Cutaneous Angiosarcoma Complicating Morbid Obesity.

Angiosarcomas are rare malignant tumors that show differentiation toward endothelial cells and account for less than 1% of all sarcomas.[1] In contrast to other sarcomas, they have a predilection for skin and superficial soft tissue, especially in the head and face region.[2] One quarter of these tumors occur in other locations, such as liver, breast, bone, and spleen.[3] A variety of conditions are known to be associated with the development of angiosarcoma, including chronic lymphedema, sun exposure, radiation, exposure to particular chemicals such as Thorotrast (contrast for angiography), and long-term exposure to certain foreign materials.[2-7] Cutaneous angiosarcomas can be broadly classified into 2 groups: cases associated with lymphedema and those unrelated to lymphedema. The most common site for the latter group is head and face. Angiosarcomas usually occur in the extremities in the chronic lymphedema group, which in turn can be congenital, postfilarial infection, or iatrogenic. Most reported chronic lymphedema-induced angiosarcoma cases are iatrogenic, primarily in patients who have undergone radical mastectomy. Moreover, the lower abdomen is an uncommon location for this neoplasm.[8] Herein, we report a case of angiosarcoma of abdominal wall panniculus associated with chronic lymphedema due to morbid obesity.

REPORT OF A CASE

Clinical Findings

A 35-year-old, morbidly obese woman weighing 407 lb presented with multiple skin nodules in the periumbilical region with focal ulcerations. The surrounding skin was thick and brawny with the typical change of peau d'orange. There was no clinical history of radiation, and family history was unremarkable.

Pathologic Findings

Following a biopsy (incisional) confirmation of angiosarcoma, a 97.5 x 41.0 x 13.0-cm portion of abdominal wall weighing 75 lb with bilateral superficial inguinal lymph node dissection was received. There were multiple 2.0- to 6.4-cm polypoid tumor nodules on the skin surface with focal ulcerations (Figure 1, A). The cut surface was hemorrhagic and fleshy. Superficial soft tissue and the cut surface of few inguinal lymph nodes from both sides contained similar nodules (Figure 1, B). Microscopically, they were all high-grade angiosarcomas with a brisk mitotic rate. They were composed of conventional vasoformative areas admixed with poorly differentiated sheets of both spindle cells and epithelioid cells (Figure 2, A). The neoplastic vascular channels were open, anastomosing, and lined by plump atypical endothelial cells with focal tuft formations. The cutaneous portion of the tumor showed characteristic scaffolding of existing collagen bundles. The epithelioid cells had moderate amphophilic cytoplasm and round pleomorphic nuclei with prominent nucleoli (Figure 2, B). Extensive necrosis with a focal peritheliomatous growth pattern was also noted. Four of 7 superficial inguinal lymph nodes contained metastatic angiosarcoma. Immunohistochemically, CD31 was strongly positive (membranous and cytoplasmic) in the both spindle and epithelioid cells (Figure 3, A), whereas factor VIII positivity (membranous) was focal (Figure 3, B). Cytokeratin (AE1/AE3) and CD34 were negative in tumor cells (Table).

[Figures 1-3 ILLUSTRATION OMITTED]

Summary of Immunohistochemistry and Immunoreactivity

Antigen/Clone   Source             Pretreatment

AE1/AE3         Dako(*)            Pepsin (5 min)
Factor VIII     Dako               Protease K (20 min)
CD31            Dako               None
CD34            Signet([dagger])   None

Antigen/Clone   Dilution   Immunoreactivity

AE1/AE3         1:800      Negative
Factor VIII     1:10 000   Focally positive
CD31            1:60       Diffusely positive
CD34            1:40       Negative

(*) Dako Corporation, Carpinteria, Calif.

([dagger]) Signet Laboratories, Dedham, Mass.

Follow-up

The margins of the resected tissue were negative, and no postoperative radiotherapy or chemotherapy was given. Six months after the surgery, the tumor recurred at the excision site. The patient died a month later, and the autopsy revealed widely metastatic angiosarcoma with extensive involvement of the abdominal cavity, gastrointestinal tract, and bilateral ovaries (right, 17.0 cm; left, 12.0 cm). Metastatic tumor was also found in the thyroid gland, pericardium, myocardium, bilateral lungs, diaphragm, bilateral kidneys, and liver.

COMMENT

Chronic lymphedema is a known predisposing condition for cutaneous and superficial soft tissue angiosarcoma. Most angiosarcoma cases occur in the upper extremities of postmastectomy patients as a component of the Stewart-Treves syndrome.[9] More than 200 cases of postmastectomy cutaneous angiosarcomas have been reported. Other iatrogenic causes of chronic edema are less frequently associated with angiosarcomas.[10] Noniatrogenic causes of chronic lymphedema, such as congenital lymphedema and postfilarial infection, are rarely associated with angiosarcoma.[11, 12] Moreover, the lower abdomen is an uncommon site for this neoplasm. Recently, one iatrogenic-related case (history of radical hysterectomy and radiotherapy) of abdominal wall angiosarcoma was reported from Japan.[8] The multicentric tumor in our case stems from the most dependent portion of the abdominal panniculus (periumbilical region). Typical changes of chronic lymphedema (peau d'orange) were noted in the adjacent skin. In 1986, Krause et al[13] reported a similar case of abdominal wall angiosarcoma in a 55-year-old, morbidly obese woman. Their patient was alive 7 months after an incisional biopsy and without therapy, and the authors concluded that the morbid obesity played some etiologic role. We believe our case is only the second report since 1960 of chronic lymphedema--induced angiosarcoma, arising as a complication of morbid obesity, attesting to the rarity of this sequence of events.

Our case represents a high-grade angiosarcoma and contains both spindle and epithelioid cells with and without vascular channels. CD31 (platelet-endothelial cell adhesion molecule) is a glycoprotein expressed during the differentiation of myelomonocytic cells and has been shown to be a reliable and sensitive vascular marker.[14] CD31 is strongly positive (membranous and cytoplasmic) in a diffuse manner, whereas factor VIII positivity is rather focal (membranous) in this case. Occasionally, CD34[15,16] and cytokeratin,[16,17] especially in epithelioid cells, can be positive in these tumors. As expected, the positivity of cytokeratin in these epithelioid tumors may cause various differential diagnosis problems. However, our case is negative for both CD34 and cytokeratin. Lymph node metastases are uncommon in all sarcomas. Fong et al[18] studied 1772 patients with sarcoma and found an overall rate of lymph node metastasis of 2.6%. However, with a rate of 13.5%, angiosarcoma is 1 of the 3 sarcomas with the highest incidence of lymph node metastases.[18]

The pathogenesis of cutaneous angiosarcoma in chronic lymphedema is unknown. Several hypotheses have been proposed, ranging from a systemic carcinogen-driven tumor growth[9] to a neoplastic transformation during the development of collateral circulation. Impaired local immunity may also play a role in the pathogenesis of angiosarcoma. Schreiber et al[19] proposed that because of the blockage of afferent lymphatic drainage and resultant impaired antigen presentation, an edematous area becomes an "immunologically privileged site" predisposed to the development of these tumors.

Early surgical excision is the treatment of choice. However, even with wide excisions, the outcome is often unfavorable. Radiotherapy[20] and chemotherapy[20] have also been used in these patients with minimal success and have proved to be of palliative value only. Although the reports vary, as a whole the prognosis of angiosarcomas associated with chronic lymphedema is dismal, with an overall expected survival of 1 to 2 years.[7] Local recurrence and early metastases are common. Lung, bone, liver, lymph nodes, and adrenal glands are preferential sites of metastasis.[2]

In summary, we present a case of cutaneous angiosarcoma that arose in the chronically lymphedematous lower abdominal panniculus of a 35-year-old, morbidly obese woman. The tumor was multicentric and high grade and presented with regional lymph node metastases. Following a local recurrence, the patient died 7 months after presentation with widely metastatic angiosarcoma.

References

[1.] Bardwil JM, Mocega EE, Butler JJ, Russin DJ. Angiosarcoma of the head and neck region. Am J Surg. 1968;116:548-553.

[2.] Naka N, Ohsawa M, Tomita Y, et al. Angiosarcoma in Japan: a review of 99 cases. Cancer. 1995;75:989-996.

[3.] Enzinger FM, Weiss SW. Malignant vascular tumors. In: Soft Tissue Tumors. 3rd ed. St Louis, Mo: Mosby-Year Book Inc; 1995:641-677.

[4.] Jennings TA, Peterson L, Axiotis CA, Friedlander GE, Cooke RA, Rosai J. Angiosarcoma associated with foreign body material: a report of three cases. Cancer. 1988;62:2436-2444.

[5.] Maddox JC, Evans HL. Angiosarcoma of skin and soft tissue: a study of forty four cases. Cancer. 1981;48:1907-1921.

[6.] Moskaluk CA, Merino MJ, Danforth DN, Mediras LJ. Low grade angiosarcoma of the skin of the breast: a complication of lumpectomy and radiation therapy for breast carcinoma. Hum Pathol. 1992;23:710-714.

[7.] Sordillo PP, Chapman R, Hajdu SI, Magil GB, Golbey RB. Lymphangiosarcoma. Cancer. 1981 ;48:1674-1679.

[8.] Funaki M, Koike S, Dekio S, Jidoi J, Ohno H. Angiosarcoma which developed on the abdominal wall: report of a case. J Dermatol. 1997;24:342-344.

[9.] Stewart FW, Treves N. Lymphangiosarcoma in postmastectomy lymphedema. Cancer. 1948;1:64-81.

[10.] Kirchmann TT, Smoller BR, Meguire J. Cutaneous angiosarcoma as a second malignancy in a lymphedematous leg in a Hodgkin's disease survivor. J Am Acad Dermatol. 1994;31:861-866.

[11.] Chan KTK, Gilbert EF. Angiosarcoma complicating generalized lymphangiectasia. Arch Pathol Lab Med. 1979;103:86-88.

[12.] Muller R, Hajdu SI, Brennan MF. Lymphangiosarcoma associated with chronic filarial lymphedema. Cancer. 1987;59:179-183.

[13.] Krause KI, Hebert AA. Sanchez RL, Solomon AR. Anterior abdominal wall angiosarcoma in a morbidly obese woman. J Am Acad Dermatol. 1986;15:327-330.

[14.] DeYoung BR, Wick MR, Fitzgibbon JF, et al. CD31: an immuno-specific marker for endothelial differentiation in human neoplasms. Appl Immunohistochem. 1993;1:97-100.

[15.] Kuzu I, Bicknell R, Harris AL, et al. Heterogeneity of vascular endothelial cells with relevance to diagnosis of vascular tumors. J Clin Pathol. 1992;45:143-148.

[16.] Wenig BM, Abbondazo SL, Heffers CS. Epithelioid angiosarcoma of the adrenal glands: a clinicopathological study of nine cases with a discussion of the implications of finding epithelial specific markers. Am J Surg Pathol. 1994;18: 62-73.

[17.] Ohsawa M, Naka N, Tomita Y, et al. Use of immunohistochemical procedures in diagnosing angiosarcoma: evaluation of 98 cases. Cancer. 1995;75: 2867-2874.

[18.] Fong Y, Coit DG, Woodruff JM, Brennan MF. Lymph node metastasis from soft tissue sarcoma in adults: analysis of data from a prospective database of 1772 sarcoma patients. Ann Surg. 1993;217:72-77.

[19.] Schreiber H, Barry FM, Russel WC, et al. Stewart-Treves syndrome. Arch Surg. 1979;114:82-85.

[20.] Al-Raschid RA. Cyclophosphamide and radiation therapy in the treatment of hemangioendothelioma with disseminated intravascular clotting. Cancer. 1971; 27:364-368.

[21.] Pierard GE, Focan C, Lapiere CM. Cell proliferation in malignant angioendothelioma during sequential chemotherapy. J Cutan Pathol. 1979;6:479-485.

Accepted for publication September 18, 2000.

From the Departments of Pathology (Drs Azam, Saboorian, and Molberg) and Surgery (Drs Bieligk and Smith), The University of Texas Southwestern Medical Center, Dallas, Tex.

Reprints: Kyle Molberg, MD, Department of Pathology, 5323 Harry Hines Blvd, Dallas, TX 75390-9073.