Elsevier

Clinics in Dermatology

Volume 32, Issue 5, September–October 2014, Pages 616-620
Clinics in Dermatology

Lymphedema-related angiogenic tumors and other malignancies

https://doi.org/10.1016/j.clindermatol.2014.04.008Get rights and content

Abstract

Chronic lymphedema has a permissive effect with certain types of malignancies, particularly angiosarcomas, in what is known as Stewart-Treves syndrome. The presumed mechanism of this effect is an immunocompromised district of the affected area. Most other cutaneous malignancies have also been described in lymphedematous areas, including basal cell carcinoma, squamous cell carcinoma, melanoma, Kaposi sarcoma, Merkel cell carcinoma, and several cutaneous lymphomas. The occurrence of such malignancies suggests a more general immunosuppression within the skin. The formation of collateral lymphatic and vascular vessels in response to lymphedema produces an environment rich in growth factors, which may also play a role. In addition to infection and other general skin care issues, regions affected by lymphedema should be monitored for malignant changes not limited to angiosarcomas.

Introduction

The role of lymphedema in cutaneous malignancy is best explained by the local immunosuppression caused by the inability to circulate lymphatic fluid, as well as the rich medium of growth factors induced by lymphatic stasis.1 Immunosuppression secondary to acquired immunodeficiency syndrome (AIDS), immunosuppressive agents, and chemotherapeutics has long been associated with various malignancies. The immunocompromised district is susceptible to many of the same complications seen in systemic immunosuppression.2

Lymphedema is classified into primary and secondary forms. Primary lymphedema may be further subdivided by age of clinical onset: (a) congenital lymphedema (before age 2 years), (b) lymphedema praecox (between age 2 and 35 years), and (c) lymphedema tarda (after age 35 years). Milroy disease (hereditary lymphedema type 1A) is the congenital familial form of primary lymphedema. It can also be seen in Turner syndrome and Noonan syndrome. Different types of lymphedema praecox include Meige disease (hereditary lymphedema type 2), lymphedema-distichiasis syndrome, yellow nail syndrome, and hypotrichosis-lymphedema-telangiectasia syndrome.

Classic causes of secondary lymphedema include chronic bacterial infections, iatrogenic causes (including radical mastectomy and vein harvesting), radiation, trauma, lymphoma, and filariasis. Lymphedema is commonly seen as a complication of breast cancer and affects approximately 14% of patients who undergo complete axillary lymph node dissection during their treatment.3 Massive localized lymphedema (MLL) secondary to obesity has emerged and is a challenging pathologic diagnosis,4 with cancers reported in these regions as well.5 The incidence of MLL is expected to rise with the global obesity epidemic6; the malignancies associated with lymphedema may accompany it. Microscopic lymphatic dysfunction in rhinophyma may give rise to occult malignancy; therefore, resected specimens should be sent to preclude the possibility of cancer.[7], [8] Venous obstruction from other diseases can lead to phlebolymphedema, another form of the immunocompromised district caused by venous stasis, and one that also may give rise to cancers.9 There may be overlap between the etiologies of lymphedema and risk factors for skin cancer such as local irradiation, chemotherapy, and malnutrition. Numerous case reports of skin cancers, including rare types of cancer, in lymphedematous areas exist. Clinicians should be vigilant in monitoring patients with lymphedema for the development of cutaneous malignancy.10

A seminal work on the lymphatic system and cancer in 197311 was the first convincing piece of evidence for enhanced neoplasia in lymphatic dysfunction. In that experiment, alymphatic pedicles of skin from guinea pigs were inoculated with liposarcoma cells and were compared with controls that received the same inocula to normal pedicled skin. The normal skin showed complete clearance of the tumor cells, whereas the alymphatic pedicles showed tumor progression in most cases. Others built on this principle by suggesting that fibrosis, infection, and immunosuppression may be underlying initial neoplasia in lymphedema.12 Cell-mediated immunity (CMI) plays an important role in the recognition and destruction of tumor cells in the human body. Immune impairment in lymphedema was first reported in 196013, when researchers noted increased survival of skin homografts after surgical destruction of regional lymph nodes. Impaired cell-mediated immunity in lymphedematous extremities was also suggested14 based on a dysfunctional response to induce contact dermatitis with dinitrochlorobenzene. The skin is rich in antigen-presenting dendritic cells (DCs), which use lymphatics to migrate15 and participate in antigen presentation with cytotoxic T-lymphocytes (CTLs). The role of newly described killer DCs in direct cytotoxic responses has been recently delineated; they may serve as powerful tools for the development of cancer immunotherapies.16

Wound-healing studies in mice have showed that lymphatic dysfunction causes increased levels of interleukin 10 (IL-10).17 IL-10 prevents DC maturation, which may inactivate the DCs that are commonly found in the tumor microenvironment.18 Pathologically, lymphangiectases are usually noted in benign and malignant skin changes, including warts and nonmelanoma skin cancer,19 suggesting that even microscopic lymphatic disease caused by common skin conditions may compromise immune trafficking.20

Ongoing inflammation, as evidenced by erythrocytes in lymphatic fluid collected from lymphedematous areas,21 may also contribute to local neoplasia by chronic irritation. Congenital lymphedema is not rare (Figure 1). Filariasis is a common cause of lymphedema worldwide. When caused by Wuchereria bancrofti and Brugia species, it is known to induce production of vascular endothelial growth factor (VEGF),22 which may promote aberrant blood vessel growth and neoplasia. VEGF receptor 3 (VEGFR-3) has been identified as an important marker of lymphatic endothelial cells, and its expression has been documented in tumor neovascularization and wound granulation tissue.23 Tumor lymphangiogenesis is part of a complex and poorly understood sequence of events that allows for metastasis.[24], [25] The natural history of lymphedema is progressive until a steady state is reached without any functional return of lymphatic flow.[26], [27] VEGF-C has been identified as a potential agent for the treatment of lymphedema, and studies in animals are promising.28

Angiosarcoma/lymphangiosarcoma arising in the setting of lymphedema was first described in 1906.29 Other researchers30 then reported six patients who developed angiosarcoma at sites of postmastectomy lymphedema. Since then, at least 400 cases of angiosarcomas developing in the context of chronic lymphedema have been reported, many of which historically were associated with the Halstead radical mastectomy. The development of upper extremity angiosarcoma after breast cancer treatment carries an adjusted odds ratio as high as 59. Lymphedema plays a role in the pathogenesis of angiosarcomas, but other factors such as radiation therapy may also increase risk.31 The onset of angiosarcoma after mastectomy ranges from 5 to 25 years in some case series. Clinically, angiosarcomas appear as multiple reddish blue macules or nodules that may become polypoid and coalesce. Most potential causes of chronic lymphedema have been linked to the development of lymphangiosarcomas.32 Lymphangiosarcomas arising in hereditary lymphedema,33 recurrent erysipelas,34 and filariasis35 are well documented, and lymphedema from other malignancies has also resulted in angiosarcoma.36 Patients with MLL are also known to develop angiosarcomas secondary to lymphatic obliteration by adipose tissue.5 There is compelling evidence that this neoplasm is the result of local immune dysfunction.37 In a patient with lymphedema and angiosarcoma, common antigens were injected intradermally in all four extremities, and no reaction was seen in the lymphedematous extremity, despite normal reactions elsewhere.37 Rhinophyma is believed to be the result of microscopic lymphatic dysfunction38; three cases of angiosarcoma have been reported overlying a rhinophyma.[39], [40], [41]

The c-myc oncogene functions as a controller of growth factors and is often amplified in angiosarcomas secondary to lymphedema. Primary angiosarcomas do not exhibit c-myc amplification, which makes fluorescent in situ hybridization studies a useful tool for distinguishing primary and secondary angiosarcomas in lymphedema.[42], [43] Differentiating lymphangiosarcomas from Kaposi sarcoma (KS) in lymphedema can be challenging, both clinically and histologically.44 In contrast to lymphangiosarcomas, KS will test positive for human herpesvirus 8 (HHV-8) and is less commonly associated with lymphedema.32 Interestingly, lymphangiosarcoma and KS have occurred together, as documented in a patient receiving immunosuppressive treatment for a kidney transplant.45

KS is best viewed as a special type of angiosarcoma and can arise in an immunocompromised district secondary to lymphedema.46 KS is a well-established complication of immunosuppressive therapy and immunodeficiency associated with HHV-8 infection (Figure 2). Upregulation of cyclooxygenase 2 (COX-2) and expression of the K15 protein by the virus are believed to be two of the major players involved in increased angiogenesis and malignant transformation.[47], [48] KS in lymphedema is believed to occur by the same mechanism, with local immunodeficiency facilitating viral oncogenesis.49 Lymphographic and lymphoscopic studies of patients with KS showed lymphatic abnormalities, including hyperplasia of the superficial vessels, lymphangectasia, and dermal reflux.50 KS is known to be endemic in areas rich in volcanic soils and is likely secondary to podoconiosis. Silica is believed to enter the skin through exposed feet and obstruct dermal lymphatics, leading to fibrosis and ultimately the creation of an immunocompromised district.51 Kaposi sarcomas overlying chronic penile lymphedema,52 postmastectomy lymphedema,53 and lower extremity lymphedema after endovascular access54 have been reported. Lymphedema-associated KS and podoconiosis-associated KS present similarly in that the lesions appear distally and extend proximally. This is in contrast to AIDS-associated KS, where the KS diffuses and appears to be distributed randomly.1 To further complicate matters, KS can also induce lymphedema, and on initial evaluation it may be difficult to determine which came first, the lymphatic dysfunction or the neoplasm.55 In general, KS has a better prognosis than most other angiosarcomas.56

Both basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs) have been reported in lymphedematous areas.1 Treatment for gynecologic malignancies is also associated with the development of lymphedema of the lower extremities; two cases of BCC have been documented in such patients.[57], [58] Recurrent erysipelas was the cause of lymphedema in a 75- year-old woman who developed multiple BCCs on her leg and was treated successfully with external beam radiation.59 Metastatic BCC and metastatic pleomorphic sarcoma have been described in a 75-year-old man with lymphedema secondary to treatment for hidradenitis suppurativa.60 BCC has also been appreciated in KS as a complication of an immunocompromised district.61

Twelve cases of SCC in lymphedema have been documented.62 Both de novo cancers and associated with other pathologies,63 SCC is another malignancy that can develop in an immunocompromised district. Verrucous hyperplasia and warts transforming into SCC have described as well,[64], [65] presumably because of a similar viral infection of an immunocompromised district as seen in KS. The penis and scrotum appear to be common sites of SCC formation in lymphedema.[66], [67] We postulate that this may be due to underlying human papillomavirus infection allowed to proliferate unchecked in the immunocompromised district. The lower extremities are also common sites for SCC formation in chronic lymphedema.[62], [68]

Malignant melanoma arising in lymphatic dysfunction is far less common than nonmelanoma skin cancer. Several cases have been reported, however, with similar predisposing factors as with the malignancies previously discussed. Melanoma has been described in lymphedema secondary to filariasis,69 postmastectomy lymphedema (two cases),[70], [71] and primary lymphedema.72 A certain degree of immune dysfunction of the lymphatic system appears to be vital to the metastasis of melanoma to regional lymph nodes. Malignant melanoma may be capable of suppressing the local immune system in this regard.73 In cases of lymphedema, the dysfunction may precede the malignancy, providing a ripe environment for tumor invasion and metastasis.

Of the many cutaneous lymphomas, diffuse large B-cell lymphoma,74 follicular lymphoma (two cases),[75], [76] cutaneous non-Hodgkin’s lymphoma,77 and cutaneous B-cell lymphoma78 have been described, all of which coexist with the various etiologies of lymphedema. Other rare and interesting tumors that have been seen in sites of chronic lymphedema include metastatic porocarcinoma,79 malignant fibrous histiocytoma,80 and Merkel cell carcinoma.81 Though these isolated cases may be incidental by Hickam’s dictum, they do not detract from the need to monitor lymphedematous areas closely for changes related to malignancy.

Section snippets

Conclusions

The repeatedly proven connection among lymph stasis, immune stasis, and locally facilitated onset of malignancies well features the overarching concept of immunocompromised district.82 In addition to being a significant risk factor for the development of cutaneous neoplasms, lymphedema causes significant disability and distress.83 As a result, lymphedema should be treated promptly, with physiotherapy and compressive therapy being first-line options. Other therapies include pneumatic

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