Lymphangiosarcoma of the pubic region: a rare complication arising in congenital non-hereditary lymphedema

ARTICLE

Lymphangiosarcoma (LAS) is a rare, vascular tumour, frequently associated with post-mastectomy lymphedema (Stewart Treves's syndrome) [1]. Exceptionally, this form of very aggressive neoplasm arises in congenital lymphedema, commonly classified into hereditary (Milroy's syndrome and Meige's syndrome) and non-hereditary lymphedemas [2-4]. Until now, only four cases of LAS arising in a non-hereditary congenital lymphedema of the lower limbs have been reported in the literature.

We report on a 42-year-old woman affected by congenital, non-hereditary lymphedema of the lower limb and left genitalia region, who developed a LAS of the pubic region. Moreover, to evaluate the involvement of KSHV in LAS, we used the polymerase chain reaction (PCR) to detect the presence of KSHV DNA sequences in tumour lesions. To our knowledge, this is the first case of LAS associated with congenital non-hereditary lymphedema confined to the pubic region.

Case report

A 42-year-old woman affected by congenital non-hereditary lymphedema of the left lower limb and the homolateral genital region, presented with a 3-month history of an indurated and hecchymotic plaque on the pubic area. There was no family history of lymphedema, neither had there been any preceding traumatic event in this area. The treatment with various systemic antibiotics and anti-inflammatory drugs during the previous month was ineffective. Physical examination showed lymphedema of the left labia majora and left lower extremity that made walking very difficult. The patient reported a rapidly extensive and severely indurated, painful plaque associated with apparent hecchymotic lesions for 3 months in the pubic and left genital region (Figs 1 and 2). No inguinal lymph nodes were palpable. Routine laboratory studies showed moderate anaemia (Hb 11.7 g/dL and erythrocytes 3.75 x 10 ⁶/gL) and an erythrocyte sedimentation rate of 78 mm/h. The differential white cell count was as follows: neutrophils 84.3%, lymphocytes 10.3%, monocytes 3.8%, eosinophils 1.3%. Pelvic and trans-vaginal ultrasound revealed no abnormalities. Chest X-ray was normal. Microscopical examination of an incisional skin biopsy from the pubic lesion revealed an extensive spindle cell infiltration into the dermis, and subcutaneous tissue showing cytological atypia and frequent mitoses (Figs 3 and 4). Numerous dilated vascular spaces, which were empty of blood, dissecting the dermal collagen were seen in the sections. Moreover, there was proliferation of endothelial cells, and in some instances, these cells protruded into the vessel lumen. A marked CD31(JC/70A) and CD34(QB-END/10) immuno-reactivity was identified (Fig. 5). In contrast, immunohistochemical labeling for CD45(2B11-PD7), CD68(KP-1), S-100, melanoma antigen (HMB45), and cytokeratin pool (AE1/AE3) were negative. Hemipelvectomy and local irradiation therapy (high dose irradiation ­ 39 and 23 grays) were performed. The patient is alive after one year following this treatment but she has developed perineal recurrence with bony and pulmonary metastases.

Biological studies

DNA was extracted from formalin-fixed, paraffin embedded tissue sections with the TaKaRa Dexpat^® Kit (Takara Shuzo Co., Ltd, Tokyo, Japan) following the manufacturer's instructions. In particular, a paraffin block not containing human tissue was taken as negative control and was processed before and after cutting the LAS specimen on the microtome. After each block was cut, the microtome blade was sequentially cleaned with 1N HCl and 2 successive 70% (vol./vol.) ethanol and ultra-pure water (SIGMA, St Louis, MS, USA) washes. Following extraction, pre- and post-extraction negative controls and LAS DNA were resuspended in 50 µl ultra-pure water. In order to rule-out major Taq polymerase inhibitors and to assess the integrity of the extracted DNA, 5 µl of the LAS specimen were subject to PCR amplification using human ß-globin specific primers amplifying a 252 bp DNA fragment of approximately the same length as the one chosen for KSHV amplification by nested PCR. Five µl of each control and an identical amount of the LAS sample DNA finally underwent nested PCR amplification using human KSHV-specific primers [5] employing a protocol that achieves single-copy sensitivity of the target [6].

The LAS DNA, as well as each of the controls were tested until exhaustion by nested PCR in 8 individual reaction (i.e., replicates) in order to exclude PCR drop-outs due to the presence of KSHV DNA sequences at extremely low concentrations in the extracted samples. Amplified products were analyzed using conventional ethidium bromide staining after horizontal agarose gel electrophoresis. Under these conditions, neither the LAS nor the control samples were found to harbor KSHV DNA sequences (data not shown).

Discussion

Lymphangiosarcoma (LAS) is a rare, aggressive tumour arising from the endothelium of blood vessels or lymphatics in chronically lymphedematous tissue that has a very poor prognosis. In 1948, for the first time, Stewart and Treves observed six cases of LAS in lymphedematous arms that complicated post-mastectomy [1], but Kettle, in 1918, had already reported a case of LAS arising in lymphedema precox [2]. Later, Woodward et al. reviewed the world literature and reported 186 cases of LAS associated with chronic lymphedema [7]. Until now, almost 200 cases of LAS arising in lymphedematous tissue have been reported in the literature. The majority of these cases have occurred in edematous upper extremities, 10-20 years after radical mastectomy and showed purplish papules or nodules, necrosis or ulceration [8-11]. In contrast, the appearance of LAS developing in congenital hereditary or non-hereditary lymphedema is extremely rare and to date only 12 cases have been reported in literature [12-19]. Congenital lymphedemas are actually classified as hereditary and non-hereditary lymphedemas. In the hereditary forms, the edema is present at birth or in early childhood (Milroy's disease), but in the late-onset form it may develop between the first decade and late puberty (Meige's disease). Milroy's and Meige's disease are considered to be two phenotypically distinct entities, but the different genetic origins are unknown.

In the non-hereditary forms, as in our case, the edema can appear at birth or later. In the last case, the idiophathic lymphedema that occur in early adolescence was called by Allen "lymphedema praecox" [20], whereas if the edema develops in patients after 35 years of age, Kinmonth named it "forme tarde" [21]. Finally, in 1995, Andersson et al. reported a first case in which LAS was associated with an hereditary forme tarde lymphedema [14].

We present the 4th case of LAS arising in a non-hereditary congenital lymphedema of the lower limb (Table 1), but the first case in which the tumour is confined to the pubic region, and not the lower extremity, where we would have expected it to be. Moreover, we emphasize the uncommon clinical picture. In fact, in our case, in contrast with most of the reports, we did not observe any purplish papules or nodules nor any necrotic or ulcerous lesions, but we exclusively found an hecchymotic, indurated plaque localized in the pubic region, associated with lymphedema of the lower limb and genital region.

The molecular studies performed in this case failed to demonstrate the presence of KSHV DNA sequences in LAS tumour cells. Although KSHV DNA sequences have been isolated from almost all cases of Kaposi's sarcoma (KS) [21] contrasting data are reported in the literature regarding the presence of these sequences in other vascular tumours such as angiosarcoma [23-25]. In particular, no data are available about the presence of KSHV in LAS. Our findings confirm and extend the previous observations that the KSHV sequence is specifically associated with KS, multicentric Castelman's disease and primary effusion lymphomas.

Finally, it is important to recall that the prognosis for this aggressive neoplasm is poor because LAS has a high risk of distant metastasis and local recurrence since histological extension of this neoplasia is often wider than the clinical aspect. In a review by Mark et al. [26], the 5-year survival was calculated to be 23%. For this reason, is very important that, for all patients affected by any chronic lymphedematous forms, frequent and accurate clinical controls be performed. LAS should be suspected everytime violaceous papules or nodules, necrosis, ulceration or apparent traumatic hecchymotic lesions appear in the context of lymphedematous tissue. The actual therapeutic strategies, similar for angiosarcoma, are based on a combined treatment of rapid, ablative surgery associated with the use of radiation therapy with the aim of increasing the patient's survival time. The use of chemotherapy in LAS is, as yet undefined [26].

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