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Lymphangioma circumscriptum, a rare long-term complication of chronic lymphedema, has been described only twice following radical mastectomy. The case discussed in this report developed 25 years after radical mastectomy and radiation therapy. Both this condition and lymphangiosarcoma, its malignant counterpart, may arise in lymphedematous extremities regardless of the etiology of the lymphatic obstruction.
From 1975 to 1986, 26 patients with soft tissue tumors of the extremities underwent a total of 29 perfusions. The cytostatics used were doxorubicin (Adriamycin, Adria Laboratories, Columbus, OH) (19 perfusions), melphalan (two perfusions), and a combination of these agents (eight perfusions). Before perfusion most patients had been treated by surgical excision(s), radiotherapy, or systemic chemotherapy. Of 17 patients perfused because of local inoperable tumor, four showed prolonged complete remission of the tumor mass, stable disease was seen in three, and ten showed progression. The complete remissions observed in three patients with aggressive fibromatosis and in one with lymphangiosarcoma occurred after perfusion with doxorubicin combined with melphalan. Doxorubicin added to the perfusate as the sole cytostatic was not effective. Local recurrence was observed in five of nine patients treated by adjuvant perfusion, always after dubiously radical tumor excision. Toxicity was high, especially in the first few years. Tissue necrosis necessitated amputation in three cases (in two after perfusion with doxorubicin and melphalan and in one after repeated perfusion with doxorubicin only). This complication was no longer seen after adjustment of the dosage and dose distribution of doxorubicin, but the morbidity after perfusion with doxorubicin remained considerable.
Incidence rates for several histologic types of soft-tissue cancers were compared between black and white residents of New York State during 1976-81, using data from the population-based New York State Cancer Registry. Incidence rates for leiomyosarcoma, neurofibrosarcoma and malignant neurolemmoma were higher for blacks than for whites in almost all age groups. Black-white differences in malignant mesenchymoma, while not statistically significant, were similar to those from other population-based studies. There was no evidence for black-white differences in certain other histologic types (e.g., blood-vessel cancers, lymphangiosarcoma). Black-white differences in leiomyosarcoma included higher rates for the uterus in black than in white females, and higher rates for the stomach in blacks of both sexes. Possible explanations for these differences in soft-tissue cancer incidence were discussed, along with comparisons with limited data on black populations in Africa.
Tumours of lymphatic vessels comprise only a small group in the heterogeneous spectrum of vascular neoplasms of skin and soft tissues. However, this discrepancy between haemangiomas/angiosarcomas and lymphangiomas/lymphangiosarcomas probably represents the present inability to reliably differentiate between lymphatic and capillary vascular endothelium. Histologically, neoplastic lymphatic vessels tend to be lined by endothelial cells with plumper and more prominent, matchstick-like nuclei (in contrast to vascular spaces in haemangiomas that are lined by flat or epithelioid endothelial cells), often show variations in the thickness of the vessel walls and are not completely surrounded by actin-positive (myo)pericytes. Endothelial cells in lymphatic neoplasms tend to be negative for CD34 or stain only focally positive for this marker and an expression of lymphatic markers as vascular endothelial growth factor-C receptor (VEGRF-3), podoplanin and M2A oncofetal antigen has been reported most recently. In addition to "traditional" lymphatic neoplasms including lymphangioma circumscriptum, cavernous lymphangioma/cystic hygroma, benign lymphangioendothelioma, lymphangiomatosis and the rare lymphangiosarcoma, histological and immunohistochemical features of a group of vascular neoplasms with a hobnail cytomorphology (hobnail haemangioma, retiform haemangioendothelioma, papillary intralymphatic angioendothelioma, benign lymphangiomatous papule following radiotherapy) suggest that these lesions also belong to the spectrum of tumours of lymphatic vessels.
Immunostaining for Factor VIII-related antigen was seen in deparaffinized sections from 19 of 20 postmastectomy angiosarcomas and from four of four sarcomas that arose in chronically edematous tissue unrelated to breast carcinoma. Staining was also seen in sections from two malignant hemangioendotheliomas, four capillary hemangiomas, and one granulation tissue specimen. Sections from two lymphangiomas were immunonegative for Factor VIII-related antigen in the endothelium of lymphatic channels, whereas staining was observed in the surrounding normal blood vessels. Electron microscopic study of four postmastectomy angiosarcomas disclosed ultrastructural features (fenestrae, intense pinocytotic activity, cell junctions, and Weibel-Palade bodies) supporting the blood vascular endothelial nature of the neoplastic cells. It is concluded that a neoplastic blood vessel component is present in sarcomas that arise in chronically edematous tissues. It is questionable whether a lymphatic component is also present. These tumors, therefore, should be regarded as angiosarcomas rather than lymphangiosarcomas.
There is controversy over the histogenesis of Kaposi's sarcoma (KS) from lymphatic or blood vessel endothelium. D2-40 is a novel monoclonal antibody to an Mr 40,000 O-linked sialoglycoprotein that reacts with a fixation-resistant epitope on lymphatic endothelium. We sought to establish the selectivity of D2-40 for lymphatic endothelium in normal tissues and compare its reactivity with the expression of the widely used vascular endothelial marker CD31 in a series of 62 formalin-fixed and paraffin-embedded vascular lesions including KS. In normal tissues, D2-40 stained the endothelium of lymphatic channels but not of blood vessels, including arteries and capillaries defined by reactivity with the blood vessel endothelial marker PAL-E. In our series of vascular lesions, D2-40 stained lymphangiomas (10/10), benign tumors of undisputed lymphatic origin, but not benign neoplasms or tumorlike lesions of blood vessel origin, including hemangiomas (0/10), glomus tumors (0/3), angiolipomas (0/2), pyogenic granulomas (0/2), vascular malformations (0/2), hemangiopericytoma (0/1), or hemangioendothelioma (0/1). D2-40 stained all cases of cutaneous KS (24/24) at all stages of progression, including patch, plaque, and nodular stages, supporting the concept that this disease originates from a cell type capable of undergoing lymphatic differentiation. D2-40 also stained three of seven angiosarcomas, indicating that a subset of these tumors can undergo at least partial differentiation along the lymphatic endothelial lineage and could be classified as lymphangiosarcomas. In comparison, CD31 was expressed in all benign and malignant vascular lesions, except for glomus tumors (0/3) and 5/10 lymphangiomas, in which staining was absent. We conclude that D2-40 is a new selective marker of lymphatic endothelium in normal tissues and vascular lesions and is valuable for studying benign and malignant vascular disorders in routinely processed tissue specimens.
This is a case report of a woman who had chronic lymphedema on one leg and who developed a primary cutaneous large B-cell lymphoma of the leg at that site. She received radiotherapy and did not show any systemic involvement thereafter. Other neoplasms may appear in a clinical setting of chronic lymphedema, namely, lymphangiosarcoma (Stewart-Treves), melanoma, and metastatic carcinoma. There are four other reports in the English literature of cutaneous lymphoma arising in an extremity with chronic lymphedema.
Suppressor oncogene p53 is expressed more frequently in the nodular portion than the superficial spreading portion of the same melanoma. PCNA expression follows the same pattern but it is strongly expressed already in the superficial spreading portion. CD34 is found to label dermatofibrosarcoma protuberans. There is the mixture of negative strands but the immunostains are predominantly positive in the three cases studied. Neurogenic tumors are reactive but the intensity of staining is only moderate. Fibrous histiocytoma, dermatofibroma and other fibrohistiocytic tumors are non-reactive. CD34 is expressed in the outer root sheath of hair follicle below the sebaceous gland level. A case of piloepidermal cyst is CD34 positive. CD34 is expressed in vascular endothelial cells; not only hemangiomas but also lymphangiosarcoma is CD34 positive. A case of indeterminate cell histiocytosis following scabies and superficial variant of clear cell sarcoma are discussed as examples of new entities.
Cutaneous non-Hodgkin's lymphoma developed within a leg affected by chronic lymphoedema. The lymphoedema had followed radiotherapy to bony metastases from a carcinoma of the prostate. Eighteen months after the development of the cutaneous tumours, extracutaneous involvement by the lymphoma became apparent. This is the second report of a non-Hodgkin's lymphoma appearing within a lymphoedematous limb. The possible reasons for such an unusual localization are discussed. Our case report illustrates that cutaneous tumours other than lymphangiosarcomas may localize to a lymphoedematous limb and clinically simulate the Stewart-Treves syndrome.
The lymphatic vasculature is essential for the maintenance of normal fluid balance and for the immune responses, but it is also involved in a variety of diseases. Hypoplasia or dysfunction of the lymphatic vessels can lead to lymphedema, whereas hyperplasia or abnormal growth of these vessels are associated with lymphangiomas and lymphangiosarcomas. Lymphatic vessels are also involved in lymph node and systemic metastasis of cancer cells. Recent novel findings on the molecular mechanisms involved in lymphatic vessel development and regulation allow the modulation of the lymphangiogenic process and specific targeting of the lymphatic endothelium. Recent results show that the homeodomain transcription factor Prox-1 is an important lymphatic endothelial cell (LEC) fate-determining factor which can induce LEC-specific gene transcription even in blood vascular endothelial cells (BECs). This suggests that the distinct phenotypes of cells in the adult vascular endothelium are plastic and sensitive to transcriptional reprogramming, which might be useful for future therapeutic applications involving endothelial cells. Vascular endothelial growth factor-C (VEGF-C) and VEGF-D are peptide growth factors capable of inducing the growth of new lymphatic vessels in vivo in a process called lymphangiogenesis. They belong to the larger family which also includes VEGF, placenta growth factor (PlGF) and VEGF-B, VEGF-C and VEGF-D are ligands for the endothelial cell specific tyrosine kinase receptors VEGFR-2 and VEGFR-3. In adult human as well as mouse tissues VEGFR-3 is expressed predominantly in lymphatic endothelial cells which line the inner surface of lymphatic vessels. While VEGFR-2 is thought to be the main mediator of angiogenesis, VEGFR-3 signaling is crucial for the development of the lymphatic vessels. Heterozygous inactivation of the VEGFR-3 tyrosine kinase leads to primary lymphedema due to defective lymphatic drainage in the limbs. Other factors that seem to be involved in lymphangiogenesis include the Tie/angiopoietin system, neuropilin-2 and integrin alpha 9. VEGF-C induces lymphatic vessel growth, but high levels of VEGF-C also resulted in blood vessel leakiness and growth. The VEGFR-3-specific mutant form of VEGF-C called VEGF-C156S lacks blood vascular side effects but is sufficient for therapeutic lymphangiogenesis in a mouse model of lymphedema. As VEGF-C156S is a specific lymphatic endothelial growth factor in the skin, it provides an attractive molecule for pro-lymphangiogenic therapy.
This review presents the diagnostic features, the pathophysiology and the available therapies for lymphedema. This disease is often able to be diagnosed by its characteristic clinical presentation, yet, in some cases, ancillary tests might be necessary to establish the diagnosis, particularly in the early stages of the disease and in edemas of mixed etiology. These diagnostic modalities are also useful in clinical studies. Available modalities include isotopic lymphoscintigraphy, indirect and direct lymphography, magnetic resonance imaging, computed tomography and ultrasonography. Lymphedema may be primary or secondary to the presence of other disease and/or to the consequences of surgery. Primary lymphedema may occur at any phase of life but it most commonly appears at puberty. Secondary lymphedema is encountered more often. The most prevalent worldwide cause of lymphedema is filariasis, which is particularly common in south-east Asia. In the USA, postsurgical lymphedema of the extremity prevails. Complications of chronic limb lymphedema include recurrent cellulitis and lymphangiosarcoma. Most patients are treated conservatively, by means of various forms of compression therapy, including complex physical therapy, pneumatic pumps and compressive garments. Volume reducing surgery is performed rarely. Lymphatic microsurgery is still in an experimental stage, although a few centers consistently report favorable outcomes.
Lymphoedema, refractory to non-operative management, may require surgical treatment. Potential indications include impaired limb function, recurrent episodes of cellulitis and lymphangitis, intractable pain, lymphangiosarcoma and cosmesis (patient unwilling to undergo more conservative treatment and willing to proceed even with experimental operations). The principle of excisional operations is to remove excess tissue to decrease volume of the extremity. Good reduction can be achieved with staged resection of the subcutaneous tissue, with resection of the excess skin and using the remainder for coverage. However, prolonged hospitalization, poor wound healing, long surgical scars, sensory nerve loss, residual oedema of the foot and ankle and poor cosmetic results can be significant problems and prevent offering such procedures short of a large and truly disabling lymphoedema, not responding to medical measures. Physiologic operations have been aimed at restoring lymphatic transport capacity, most frequently with lymphovenous anastomoses or lymphatic grafting. Chylous reflux due to valvular incompetence has been treated effectively by ligation and excision of retroperitoneal lymphatics, with or without lymphovenous anastomoses. Lymphovenous anastomoses operations for obstructive lymphoedema have been performed for several decades, but their use continues to be controversial. Such reconstructions can be indicated in a subset of patients who have proximal obstruction with preserved or dilated lymphatics distally. While few groups have reported good late clinical results, direct confirmation of long-term patency of lymphovenous anastomoses in patients is unavailable. Lymphatic grafting is a promising operation, but it requires true microsurgical expertise and commitment to treat this frequently frustrating and difficult disease. Long-term patency rates associated with documented clinical improvement have to be reported in larger number of patients, operated on in more than one centre before this operation can be recommended for treatment as an alternative to conservative measures. The large number of individual surgical techniques of physiological and excisional operations that are practiced today worldwide to treat lymphoedema continues to be testimony to our frustration in dealing with this difficult problem.
Plasmid DNA containing the human T24 H-ras oncogene, with or without viral transcriptional enhancer sequences, was applied to scarified mouse skin, followed by multiple treatments with the tumour promoter 12-O-tetradecanoyl-phorbol-13-acetate. This resulted in the formation of vasoformative tumours histologically characterized as lymphangiosarcomas. All of the animals treated developed cystic fluid-filled swellings. Polymerase chain reaction analysis revealed the presence of human H-ras sequences within the cystic fluid from 3 out of 4 swellings. An endothelial cell line established from the cystic fluid removed from one of these swellings was found to contain human H-ras sequences and to express the mutant human p21ras. Injection of the cell line into nude mice, or adult syngeneic mice, resulted in the formation of aggressive angiosarcomas. Further experiments showed that 12-O-tetradecanol-phorbol-13-acetate promotion is not required for tumour formation and would appear to reduce the yield of tumours. These results indicate that a single application of the human H-ras oncogene is sufficient to induce endothelial cell transformation in vivo, even in the absence of any further promotional stimulus.
The origin of spindle-shaped cells in Kaposi's sarcoma (KS) remains controversial. Non-specific histochemical reactions, electron microscopic examinations and immunostainings using antibody against factor VIII-related antigen (F VIII-RAG) and Ulex europaeus agglutinin I (UEAI) lectin as endothelial markers have given contradictory results. Immunohistochemical techniques were applied to 7 frozen skin biopsy specimen of KS from 5 elderly Mediterranean people and 1 renal allograft recipient, and a group of 27 other frozen cutaneous tumours including haemangio and lymphangiosarcomas, benign vascular lesions and various epithelial, melanocytic, fibrohistiocytic, fibrosarcomatous and muscular tumours. Using UEAI and antibodies against F VIII-RAG, HLA-DR and vimentin, a large proportion of positive KS spindle cells was found in all cases whereas cells were negative for keratin. Among the various immunoreactivity patterns observed in this study, a unique immunohistochemical profile was demonstrated for KS, angiosarcoma and endothelial cell, which strongly supports the endothelial origin of spindle cells in KS. Whereas F VIII-RAG, HLA-DR, vimentin and UEAI were sensitive endothelial markers, only F VIII-RAG appeared specific for endothelial cells since UEAI stained 2 squamous cell carcinomas and HLA-DR and vimentin were present in various mesenchymal and melanocytic tumours.
Ultrastructural studies of angiosarcoma in chronic lymphedema (Stewart-Treves syndrome) at various stages of development show that endothelial cell proliferation originates not in the lymphatic but in the blood capillary vessels. The results indicate that the term "lymphangiosarcoma" is no longer suitable to describe the histopathologic characteristics of Stewart-Treves syndrome.
Among 41,109 women diagnosed with breast cancer between 1935 and 1982 in Connecticut, 3,984 developed a second cancer, whereas 2,426 were expected [relative risk (RR) = 1.64; 95% CI = 1.6-1.7]. This increased risk persisted for 30 years and was highest in women under 55 years of age at the time of breast cancer diagnosis. Second primary breast cancers (RR = 3.0) accounted for almost one-half of all new neoplasms. However, if subsequent breast cancers were excluded, the risk for all other second cancers was only 1.15 (95% CI = 1.10-1.20), and no excess risk was seen among women over age 55 at initial breast cancer. Significant risks were found for cancers of the ovary (RR = 1.7) and uterine corpus (RR = 1.4), possibly linked with shared reproductive factors such as nulliparity or late age at menopause. Malignant melanoma (RR = 1.5), thyroid cancer (RR = 1.6), and colon cancer (RR = 1.2) were also significantly elevated; possible shared risk factors remain to be elucidated. Significant deficits of multiple myeloma and chronic lymphocytic leukemia were noted. Women who received initial radiotherapy compared with those who did not were at slightly higher risk of developing a second cancer, most notably acute nonlymphocytic leukemia, non-Hodgkin's lymphoma, and cancers of the esophagus, kidney, and connective tissue, although the nature of the associations was not always clear. Some of the soft tissue sarcomas were lymphangiosarcomas of the arm, a consequence of the lymphedema that may complicate radical mastectomy (Stewart-Treves syndrome). Women treated with radiation were at higher risk of developing a second breast neoplasm (RR = 3.9) than nonirradiated women (RR = 2.8). Further investigation should focus on the mechanisms underlying the relationships between breast, genital tract, and colon cancers, and on the effects of treatment modalities on the risk of subsequent neoplasms.
After a 20-year latent period an angiosarcoma developed in the edematous leg of a 74-year-old woman with primary lymphedema. A deep venous thrombosis of the leg which further aggravated tissue swelling preceded the appearance of angiosarcoma. Histogenetic classification of the tumor as hemangiosarcoma rather than lymphangiosarcoma was favored by positive immunohistochemical staining for Factor VIII. Despite high amputation and isolated perfusion with hyperthermal cytostatic infusion, she developed local recurrence and distant metastases and died 16 months after operation. Patients with chronic primary or secondary lymphedema are susceptible to angiosarcoma although the overall risk is small.
Three angiosarcomas of serous membrane are described. One originated in peritoneum, one in pleura, and one in pericardium. The tumor arising in peritoneum was a cystic lymphangiosarcoma and may have been caused by previous therapeutic irradiation for carcinoma of the endometrium. This tumor invaded the peritoneal and right pleural cavities extensively and thus resembled diffuse mesothelioma in its behavior. The tumors arising in pleura and pericardium were hemangiosarcomas.