Cutaneous Melanoma Metastases Research Articles

Item 149 – Tumeurs cutanées épithéliales et mélaniques : mélanomes

We report the case of an 83 years old man supported for painless indurated and nodular lesion of the left testicle. Histological analysis identified a primary cutaneous melanoma metastasis although it has never been found on physical examination.The discovery of a testicular mass should suggest first a germ cell tumor, despite in some populations (age over 60 years), other diagnosis are more frequent, including metastasis.Due to rapid disease progression and high mortality rate within a short interval, a complete staging looking for other secondary locations must be done and a multidisciplinary care and palliative involvement must also be initiated in the context of metastatic melanoma.

Correlation among metallothionein expression, intratumoural macrophage infiltration and the risk of metastasis in human cutaneous malignant melanoma

The formation of metastases and the efficacy of systemic therapies in cutaneous malignant melanoma (CMM) depend on the characteristics of the tumour cells and the host immune response. Aberrant expression of metallothionein (MT) has been observed in several types of cancers with poor prognoses. To perform an immunohistochemical study on primary CMM comparing the MT expression of tumours without metastases (n = 23) to that of samples with haematogenous metastases (n = 23) and to examine the correlation between MT staining and immunological markers relevant in CMM progression. The immunohistochemical labelling of different tumour sections was analysed using tissue microarrays for the evaluation of the suitability of this method in future studies. Our results suggest that MT overexpression is significantly more frequent in primary CMM with haematogenous metastases (P = 0.018) and that the overexpression is independent of the Breslow tumour thickness (R = 0.102, P = 0.501). Interestingly, MT overexpression of the tumour cells was correlated with the presence of tumour-infiltrating CD68(+) macrophages (P = 0.003), a known predictive factor for melanoma progression, thereby suggesting a role for MT in the development of a defective host immune response. Furthermore, the presence of CD163(+) macrophages infiltrating the tumours correlated with metastasis formation (P < 0.001), whereas the presence CD1a(+) dendritic cells surrounding the tumours was associated with a lower risk of haematogenous spread (P = 0.003). Our results demonstrate that MT may represent a suitable prognostic factor that can characterize the metastasising ability of CMM and the tumour-promoting host immune response.

The miRNA machinery in primary cutaneous malignant melanoma, cutaneous malignant melanoma metastases and benign melanocytic nevi

Although several studies have shown a dysregulation of microRNA (miRNA) expression profiles in cutaneous melanoma, there has been little research on the miRNA machinery itself. In this study, we investigated the mRNA expression profiles of different miRNA machinery components in primary cutaneous malignant melanoma (PCMM), cutaneous malignant melanoma metastases (CMMM) and benign melanocytic nevi (BMN). Patients with PCMM (n = 7), CMMM (n = 6) and BMN (n = 7) were included in the study. Punch biopsies were harvested from the centers of tumors (lesional) and from BMN (control). In contrast to previous reports exploring specific clusters of miRNAs in PCMM, the present study investigates mRNA expression levels of Dicer, Drosha, Exp5, DGCR8 and the RISC components PACT, argonaute-1, argonaute-2, TARBP1, TARBP2, MTDH and SND1, which were detected by TaqMan real-time reverse transcription polymerase chain reaction (RT-PCR). Argonaute-1, TARBP2 and SND1 expression levels were significantly higher in BMN compared to PCMM (p < 0.05). TARBP2 expression levels were significantly higher in CMMM compared to PCMM (p < 0.05). SND1 expression levels were significantly higher in CMMM compared to PCMM and BMN (p < 0.05). Dicer, Drosha, DGCR8, Exp5, argonaute-2, PACT, TARBP1 and MTDH expression levels showed no significant differences within groups (p > 0.05). The results of this study show that the miRNA machinery components argonaute-1, TARBP2 and SND1 are dysregulated in PCMM and CMMM compared to BMN and may play a role in the process of malignant transformation.

Tracking and Treating Malignant Melanoma Metastases

Tracking and Treating Malignant Melanoma Metastases

Lymphatic Invasion Is Independently Prognostic of Metastasis in Primary Cutaneous Melanoma

Lymphatic invasion (LI) in primary cutaneous melanomas was recently found to be common. In this study, we evaluated LI as an independent prognostic factor. This study included 251 patients with vertical growth phase (VGP) primary cutaneous melanomas who had paraffin-fixed lesional tissue and were in a prospective cohort seen between 1972 and 1991, had no clinical evidence of regional nodal disease at diagnosis, and had at least ten years of follow-up. Dual immunohistochemical staining was used to detect lymphatic endothelium (podoplanin) and melanoma cells (S-100). Multivariate logistic regression for ten-year metastasis was used to define independent prognostic factors, and a prognostic tree was developed to characterize and discriminate risk groups. Kaplan-Meier disease-free survival curves for those with and without LI within current American Joint Committee on Cancer stages were compared using the log-rank statistic. LI was observed in 43% (108 of 251) of the study melanomas. The multivariate model for ten-year metastasis identified four independent prognostic factors: tumor thickness, mitotic rate, LI, and anatomic site. The prognostic tree identified a group of patients with thin (≤1 mm thick) melanomas and poor prognosis: stage IB melanomas with LI. Survival curves for time to first metastasis showed significantly poorer prognosis for patients with LI compared with those without it for both stages IB and IIA. LI is common across the range of tumor thicknesses in primary VGP melanomas. It is an independent prognostic factor and significantly increases the risk of metastasis in patients in clinical stages IB and IIA.

Topical Diphencyprone as an Effective Treatment for Cutaneous Metastatic Melanoma

Dear Editor: Although melanoma mortality has levelled in many countries, the incidence is still rising1. Metastatic melanoma is very resistant to standard treatment modalities, including chemotherapy and radiotherapy2. Since melanoma is known to be a very immunogenic tumour, various immune targeted therapies are under trial3. For local cutaneous melanoma metastasis, Rose Bengal, a water soluble xanthine dye, and intralesional bleomycin have been used and are under ongoing research4. Diphencyprone (DPCP) is a contact sensitizer with immunomodulator effects, commonly used for alopecia areata and warts5. DPCP was reported as an effective treatment for the local cutaneous metastatic melanoma on its own6,7 and in combination with cimetidine8 or dacarbazine and radiation therapy9. However DPCP alone as a treatment for cutaneous metastatic melanoma was reported from only one center so far6,7. We present a case of metatstatic melanoma successfully treated with DPCP. A fifty seven year old Caucasian male presented with multiple enlarging asymptomatic pink nodules on his right shin for 6 months. He had superficial spreading malignant melanoma of Breslow thickness 1.20 mm, Clark level 4 excised from his right ankle 6 years prior. On examination, he had multiple erythematous superficial and deep nodules on right shin ranging in size from 5 to 25 mm. Histological examination of the lesions confirmed melanoma, consistent with metastatic melanoma. Subsequent pelvic computed tomography scan and positron emission tomography scan showed no evidence of distant metastasis. Based upon the impression of metastatic melanoma limited to local spread, he was started on DPCP therapy. Intralesional interferon and radiation therapy were considered not suitable due to the cost, location, and extent of the disease. Initially he was sensitized with 2% DPCP in acetone in right inner upper arm. Two weeks later, he was started on 0.005% DPCP in aqueous cream weekly on the whole surface of right shin. He was instructed not to wash the area for 48 hours after the DPCP application. Subsequently the concentration of DPCP was increased to 0.01% for 3 weeks then 0.03% thereafter in order to achieve 2 to 3 days of eczematous reaction. On examination after 18 weeks of weekly DPCP application, his right shin showed moderate dry eczematous changes with no evidence of nodules. Further histological examination from the two sites of the previous nodules revealed marked spongiosis with numerous eosinophils, consistent with allergic contact dermatitis, but no evidence of melanoma. The patient has continued on the weekly 0.03% DPCP. The patient tolerated the treatment very well with no notable side effects. A previously reported case series showed variable response to DPCP among seven patients7. Later Th17 up-regulation was implicated as a mechanism for the regression of metastatic melanoma by DPCP10. However this was based on Th17 expressions of before and after treatment biopsy specimens from a single patient. Further studies are needed to characterize patients who will respond to DPCP therapy. Th17 expression was not studied in our case. It is not clear how long the treatment should continue once the metastatic melanoma clears. There are not enough cases to assess the response rate and survival benefits. Since DPCP is a relatively very cheap, safe and easily accessible medication, further trials from various centers would be warranted. DPCP should be considered by the clinicians as a treatment option for the patient with cutaneous metastatic melanoma with no distant metastases.

The spectrum of dermatoscopic patterns in blue nevi

Blue nevi are congenital or acquired, dermal dendritic melanocytic proliferations that can simulate melanocytic and nonmelanocytic lesions including melanoma, cutaneous metastasis of melanoma, Spitz/Reed nevi, and basal cell carcinoma. We sought to investigate global and local dermatoscopic patterns of blue nevi compared with melanomas and basal cell carcinomas. We retrospectively analyzed global and local features in 95 dermatoscopic images of blue nevi and in 190 melanomas and basal cell carcinomas that were selected as control lesions on the basis of similar pigmentation. Lesion pigmentation was classified as monochromatic, dichromatic, or multichromatic. A global pattern characterized by homogeneous pigmentation was observed in all of 95 (100%) blue nevi. Eighty of 95 (84.2%) blue nevi presented a homogeneous pattern consisting of one color (blue, black, or brown) or two colors (blue-brown, blue-gray, or blue-black). Fifteen of 95 (15.8%) blue nevi had a multichromatic (blue, gray, black, brown, and/or red) pigmentation. In all, 47 of 95 (49.5%) blue nevi were characterized by pigmentation in the absence of pigment network or any other local dermatoscopic features. And 48 of 95 (50.5%) blue nevi showed local dermatoscopic patterns including whitish scarlike depigmentation, dots/globules, vascular pattern, streaks, and networklike pattern. The study was retrospective and involved only Caucasian people of Italian origin. The characteristic feature of blue nevi is a homogeneous pigmentation that is blue, blue-gray, blue-brown, or blue-black. We showed that a wide spectrum of local dermatoscopic features (whitish scarlike depigmentation, dots/globules, peripheral streaks or vessels) may also be present. In such cases, clinical and dermatoscopic distinction from melanoma or nonmelanocytic lesions may be difficult or impossible, and surgical excision is necessary.

Role of serum S100B and PET-CT in follow-up of patients with cutaneous melanoma

BackgroundIncreased level of serum S100B can serve as a marker of metastatic spread in patients with cutaneous melanoma (CM). In patients with elevated S100 B and/or clinical signs of disease progression PET-CT scan is a valuable tool for discovering metastases and planning treatment.The aims of this study were to determine whether regular measurements of serum S100B are a useful tool for discovering patients with CM metastases and to evaluate the diagnostic value of PET-CT during the follow-up.MethodsFrom September 2007 to February 2010, 115 CM patients included in regular follow up at the Institute of Oncology Ljubljana were appointed to PET-CT. There were 82 (71.3%) patients with clinical signs of disease progression and 33 (28.7%) asymptomatic patients with two subsequent elevated values of S100B. Sensitivity, specificity, positive and negative predictive value (PPV, NPV) of S100B and PET-CT were calculated using standard procedures.ResultsDisease progression was confirmed in 81.7% of patients (in 86.5% of patients with clinical signs of disease progression and in 69.7% of asymptomatic patients with elevated S100B). Sensitivity, specificity, PPV and NPV of S100B was 33.8%, 90.9%, 96.0% and 17.5% in patients with clinical signs of disease progression. In 20.0% of patients increased serum S100B was the only sign of disease progression. Sensitivity and PPV of S100 in this group of patients were 100.0% and 69.7%.With PET-CT disease progression was diagnosed in 84.2% of symptomatic patients and in 72.7% of asymptomatic patients with elevated S100B. The sensitivity, specificity, PPV and NPV of PET-CT for symptomatic patients was 98.5%, 90.9%, 98.5% and 90.9% and 100%, 90.0%, 95.8% and 100% for asymptomatic patients with elevated S100.ConclusionsMeasurements of serum S100B during regular follow-up of patients with CM are a useful tool for discovering disease progression in asymptomatic patients. The value of its use increases if measurements are followed by extended whole body PET-CT.

MMP-2 and TIMP-2 in Cutaneous Melanoma: Association With Prognostic Factors and Description in Cutaneous Metastases

MMP-2 and TIMP-2 in Cutaneous Melanoma: Association With Prognostic Factors and Description in Cutaneous Metastases

Two Cases of Multiple Spitz Nevi

The occurrence of multiple Spitz nevi is rare, especially the disseminated variant. Multiple Spitz nevi may be confused with, and must be differentiated from, primary spitzoid melanoma and cutaneous melanoma metastases. Over the past decade, fluorescence in situ hybridization (FISH) has emerged as a tool for studying melanocytic neoplasms, helping to differentiate between melanoma and benign melanocytic nevi. We describe 2 cases of patients with multiple Spitz nevi and their FISH results. One case of disseminated Spitz nevi, in a 17-year-old female, showed balanced tetraploidy using FISH, while the other case, in a 51-year-old female with multiple Spitz nevi, showed normal diploid cells without significant gains or losses in chromosomes 6 or 11. Patients may present with multiple, even disseminated, Spitz nevi. This phenotype should not be confused with melanoma and/or cutaneous metastasis. The use of FISH studies in context with careful correlation of clinical features and dermoscopic and histologic findings can assist in the diagnostic workup.

Application of Sentinel Lymph Node Biopsy in Cutaneous Basosquamous Carcinoma

Basosquamous carcinoma of the skin is a relatively rare cutaneous neoplasm that has significant metastatic potential and a metastatic rate greater than that of basal cell and squamous cell carcinoma. We describe the use of lymphatic mapping and sentinel lymph node biopsy in a 63-year-old man after identification of basosquamous carcinoma. Sentinel lymph node biopsy, which is a standard tool to detect regional lymphatic metastasis in cutaneous melanoma, has been rarely employed to detect lymphatic metastasis of basosquamous carcinoma. The approach was successful in detecting a regional lymphatic metastasis of two nodal basins with minor morbidity. Sentinel lymph node biopsy may be useful for certain high-risk lesions of basosquamous carcinoma.

Response of subcutaneous and cutaneous metastases of malignant melanoma to combined cytostatic plus interferon therapy.

A chemotherapy regimen consisting of dacarbazine (DTIC), vincristine, bleomycin and lomustine (CCNU) was combined with natural leucocyte interferon (IFN) in the treatment of 37 patients with cutaneous and subcutaneous metastases of malignant melanoma. Twenty-five also had concomitant lymph node, visceral, bone or brain metastases. Fifteen patients (41%) experienced complete response (CR) and 10 (27%) partial response (PR) of the superficial lesions. In addition, three patients were rendered surgically tumour-free after PR or disease stabilization during drug therapy. The median overall duration of response was 10.2 months (range 1-53 months). In disseminated disease, the combined therapy produced favourable results, particularly with regard to superficial lesions. It is also possible that this therapy may retard the growth of aggressive subcutaneous metastases in patients who have previously had multiple surgical procedures in an attempt to stabilize their disease. In a small proportion of patients, the long-term complete remission with the drug therapy alone, or in combination with surgery, suggests that this regimen might have been curative.

Expression of MCSP and PRAME in conjunctival melanoma

BackgroundTo analyse the expression of melanoma chondroitin sulfate proteoglycan (MCSP) and the preferentially expressed antigen of melanoma (PRAME) in conjunctival melanoma (CoM), lymph node (LN) metastases of cutaneous melanoma (CM)...

High-resolution ultrasonography assists the differential diagnosis of blue naevi and cutaneous metastases of melanoma

Metastases of cutaneous melanoma may simulate benign blue naevi clinically. To investigate the value of ultrasonography in the differential diagnosis of lesions that look similar clinically, i.e. blue naevi and cutaneous metastases of melanoma. Participants were invited for inclusion in the study if they had a cutaneous blue lesion clinically suggestive of a blue naevus or cutaneous metastasis of melanoma. After obtaining signed consent, the lesion was photographed and studied using dermoscopy and high-resolution ultrasonography before being removed for histological examination. Clinical, dermoscopic and ultrasonographic images were reviewed anonymously by four dermatologists to assign the diagnosis of blue naevus or metastasis of melanoma. The diagnostic performance of clinical examination, dermoscopy and sonography was assessed for the ability of each to differentiate between metastases of melanoma and blue naevi with reference to the histological diagnosis. Moreover, experts undertook a semeiological description of each ultrasonographic image according to seven items: location of the lesion, echogenicity, homogeneity, shape of the lesion, definition of margins, posterior acoustic shadow and increased posterior echogenicity. Twenty-eight patients were included with a total of 39 blue skin lesions, and 17 of the 28 patients had a previous history of melanoma. Interobserver agreement in the semeiological description of the sonographic images was good (κ≥0·6) for five of seven items. Sonography was more specific (94%) than clinical examination (77%) and dermoscopy (74%). The sonographic features contributing to the differential diagnosis were: location of the lesion (P=0·027), shape of the lesion (P<0·001), homogeneity (P=0·001) and increased posterior echogenicity (P=0·007). Ultrasonography is a reproducible and specific tool that can assist the differential diagnosis between blue naevi and metastases of melanoma. A blue naevus is a homogeneous, hypoechoic, 'dish-shaped' lesion, located in the superficial dermis, whereas metastases of melanoma are 'potato-shaped', hypoechoic, heterogeneous lesions, located in the hypodermis.

Distinguishing Epithelioid Blue Nevus From Blue Nevus-like Cutaneous Melanoma Metastasis Using Fluorescence In Situ Hybridization

Blue nevus (BN)-like cutaneous melanoma metastasis is a well-recognized variant of melanoma metastasis. These lesions may clinically and histologically simulate benign blue nevi. The histologic changes may be indistinguishable from conventional blue nevi or epithelioid blue nevi (EBN), a benign dermal-based melanocytic neoplasm with epithelioid morphology and heavily pigmented cytoplasm. Distinguishing BN-like cutaneous melanoma metastasis from benign conventional or EBN is important for staging and treatment. We evaluated a fluorescence in situ hybridization (FISH) assay using probes targeting 6p25 (RREB1), 6q23 (MYB), 11q13 (CCND1), and centromere 6 (Cep6) with previously determined criteria, to distinguish EBN and BN-like melanoma metastasis. Ten BN-like cutaneous melanoma metastatic lesions and 10 EBN were blindly evaluated with the above mentioned FISH probes. FISH enumeration and criteria for diagnosis of melanoma was as previously described. Nine of 10 BN-like cutaneous metastatic lesions showed significant aberrations and met previously established criteria for melanoma. None of the EBN cases showed evidence of significant copy number changes or met FISH criteria for a diagnosis of melanoma. FISH is an important diagnostic adjunct for melanocytic neoplasms. In this study, we show that a FISH assay targeting 6p25, 6q23, 11q13, and centromere 6 can distinguish EBN from BN-like metastatic melanoma with high accuracy. The test and the parameters previously established can perform with high sensitivity and specificity when dealing with this differential diagnosis.

Perilesional treatment of metastatic melanoma with interferon-β

Previous trials with various treatments have not shown satisfactory therapeutic results for cutaneous metastasis of malignant melanoma (MM). We report three patients who were treated with peritumoral injection of interferon (IFN)-beta for multiple skin metastases of MM. The metastatic tumours were infiltrated by significant numbers of CD8+ TIA+ cytotoxic lymphocytes, and the numbers of CD4+ cells and human leucocyte antigen-DR+ cells increased after IFN-beta injection. These results suggest that the peritumoral administration of IFN-beta enhanced the antitumour immune response against the MM, suggesting that it is a promising supportive treatment for skin metastasis of MM.

Melanoma of the small intestine

Intestinal melanomas can be primary tumours or metastases of cutaneous, ocular, or anal melanomas. Primary intestinal melanoma is extremely rare, whereas metastatic melanoma of the small bowel is common because of the tendency for cutaneous melanoma to metastasise to the gastrointestinal tract. Because distinguishing between primary and metastatic intestinal melanoma can be difficult, the main features of each are discussed, and the diagnostic images used to detect intestinal melanoma are assessed. Routine barium examinations and CT have limited sensitivity, but PET imaging can improve detection of melanoma metastases to the small bowel. Although various treatment strategies have been tried in patients with intestinal melanoma, surgical removal of intestinal metastases is the treatment of choice in patients with resectable tumours. No systemic therapy improves survival in patients with melanoma metastatic to the intestines; thus, the prognosis for these patients is poor. Patients with primary melanoma of the small intestine have a worse prognosis than do patients with metastases of cutaneous melanoma.

Dermoscopic and histopathological findings of polymorphous vessels in amelanotic cutaneous metastasis of pigmented cutaneous melanoma

Dermoscopic and histopathological findings of polymorphous vessels in amelanotic cutaneous metastasis of pigmented cutaneous melanoma

Clinical characteristics of cutaneous melanoma and second primary malignancies in a dutch hospital-based cohort of cutaneous melanoma patients.

The increasing number of living cutaneous melanoma patients and the increased risk of developing a second primary tumour incited us to analyse the clinical characteristics of cutaneous melanoma and define the frequency, site, and type of second primary cancers in cutaneous melanoma patients. We collected data on patients who visited the Department of Dermatology at the Radboud University Nijmegen Medical Centre and were newly diagnosed with cutaneous melanoma or metastasis of melanoma with unknown primary localization between 2002 and 2006. A total of 194 cases were included; eleven patients developed a subsequent melanoma, 24 had at least one basal cell carcinoma, three had at least one squamous cell carcinoma, and 21 patients had a second non-cutaneous primary malignancy. In conclusion, 48 patients developed a subsequent malignancy. As nonmelanoma skin cancer is the most frequent second malignancy, our results subscribe to the necessity of follow-up by a dermatologist.

Cutaneous matastasis from sino-nasal malignant melanoma — a rare case report

To report a case of disseminated cutaneous metastasis from malignant melanoma of sino-nasal region. A 53-year-old man from rural parts of West Bengal presented with progressive nasal obstruction. CT scanning was done to know the extent of the mass and punch biopsy from the mass was performed. Malignant melanoma of sino-nasal region was diagnosed and chemotherapy was started. The patient developed cutaneous deposits after two cycles of chemotherapy. The patient developed cutaneous deposits during the course of chemotherapy. Excision biopsy from cutaneous deposits revealed malignant melanoma. A rare case of diffuse cutaneous metastasis of malignant melanoma is presented here along with review of literature.