelioid hemangiomas express CD31, CD34, Fli-1 and vwf, and occasionally show anomalous expression of low molecular weight cytokeratins. This latter feature may result in confusion with an epithelial neoplasm, emphasizing the need to employ a panel of immunostains. In particularly solid and cellular examples of epithelioid hemangioma, immunostaining for smooth muscle actin may be helpful for highlighting surrounding pericytes and vascular smooth muscle, revealing the well-formed and vaguely lobular nature of the proliferating vessels. 3
Epithelioid hemangiomas are typically confused with true epithelial neoplasms, such as metastatic carcinomas, and with other epithelioid vascular tumors, such as epithelioid hemangioendothelioma and epithelioid angiosarcoma. Identification of a centrally located damaged blood vessel, when present and recognition of the vaguely lobular growth pattern and associated eosinophilic infiltrate of epithelioid hemangioma are important in distinguishing it from carcinoma. In particularly difficult cases, immunohistochemistry for endothelial markers may be helpful. Although epithelioid hemangiomas may show intracytoplasmic lumen formation, a hallmark of epithelioid hemangioendothelioma, it lacks the distinctive myxochondroid matrix, single-file growth, and infiltration invariably present in epithelioid hemangioendothelioma. Although epithelioid hemangioendotheliomas may show origin from a larger blood vessel, they lack the lobular growth pattern and inflammatory cell infiltrate seen in epithelioid hemangioma. Epithelioid forms of angiosarcoma are much more extensive, obviously malignant-appearing tumors that typically grow in solid sheets and irregularly anastomosing vascular channels. Case 5: Anastomosing hemangioma Anastomosing hemangioma is a recently described benign vascular neoplasm originally reported in the genitourinary tract, in particular the kidney. Anastomosing hemangiomas are often mistaken for well-differentiated angiosarcomas, because of their anastomosing architecture, non-lobular growth pattern and mild endothelial cell atypia, with hobnail endothelial cells. In addition to the kidney, anastomosing hemangiomas have been reported in the testis, adrenal gland, ovary, liver and gastrointestinal tract. We have recently reported a large series of anastomosing hemangiomas involving soft tissue sites, in particular the paraspinal soft tissues. Microscopically, anastomosing hemangioma typically display a non-lobular architecture somewhat reminiscent of splenic red pulp, an anastomosing proliferation of capillary-sized vessels with mild endothelial cell nuclear variability, scattered hobnailed endothelial cells, and small fibrin thrombi. Mitotic activity is absent or rare. Mature fat and extramedullary hematopoiesis are commonly present. Anastomosing hemangiomas should be distinguished from well- 4
differentiated angiosarcoma (absence of diffuse infiltration, hyperchromatic cells, mitotic activity and necrosis; presence of small thrombi, fat and extramedullary hematopoiesis). Other vascular neoplasms that enter the differential diagnosis include retiform hemangioendothelioma, sinusoidal hemangioma, hobnail hemangioma and ectopic splenic tissue. Case 6: Epithelioid hemangioendothelioma Epithelioid hemangioendothelioma (EHE) is a rare low-grade malignant vascular tumor which most often occurs in adults, but may also involve children. EHE involves the sexes equally. EHE may occur in the skin, deep soft tissues, bone, or viscera, in particular the liver and lung (so-called intravascular bronchoalveolar tumor). Many cases arise from a small blood vessel and EHE may rarely present as an entirely intravascular tumor. Microscopically, early lesions may show expansion of the affected blood vessel, with surrounding involvement of the adjacent soft tissues. Necrotic debris, hyaline collagen, and thrombotic material may be present within the vessel. EHE typically elaborates a dense, myxochondroid or myxohyaline matrix, in which are embedded nests, cords, chains and single file arrays of small, uniform, epithelioid to slightly spindled cells with occasional intraluminal vacuoles. Multicellular vascular channels are uncommon. The neoplastic cells are very bland, with uniform nuclei and infrequent mitotic activity. Metaplastic bone may occasionally be present. Approximately one-third of EHE show anaplastic features, including high nuclear grade, frequent mitotic activity, necrosis, and sheet-like growth; tumors with these features typically pursue a more aggressive clinical course, and have been referred to as malignant or high-grade EHE. EHE show a typical endothelial phenotype, with expression of vwf, CD31, CD34 and FLI-1 protein. Low molecular weight cytokeratins may be expressed in approximately 25% of cases. Epithelioid hemangioma lacks the distinctive myxochondroid matrix, single-file growth, and infiltration invariably present in EHE, and display a lobular growth pattern and a prominent inflammatory cell infiltrate. Epithelioid forms of angiosarcoma are much more extensive, obviously malignant-appearing tumors that typically grow in solid sheets and 5
irregularly anastomosing vascular channels. The distinction of high-grade forms of EHE from epithelioid angiosarcoma rests on identification of areas of more typical EHE. Although EHE is generally considered a vascular tumor of intermediate malignancy, it is perhaps better thought of a low-grade form of angiosarcoma, given its much more aggressive behavior as compared with other hemangioendotheliomas. Case 7: Kaposiform hemangioendothelioma Kaposiform hemangioendothelioma (KHE) is a distinctive vascular neoplasm of childhood, which shows mixed features of a juvenile capillary hemangioma and Kaposi sarcoma. Unlike juvenile capillary hemangioma, KHE is frequently associated with the Kasabach-Merritt phenomenon (thrombocytopenia and hemorrhage, KMP) and does not spontaneously regress. KHE is not associated with immunosuppression. KHE typically present in early childhood, most often in the first year of life. Extremely rare cases have been reported in adults. Although it was originally thought to occur most often in the retroperitoneum, it now appears that KHE is actually much more common in the skin and soft tissues of the extremities and head and neck, where it presents as a large, vascular appearing mass. Both superficially located and deep KHE grow in an infiltrative and nodular pattern, often with associated fibrosis. Frequently, dilated lymphatics are seen at the periphery of the tumor mass, sometimes resembling lymphangioma. Crescentic vascular spaces, identical to those seen in so-called tufted angioma are frequently present. The tumor nodules are composed of an admixture of well-formed, capillary sized vessels (resembling juvenile hemangioma) and solid appearing foci, with spindled cells and slit-like vascular spaces (resembling Kaposi sarcoma). Epithelioid, or glomeruloid, foci containing small fibrin/platelet thrombi are found scattered throughout the tumor. By IHC, the spindled and epithelioid cells express CD31, CD34 and FLI-1 protein, but not von Willebrand factor. GLUT-1 protein, a sensitive marker of juvenile hemangiomas, is absent in KHE. Nearly 50% of patients with KHE will develop KMP. Complete surgical resection is the therapy of choice for KHE, but is not always possible, owing to the extent of local disease. Approximately 10% of patients with KHE will die either from local effects of the tumor or from 6
complications related to KMP. KHE appear to be less responsive to interferons than are juvenile hemangiomas. Rare cases may metastasize to lymph nodes or perinodal soft tissue, although distant metastases have not yet been seen. The differential diagnosis of KHE includes juvenile capillary hemangioma, so-called tufted angioma, Kaposi sarcoma and spindle cell hemangioma. Although foci within KHE may closely resemble juvenile hemangioma, they differ significantly by virtue of their infiltrative growth, associated desmoplasia, absence of a uniform lobular architecture, and spindled and glomeruloid foci. In small biopsies, immunohistochemistry for GLUT-1 protein, which is positive in juvenile hemangioma and negative in KHE, may be helpful. The histologic features of tufted angioma (angioblastoma of Nakagawa) are essentially identical to those of KHE. Although tufted angioma was originally thought not to be associated with KMP, cases have now been reported. Most likely tufted angioma and KHE are the same tumor, some of which occur in more superficial locations and are less often associated with KMP. Kaposi sarcoma typically occurs in much older patients than does KHE, and grows in a diffuse pattern, without the nodularity of KHE. The cells of Kaposi sarcoma are larger and more hyperchromatic than those of KHE, and glomeruloid foci and microthrombi are not seen. Spindle cell hemangioma is a distinctive benign vascular lesion characterized by a well circumscribed collection of thick walled blood vessels, thrombi, phleboliths, and an admixture of spindled and vacuolated, epithelioid endothelial cells. It is frequently associated with Mafucci syndrome, and often recurs by propagation along a damaged blood vessel. It lacks the infiltrative growth and capillary hemangioma-like areas seen in KHE, and typically occurs in much older patients. Case 8: Retiform hemangioendothelioma Case 9: Dabska-type hemangioendothelioma arising in a lymphangioma Dabska-type and retiform hemangioendotheliomas show significant histologic overlap, and are increasingly regarded as different manifestations of a single entity, recently termed hobnail hemangioendothelioma. Classic Dabska-type hemangioendotheliomas 7
occur largely in infants and young children and present as ill defined, sometimes violaceous lesions of the head, neck and extremities. Retiform hemangioendotheliomas present as a slowly growing mass in the extremities, usually in older children and adults. Both Dabska-type and retiform hemangioendotheliomas are associated with lymphedema and lymphatic proliferations. Both lesions are fundamentally characterized by a proliferation of hobnail-like endothelial cells, showing cuboidal shape, scant cytoplasm, and irregular, hyperchromatic nuclei (34, 35). In classic Dabska-type hemangioendotheliomas, these cells are found within relatively well-formed vessels containing distinctive intraluminal papillations, consisting of hyaline cores with hobnailed endothelial lining. These vessels are often surrounded by dense fibrosis and a prominent lymphocytic infiltrate. Occasionally, dilated lymphatics are present adjacent to areas of typical Dabska-type hemangioendothelioma. Mitotic activity is usually sparse. Retiform hemangioendotheliomas consist of an infiltrative proliferation of elongated, branching vessels, reminiscent of the rete testis, which are lined by hobnailed endothelial cells (39). As in Dabska-type hemangioendotheliomas, hyaline fibrosis and chronic inflammation are commonly present. Occasional cases of retiform hemangioendothelioma may contain intraluminal papillae, identical to those seen in Dabska-type tumors. By immunohistochemistry, both tumors express common endothelial markers, such as CD31, CD34 and von Willebrand factor, as well as putative lymphatic markers, such as VEGFR-3 and D2-40 (34, 40, 41). The differential diagnosis of Dabska-type and retiform hemangioendotheliomas includes hobnail hemangioma, glomeruloid hemangioma and conventional angiosarcoma. Hobnail hemangioma is the currently preferred term for the lesion originally reported as targetoid hemosiderotic hemangioma, as it has become clear that not all such lesions have this distinctive clinical appearance. Hobnail hemangiomas differ from hobnail hemangioendotheliomas in that they are confined to the dermis and show a distinctive biphasic appearance, with a superficial portion showing dilated vessels lined by hobnail endothelial cells (occasionally with intraluminal papillae) and a deeper portion of slit-like capillaries, which infiltrate the dermal collagen. In general, the cells of hobnail 8
hemangioma do not show the hyperchromatism of those seen in hobnailed hemangioendotheliomas, and hyaline fibrosis is not conspicuous. Both tumors are considered vascular neoplasms of intermediate malignancy, based on their limited capacity for lymph node metastasis, and very rarely distant metastasis. Dabska-type and retiform hemangioendotheliomas should be widely excised. Case 10: Epithelioid sarcoma-like/ pseudomyogenic hemangioendothelioma This distinctive vascular neoplasm was described as epithelioid sarcoma-like hemangioendothelioma and subsequently described in a larger series as pseudomyogenic hemangioendothelioma. The current WHO book uses both terms. Epithelioid sarcoma-like/ pseudomyogenic hemangioendothelioma most often arises in the soft tissues of the upper and lower extremities, has a male predominance, and usually affects individuals in the 2nd 4th decades of life. Primary soft tissue disease typically presents with multifocal tumors that involve different anatomic depths, including dermis, subcutis, and skeletal muscle. Concurrent bone involvement is present in approximately 25% of cases. Morphologically, this tumor is characterized by ill-defined nodules of plump spindle and epithelioid cells with abundant densely eosinophilic cytoplasm growing in sheets and fascicles. Some cells resemble rhabdomyoblasts, with dense eosinophilic cytoplasm that displaces the nucleus to the periphery. Importantly, vasoformation is not a microscopic feature of this tumor, and classification as an endothelial cell neoplasm requires immunohistochemistry. By immunohistochemistry the neoplastic cells typically express keratin and endothelial markers (FLI-1, ERG, and CD31), but are negative for CD34 and muscle markers. SMARCB1 expression is retained. Recently, the specific balanced translocation t(7;19)(q22;q13) producing fusion of the SERPINE1 and FOSB genes has been shown to be a specific feature of these tumors. Epithelioid sarcoma-like/ pseudomyogenic hemangioendothelioma may present with multifocal disease, sometimes with innumerable tumors. Although local recurrences are common, distant metastases are extremely rare. Advanced local disease may sometimes require amputation for treatment. Epithelioid sarcoma-like/ pseudomyogenic hemangioendothelioma should be distinguished from epithelioid sarcoma (higher 9
nuclear grade, often CD34-positive, shows loss of expression of SMARCB1) and from various smooth and skeletal muscle tumors (absent expression of muscle markers, expression of endothelial markers). Case 11: Post-irradiation angiosarcoma Case 12: Epithelioid angiosarcoma, simulating mesothelioma or metastatic carcinoma Angiosarcomas are rare sarcomas that occur in several different distinct clinical settings. The most common group of angiosarcomas is cutaneous, occurring most often in the head/neck region of elderly adults with significant solar damage. Angiosarcomas of deep soft tissue are very uncommon and have no well-defined clinical associations. A significant number of angiosarcomas may be thought of as iatrogenic in nature, including lymphedema-associated angiosarcomas seen most often following radical and modified radical mastectomies ( Stewart-Treves angiosarcoma ), post-irradiation cutaneous angiosarcoma, frequently seen in patients who have received breast conserving surgery and adjuvant irradiation, angiosarcomas associated with the use of Thorotrast contrast media, angiosarcomas associated with implanted Dacron vascular grafts, and angiosarcomas associated with arteriovenous fistulae. Angiosarcomas may also arise in association with implanted foreign material such as shrapnel, secondary to industrial vinyl chloride exposure, and in patients with syndromes associated with benign vascular proliferations, such as Klippel- Trenaunay syndrome. Finally, angiosarcomas may very rarely arise within other soft tissue tumors, in particular nerve sheath tumors. Cutaneous angiosarcomas usually present as a multifocal, erythematous or violaceous lesion. Post-irradiation cutaneous angiosarcomas may arise in a very short time following irradiation (median 59 months), in contrast to other types of post-irradiation sarcomas. Angiosarcomas of deep soft tissue present as large, hemorrhagic masses which may clinically be confused with hematomas. 10
Angiosarcomas are extremely variable in appearance, ranging from very welldifferentiated lesions that may be difficult to distinguish from hemangiomas, to exclusively spindled lesions resembling fibrosarcoma or purely epithelioid lesions easily mistaken for carcinoma. The majority of angiosarcomas are high-grade lesions characterized by somewhat epithelioid cells having high nuclear grade and an architectural pattern that varies from sieve-like to solid. Vasoformative growth, with production of highly infiltrative, irregularly configured vascular channels, often with intraluminal papillary projections, is frequently seen. Necrosis and frequent mitotic figures including atypical forms are present. Well-differentiated lesions consist of highly differentiated, ramifying vessels composed of cells of low nuclear grade without mitotic activity, which dissect through the adjacent connective tissues. Epithelioid angiosarcomas are composed of sheets of epithelioid endothelial cells with abundant eosinophilic cytoplasm and uniformly high nuclear grade. Such lesions may show only very focal vascular channel formation and are easily mistaken for carcinomas. The most sensitive markers of angiosarcoma are CD31, FLI-1 and ERG, followed by CD34. vwf is the least sensitive marker of angiosarcomas, particularly poorly differentiated ones. Subsets of angiosarcomas express putative lymphatic markers, such as D2-40 and VEGFR-3; the specificity of these markers for lymphatic endothelial differentiation in malignant vascular tumors is questionable. All angiosarcomas may express lowmolecular weight cytokeratins; cytokeratin expression is particularly common in epithelioid angiosarcomas. As noted above, angiosarcomas are notoriously protean tumors, and thus their differential diagnosis is very wide. Well-differentiated angiosarcomas can be distinguished from benign vascular proliferations such as diffuse hemangioma, dermal angiomatosis and post-irradiation atypical vascular lesions by virtue of their infiltrative growth, absence of well-formed vessels with smooth muscle coats, endothelial stratification, presence of (sometimes subtle) nuclear atypia and hyperchromatism, and mitotic activity. Unlike carcinomas and epithelioid sarcomas, epithelioid angiosarcomas usually show at least focal vascular channel formation, a helpful clue. 11
Immunohistochemistry may be very valuable in this differential diagnosis; expression of high molecular weight cytokeratins is seen in many carcinomas and epithelioid sarcomas, but not in angiosarcomas. Conversely, CD31 expression is seen in angiosarcomas, but not in carcinomas or epithelioid sarcomas. It is important to remember that many epithelioid sarcomas express CD34. Loss of SMARCB1 protein is seen in epithelioid sarcomas but not in angiosarcomas or carcinomas. Epithelioid hemangioendotheliomas produce distinctive myxochondroid matrix, lack formation of true vascular channels, and typically have low nuclear grade. The distinction of spindled angiosarcomas, particularly those arising in sun-damaged skin, from sarcomatoid carcinomas and melanomas may be very difficult on purely histologic grounds. It is critically important to include angiosarcoma in this differential diagnosis, to avoid misdiagnosis and undertreatment. Again, immunohistochemistry for vascular markers, S100 protein, and high molecular weight cytokeratins may be very valuable. In deep soft tissue sites, other spindle cell sarcomas such as monophasic synovial sarcoma, fibrosarcoma, and leiomyosarcoma should be excluded through a combination of morphology (e.g., identification of occult glands and wiry collagen in synovial sarcoma and intersecting fascicles of eosinophilic cells in leiomyosarcoma) and immunohistochemistry for markers such as CD31, FLI-1 protein, cytokeratins, EMA, smooth muscle actins and desmin. Angiosarcomas in any location are aggressive sarcomas, with very high rates of local recurrence, distant metastasis, and death from disease. The most common metastatic sites are the lungs, followed by soft tissue and skeleton. Approximately 35% of patients with angiosarcoma die of disease in less than 3 years. In general angiosarcomas are resistant to all therapies, although there has been some recent success in the treatment of cutaneous angiosarcomas with taxane-based chemotherapy. Case 13: Bacillary angiomatosis Bacillary angiomatosis is a reactive vascular proliferation caused by infection with the bacteria Bartonella henselae and B. quintana. It occurs almost exclusively in immunocompromised patients, typically men with HIV infection, and usually presents as 12
multiple, elevated, pink skin or mucosal lesions. This process may also involve visceral organs, such as the liver, where it produces peliosis. Bacillary angiomatosis usually shows a vaguely lobular growth pattern, with capillary sized vessels lined by epithelioid endothelial cells with clear cytoplasm. Numerous stromal neutrophils are seen, as are amorphous, eosinophilic aggregates containing fibrin and bacilli. The bacilli may be identified with a Warthin-Starry stain. In the liver, peliosis hepatis is seen, with surrounding aggregates of fibrin and bacilli. Occasionally the vaguely lobular growth pattern and the clear endothelial cells may be relatively inapparent, and bacillary angiomatosis may closely resemble ordinary granulation tissue. Clinical correlation may be very valuable here. Careful inspection should reveal the characteristic clear endothelial cells and eosinophilic debris seen in bacillary angiomatosis. The clinical setting of bacillary angiomatosis also often raises the possibility of Kaposi sarcoma, a lesion which shows as its hallmark spindled cells forming slit-like vascular spaces, rather than lobules of clear, epithelioid cells. Therapy of bacillary angiomatosis is aimed at eradicating the underlying infectious etiology, most often with erythromycin. In problematic cases, IHC for the HHV8-associated LANA protein, which is positive in KS but not bacillary angiomatosis, may be valuable. Case 14: Kaposi sarcoma Kaposi sarcoma (KS) occurs in 4 distinct clinical settings: 1) Classical Kaposi sarcoma, typically occurring as lower extremity skin lesions in older males of Mediterranean, Central European and African origin, 2) Endemic Kaposi sarcoma, occurring in African young males and very young children as bulky lymph node and soft tissue disease, 3) Epidemic (AIDS-related) Kaposi sarcoma, occurring on the skin, mucosal surfaces and viscera of HIV-infected patients (in particular in homosexual males), and 4) Iatrogenic Kaposi sarcoma, occurring as cutaneous or visceral lesions in renal transplant patients. In any of these setting, cutaneous Kaposi sarcoma appears as a violaceous patch, plaque, papule, macule, or tumor, occasionally with associated limb edema. Visceral and lymph node involvement presents as a hemorrhagic mass. All forms of KS are now understood to be directly related to infection by Human Herpesvirus 8 (HHV-8), which 13
can be detected in essentially all cases of Kaposi sarcoma by RT-PCR or with immunohistochemistry for the HHV-8 latency associated nuclear antigen (LANA). In immunocompetent patients with limited cutaneous disease, the disease-related mortality of KS is approximately 10-20%. In immunocompromised patients, treatment of KS is aimed first at elimination or amelioration of the underlying immune defect. Prior to the development of highly active antiviral therapy, the disease-specific mortality for KS in AIDS patients was close to 90%; with effective therapy this has been reduced to less than 50%. Cryotherapy and radiotherapy have also been used successfully in KS patients with limited cutaneous disease. The histological appearance of KS is the same in all patients, regardless of clinical scenario. The earliest patch lesions of KS appear as proliferations of small, infiltrative vessels surrounding larger, ectatic vessels, with associated chronic inflammation. In later plaque stage lesions a proliferation of relatively bland, vaguely myoid spindled cells producing slit-like vascular channels is more prominent, with extravasated red blood cells and extracellular hyaline globules. The lesion may trap pre-existing blood vessels, creating the so-called promontory sign. This spindle cell component predominates in later nodular or tumoral lesions of KS. In lymph nodes, early lesions of KS are often visible as subtle spindle cell proliferations in the subcapsular sinus. Pleomorphism and mitotic activity are not generally features of classical, epidemic, or iatrogenic KS but may be seen in African endemic KS. KS expresses typical endothelial markers (e.g., CD31, FLI1, ERG) in addition to markers of lymphatic endothelium, such as D240. Detection of the HHV8 LANA protein by IHC is diagnostic of KS, and is a highly sensitive test. Vascular proliferations associated with vascular stasis (acroangiodermatitis) may be very difficult to distinguish from KS on histological grounds alone. Correlation with clinical history and LANA immunostains may be very valuable in making this distinction. Relatively low-grade-appearing angiosarcomas may mimic the earliest patch stage of KS, but typically show greater cytologic atypia and more pronounced infiltrative growth. The absence of LANA expression may be helpful here as well. Spindle cell 14
hemangiomas are well-circumscribed, typically subcutaneous lesions that contain phleboliths and calcifications and consist of an admixture of cavernous hemangiomalike zones with cellular spindled zones, showing both spindle cells and vacuolated epithelioid cells. Case 15: Spindle cell hemangioma Spindle cell hemangioma was originally described as spindle cell hemangioendothelioma and was felt to represent an unusual form of low-grade angiosarcoma. Subsequent studies have convincingly shown it to be a benign, and possibly reactive lesion, and it has been reclassified by the World Health Organization as spindle cell hemangioma. SCH typically occur in the dermis or subcutis of the distal extremities, in young adults. Very rare cases have been reported in deep soft tissue. In a significant subset of patients the lesion are reported to have been present for many years, without symptoms. Approximately 5% of SCH occur in patients with Maffucci syndrome (multiple enchondromas and vascular tumors), and one should always raise this possibility in a patient with a new diagnosis of spindle cell hemangioma. SCH are benign tumors, without capacity for metastasis. A significant percentage of patients may have multiple lesions and local recurrences. The latter is most likely related to propagation of the process along adjacent, possibly abnormal blood vessels. SCH typically grow in a well-circumscribed fashion and frequently are at least in part intravascular. Organizing thrombi, calficifcations and phleboliths are frequently present. A characteristic feature is the presence of two distinct zones, one characterized by thinwalled, dilated vessels, reminiscent of cavernous hemangioma, and the second by a proliferation of normochromatic, eosinophilic spindle cells, creating slit-like vascular spaces. Within these spindled areas, vacuolated, epithelioid cells are identified, a useful diagnostic feature of SCH. Mitotic figures are very rare and necrosis is absent. A chronic inflammatory cell infiltrate is absent, helping to distinguish SCH from Kaposi sarcoma (KS). By immunohistochemistry, SCH contain a mixture of spindled and epithelioid endothelial cells, which almost always express typical vascular markers such 15
as CD31 and CD34, and smooth muscle/pericytic cells, which variably express smooth muscle actins and desmin. The HHV-8 LANA protein is not present. SCH is most often mistaken for KS. Although KS may on rare occasions grow in a nodular fashion, it lacks the superb circumscription of SCH, does not show intravascular extension, and invariably shows infiltration of the spindled cells into the surrounding stroma. Additionally, KS lacks the admixture of spindled and vacuolated endothelial cells characteristic of SCH, and typically shows an associated chronic inflammatory cell infiltrate. The cells of KS also display a greater degree of nuclear enlargement and hyperchromasia, contrasting with the bland spindled cells of SCH, and frequently contain intracytoplasmic hyaline globules. Occasional angiosarcomas show predominantly spindled features and can be confused with SCH. Again, careful attention to the absence of circumscription and the presence of diffusely infiltrating growth should point one towards the correct diagnosis. The great majority of spindled angiosarcomas show focal areas of typical angiosarcoma, characterized by more epithelioid cells forming primitive vascular channels. Angiosarcomas also show significant nuclear atypia, frequent mitoses, and will often have foci of necrosis, all features typically absent in SCH.In a child, the differential diagnosis of SCH may also include kaposiform hemangioendothelioma (KHE). KHE is characterized by a distinctly lobular proliferation of spindled endothelial cells, surrounded by a fibrous stroma. Dilated blood vessels and lymphatics are often noted in association with the tumors. Features that allow the distinction of SCH from cutaneous KHE include circumscription of the lesion, intravascular growth, the presence of vacuolated epithelioid endothelial cells, and the absence of lobular growth or fibrosis. Case 16: Benign vascular malformation with diffuse growth pattern (diffuse hemangioma, angiomatosis) It is now recognized that the overwhelming majority of lesions previously diagnosed as some variant of hemangioma in the deep soft tissues represent instead examples of benign vascular malformation (BVM). As such, most of the these lesions show an admixture of vessels resembling arteries, veins and lymphatics, as well as other vessels 16
without obvious normal counterpart. Subclassification of these lesions as venous, arteriovenous, etc is subjective and not of clinical relevance. Local recurrences are common in all of these tumors, with up to 50% of patients with angiomatosis eventually suffering a local recurrence. These recurrences may be difficult to extirpate surgically, but are usually non-destructive. Malignant transformation is essentially unheard of. Deeply situated BVM, principally intramuscular forms, account for less than 1% of all vascular tumors. Clinically, deep BVM often present as large, non-specific masses, which may be confused with a variety of sarcomas. Commonly, these lesions contain a large component of benign fat, and may be mistaken clinically and radiographically for fatty tumors. They may occur in any location, including synovium ( synovial hemangioma ) and nerve ( intraneural hemangioma ). In order for a lesion to be classified as angiomatosis it must either show extensive involvement of multiple tissues planes, such as skin, subcutis, muscle and bone, or must involve more than one muscle in a contiguous fashion. Deep BVM may show principally features of capillary hemangioma or cavernous hemangioma, and frequently show an admixture of both areas, as well as larger, malformed vessels resembling both arteries and veins. Intramuscular BVM typically splay apart the skeletal muscle in a checkerboard pattern, and usually contain abundant adipose tissue. This presence of this adipose tissue may make the determination of surgical margin status very difficult. The extensive nature of angiomatoses and deep BVM, and their infiltrative growth in the deep soft tissues may raise concern for an angiosarcoma. Unlike angiosarcomas, angiomatoses and deep BVM consist of uniformly well-formed vessels, which contain a muscular coat and bland, monolayered endothelial cells. Diffuse infiltration by irregular, elaborately anastamosing, poorly formed vessels, a characteristic feature of angiosarcoma, is not seen. Angiomatoses and deep BVM with a prominent adipocytic component may be confused with both benign and malignant fatty tumors. Although lipomas and liposarcomas are highly vascular, they do not show the gaping vascular 17
channels or the lobular vascular proliferation generally present in BVM. Atypical, hyperchromatic cells, a diagnostic feature of well-differentiated liposarcomas, are absent. Case 17: Angiolipoma Despite their name, angiolipomas represent vascular, rather than adipocytic tumors. This is supported by a number of pieces of evidence, including the abnormal nature of the proliferating capillaries (with characteristic thrombi), the presence of cellular forms largely lacking fat, and the absence of karyotypic abnormalities (seen in essentially all true fatty tumors). Angiolipoma usually presents as multiple, painful subcutaneous nodules. Peak incidence is between the second and the third decades. They most frequently affect the upper limbs (approximately two thirds occur in the forearm), followed by the trunk and the lower limbs. The breast is a common location, where they may be confused with angiosarcoma. Angiolipomas are composed of capillary proliferation with a variable component of mature fat. Characteristically blood vessels contain fibrin microthrombi, representing the diagnostic hallmark of this lesion. The amount of the capillary proliferation can vary from minimal to very abundant, to the extent that the adipocytic component can be overlooked ( cellular angiolipoma ). Angiolipomas are benign lesions. Local excision is curative and local recurrence never occurs. Most diagnostic problems are with lesions laying at the extremes of the spectrum. Sometimes the vascular component can be minimal and therefore overlooked, sometimes it is predominant to the extent that the lesion is mistaken for a vascular lesion, including angiosarcoma and Kaposi sarcoma. Suggested References Given the scope of this Interactive Microscopy session, I have elected not to provide an exhaustive list of primary peer-reviewed articles. Instead I highly recommend the relevant chapters in the 6 th Edition of Enzinger and Weiss s Soft Tissue Tumors, the current WHO Soft Tissue and Bone book, the 4 th Series AFIP Atlas on Tumors of the Soft Tissues, and the current edition of Fletcher s Diagnostic Histopathology of Tumors. 18