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Lymphedema: An immunologically vulnerable site for development of neoplasms
CONCEPTS
Lymphedema: An immunologically vulnerable site for development of neoplasms Vincenzo Ruocco, MD,a Robert A. Schwartz, MD, MPH,b and Eleonora Ruocco, MDa Naples, Italy, and Newark, New Jersey Lymphedema is the result of accumulation of protein-rich interstitial fluid (lymph stasis) caused by a failure of lymph drainage in the face of a normal capillary filtration. Whether the origin is congenital or acquired from infection, radiation, trauma, or surgery, chronic lymph stasis impairs local immune surveillance by disrupting trafficking of the immunocompetent cells in the lymphedematous district and stimulates vicarious angiogenesis by promoting development of a collateral lymphatic and hematic network in the lymphedematous district. When the local mechanisms of immune surveillance begin to fail, the lymphedematous region becomes an immunologically vulnerable area, predisposed to malignancy, chiefly vascular tumors such as Stewart-Treves syndrome and Kaposi’s sarcoma, because of the continual angiogenic stimulus. (J Am Acad Dermatol 2002;47:124-7.)
E
dema and lymphedema both denote a clinical condition featuring a swelling of soft tissues. However, whereas edema is caused by an increased capillary filtration that overwhelms a regular lymph drainage, lymphedema is the result of accumulation of protein-rich interstitial fluid, lymph stasis, caused by a failure of lymph drainage in the face of a normal capillary filtration.1 Lymphedema mainly affects limbs or terminal sites, because options for collateral escape-lymph-drainage are reduced in an extremity, including the toes, penis, or an amputation stump. The cause of lymph stasis may be a genetic abnormality (congenital lymphatic hypoplasia), infection (recurrent erysipelas), infestation (filariasis), trauma, malignancy, surgery, radiation (the latter two often linked with the management of a malignancy), and extreme chronic immobility. Primary lymphedema seen at birth (Milroy disease) is a rare autosomal dominant disorder that, in some families, is caused by missense mutations that interfere with vascular endothelial growth factor receptor-3 signaling and result in abnormal lymphatic vascular function.2
From the Department of Dermatology, 2nd University of Naples,a and the Department of Dermatology, New Jersey Medical School, Newark.b Conflict of interest: None. Reprint requests: R. A. Schwartz, MD, MPH, Professor & Head, Dermatology, New Jersey Medical School, 185 S Orange Ave, Newark, NJ 07103-2714. Copyright © 2002 by the American Academy of Dermatology, Inc. 0190-9622/2002/$35.00 ⫹ 0 16/1/120909 doi:10.1067/mjd.2002.120909
124
LYMPHEDEMA AND LOCAL IMMUNE DYSFUNCTION Whichever is the cause, the lymphedematous region in time becomes a site of altered immunocompetence. In fact, cutaneous dendritic cells, T lymphocytes, and macrophages exert their immune functions by migrating from peripheral sites through dermal lymphatic vessels to regional lymph nodes.3 A study of immune cells in peripheral lymph nodes and skin of 17 patients with obstructive lymphedema of the lower extremities suggested impaired lymphocyte and Langerhans cell trafficking, presumably resulting in ineffective removal of foreign antigens.4 In any case, inadequate lymphatic drainage caused by lymphedema may disrupt the regularity of this cell trafficking, on which immunocompetence depends, and makes the lymphedematous region an immunologically vulnerable area (IVA). It has been known since the 1960s that an obstacle to lymphatic drainage delays the rejection of skin homografts in the lymphedematous extremities.5,6
STEWART-TREVES SYNDROME More than 200 cases of angiosarcomas occurring in chronic lymphedema have been collected7-11 since the original report of Stewart and Treves in 1948 (quoted in Offori et al8). Although described originally only in patients having undergone mastectomy (and as a consequence of lymphedema induced iatrogenically by axillary lymph node dissection), the Stewart-Treves syndrome has been observed in several cases of lymphedema unassociated with breast carcinoma and mastectomy, which has made it clear that chronic lymph stasis (and not
J AM ACAD DERMATOL VOLUME 47, NUMBER 1
the primary cancer) predisposes to the onset of the angiosarcoma. The coexistence of an immune dysfunction in the lymphedematous region was first proven in 1982.7 In a patient with Stewart-Treves syndrome of the right lower limb, intradermal skin tests to common antigens were performed on the 4 limbs (forearms and thighs). The tests revealed no (or weak) skin reactions on the affected limb, in the face of the normal skin reactions observed on the 3 uninvolved limbs.7 In another study of a patient with StewartTreves syndrome, after intralesional administration of BCG, skin test responses were increased both in intensity and in the number of antigens eliciting reactions.12 Intralesional BCG or PPD resulted in the regression and complete disappearance of both challenged and unchallenged skin tumors within the same lymphatic drainage region. Evidence for an impairment of the cell immunity in post-mastectomy lymphedema was obtained in an ample investigative study.13 A total of 35 women with post-mastectomy lymphedema were investigated using dinitrochlorobenzene to test the afferent and efferent loops of the cell-mediated immune response on the lymphedematous and normal arms. The findings showed a statistically significant impairment to both the sensitization (afferent loop) and the elicitation (efferent loop) phase of the immune response on the lymphedematous arms compared with the normal ones, thus demonstrating selective suppression of immune competence in the lymphedematous limbs.13
KAPOSI’S SARCOMA The classical form of Kaposi’s sarcoma (KS) is known to usually appear on the acral sites (especially lower extremities) accompanied or preceded by local lymphedema.14 The finding of dynamic abnormalities of the lymph drainage in the lower extremities affected by KS15 supports the clinical data. Similarly to what occurs in the Stewart-Treves syndrome, the coexistence of the 2 events (lymph stasis and vascular oncogenesis) is not coincidental.16 Interestingly, 2 cases of KS or KS-like angiosarcoma arising in chronic postmastectomy lymphedematous arms have recently been described.17 As mentioned previously, acral (or terminal) sites represent privileged areas for onset of overt or subtle lymphedema because of the reduced collateral lymph drainage existing there. Starting as a budding multicentric endothelial proliferation of lymphatic channels, the changes progressively lead to an intense blockage of lymphatic transport resulting in chronic lymph stasis. We postulate that, in time, acral lymphostatic sites undergo a regional immune
Ruocco, Schwartz, and Ruocco 125
dysfunction that paves the way for the local onset of the opportunistic HHV-8 –associated neoplasm. The link between the impairment of lymph circulation and regional immune dysfunction in classical KS was first proven in 1984.18 KS appeared on a lymphedematous leg of a patient with altered lymph drainage and lack of cell immune response confined to the lymphedematous limb. Intradermal skin tests to common antigens performed on the 4 limbs (forearms and legs) revealed no immune responses on the affected limb versus normal or even strong responses on the 3 unaffected limbs.18 Five years later, the same patient presented with lymphedema and new KS lesions on the other leg. On this occasion, skin tests were negative on both the affected legs, whereas normal responses were observed on the forearms.19 Two years later, KS lesions also appeared on both the forearms: at this time, skin tests were negative on all 4 of the extremities. A lymphologic and immunologic investigation performed in patients with classical KS sensitized with dinitrochlorobenzene proved that the affected limbs presented concomitant alteration of the lymph drainage and of the immune response.20 The role of chronic lymphedema in facilitating the onset of KS was stressed in an unusual localization (penis) of the classical form21 and the epidemic AIDS-related type.22 Although rarely emphasized in HIV-related KS, a variable degree of lymphedema (overt or subtle, a sort of microlymphedema) of the KS-involved areas is somewhat common in homosexual men and has a wide anatomic distribution, often without notable lymphadenopathy.16 The same might be postulated in diabetic microangiopathy, a possible link between classical KS and the increased incidence of diabetes mellitus in these patients.23 As for the African endemic form, lymphedema of the lower limbs may be the consequence of a lymphatic disease of the legs, podoconiosis, which has been etiologically associated with chronic, barefoot exposure to volcanic soils.24 Microparticles of silica dust, present in these soils, penetrate the skin of the foot during barefoot walking and are then taken up by the lymphatics, causing damage. Iron may possibly be the responsible component producing this soil toxicity.25 If soil exposure is crucial in the endemic KS, it has been postulated that it acts by inducing localized immune suppression of the extremities.24,25 In this lymphologic perspective, one can argue that in classical and certain cases of endemic KS the immune functions decay in a progressive and centripetal way because of the increasing difficulty in lymph drainage, which results in increasing formation of lymphaticovenous shunts, which in turn
126 Ruocco, Schwartz, and Ruocco
causes more and more immune tolerance. Consequently, cutaneous lesions appear acrally and extend centripetally. On the contrary, in epidemic and iatrogenic KS, where the immune dysfunction and a sort of microlymphedema are primarily generalized, the distribution of the lesions usually features a random pattern from the beginning. Compatible with this theory are in these patients the findings of diffuse lymphatic changes26 and of negative intradermal skin reactions to standard antigens (Multitest Me´ rieux) on all the 4 extremities.27
OTHER TUMORS Areas of chronic lymphedema (ie, IVAs) are also sites at risk for onset of cutaneous malignancy other than Stewart-Treves syndrome and KS. Two cases of non-Hodgkin’s lymphomas initially confined to lymphedematous limbs, which then progressed centripetally (as occurs in KS), perfectly fit in with the theory of IVA in the lymphedematous region.28,29 Further evidence is provided by 2 other cases of cutaneous non-Hodgkin’s lymphoma arising in the postmastectomy lymphedematous arms30 and of a primary cutaneous B-cell lymphoma of the leg in a chronically lymphedematous extremity.31 Also of interest are the appearance of cutaneous metastases in a lymphedematous leg from a follicular center cell lymphoma,32 the appearance of an anaplastic largecell cutaneous lymphoma on a chronic lymphedema of the arm,33 and the observation of chronic facial lymphedema preceding the onset of retro-orbital B-cell lymphoma.34 Other neoplasms may also occur in IVAs, such as basal cell carcinoma (including in 1 patient with more than 20 tumors35 and in another associated with KS36), verrucous carcinoma, squamous cell carcinoma, and reactive angiomatosis (pseudo-Kaposi’s sarcoma).35-47 Malignant melanoma occurring in postmastectomy lymphedematous arms41,42 and a single case of malignant fibrous histiocytoma arising in congenital lymphedema of the leg43 are additional examples of “opportunistic” malignancies in IVAs.
CONCLUDING REMARKS Localized lymphedema becomes a site of altered immunocompetence, with neoplasms, but also infections (often sustained by opportunistic pathogens), and immunity-related disorders (such as bullous pemphigoid, toxic epidermal necrolysis, and neutrophilic dermatosis) occurring.48-54 Of particular interest are 3 cases of bullous pemphigoid that appeared at the site of a previous irradiation that had been complicated by the onset of local lymphedema48-50 and one report of ampicillin-induced toxic epidermal necrolysis that was, on two occasions,
J AM ACAD DERMATOL JULY 2002
strictly confined to an area of lymphedema.51 The IVA concept should benefit from further study. REFERENCES 1. Mortimer PS. Managing lymphedema. Clin Exp Dermatol 1995; 20:98-106. 2. Karkkainen MJ, Ferrell RE, Lawrence EC, Kimak MA, Levinson KL, McTigue MA, et al. Missense mutations interfere with VEGFR-3 signalling in primary lymphedema. Nature Genetics 2000;25:153-9. 3. Lukas M, Sto¨ssel H, Hefel L, Imamura S, Fritsch P, Sepp NT, et al. Human cutaneous dendritic cells migrate through dermal lymphatic vessels in a skin organ culture model. J Invest Dermatol 1996;106:1293-9. 4. Olszewski WL, Engeset A, Romaniuk A, Grzelak I, Ziolkowska A. Immune cells in peripheral lymph and skin of patients with obstructive lymphedema. Lymphology 1990;23:23-33. 5. Stark RB, Dwyer EM, De Forest M. Effect of surgical ablation of regional lymph nodes on survival of skin homografts. Ann NY Acad Sci 1960;87:140-8. 6. Lambert PB, Frank HA, Bellman S, Farnsworth B. The role of lymph trunks in the response to allogenic skin transplants. Transplantation 1965;36:62-73. 7. Ruocco V, Pisani M, Astarita C. Syndrome de Stewart-Tre`ves avec de´ficit re´gional de l’immunite´ cellulare possibile: hypothe`se pathoge´nique. Ann Dermatol Venereol 1982;109:489-92. 8. Offori TW, Platt CC, Stephens M, Hopkinson GB. Angiosarcoma in congenital hereditary lymphedema (Milroy’s disease): diagnostic beacons and a review of the literature. Clin Exp Dermatol 1993;18:174-7. 9. Kirchmann TTT, Smoller BR, McGuire J. Cutaneous angiosarcoma as a second malignancy in a lymphedematous leg in Hodgkin’s disease survivor. J Am Acad Dermatol 1994;31:861-6. 10. Sinclair SA, Sviland L, Natarajan S. Angiosarcoma arising in a chronically lymphedematous leg. Br J Dermatol 1998;138:692-4. 11. Azurdia RM, Guerin DM, Verbov JL. Chronic lymphoedema and angiosarcoma. Clin Exp Dermatol 1999;24:270-2. 12. Klein E, Schwartz RA, Case RW, Holtermann OA, Solomon J, Hahn GM, et al. Accessible tumors. In: LoBuglio AF, editor. Clinical immunotherapy. New York: Marcel Dekker, Inc; 1980. p. 31-71. 13. Mallon E, Powell S, Mortimer P, Ryan TJ. Evidence for altered cell-mediated immunity in postmastectomy lymphoedema. Br J Dermatol 1997;137:928-33. 14. Schwartz RA. Kaposi’s sarcoma: advances and perspectives. J Am Acad Dermatol 1996;34:804-14. 15. Fei L, Ruocco V, Ayala F, Guerrera V, Del Genio A. Sarcome de Kaposi classique: e´tude des voies lymphatiques des membres infe´rieurs. Presse Me´d 1987;16:1188-90. 16. Witte MH, Stuntz M, Witte CL. Kaposi’s sarcoma: a lymphologic perspective. Int J Dermatol 1989;28:561-70. 17. Allan A, Shoji T, Li N, Burlage A, Davis B, Bhawan J. Kaposi’s sarcoma arising in chronic post-mastectomy lymphedematous arms is found to be HHV8 positive by polymerase chain reaction [abstract]. J Cutan Pathol 1998;25:485. 18. Ruocco V, Astarita C, Guerrera V, Lo Schiavo A, Moscariello CG, Satriano RA, et al. Kaposi’s sarcoma on a lymphedematous immunocompromised limb. Int J Dermatol 1984;23:56-60. 19. Ruocco V. Linfostasi: importante fattore patogenetico nel sarcoma di Kaposi classico. Ann It Dermatol Clin Sper 1992;46:15360. 20. Ruocco V, Satriano RA, Bernabo` R, Astarita C. Anomalies re´gionales des voies lymphatiques et de la re´ponse au D.N.C.B. dans le sarcome de Kaposi classique. Ann Dermatol Venereol 1985;112: 283-6. 21. Schwartz RA, Cohen JB, Watson RA, Gasco´n P, Ahkami RN, Ruszc-
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22.
23. 24. 25. 26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
zak Z, et al. Penile Kaposi’s sarcoma preceded by chronic penile lymphoedema. Br J Dermatol 2000;142:153-6. Hengge UR, Stocks K, Goos M. Acquired immune deficiency syndrome-related hyperkeratotic Kaposi’s sarcoma with severe lymphoedema: report of five cases. Br J Dermatol 2000;142:501-5. Laor Y, Schwartz RA. Epidemiologic aspects of American Kaposi’s sarcoma. J Surg Oncol 1979;12:299-303. Ziegler JL. Endemic Kaposi’s sarcoma in Africa and local volcanic soils. Lancet 1993;342:1348-51. Ziegler JL, Simonart T, Snoeck R. Kaposi’s sarcoma, oncogenic viruses, and iron. J Clin Virol 2001;20:127-30. Witte MH, Fiala M, McNeill GC, Witte CL, Williams WH, Szabo J. Lymphangioscintigraphy in AIDS-associated Kaposi sarcoma. Am J Roentgenol 1990;155:311-5. Ruocco V, Marfella A, Satriano RA. Valutazione della risposta immunitaria cellulo-mediata sui quattro arti in pazienti con sarcoma di Kaposi. Bollettino di Dermatologia Allergologica e Professionale 1991;6:173-81. Waxman M, Fatteh S, Elias JM, Vuletin JC. Malignant lymphoma of the skin associated with postmastectomy lymphoedema. Arch Pathol Lab Med 1984;108:206-8. Tatnall FM, Mann BS. Non-Hodgkin’s lymphoma of the skin associated with chronic limb lymphoedema. Br J Dermatol 1985; 113:751-6. d’Amore ESG, Wick MR, Geisinger KR, Frizzera G. Primary malignant lymphoma arising in post-mastectomy lymphedema: another facet of the Stewart-Treves syndrome. Am J Surg Pathol 1990;14:456-63. Torres-Paoli D, Sanchez JL. Primary cutaneous B-cell lymphoma of the leg in a chronic lymphedematous extremity. Am J Dermatopathol 2000;22:257-60. Hills RJ, Ive FA. Cutaneous secondary follicular centre cell lymphoma in association with lymphoedema praecox. Br J Dermatol 1993;129:186-9. Beylot-Barry M, Vergier B, Beylot C, Demascarel A, Doutre MS. Ki-1-positive large-cell cutaneous lymphoma mimicking a Stewart-Treves angiosarcoma. Dermatology 1995;190:77-82. Dragan LR, Baron JM, Stern S, Shaw JC. Solid facial edema preceding a diagnosis of retro-orbital B-cell lymphoma. J Am Acad Dermatol 2000;42:872-4. Lotem M, Tamir G, Loven D, David M, Hauben D. Multiple basal cell carcinomas of the leg after recurrent erysipelas and chronic lymphedema. J Am Acad Dermatol 1994;31:812-3. Ruocco V, Satriano RA. Basal cell cancer and classic Kaposi’s sarcoma in a locally immunocompromised patient. Int J Dermatol 1986;25:594-6. Benson PM, Pessoa CM, Lupton GP, Winton GB. Basal cell carcinomas arising in chronic lymphedema. J Dermatol Surg Oncol 1988;14:781-3. Rytter BM. Metachronous angioplastic sarcoma (Stewart-Treves
39.
40.
41.
42.
43. 44.
45. 46.
47.
48.
49.
50.
51.
52.
53. 54.
syndrome) with concomitant basal cell carcinoma in chronic lymph node edema of the arm following ablatio mammae. Dtsch-Gesundheitsw 1972;27:118-22. Lister RK, Black MM, Calonje E, Burnand KG. Squamous cell carcinoma arising in chronic lymphoedema. Br J Dermatol 1997; 136:384-7. Shelley WB, Wood MG. Transformation of the common wart into squamous cell carcinoma in a patient with primary lymphedema. Cancer 1981;48:820-4. Sarkany I. Malignant melanomas in lymphoedematous arm following radical mastectomy for breast carcinoma (an extension of the syndrome of Stewart and Treves). Proc R Soc Med 1972; 65:253-4. Bartal AH, Pinsky CM. Malignant melanoma appearing in a postmastectomy lymphedematous arm: a novel association of double primary tumours. J Surg Oncol 1985;30:16-8. Fergusson CM, Copeland SA. Unusual sarcoma arising in lymphedema. J Soc Med 1985;78:497-8. Rosso R, Gianelli U, Carnevali L. Acquired progressive lymphangioma of the skin following radiotherapy for breast carcinoma. J Cutan Pathol 1995;22:164-7. Hodl S, Kresbach H. Kaposiform angiodermatitis on an amputation stump: a new entity. Hautarzt 1988;39:302-3. Kolde G, Worheide J, Baumgartner R, Brocker EB. Kaposi-like acroangiodermatitis in an above-knee amputation stump. Br J Dermatol 1989;120:575-80. Schwartz RA, Bagley MP, Janniger CK, Lambert WC. Verrucous carcinoma of a leg amputation stump. Dermatologica 1991;182: 193-5. Callens A, Vaillant L, Machet MC, Arbeille B, Machet L, De Muret A, et al. Localised atypical pemphigoid on lymphoedema following radiotherapy. Acta Derm Venereol (Stockh) 1993;73:461-4. Cliff S, Harland CC, Fallowfield ME, Mortimer PS. Localised bullous pemphigoid following radiotherapy. Acta Derm Venereol (Stockh) 1996;76:330-1. Leconte-Boulard C, Dompmartin A, Verneuil L, Thomine E, Joly P, Rogerie MJ, et al. Pemphigoı¨de localise´e apre`s radiothe´rapie. Ann Dermatol Venereol 2000;127:70-2. Wilkinson SM, Heagerty AHM, Smith AG. Toxic epidermal necrolysis localized to an area of lymphoedema. Clin Exp Dermatol 1992;17:456-7. Demitsu T, Tadaki T. Atypical neutrophilic dermatosis on the upper extremity affected by postmastectomy lymphedema: report of 2 cases. Dermatologica 1991;183:230-3. Krywonis N, Kaye VN, Lynch PJ. Cryptococcal cellulitis in congenital lymphedema. Int J Dermatol 1990;29:41-4. Albanese A, Amadeo G, Colonna M, Polimeni M, Ronchi A, Scaglione R. Associazione linfangioma superficiale, condilomi acuminati e granuloma inguinale. Dermatologia Oggi 1991;5: 13-8.
Lymphedema: An immunologically vulnerable site for development of neoplasms Vincenzo Ruocco, MD,a Robert A. Schwartz, MD, MPH,b and Eleonora Ruocco, MDa Naples, Italy, and Newark, New Jersey Lymphedema is the result of accumulation of protein-rich interstitial fluid (lymph stasis) caused by a failure of lymph drainage in the face of a normal capillary filtration. Whether the origin is congenital or acquired from infection, radiation, trauma, or surgery, chronic lymph stasis impairs local immune surveillance by disrupting trafficking of the immunocompetent cells in the lymphedematous district and stimulates vicarious angiogenesis by promoting development of a collateral lymphatic and hematic network in the lymphedematous district. When the local mechanisms of immune surveillance begin to fail, the lymphedematous region becomes an immunologically vulnerable area, predisposed to malignancy, chiefly vascular tumors such as Stewart-Treves syndrome and Kaposi’s sarcoma, because of the continual angiogenic stimulus. (J Am Acad Dermatol 2002;47:124-7.)
E
dema and lymphedema both denote a clinical condition featuring a swelling of soft tissues. However, whereas edema is caused by an increased capillary filtration that overwhelms a regular lymph drainage, lymphedema is the result of accumulation of protein-rich interstitial fluid, lymph stasis, caused by a failure of lymph drainage in the face of a normal capillary filtration.1 Lymphedema mainly affects limbs or terminal sites, because options for collateral escape-lymph-drainage are reduced in an extremity, including the toes, penis, or an amputation stump. The cause of lymph stasis may be a genetic abnormality (congenital lymphatic hypoplasia), infection (recurrent erysipelas), infestation (filariasis), trauma, malignancy, surgery, radiation (the latter two often linked with the management of a malignancy), and extreme chronic immobility. Primary lymphedema seen at birth (Milroy disease) is a rare autosomal dominant disorder that, in some families, is caused by missense mutations that interfere with vascular endothelial growth factor receptor-3 signaling and result in abnormal lymphatic vascular function.2
From the Department of Dermatology, 2nd University of Naples,a and the Department of Dermatology, New Jersey Medical School, Newark.b Conflict of interest: None. Reprint requests: R. A. Schwartz, MD, MPH, Professor & Head, Dermatology, New Jersey Medical School, 185 S Orange Ave, Newark, NJ 07103-2714. Copyright © 2002 by the American Academy of Dermatology, Inc. 0190-9622/2002/$35.00 ⫹ 0 16/1/120909 doi:10.1067/mjd.2002.120909
124
LYMPHEDEMA AND LOCAL IMMUNE DYSFUNCTION Whichever is the cause, the lymphedematous region in time becomes a site of altered immunocompetence. In fact, cutaneous dendritic cells, T lymphocytes, and macrophages exert their immune functions by migrating from peripheral sites through dermal lymphatic vessels to regional lymph nodes.3 A study of immune cells in peripheral lymph nodes and skin of 17 patients with obstructive lymphedema of the lower extremities suggested impaired lymphocyte and Langerhans cell trafficking, presumably resulting in ineffective removal of foreign antigens.4 In any case, inadequate lymphatic drainage caused by lymphedema may disrupt the regularity of this cell trafficking, on which immunocompetence depends, and makes the lymphedematous region an immunologically vulnerable area (IVA). It has been known since the 1960s that an obstacle to lymphatic drainage delays the rejection of skin homografts in the lymphedematous extremities.5,6
STEWART-TREVES SYNDROME More than 200 cases of angiosarcomas occurring in chronic lymphedema have been collected7-11 since the original report of Stewart and Treves in 1948 (quoted in Offori et al8). Although described originally only in patients having undergone mastectomy (and as a consequence of lymphedema induced iatrogenically by axillary lymph node dissection), the Stewart-Treves syndrome has been observed in several cases of lymphedema unassociated with breast carcinoma and mastectomy, which has made it clear that chronic lymph stasis (and not
J AM ACAD DERMATOL VOLUME 47, NUMBER 1
the primary cancer) predisposes to the onset of the angiosarcoma. The coexistence of an immune dysfunction in the lymphedematous region was first proven in 1982.7 In a patient with Stewart-Treves syndrome of the right lower limb, intradermal skin tests to common antigens were performed on the 4 limbs (forearms and thighs). The tests revealed no (or weak) skin reactions on the affected limb, in the face of the normal skin reactions observed on the 3 uninvolved limbs.7 In another study of a patient with StewartTreves syndrome, after intralesional administration of BCG, skin test responses were increased both in intensity and in the number of antigens eliciting reactions.12 Intralesional BCG or PPD resulted in the regression and complete disappearance of both challenged and unchallenged skin tumors within the same lymphatic drainage region. Evidence for an impairment of the cell immunity in post-mastectomy lymphedema was obtained in an ample investigative study.13 A total of 35 women with post-mastectomy lymphedema were investigated using dinitrochlorobenzene to test the afferent and efferent loops of the cell-mediated immune response on the lymphedematous and normal arms. The findings showed a statistically significant impairment to both the sensitization (afferent loop) and the elicitation (efferent loop) phase of the immune response on the lymphedematous arms compared with the normal ones, thus demonstrating selective suppression of immune competence in the lymphedematous limbs.13
KAPOSI’S SARCOMA The classical form of Kaposi’s sarcoma (KS) is known to usually appear on the acral sites (especially lower extremities) accompanied or preceded by local lymphedema.14 The finding of dynamic abnormalities of the lymph drainage in the lower extremities affected by KS15 supports the clinical data. Similarly to what occurs in the Stewart-Treves syndrome, the coexistence of the 2 events (lymph stasis and vascular oncogenesis) is not coincidental.16 Interestingly, 2 cases of KS or KS-like angiosarcoma arising in chronic postmastectomy lymphedematous arms have recently been described.17 As mentioned previously, acral (or terminal) sites represent privileged areas for onset of overt or subtle lymphedema because of the reduced collateral lymph drainage existing there. Starting as a budding multicentric endothelial proliferation of lymphatic channels, the changes progressively lead to an intense blockage of lymphatic transport resulting in chronic lymph stasis. We postulate that, in time, acral lymphostatic sites undergo a regional immune
Ruocco, Schwartz, and Ruocco 125
dysfunction that paves the way for the local onset of the opportunistic HHV-8 –associated neoplasm. The link between the impairment of lymph circulation and regional immune dysfunction in classical KS was first proven in 1984.18 KS appeared on a lymphedematous leg of a patient with altered lymph drainage and lack of cell immune response confined to the lymphedematous limb. Intradermal skin tests to common antigens performed on the 4 limbs (forearms and legs) revealed no immune responses on the affected limb versus normal or even strong responses on the 3 unaffected limbs.18 Five years later, the same patient presented with lymphedema and new KS lesions on the other leg. On this occasion, skin tests were negative on both the affected legs, whereas normal responses were observed on the forearms.19 Two years later, KS lesions also appeared on both the forearms: at this time, skin tests were negative on all 4 of the extremities. A lymphologic and immunologic investigation performed in patients with classical KS sensitized with dinitrochlorobenzene proved that the affected limbs presented concomitant alteration of the lymph drainage and of the immune response.20 The role of chronic lymphedema in facilitating the onset of KS was stressed in an unusual localization (penis) of the classical form21 and the epidemic AIDS-related type.22 Although rarely emphasized in HIV-related KS, a variable degree of lymphedema (overt or subtle, a sort of microlymphedema) of the KS-involved areas is somewhat common in homosexual men and has a wide anatomic distribution, often without notable lymphadenopathy.16 The same might be postulated in diabetic microangiopathy, a possible link between classical KS and the increased incidence of diabetes mellitus in these patients.23 As for the African endemic form, lymphedema of the lower limbs may be the consequence of a lymphatic disease of the legs, podoconiosis, which has been etiologically associated with chronic, barefoot exposure to volcanic soils.24 Microparticles of silica dust, present in these soils, penetrate the skin of the foot during barefoot walking and are then taken up by the lymphatics, causing damage. Iron may possibly be the responsible component producing this soil toxicity.25 If soil exposure is crucial in the endemic KS, it has been postulated that it acts by inducing localized immune suppression of the extremities.24,25 In this lymphologic perspective, one can argue that in classical and certain cases of endemic KS the immune functions decay in a progressive and centripetal way because of the increasing difficulty in lymph drainage, which results in increasing formation of lymphaticovenous shunts, which in turn
126 Ruocco, Schwartz, and Ruocco
causes more and more immune tolerance. Consequently, cutaneous lesions appear acrally and extend centripetally. On the contrary, in epidemic and iatrogenic KS, where the immune dysfunction and a sort of microlymphedema are primarily generalized, the distribution of the lesions usually features a random pattern from the beginning. Compatible with this theory are in these patients the findings of diffuse lymphatic changes26 and of negative intradermal skin reactions to standard antigens (Multitest Me´ rieux) on all the 4 extremities.27
OTHER TUMORS Areas of chronic lymphedema (ie, IVAs) are also sites at risk for onset of cutaneous malignancy other than Stewart-Treves syndrome and KS. Two cases of non-Hodgkin’s lymphomas initially confined to lymphedematous limbs, which then progressed centripetally (as occurs in KS), perfectly fit in with the theory of IVA in the lymphedematous region.28,29 Further evidence is provided by 2 other cases of cutaneous non-Hodgkin’s lymphoma arising in the postmastectomy lymphedematous arms30 and of a primary cutaneous B-cell lymphoma of the leg in a chronically lymphedematous extremity.31 Also of interest are the appearance of cutaneous metastases in a lymphedematous leg from a follicular center cell lymphoma,32 the appearance of an anaplastic largecell cutaneous lymphoma on a chronic lymphedema of the arm,33 and the observation of chronic facial lymphedema preceding the onset of retro-orbital B-cell lymphoma.34 Other neoplasms may also occur in IVAs, such as basal cell carcinoma (including in 1 patient with more than 20 tumors35 and in another associated with KS36), verrucous carcinoma, squamous cell carcinoma, and reactive angiomatosis (pseudo-Kaposi’s sarcoma).35-47 Malignant melanoma occurring in postmastectomy lymphedematous arms41,42 and a single case of malignant fibrous histiocytoma arising in congenital lymphedema of the leg43 are additional examples of “opportunistic” malignancies in IVAs.
CONCLUDING REMARKS Localized lymphedema becomes a site of altered immunocompetence, with neoplasms, but also infections (often sustained by opportunistic pathogens), and immunity-related disorders (such as bullous pemphigoid, toxic epidermal necrolysis, and neutrophilic dermatosis) occurring.48-54 Of particular interest are 3 cases of bullous pemphigoid that appeared at the site of a previous irradiation that had been complicated by the onset of local lymphedema48-50 and one report of ampicillin-induced toxic epidermal necrolysis that was, on two occasions,
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strictly confined to an area of lymphedema.51 The IVA concept should benefit from further study. REFERENCES 1. Mortimer PS. Managing lymphedema. Clin Exp Dermatol 1995; 20:98-106. 2. Karkkainen MJ, Ferrell RE, Lawrence EC, Kimak MA, Levinson KL, McTigue MA, et al. Missense mutations interfere with VEGFR-3 signalling in primary lymphedema. Nature Genetics 2000;25:153-9. 3. Lukas M, Sto¨ssel H, Hefel L, Imamura S, Fritsch P, Sepp NT, et al. Human cutaneous dendritic cells migrate through dermal lymphatic vessels in a skin organ culture model. J Invest Dermatol 1996;106:1293-9. 4. Olszewski WL, Engeset A, Romaniuk A, Grzelak I, Ziolkowska A. Immune cells in peripheral lymph and skin of patients with obstructive lymphedema. Lymphology 1990;23:23-33. 5. Stark RB, Dwyer EM, De Forest M. Effect of surgical ablation of regional lymph nodes on survival of skin homografts. Ann NY Acad Sci 1960;87:140-8. 6. Lambert PB, Frank HA, Bellman S, Farnsworth B. The role of lymph trunks in the response to allogenic skin transplants. Transplantation 1965;36:62-73. 7. Ruocco V, Pisani M, Astarita C. Syndrome de Stewart-Tre`ves avec de´ficit re´gional de l’immunite´ cellulare possibile: hypothe`se pathoge´nique. Ann Dermatol Venereol 1982;109:489-92. 8. Offori TW, Platt CC, Stephens M, Hopkinson GB. Angiosarcoma in congenital hereditary lymphedema (Milroy’s disease): diagnostic beacons and a review of the literature. Clin Exp Dermatol 1993;18:174-7. 9. Kirchmann TTT, Smoller BR, McGuire J. Cutaneous angiosarcoma as a second malignancy in a lymphedematous leg in Hodgkin’s disease survivor. J Am Acad Dermatol 1994;31:861-6. 10. Sinclair SA, Sviland L, Natarajan S. Angiosarcoma arising in a chronically lymphedematous leg. Br J Dermatol 1998;138:692-4. 11. Azurdia RM, Guerin DM, Verbov JL. Chronic lymphoedema and angiosarcoma. Clin Exp Dermatol 1999;24:270-2. 12. Klein E, Schwartz RA, Case RW, Holtermann OA, Solomon J, Hahn GM, et al. Accessible tumors. In: LoBuglio AF, editor. Clinical immunotherapy. New York: Marcel Dekker, Inc; 1980. p. 31-71. 13. Mallon E, Powell S, Mortimer P, Ryan TJ. Evidence for altered cell-mediated immunity in postmastectomy lymphoedema. Br J Dermatol 1997;137:928-33. 14. Schwartz RA. Kaposi’s sarcoma: advances and perspectives. J Am Acad Dermatol 1996;34:804-14. 15. Fei L, Ruocco V, Ayala F, Guerrera V, Del Genio A. Sarcome de Kaposi classique: e´tude des voies lymphatiques des membres infe´rieurs. Presse Me´d 1987;16:1188-90. 16. Witte MH, Stuntz M, Witte CL. Kaposi’s sarcoma: a lymphologic perspective. Int J Dermatol 1989;28:561-70. 17. Allan A, Shoji T, Li N, Burlage A, Davis B, Bhawan J. Kaposi’s sarcoma arising in chronic post-mastectomy lymphedematous arms is found to be HHV8 positive by polymerase chain reaction [abstract]. J Cutan Pathol 1998;25:485. 18. Ruocco V, Astarita C, Guerrera V, Lo Schiavo A, Moscariello CG, Satriano RA, et al. Kaposi’s sarcoma on a lymphedematous immunocompromised limb. Int J Dermatol 1984;23:56-60. 19. Ruocco V. Linfostasi: importante fattore patogenetico nel sarcoma di Kaposi classico. Ann It Dermatol Clin Sper 1992;46:15360. 20. Ruocco V, Satriano RA, Bernabo` R, Astarita C. Anomalies re´gionales des voies lymphatiques et de la re´ponse au D.N.C.B. dans le sarcome de Kaposi classique. Ann Dermatol Venereol 1985;112: 283-6. 21. Schwartz RA, Cohen JB, Watson RA, Gasco´n P, Ahkami RN, Ruszc-
Ruocco, Schwartz, and Ruocco 127
J AM ACAD DERMATOL VOLUME 47, NUMBER 1
22.
23. 24. 25. 26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
zak Z, et al. Penile Kaposi’s sarcoma preceded by chronic penile lymphoedema. Br J Dermatol 2000;142:153-6. Hengge UR, Stocks K, Goos M. Acquired immune deficiency syndrome-related hyperkeratotic Kaposi’s sarcoma with severe lymphoedema: report of five cases. Br J Dermatol 2000;142:501-5. Laor Y, Schwartz RA. Epidemiologic aspects of American Kaposi’s sarcoma. J Surg Oncol 1979;12:299-303. Ziegler JL. Endemic Kaposi’s sarcoma in Africa and local volcanic soils. Lancet 1993;342:1348-51. Ziegler JL, Simonart T, Snoeck R. Kaposi’s sarcoma, oncogenic viruses, and iron. J Clin Virol 2001;20:127-30. Witte MH, Fiala M, McNeill GC, Witte CL, Williams WH, Szabo J. Lymphangioscintigraphy in AIDS-associated Kaposi sarcoma. Am J Roentgenol 1990;155:311-5. Ruocco V, Marfella A, Satriano RA. Valutazione della risposta immunitaria cellulo-mediata sui quattro arti in pazienti con sarcoma di Kaposi. Bollettino di Dermatologia Allergologica e Professionale 1991;6:173-81. Waxman M, Fatteh S, Elias JM, Vuletin JC. Malignant lymphoma of the skin associated with postmastectomy lymphoedema. Arch Pathol Lab Med 1984;108:206-8. Tatnall FM, Mann BS. Non-Hodgkin’s lymphoma of the skin associated with chronic limb lymphoedema. Br J Dermatol 1985; 113:751-6. d’Amore ESG, Wick MR, Geisinger KR, Frizzera G. Primary malignant lymphoma arising in post-mastectomy lymphedema: another facet of the Stewart-Treves syndrome. Am J Surg Pathol 1990;14:456-63. Torres-Paoli D, Sanchez JL. Primary cutaneous B-cell lymphoma of the leg in a chronic lymphedematous extremity. Am J Dermatopathol 2000;22:257-60. Hills RJ, Ive FA. Cutaneous secondary follicular centre cell lymphoma in association with lymphoedema praecox. Br J Dermatol 1993;129:186-9. Beylot-Barry M, Vergier B, Beylot C, Demascarel A, Doutre MS. Ki-1-positive large-cell cutaneous lymphoma mimicking a Stewart-Treves angiosarcoma. Dermatology 1995;190:77-82. Dragan LR, Baron JM, Stern S, Shaw JC. Solid facial edema preceding a diagnosis of retro-orbital B-cell lymphoma. J Am Acad Dermatol 2000;42:872-4. Lotem M, Tamir G, Loven D, David M, Hauben D. Multiple basal cell carcinomas of the leg after recurrent erysipelas and chronic lymphedema. J Am Acad Dermatol 1994;31:812-3. Ruocco V, Satriano RA. Basal cell cancer and classic Kaposi’s sarcoma in a locally immunocompromised patient. Int J Dermatol 1986;25:594-6. Benson PM, Pessoa CM, Lupton GP, Winton GB. Basal cell carcinomas arising in chronic lymphedema. J Dermatol Surg Oncol 1988;14:781-3. Rytter BM. Metachronous angioplastic sarcoma (Stewart-Treves
39.
40.
41.
42.
43. 44.
45. 46.
47.
48.
49.
50.
51.
52.
53. 54.
syndrome) with concomitant basal cell carcinoma in chronic lymph node edema of the arm following ablatio mammae. Dtsch-Gesundheitsw 1972;27:118-22. Lister RK, Black MM, Calonje E, Burnand KG. Squamous cell carcinoma arising in chronic lymphoedema. Br J Dermatol 1997; 136:384-7. Shelley WB, Wood MG. Transformation of the common wart into squamous cell carcinoma in a patient with primary lymphedema. Cancer 1981;48:820-4. Sarkany I. Malignant melanomas in lymphoedematous arm following radical mastectomy for breast carcinoma (an extension of the syndrome of Stewart and Treves). Proc R Soc Med 1972; 65:253-4. Bartal AH, Pinsky CM. Malignant melanoma appearing in a postmastectomy lymphedematous arm: a novel association of double primary tumours. J Surg Oncol 1985;30:16-8. Fergusson CM, Copeland SA. Unusual sarcoma arising in lymphedema. J Soc Med 1985;78:497-8. Rosso R, Gianelli U, Carnevali L. Acquired progressive lymphangioma of the skin following radiotherapy for breast carcinoma. J Cutan Pathol 1995;22:164-7. Hodl S, Kresbach H. Kaposiform angiodermatitis on an amputation stump: a new entity. Hautarzt 1988;39:302-3. Kolde G, Worheide J, Baumgartner R, Brocker EB. Kaposi-like acroangiodermatitis in an above-knee amputation stump. Br J Dermatol 1989;120:575-80. Schwartz RA, Bagley MP, Janniger CK, Lambert WC. Verrucous carcinoma of a leg amputation stump. Dermatologica 1991;182: 193-5. Callens A, Vaillant L, Machet MC, Arbeille B, Machet L, De Muret A, et al. Localised atypical pemphigoid on lymphoedema following radiotherapy. Acta Derm Venereol (Stockh) 1993;73:461-4. Cliff S, Harland CC, Fallowfield ME, Mortimer PS. Localised bullous pemphigoid following radiotherapy. Acta Derm Venereol (Stockh) 1996;76:330-1. Leconte-Boulard C, Dompmartin A, Verneuil L, Thomine E, Joly P, Rogerie MJ, et al. Pemphigoı¨de localise´e apre`s radiothe´rapie. Ann Dermatol Venereol 2000;127:70-2. Wilkinson SM, Heagerty AHM, Smith AG. Toxic epidermal necrolysis localized to an area of lymphoedema. Clin Exp Dermatol 1992;17:456-7. Demitsu T, Tadaki T. Atypical neutrophilic dermatosis on the upper extremity affected by postmastectomy lymphedema: report of 2 cases. Dermatologica 1991;183:230-3. Krywonis N, Kaye VN, Lynch PJ. Cryptococcal cellulitis in congenital lymphedema. Int J Dermatol 1990;29:41-4. Albanese A, Amadeo G, Colonna M, Polimeni M, Ronchi A, Scaglione R. Associazione linfangioma superficiale, condilomi acuminati e granuloma inguinale. Dermatologia Oggi 1991;5: 13-8.