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Lymphedematous areas: Privileged sites for tumors, infections, and immune disorders [3]
... Disorders of the lymph system, whether systemic (macrolymphedema) or localized (micro-lymphedema), produce cutaneous regions susceptible to infection, inflammation, and carcinogenesis [7,9,10]. The inter-relationship of the lymphatic and integumentary systems is starting to become more readily appreciated as a functional lymphatic system is essential to an organism's overall health given its role in fluid homeostasis, removal of cellular debris and mediating immunity and inflammation [11]. ...
... The chronic inflammation resulting from lymphedema creates a region of cutaneous immune deficiency or a localized skin barrier failure. The associated abnormalities are called lymphostatic dermopathy, which is the failure of the skin as an immune organ [7,9,10]. Because of this, alterations in skin integrity, recurrent infections (commonly cellulitis), diminished wound healing, various dermatological conditions, and even skin malignancies become more prevalent highlighting the inter-connectedness of the lymphatic and integumentary systems. ...
Purpose of Review
This review’s aim is to coalesce current evidence regarding the lymphatic system and lymphedema, bridge the gap from traditional approaches to emerging concepts, and present simple strategies that can be immediately implemented into everyday clinical practice.
Recent Findings
New evidence of the microcirculation redefines all edema as lymphedema and having the potential to result in chronic inflammation and deleterious soft tissue changes. These soft tissue changes are easily identifiable through simple manual tests that also help direct interventions. CDT is the gold standard of treatment, but components are evolving with the emergence of new technologies and new understandings of mechanobiology. The lymphatic and integumentary systems are interdependent, requiring concurrent lymphedema and wound management strategies.
Summary
Optimization of the lymphatic system is key to edema management and wound healing. Future research is needed to progress individualized diagnostics of lymphatic vasculature so treatment interventions can be customized to each patient.
... It unites different phenomena such as isomorphic (Koebner) and isotopic (Wolf) responses of skin and helps to understand macromorphology of dermatoses. Although the concept had been developed during the last decade, it has yet to gain widespread knowledge [8], [9]. ...
... Lymphedema disrupts immune cell trafficking which leads to localised immunosuppression, predisposing to chronic inflammation, infection, and malignancy. Thus, lymphatic impairment can result in localised skin disease in an ICD [8]. ...
BACKGROUND: The concept of immunocompromised districts of skin has been developed by Ruocco and helps to explain certain aspects of the macromorphology of skin diseases. This concept unites the isomorphic response of Koebner and the isotopic response of Wolf.
CASE REPORTS: We present different cutaneous conditions which can lead to immunocompromised districts of skin such as scars, radiodermatitis, lymphedema, disturbed innervation or mechanical friction etc. Typical and rarer skin disorders associated with them are discussed and illustrated by their observations.
CONCLUSION: At this moment, we wish to inform dermatologists and non-dermatologists about Ruocco’s concept and its implications.
... Radiological imaging is rarely necessary as the diagnosis may be based solely on the patient's medical history and physical examination. However, a biopsy is necessary due to the possibility of an associated malignancy [4,5]. ...
Chronic edema, which has multiple etiologies, is predicted to be a significant underlying cause of lymphedema, potentially leading to serious complications. Elephantiasis, characterized by massive swelling of any body part, is a rare but debilitating condition often associated with lymphatic obstruction or anomalies in the lymphatic system. Lymphedema can predispose a patient to cellulitis, an infectious condition with multiple risk factors. This case study presents a 45-year-old male with a history of chronic lymphatic obstruction due to elephantiasis and recurrent cellulitis in his lower limb. Despite receiving multiple courses of antibiotics, the patient continued to experience multiple episodes of cellulitis, along with worsening lymphedema and functional impairment of the limb. The mainstay of treatment for this condition includes compression stockings and surgery, but addressing the root cause of the disease is crucial. Typically, a multidisciplinary approach is required, involving antibiotics, lymph drainage, and compression therapy. This case highlights the challenges faced in managing elephantiasis and its related complications and emphasizes the need for preventive strategies.
... Therefore, impairment of the regional lymphatic system causes not only swelling of the extremities but also impaired immune surveillance, which leads to various immune disorders, chronic inflammatory conditions, and neoplasms (Azhar et al., 2020;Olszewski et al., 1990;Ruocco et al., 2002Ruocco et al., , 2007. A study of immune cells in the peripheral LNs and skin of 17 patients with lymphedema suggested impaired lymphocyte and Langerhans cell trafficking, presumably resulting in ineffective removal of foreign antigens (Olszewski et al., 1990). ...
Background:
Recent reports have indicated that vascularized lymph node transfer (VLNT) may improve the impaired immunity in lymphedema but there has been no report concerning anti-cancer immunity. In the early tumor immune response, dendritic cells (DCs) participate in tumor recognition and antigen presentation in local lymphatics. Here, we investigated the impact of VLNT on DC dynamics against cancer in mouse models.
Methods:
Forty-seven 8-week-old C57BL/6 N male mice were divided into three surgical groups: a VLNT model in which a vascularized inguinal lymph node (LN) flap was transferred into the ipsilateral fossa after a popliteal LN was removed; a LN dissection (LND) model in which the popliteal LN was dissected; and a control model in which a skin incision was made at the popliteal fossa and an ipsilateral inguinal LN was removed. Postoperative lymphatic flows were observed by indocyanine green lymphography and B16-F10-luc2 mouse melanoma were implanted into the ipsilateral footpad. The proportion of DCs in the transplanted nodes was measured by CD11c immunohistochemistry using digital imaging analysis 4 days after cancer implantation. Metastases to the lungs and LNs were quantitatively evaluated by luciferase assay 4 weeks after cancer implantation.
Results:
After VLNT, lymphatic reconnection was observed in 59.2% of mice. The proportion of DCs was significantly higher in the VLNT group with lymphatic reconnection (8.6% ± 1.0%) than in the naïve LN (4.3% ± 0.4%) (p < .001). The tumor burden of lung metastases was significantly less in the VLNT group with lymphatic reconnection compared with the LND group (p = .049).
Conclusions:
Metastasis decreased in mice with reconnected lymphatics after VLNT. A possible explanation was that lymphatic restoration may have contributed to the tumor immune response by allowing DC migration to LNs.
... 9 Therefore, it is conceivable that both, rapid and chronic abnormal interstitial fluid and transcapillary fluid imbalance, result in tissue damage and local ischemia, leading to activation of damage-associated molecular pattern molecules with an inflammatory reaction, 5 with cytokines activating neutrophilic leukocytes. 10 In this setting, the presence of bacterial antigens, such as lipopolysaccharides, might also contribute to the inflammation. 2 Better knowledge of these reactive, noninfectious disorders, which fulfill the criteria for an autoinflammatory disorder, is important to improve diagnostic accuracy and decrease hospital admissions and unnecessary antibiotic use. ...
... Chronic lymph stasis may impair local immune surveillance by disrupting trafficking of the immunocompetent cells: the region with lymph flow dysfunction becomes an immunologically vulnerable area, predisposed to malignancies, especially those of vascular origin, such as KS, because of the continual angiogenic stimulus [4]. Furthermore, lymphedema often leads to trophic alterations, such as plantar hyperkeratosis, papillomatosis, and interdigital desquamation, thus encouraging cutaneous infections [5], especially due to facultative anaerobic bacteria or dermatophytes. Nevertheless, infections and the consequent inflammatory reaction may cause a worsening of KS. ...
Kaposi ‘s sarcoma (KS) is a rare multifocal angioproliferative disease associated with human herpes virus 8 (HHV-8) infection, characterized by cutaneous nodules or plaques especially on the lower limbs. Some skin modifications, such as chronic lymphedema, plantar hyperkeratosis and interdigital desquamation, may be associated with consequent impairment of the local immunosurveillance and increased risk of some bacterial or mycotic infections. With the objective of evaluating if bacterial or mycotic infections in KS patients are supported by different microorganisms compared to control patients, we performed an observational retrospective study, comparing positive cultural swabs of interdigital intertrigo of KS patients with positive cultural swabs of interdigital intertrigo of patients admitted to our dermatologic unit during the last 10 years. One hundred KS patients and 84 control patients were admitted to this study. Some of the skin swabs from interdigital spaces were positive for more than one microorganism, and therefore we found 187 microorganisms among the KS group and 182 microorganisms in the control group. The most common microrganisms among KS patients were T. mentagrophytes (16%), S. aureus (14.9%), P. aeruginosa (13.9%), S. marcescens (5,9%), while among non-KS patients were S. aureus (26,9%), C. albicans (22%), S. agalactiae (7.7%) and E. coli (9.9%). These differences are statistically significant (p < 0.01). KS patients may be more affected by toe web intertrigo due to other bacteria and dermatophytes than the general population. During clinical examination, a careful inspection is necessary for an early diagnosis of toe web intertrigo, in order to prevent serious complications, such as cellulitis and sepsis. Consequently, a cultural examination with antibiogram is required to identify the causative agent of intertrigo and guide antimicrobial therapy.
... Subcutaneous enlargement of fibroadipous tissue leads to progressive limb swelling, loss of functionality, mobility and quality of life. Lymphedematous skin is an immunocompromised district predisposing to infection and tumours [4]. ...
Primary of hereditary lymphedema is a rare but progressive disease. It is yet not curable. We present a 48-year-old male patient with hereditary lymphedema of his left leg, that was realised by minor trauma (able twist) when he was seven years old. He had never been treated for lymphedema but experienced multiple erysipelas during his life. After diagnostic procedures to exclude other causes of leg swelling, the diagnosis of hereditary lymphedema of the leg, stage III was confirmed. We initialized complex decongestive therapy. During two weeks of intensive treatment, the circumference of the left leg could be reduced by 10 cm. This case illustrates the "natural course" hereditary lymphedema. But it raises the hope that even after decades of ignorance, the patients benefits from complex decongestive treatment. Therapeutic nihilism is unnecessary and poses lymphedema patients to risks of infection and secondary malignancies like Stewart-Trewes syndrome.
... Subcutaneous enlargement of fibroadipous tissue leads to progressive limb swelling, loss of functionality, mobility and quality of life. Lymphedematous skin is an immunocompromised district predisposing to infection and tumours [4]. ...
Primary of hereditary lymphedema is a rare but progressive disease. It is yet not curable. We present a 48-year-old male patient with hereditary lymphedema of his left leg, that was realised by minor trauma (ankle twist) when he was seven years old. He had never been treated for lymphedema but experienced multiple erysipelas during his life. After diagnostic procedures to exclude other causes of leg swelling, the diagnosis of hereditary lymphedema of the leg, stage III was confirmed. We initialized complex decongestive therapy. During two weeks of intensive treatment, the circumference of the left leg could be reduced by 10 cm. This case illustrates the "natural course" hereditary lymphedema. But it raises the hope that even after decades of ignorance, the patients benefits from complex decongestive treatment. Therapeutic nihilism is unnecessary and poses lymphedema patients to risks of infection and secondary malignancies like Stewart-Trewes syndrome.
... Whatever the cause, inadequate lymph drainage of a given region makes it an immunologically vulnerable area, i.e., a privileged site for the subsequent development of diseases that escape from immune control, such as tumors, infections, and immune disorders. 46,47 Chronic lymphedema has a well-known permissive effect with certain types of malignancies, particularly angiosarcomas (Stewart-Treves syndrome). 48,49 This condition typically features an instance of ICD ensuing from chronic lymph stasis. ...
The concept of 'locus minoris resistentiae' (lmr) is an old but still effective way of thinking in Medicine. In Dermatology, there are many reports of privileged localization of cutaneous diseases on injured skin, which therefore represents a typical condition of lmr. Lately the innovative concept of immunocompromised cutaneous district (ICD) has been introduced to explain why a previously injured cutaneous site may become in time a privileged location for the outbreak of opportunistic infections, tumors, and immune reactions. An ample documentation of multifarious disorders (infectious, neoplastic, immune) appearing in ICDs was delineated by Ruocco et al. in 2009. These cases were grouped according to the clinical settings responsible for the local immune imbalance: regional chronic lymphedema; herpes-infected sites, which feature the well-known Wolf's isotopic response; and otherwise damaged areas, comprising sites of vaccination, ionizing or UV radiation, thermal burns, and traumas. In the following five years, what was a "novel" pathogenic concept has been extended to an enlarging variety of clinical conditions. This paper focuses on ICD and the expanding spectrum of this now established pathogenic concept.
... UVR induced localized immune suppression may also contribute to field cancerization and the pathogenesis of skin cancer. Lymphedema and its inherent decrease in immune trafficking is another cause of localized immune suppression, which might contribute to field cancerization [167,168]. Indeed, lymphatic vessels are reduced in sun-damaged skin supporting localized lymphedema as a cofactor in field cancerization [169]. For example, lymphedematous (phymatous) rosacea has a higher incidence of BCC than non-phymatous facial skin [170]. ...
Skin cancer is the most common malignancy in humans, likely due to its location at the interface between internal and external environments and exposure to multiple carcinogens, mostly ultraviolet radiation (UVR) and human papillomaviruses (HPV). With increased longevity, changing patterns of sun exposure and greater UVR reaching the earth's surface due to ozone depletion, the incidence of skin cancer is steadily increasing worldwide. Moreover, skin cancer, mostly basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) (collectively known as non-melanoma skin cancer (NMSC), is a substantial public health concern and one of the largest Medicare health expenditures. Individuals presenting with skin cancer are at high risk for synchronous and metachronous second primary skin cancers. This phenomenon is known as "field cancerization", where the entire cutaneous site affected is presumed to be mutagenized and is therefore at risk for multiple cancers. The recent application of molecular technologies to the examination of peri-lesional and more distant adjacent normal skin samples has demonstrated many of the genotypic aberrations found in cancer. These defects are the earliest changes of oncogenesis that occur in a stepwise, cumulative fashion culminating in metastatic cancer via initiation, promotion, selection, and clonal expansion. Moreover, these findings implicate two distinct levels of field cancerization: 1) molecular progression where histologically normal cells accumulate genomic damage; and 2) phenotypic progression denoted by evolution of histologically normal skin to precursors to in situ cancer that can be followed by invasion and ultimately metastatic disease. Phenotypic progression is also characterized by the expansion of genetically damaged tumor cells in the modified environment that facilitate tumor growth and suppress the host response. In this model, the cutaneous field develops a "tumor stem cell", which acquires a growth advantage and exhibits a "mutator phenotype" [i.e. genomic instability (GIS)] that enables it to expand beyond its histologically defined stem cell niche, form diverse clonal fields, and accrue further genetic alterations that eventuate into invasive cancer. GIS is manifested as single base mutations, gain or loss of whole or partial chromosomes, amplification of oncogenes, mismatch repair gene defects, and epigenetic alterations including hypermethylation of promoter DNA of key tumor suppressor genes, or genomic incorporation of the oncogenic HPV. The facilitating environment for tumor growth represents the local production of factors that allow the tumor cells to escape the immune system, to leave the tumor stem cell niche and expand into the surrounding environment. In this chapter, we review the epidemiologic evidence of field cancerization; etiologic factors that lead to genomic instability in the skin; the stem cell niche where cancer-causing genetic defects are most likely to be initiated, and from which the mutated clone must expand beyond; host factors that augment and accelerate the process such as immunosuppression; and the growing body of evidence that supports the concept of cutaneous field cancerization. Moreover, we discuss the potential utilization of field effect biomarkers in risk assessment, cancer prevention, margin control, and prognosis.
... Conway et al. [22] recently reported prolonged radiocolloid transit time and uptake within the SLN, suggesting diminished or obstructed lymphatics with advancing age. Lymphostasis or lymphatic failure may impair regional immunity by disrupting normal immune cell trafficking leading to impaired antigen presentation and the inability of activated T cells to traffic to the primary tumor [23,24]. Support for this hypothesis is found in experimental animal and human studies documenting a delay of allogenic graft rejection when the lymphatic drainage has been compromised [25][26][27]. ...
Tumor-infiltrating lymphocytes (TILs) and regression are manifestations of the host immune response to tumor, but their influence on outcome remains undefined. There is a paucity of data on the elderly who represent a growing proportion of melanoma patients. The aim of this study was to evaluate the influence of TILs and regression as an indirect measure of immunity on outcome in elderly patients with melanoma. From a prospective database, we identified 250 consecutive cutaneous melanoma patients aged at least 65 years at the time of diagnosis. Data were verified by record review. Within the primary melanoma, a brisk TIL response was present in 66 (31%), nonbrisk TILs in 36 (17%), and absent in 111 (52%). The presence of a brisk infiltrate conferred a three-fold increased risk of sentinel lymph node (SLN) metastasis (P=0.02). Despite this, nonbrisk or absent TILs were associated with a five-fold increased risk of recurrence (P=0.0001). In multivariate analysis, nonbrisk or absent TILs were independently associated with recurrence (P<0.0001), diminished 5-year disease-free survival (76 vs. 91%, P=0.0006), and 5-year melanoma-specific survival (82 vs. 95%, P=0.0008). Regression was not an independent predictor of SLN metastasis, disease-free survival, or melanoma-specific survival. Our study demonstrates that an active antitumor immune response exists in elderly melanoma patients that, paradoxically, predicts both SLN metastasis and improved melanoma-specific outcomes. Further investigation to characterize this lymphocytic infiltrate and to confirm its clinical significance as a predictor of nodal status, patient outcome, and response to immunotherapy in elderly melanoma patients appears warranted.
... Lymphatics are an important pathway for immune cell trafficking (e.g., lymphocytes, Langerhans cells, and macrophages), antigen delivery to the lymph node, and clearance of foreign antigens (Olszewski et al., 1990). The occurrence of malignancy in the setting of LE is the suspected consequence of impaired local immune surveillance due to the disruption of trafficking of immunocompetent cells in the lymphedematous region (Ruocco et al., 2002(Ruocco et al., , 2007. ...
In-transit metastasis (ITM) is a unique manifestation of intralymphatic tumor dissemination, characterized by the presence of melanoma cells between the primary lesion and the draining regional lymph node basin that is clinically associated with poor prognosis. In this study, we aimed to establish an experimental animal model of melanoma ITM, as research progress in this field has been hampered by a lack of suitable experimental models. We reproduced melanoma ITM in a mouse hind limb by transplanting melanoma cells into the footpad of a mouse with lymphedema (LE). The tumor cells at the ITM site were highly proliferative, and mice with ITMs were more likely than control mice to develop distant lymph node and lung metastases. Peritumoral lymphatic vessels and tumor-associated blood vessels were increased in the primary tumor site of the LE mice. Our established ITM melanoma mouse model enabled us to clarify the molecular determinants and pathophysiology of ITM. This ITM model is also comparable to the unfavorable clinical behavior of melanoma ITM in humans and, moreover, underlined the importance of lymphangiogenic factors in the tumor dissemination through the lymphatic system.Journal of Investigative Dermatology advance online publication, 6 September 2012; doi:10.1038/jid.2012.274.
I read with great interest a case report by Bishnoi et al. published recently in the journal of European Academy of Dermatology and Venereology. The authors presented a case of a 43-year old man who had history of penile SCC, presented with bullous pemphigoid (BP) lesions. Interestingly, the BP lesion was limited to the inguinal region, suprapubic area and inner aspect of the right thigh, that was predominantly on top of the bilateral metastatic inguinal lymphadenopathy(LN). This article is protected by copyright. All rights reserved.
Whether primary or secondary, lymphedema is caused by failure to drain protein-rich interstitial fluid. Typically affecting a whole limb, it has become apparent that lymphedema can also affect localized regions of the skin, or it can be clinically silent but histologically evident, denoted by dilated lymphangiectases (latent lymphedema). Chronic lymph stasis has numerous consequences, including lipogenesis, fibrosis, inflammation, lymphangiogenesis, and immunosuppression. For example, lymphedema’s disruption of immune cell trafficking leads to localized immune suppression, predisposing the area affected to chronic inflammation, infection (cellulitis and verrucosis), and malignancy (angiosarcoma and nonmelanoma skin cancer). The pathogenesis of lymphedema is reviewed and exemplified by describing how a combination of lymph stasis–promoting factors such as trauma, obesity, infection, and inflammatory disorders produces localized elephantiasis; furthermore, the finding of lymphangiectases is found to be common in numerous dermatologic disorders and argued to play a role in their pathogenesis. Lastly, it is discussed how antigen burden, which is controlled by lymphatic clearance, affects the immune response, resulting in immune tolerance, immunopathology, or normal adaptive immunity.
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.
Idiopathic immune myopathies (IIM) are an heterogeneous group of autoimmune muscle disorders characterized by progressive muscle involvement. Dermatomyositis (DM) is the most common form of IIM. It is a multi system disorder characterized by symmetric proximal, extensor, inflammatory myopathy, vascular involvement and a characteristic cutaneous eruption. Six types of DM have been identified: idiopathic, juvenile (JDM), associated to cancer, associated to other autoimmune diseases, iatrogenic DM and amyopathic DM. Cutaneous manifestations of DM are the most important aspect of this disease and can precede from several months to years muscle or systemic involvement. Three groups of signs have been described: pathognomonic, highly characteristic and compatible. Although differences exist among the different clinical presentation of skin lesions, they share common histological findings including the presence of interface dermatitis with epidermal atrophy, basement membrane degeneration, vacuolar alteration of basal keratinocytes, and dermal changes consisting of interstitial mucin deposition and a sparse lymphocytic infiltrate. DM is a serious disease; the correct evaluation of any skin lesion suggesting an early diagnosis is of utmost importance. Skin signs may, also, represent a marker of treatment efficacy even though systemic symptoms worsening may not always be followed by more severe skin lesions.
Hair disorders are frequently observed in various systemic diseases, including autoimmune connective tissue diseases (CTDs), with predilection of lupus erythematosus (LE), followed by dermatomyositis (DM) and scleroderma. Hair disorders in CTDs may manifest as various clinical patterns, such as telogen hair loss, diffuse thinning or fragility of hair, and scarring alopecia. Less common hair disorders include anagen effluvium, alopecia areata, and trichomegaly. Some drugs used to treat CTDs may cause hair loss in a drug related manner or hyperthricosis. In the assessment of common hair loss patterns, such as telogen effluvium, the possible association with CTDs must be borne in mind and should not be overlooked. Alopecia appears to be a significant sign in the course of LE and especially systemic LE. In DM, the involvement of the scalp is common, and is often characterized by a diffuse, violaceous, scaly, non scarring and symptomatic hair loss. Linear scleroderma "en coup de sabre" is an uncommon localized form of morphea with involvement of the paramedian forehead and frontal scalp, where it is associated with cicatricial alopecia. The most important variant of scarring alopecia in the context of CTDs is that associated with discoid lupus erythematosus (DLE). In the diagnostic workup of DLErelated cicatrical alopecia, histopathological and immunopathological studies are useful, and a relevant role has been attributed to dermatoscopy (trichoscopy) over the last years. Hair loss has been reported in several other CTDs, including mixed and undifferentiated CTDs, and primary Sjögren's syndrome, although it is likely to be underestimated in such diseases.
Connective tissue diseases (CTDs) are defined as a group of acquired disorders resulting from persistent immuno--mediated inflammation. Several classes of drugs seem to be capable of inducing or exacerbating CTDs. A drug--induced (DI) syndrome is defined as a condition temporally related to continuous drug exposure, which resolves upon drug discontinuation. Among CTDs, lupus erythematosus is the most widely known and investigated DI syndrome. However, in recent years, the association between the onset of other CTDs, such as dermatomyositis (DM) and morphea/systemic sclerosis (SSc) has increased in patients with preceding exposure to particular substances. Herein, we conducted a review of published case reports including DM and morphea/SSc, evaluating the real causality among drugs and these syndromes.
The association between idiopathic inflammatory myopathy (IIM) and cancer has been extensively studied in adults. Many epidemiological studies demonstrated this association , which appears stronger for dermatomyositis (DM) than for polymyositis (PM). The first case suggesting an association between cancer and DM was reported in 1916. At present the reported incidence of cancer association with DM varies widely, from less than 7% to over 30 %. Many early evidences came from case reports, but this association was later confirmed in case -control as well as in population-based studies. Ovarian cancer or breast cancer in females and lung cancer in males are the main malignancies associated with DM. Given the frequency of the association of dermatomyositis with cancer, for cost-effectiveness reasons it might be important to develop simple and appropriate diagnostic tests for identification of patients with DM, who may be at higher risk of developing a malignancy. Clinicians should plan followup schedules to optimize both cancer detection and treatment, and thus to improve patient survival. Many different clinical and serological signs have been suggested as possible predictive factors for malignancy in dermatomyositis: age,increased erythrocyte sedimentation rate (ESR), presence of cutaneous leukocytoclastic vasculitis, cutaneous rash and skin lesions as cutaneous necrosis and periungueal erythemas, neoplastic markers or dysphagia . The results of the different studies are quite discordant. Therefore, we conducted a systematic review of the scientific literature to evaluate the level of the risk of cancer in patients with dermatomyositis and to explore whether certain patient characteristics may be linked to different levels of cancer risk.
Lymphangiectases are a histologic sign of lymphostasis, which is associated with decreased immune cell trafficking and cell-mediated immunity.
To determine if latent lymphedema is apparent underlying warts and in skin affected by cutaneous neoplasia.
The number and maximal dilation of lymphangiectases were measured in the upper half of the dermis of 51 consecutive biopsies of warts, 230 consecutive normal skin samples from primary skin tumor excisions, and 14 normal skin samples from breast reduction (11) and panniculectomy (3) specimens.
All warts had one or more underlying lymphangiectases compared with 79% of peritumor normal skin samples and 50% of cosmetic specimens. The mean number of lymphangiectases and mean maximal dilation were significantly greater in warts than in peritumor skin, which was significantly greater than cosmetic skin samples (3.6 vs. 1.3 vs. 0.12 lymphangiectases per square millimeter and 54 vs. 23 vs. 1 μm, respectively; P = 0.0001). Warts exhibited mild fibrosis significantly more frequently than peritumor skin (57% vs. 5%; P = 0.0001). For peritumor (normal) skin, age, solar elastosis, and adjacent malignancy correlated with greater dilation of lymphatics. Solar elastosis also correlated with increased number of lymphangiectases.
Minor trauma and solar elastosis from chronic ultraviolet radiation exposure are likely the etiologic factors in the development of lymphostasis. By decreasing immune surveillance, latent lymphedema ostensibly facilitates human papillomavirus infection and carcinogenesis.
Systemic immunodeficiency is known to facilitate the onset of opportunistic infections, tumours and immune disorders in any district of the body. There are clinical events, such as chronic lymphoedema, herpetic infections, vaccinations and heterogeneous physical injuries which can selectively damage and immunologically mark the cutaneous district they act upon. After the causing event has disappeared, the affected district may appear clinically normal, but its immune behaviour is often compromised forever. An immunocompromised district becomes a site which is particularly susceptible to subsequent outbreaks of opportunistic infections, tumours and immune disorders confined to the district itself.
In this review, there is an ample case‐report collection of opportunistic disorders (infectious, neoplastic, immune) which appeared in immunocompromised districts. The cases have been grouped according to the clinical settings responsible for the local immune imbalance: regional chronic lymphoedema; herpes‐infected sites, which feature the well‐known Wolf's isotopic response; and otherwise damaged areas, comprising sites of vaccination, ionizing or UV radiation, thermal burns and traumas.
Whatever the immunocompromising factor, a common denominator which facilitates the occurrence of tumours, infections and dysimmune reactions in an immunocompromised district may reside in locally hampered lymph drainage and/or locally altered neuromediator signalling. In fact, any obstacle to the normal trafficking of immunocompetent cells through lymphatic channels or any interference with the signals that the neuropeptides and neurotransmitters released by peripheral nerves send to cell membrane receptors of immunocompetent cells, can significantly alter the local immune response, thus paving the way for heterogeneous opportunistic disorders in the immunocompromised district.
Phymas (swellings, masses, or bulbs) are considered the end-stage of rosacea and mostly affect the nose (rhinophyma), and rarely involve the chin (gnatophyma), the cheek (metophyma), eyelids (blepharophyma), or ears (otophyma). Herein, we report the case of a 57-year-old man who developed unilateral enlargement of his left ear over 2 years. Biopsy revealed changes of rosaceous lymphedema associated with Demodex infestation. Corticosteroid and minocycline therapies resulted in partial reduction of the ear enlargement. Literature review examining for cases of lymphedema (elephantiasis) of the ear revealed that chronic inflammatory disorders (rosacea (most frequent), psoriasis, eczema), bacterial cellulitis (erysipelas), pediculosis, trauma, and primary (congenital) lymphedema can all lead to localized, lymphedematous enlargement of the ear. Depending on the severity, medical treatment directed at the inflammatory condition for mild, diffuse enlargement to surgical debulking for extensive diffuse enlargement or tumor formation can improve the signs and symptoms of otophyma. Decreased immune surveillance secondary to rosaceous lymphedema may explain why Demodex infestation is common in rosacea and support the suspicion that phymatous skin is predisposed to skin cancer development.
Lymphedema typically affects a whole limb. Rarely, lymphedema can present as a circumscribed plaque or an isolated skin tumor.
To describe the clinical and pathologic characteristics and etiologic factors of localized lymphedema.
Case-control study of skin biopsy and excision specimens histologically diagnosed with lymphedema and presenting as a localized skin tumor identified during a 4-year period.
We identified 24 cases of localized lymphedema presenting as solitary large polyps (11), solid or papillomatous plaques (7), pendulous swellings (4), or tumors mimicking sarcoma (2). Patients were 18 females and 6 males with a mean age of 41 years (range 16-74). Anogenital involvement was most frequent (75%)--mostly vulva (58%), followed by eyelid (13%), thigh (8%) and breast (4%). Causative factors included injury due to trauma, surgery or childbirth (54%), chronic inflammatory disease (rosacea, Crohn's disease) (8%), and bacterial cellulitis (12%). Eighty-five percent of these patients were either overweight (50%) or obese (35%). Compared with a series of 80 patients with diffuse lymphedema, localized lymphedema patients were significantly younger (41 vs. 62 years old, p = 0.0001), had no history of cancer treatment (0% vs. 18%, p = 0.03), and had an injury to the affected site (54% vs. 6%, p = 0.0001). Histologically, all cases exhibited dermal edema, fibroplasia, dilated lymphatic vessels, uniformly distributed stromal cells and varying degrees of papillated epidermal hyperplasia, inflammatory infiltrates and hyperkeratosis. Tumor size significantly and positively correlated with history of cellulitis, obesity, dense inflammatory infiltrates containing abundant plasma cells, and lymphoid follicles (p < 0.05). A history of cellulitis, morbid obesity, lymphoid follicles and follicular cysts predicted recurrent or progressive swelling despite excision (p < 0.05).
Localized lymphedema should be considered in the etiology of skin tumors when assessing a polyp, plaque, swelling or mass showing dermal edema, fibrosis and dilated lymphatics on biopsy. A combination of lymph stasis promoting factors (trauma, obesity, infection and/or inflammatory disorders) produces localized elephantiasis.
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.
Angiosarcoma is a rare vascular malignant tumor most commonly seen on the scalp of elderly people. We report here two cases of angiosarcoma of the face in 74- and 75-year-old males. It is very unusual to find the development of an angiosarcoma with a rosacea on the face. To the best of our knowledge, only three such cases have been reported.
A persistent erythema and edema of the midthird and upper aspect of the face, which bears some resemblance to Melkersson-Rosenthal syndrome and rosaceous lymphedema, has been characterized as morbus morbihan (MM) by French dermatologists. The disease of yet unknown cause starts with recurrent facial edema of short duration, which ultimately leads to persistent swelling after a period of weeks or months.
We recruited 6 patients with MM and acquired their history, routine blood tests, and individual UV light tolerability. To check for contact allergies the allergen patch test and the open epicutaneous patch test were performed. To objectify the skin conditions laser Doppler flowmetry and 20-MHz ultrasound were used. Five patients with similar symptoms, but with definitely transient facial erythema and edema caused by proven contact urticaria on cosmetics served as a comparison group.
In all patients, routine blood tests and UVA/UVB light tests showed no pathologic results. Observations of 6 patients with MM revealed the common feature of a clinically relevant immunologic contact urticaria caused by various cosmetic ingredients, which could be diagnosed in all of them. Delayed resorption of the acute edema and prolonged inflammation were shown by laser Doppler flowmetry and 20-MHz ultrasound in the affected skin areas in patients with MM after induction of immunologic contact urticaria by a cosmetic ingredient. Strict avoidance of cosmetics yielded a remarkable clinical benefit in the follow-up examinations.
We conclude that recurrent and possibly subclinical inflammation caused by immunologic contact urticaria in conjunction with a locally pre-existing lowered lymphatic drainage plays a crucial role in the evolution of MM.
Sweet's syndrome (SS) has been reported in association with many conditions, including malignancy, infections, autoimmune disorders, pregnancy and drugs.
We reviewed patients with SS-like lesions on the lymphoedema area seen in our department. Clinical manifestations, histopathologic characteristics, treatment and outcome data were recorded and analysed.
We report seven women with a history of surgery for breast cancer with axillary lymphadenectomy. Six of them were on tamoxifen. All of them had various lesions consistent with SS localized predominantly on the limb affected by the postmastectomy lymphoedema, and on the ipsilateral chest, trunk and back. One of them presented bullous lesions. Three of the cases underwent spontaneous remission, two resolved with antibiotic therapy, one healed with corticosteroids, and one with corticosteroids plus antibiotic.
Erythematous tender plaques on the area of postmastectomy lymphoedema could be considered an unusual manifestation of Sweet's syndrome. We have found only three similar cases in the literature. Although it is difficult to elucidate the pathogenesis of this entity, it has been suggested that it could be due to immune surveillance impairment.
Despite common endothelial origins, angiosarcoma and Kaposi's sarcoma are clinically and histologically distinct vascular proliferations. The development of angiosarcoma in a chronically edematous abdominal pannus is extremely uncommon. Similarly, tumors with the combined histologic features of angiosarcoma and Kaposi's sarcoma have rarely been described.
We reviewed the literature on angiosarcoma arising in a lymphedematous abdominal pannus and evaluated an 81-year-old morbidly obese woman who had profound, long-standing edema of the lower abdominal wall in which an aggressive vascular tumor developed.
Three clinically similar cases were identified in the literature. All patients were women who generally experienced rapid disease progression. In addition, in our patient, sequential cutaneous sampling from different lesional sites demonstrated disparate histologic changes, ranging from those of classic Kaposi's sarcoma to high-grade angiosarcoma, to areas with combined features of the two tumors. A polymerase chain reaction performed on lesional tissue was negative for human herpesvirus-8 DNA.
It is important to note that angiosarcoma may develop in the abdomen in association with chronic lymphedema, as demonstrated by the cases noted in this report. In addition, our case highlights the difficulty in differentiating histologically angiosarcoma from Kaposi's sarcoma in some situations, and demonstrates the value of close clinicopathologic correlation and sequential tissue sampling in evaluating problematic cases.