Adjuvant prophylactic regional radiotherapy versus observation in stage I Merkel cell carcinoma: a multicentric prospective randomized study.

BACKGROUND: The treatment of stage I Merkel cell carcinoma (MCC) usually includes wide local excision (WLE) combined with irradiation of the tumor bed (ITB). No randomized study has ever been conducted in MCC. The purpose of this study was to assess the efficacy and safety of prophylactic adjuvant radiotherapy on the regional nodes. PATIENTS AND METHODS: In this randomized open controlled study, patients for a stage I MCC treated by WLE and ITB were randomly assigned to regional adjuvant radiotherapy versus observation. Overall survival (OS) and probability of regional recurrence (PRR) were primary end points. Progression-free survival (PFS) and tolerance of irradiation were secondary end points. RESULTS: Eighty-three patients were included before premature interruption of the trial, due to a drop in the recruitment mainly due to the introduction of the sentinel node dissection in the management of MCC. No significant improvement in OS (P = 0.989) or PFS (P = 0.4) could be demonstrated after regional irradiation, which, however, significantly reduced the PRR (P = 0.007) with 16.7% regional recurrence rate in the observation arm versus 0% in the treatment arm. The treatment was well tolerated. CONCLUSION: The adjuvant regional irradiation significantly decreased the PRR in MCC, but benefit in survival could not be demonstrated.

A case of primary cutaneous nasal type NK/T-cell lymphoma and review of the literature.

INTRODUCTION: Cutaneous T-cell lymphoma subtypes are now better identified thanks to progress in immunohistochemistry. This article describes a new case of primary cutaneous natural killer/T-cell lymphoma of nasal type (NKTL-NT) and reviews 18 other cases of this rare neoplasm. CASE REPORT: A 79-year-old man presented with a 3-cm nodular tumor of the left leg occurring on a primary chronic lymphedema of the legs. The lesion was CD56+, CD3 intracytoplasmic+, CD45+ and Epstein-Barr virus+. A comprehensive workup including CT scan and bone marrow biopsy was negative and a diagnosis of NKTL-NT with a primary cutaneous involvement was made. The patient was free of disease under multi-agent chemotherapy after 24 months of follow-up. DISCUSSION: After reviewing 18 other cases of primary cutaneous NKTL-NT, we conclude that the prognosis of these lymphomas is usually poor. However, limited cutaneous forms have a longer median survival than extracutaneous variants.

Clinical variants of the preprotuberant stage of dermatofibrosarcoma protuberans.

BACKGROUND: Some cases of dermatofibrosarcoma protuberans (DFSP) do not protrude above the skin. OBJECTIVES: To assess the prevalence of these DFSPs and further to describe their presentation and course. METHODS: One hundred and forty-three patients were retrospectively collected. They were asked to complete a standardized questionnaire indicating the history and appearance of the DFSP from the first skin changes identified to the time of diagnosis. RESULTS: Eighty-one DFSPs were described as protuberant ab initio, and 62 as initially nonprotuberant (npDFSP). The latter remained at this stage for a mean period of 7.6 years. Twenty-nine per cent of npDFSPs were 'morphoea-like', 19% were 'atrophoderma-like' and 42% were 'angioma-like'. Age at diagnosis was similar for both initial presentations. npDFSPs were most often misdiagnosed by physicians. CONCLUSIONS: Nearly half the patients first identified their early DFSP-related skin changes as patches. Both this frequency and the long duration at this preprotuberant stage should prompt dermatologists to consider the diagnosis of DFSP earlier, in order to make surgical treatment easier.

[Randomised phase III trial of fotemustine versus fotemustine plus whole brain irradiation in cerebral metastases of melanoma]. / Essai de phase III randomisé comparant la fotémustine seule ou associée à une irradiation encéphalique dans les métastases cérébrales de mélanome.

PURPOSE: The main objective of this prospective multicenter randomised phase III study was to compare a combined regimen of fotemustine plus whole brain irradiation versus fotemustine alone in terms of cerebral response and time to cerebral progression in patients with melanoma brain metastases. PATIENTS AND METHODS: Seventy-six patients (instead of the 106 planned patients; study was stopped after the interim analysis) were randomised receiving either fotemustine (arm A, n = 39) or fotemustine and whole brain irradiation (arm B, n = 37). Fotemustine was administered intravenously at 100 mg m(-2) on day 1, 8 and 15, followed by a 5-week rest period, then every 3 weeks in non-progressive patients. In arm B, a concomitant whole brain irradiation was performed at the total dose of 37.5 Gy (2.5 Gy/d(-1), days 1-5, 3 consecutive weeks). RESULTS: Although patients who received fotemustine alone had worse prognostic factors, there was no significant difference in brain response (arm A: 7.4%, B: 10.0%) or control rates (objective response plus stable disease) after seven weeks (arm A: 30%, B: 47%) and overall survival (arm A: 86d, B: 105d). However, there was a significant difference in favour of arm B for the time to brain progression (p = 0.028, Wilcoxon test). CONCLUSION: Fotemustine plus whole brain irradiation delayed the time to brain progression of melanoma cerebral metastases compared to fotemustine alone but without a significant improvement in terms of objective control or overall survival.

A prospective randomized multicentre phase III trial of fotemustine plus whole brain irradiation versus fotemustine alone in cerebral metastases of malignant melanoma.

The main objective of this prospective multicentre randomized phase III study was to compare a combined regimen of fotemustine plus whole brain irradiation with fotemustine alone in terms of cerebral response and time to cerebral progression in patients with melanoma cerebral metastases. Seventy-six patients were randomized to receive either fotemustine (arm A, n = 39) or fotemustine plus whole brain irradiation (arm B, n = 37). Fotemustine was administered intravenously at 100 mg/m(2) on days 1, 8 and 15, followed by a 5 week rest period, then every 3 weeks in non-progressive patients. In arm B, concomitant whole brain irradiation was performed at a total dose of 37.5 Gy (2.5 Gy/day on days 1-5 for three consecutive weeks). Although patients who received fotemustine alone had worse prognostic factors, there was no significant difference in cerebral response (arm A, 7.4%, arm B, 10.0%) or control rates (objective responses plus stable disease) after 7 weeks (arm A, 30%; arm B, 47%) or in overall survival (arm A, 86 days; arm B, 105 days). However, there was a significant difference in favour of arm B for the time to cerebral progression (P = 0.028, Wilcoxon test). In conclusion, fotemustine plus whole brain irradiation delayed the time to cerebral progression of melanoma cerebral metastases compared with fotemustine alone but without a significant improvement in terms of objective control or overall survival.

[Treatment of periocular carcinoma by interstitial iridium curietherapy. 77 patients]. / Traitement des carcinomes de la région péri-oculaire par curiethérapie interstitielle à l'iridium. 77 patients.

OBJECTIVES: We used a pluridisciplinary approach with the participation of ophthalmologists, dermatologists and oncologists-radiotherapists to assess therapeutic results after interstitial indium 192 curietherapy for carcinomas located in the periocular region. PATIENTS AND METHODS: A retrospective study included 77 patients with stage T1T2 carcinoma treated from 1997 to 1988. Median survival was 42 months. RESULTS: Disease control was obtained in 100% of the cases. Functional and esthetic results were evaluated using 4 criteria. Esthetic results were excellent in 71.4% of cases with no functional disorders in 88.3%. CONCLUSION: Interstitial curietherapy is a good indication for the treatment of small tumors of the periocular region. The esthetic result is excellent with few minor complications which have little effect on patientsí quality of life.

Statistical evaluation of diagnostic and prognostic features of CD30+ cutaneous lymphoproliferative disorders: a clinicopathologic study of 65 cases.

Several clinical and histopathologic features of 65 CD30+ cutaneous lymphoproliferations were evaluated for their diagnostic value between CD30+ primary versus secondary cutaneous lymphomas and for their prognostic significance. Primary cutaneous disease, spontaneous regression, and absence of extracutaneous spreading (but not age < or =60 years) were associated with a better prognosis. Epithelial membrane antigen, BNH9, CD15 or CBF.78 antigen were expressed in all types of cutaneous lymphoproliferations. However, epithelial membrane antigen immunoreactivity was more frequently expressed in CD30+ secondary cutaneous large-cell lymphoma. Among CD30+ primary cutaneous large-cell lymphoma, CD15 expression was only seen in localized skin lesions. P53 expression was not associated with spontaneous regression, extracutaneous spreading, or survival. Nested reverse transcriptase-polymerase chain reaction allowed the detection of NPM-ALK transcripts in 10 of 26 CD30+ primary and in 3 of 11 secondary cutaneous large-cell lymphomas. The ALK protein was detected in only 1 of 50 primary and in 4 of 15 secondary cutaneous CD30+ lymphoproliferations. In CD30+ primary cutaneous lymphoproliferation, NPM-ALK transcripts might be expressed by very rare normal or tumoral cells that are undetectable by immunohistochemistry. However, the expression of either NPM-ALK transcripts or ALK-protein was not correlated with prognosis or age in CD30+ cutaneous lymphoproliferations.

[Melanoma of soft tissues]. / Mélanome des tissus mous.

INTRODUCTION: Soft tissue melanoma was described in 1965 by Enzinger who used the term clear-cell sarcoma. In 1983, Chung and Enzinger coined the term soft tissue melanoma due to the immunohistochemical similarity with melanoma. We report a case of this rare type of melanoma. CASE REPORT: A 59-year-old woman had pain between the first two toes for 3 years. A subcutaneous tumor was found at examination. Histologically, the tumor was composed of weakly eosinophilic cell proliferation. Protein S100 and HMB45 were positive. The cells were organized in theques. Pathology diagnosis was soft tissue melanoma. Complete remission was obtained for 3 years when several local recurrences required surgery and chemotherapy then surgery and radiotherapy. Complete remission has been achieved for 9 months. DISCUSSION: This case presented the main characteristics of soft tissue melanoma as described in a review of 209 analyzable cases reported in the literature. This tumor occurs in young subjects with no sex or race predominance. It is an ubiquitous tumor which develops in close relation with tendons and aponevroses, usually in limbs (especially feet). Pain is sometimes the revealing manifestation, but the tumor is often asymptomatic, so the volume is often important at diagnosis. Pathology examination shows rather monomorphic proliferation of cells with a clear or weakly eosinophilic cytoplasm grouped in clusters or theques separated by fibrous septa. Intracytoplasmic melanin is sometimes observed, indicating interest of protein S100 and HMB45 immunohistochemistry which is almost always positive. The principle differential diagnoses are metastasic melanoma and epithelioid sarcoma. Prognosis of soft tissue melanoma is similar to that in sarcomas with a high rate of local recurrence and metastases (lymph nodes, lungs). Mortality reaches 56 p. 100. Treatment is wide surgical exeresis. CONCLUSION: Soft tissue melanoma is a rare tumor of the melanocyte. It differs from melanoma by the population involved, its clinical expression and its prognosis which is similar to that in sarcoma.

Contribution of histopathologic and molecular analyses to the diagnosis of cutaneous B-cell infiltrates.

To evaluate the value of morphologic, immunohistochemical and molecular analyses, we studied 21 skin biopsy specimens from 19 patients with primary cutaneous B-cell infiltrates. Morphologic review by two independent dermatopathologists confirmed the consensus diagnoses of lymphoma (n = 6) or benign lymphoid hyperplasia (n = 6). A discordant diagnosis was made for the other samples (n = 9), which were thereafter considered as unclassified lymphoid infiltrates. Immunohistochemical analysis showed either a monotypic expression of immunoglobulin light chain or a positive staining with anti-bcl-2 antibodies in three and four samples, respectively, of lymphoma. Polymerase chain reaction was used to analyze immunoglobulin heavy chain and T-cell receptor gamma chain gene rearrangement and to amplify t(14;18) and t(11;14) break points. A clonal molecular marker was detected in 12 of 19 patients. Among these 12 patients, a final diagnosis of lymphoma was confirmed in 8 patients, including the 6 with a morphologic diagnosis of lymphoma. Two patients with clonal benign lymphoid hyperplasia and two with clonal unclassified lymphoid infiltrate presented a benign clinical outcome; one patient was lost to follow-up. Alternatively, no clonal molecular marker was found in two of the patients with lymphoma. The morphologic and molecular criteria, therefore, provided complementary and partially overlapping information for the diagnosis of cutaneous B-cell infiltrates. We proposed a practical use for these data.

CD30-positive cutaneous large cell lymphomas. A comparative study of clinicopathologic and molecular features of 16 cases.

The authors have analyzed and compared the clinicopathologic and molecular features of 16 cases of large cell cutaneous lymphomas expressing CD30 antigen. Three main clinical groups were defined: (1) a group of localized skin disease (7 cases); (2) a group of multicentric skin disease (5 cases); and (3) a group of concomitant skin and extracutaneous disease. Good prognosis was associated with localized skin disease and no history of lymphoma. Interestingly, a majority of Reed Sternberg-like cells was only observed in this group (5 of 6 cases). The two other groups did not show distinctive evolutive nor morphologic features. Southern blot and/or polymerase chain reaction (PCR) technique showed clonality and a T-cell genotype in respectively 13 of 14 and 12 of 12 analyzed cases. Viral infection of tumoral cells was investigated by PCR, in situ hybridization (ISH) or electron microscopy. Epstein-Barr virus (EBV) sequences were detected by PCR and ISH in tumoral cells of cutaneous lesions in one case of skin lymphoma with extracutaneous spreading. No EBV sequence was detected by ISH in the localized lymphomas, whereas HIV particles were visible in tumoral cells in one of these cases. No human T-cell lymphotropic virus (HTLV) tax sequence was amplified by PCR in any case of our series. Our results confirm that CD30-positive cutaneous large cell lymphomas are different clinical and molecular entities. However, a combined clinical and morphologic analysis may help to identify a subset of CD30 cutaneous lymphomas with favorable prognosis.

Thin melanomas with unusual aggressive behavior: a report on nine cases. Melanoma Group of French Federation of Cancer Centers.

BACKGROUND: The major factor influencing the prognosis of cutaneous malignant melanoma (MMs) is the maximum thickness of the tumor as measured by Breslow's method. However, it has been reported that thin melanomas, which should have an excellent prognosis, may have the potential to metastasize, some with an unusually rapid course. OBJECTIVE: Our purpose was to examine prognostic indicators in relation to unusually rapid aggressive behavior in patients with thin MMs (<0.76mm). METHODS: We describe nine cases of thin MM (<.76mm) that exhibited a recurrence or metastasis during a follow-up period ranging from 3 to 10 years, among computerized records of 1118 MMs treated in a multicenter epidemiologic study. The data obtained from these nine cases were compared with nonrecurring thin MM (149 cases) of the same cohort. RESULTS: The particular aggressiveness of these thin melanomas was reflected by the short disease-free interval (3 years or less) in all ine patients. The recurring thin MM more frequently involved head and neck sites, occurred in male patients, and showed Clark's level III and IV. CONCLUSION: Our review suggests that the head and neck area is particularly involved by unusually rapidly recurring thin MM. Possible explanations are the specific problems of surgical management and the greater sun exposure of this location.

[Post-radiotherapy cutaneous neuro-endocrine carcinoma]. / Carcinome neuro-endocrine cutané en zone irradiée.

INTRODUCTION: Merkel cell carcinoma or cutaneous neuroendocrine carcinoma is an uncommon severe disease. The carcinogenic effect of ionizing radiations has been suspected in exceptional observations. We report the sixth case of Merkel cell neuroendocrine carcinoma in a patient with prior radiotherapy. CASE REPORT: An 86-year-old man underwent radiotherapy for a basal cell carcinoma of the tip of the nose and developed a highly aggressive Merkel cell carcinoma at the same location 6 years later. DISCUSSION: The development of Merkel cell carcinoma on irradiated tissue accounts for 2.6 p. 100 of the 227 publications where dermatological history was reported. This percentage may be underestimated. The similar localizations of the irradiated zone and the site of cancer development 5 years later suggest that the Merkell cell carcinoma may be a radio-induced tumor. The delay may vary from 5 to 47 years. The similarity of the carcinogenic factors involved in Merkel cell carcinoma and squamous cell or basal cell carcinomas (ultraviolet, ionizing irradiation) and the frequent association of different types favor an epidermal origin for Merkel cell carcinoma. In clinical practice, past history of radiotherapy in an area where Merkell cell carcinoma develops indicates that therapeutic management must exclude post-operative radiotherapy.

A phase I trial of repeated tumour-infiltrating lymphocyte (TIL) infusion in metastatic melanoma.

The aim of the protocol was to evaluate the side-effects induced by repeated tumour-infiltrating lymphocyte (TIL) infusions in patients with metastatic melanoma (MM). Patients were to receive four TIL infusions at given intervals: every 3 weeks (two patients), every 2 weeks (3 patients) and weekly (4 patients). All patients were evaluated and received a total of 34 TIL infusions. The total number of TILs administered varied from 0.65 to 2.34 x 10(11) cells. TIL phenotypes were predominantly CD8+ (two patients), CD4+ (4 patients), CD4+ then CD8+ (two patients) or CD56+ (two patient). Autocytotoxicity was only observed for one culture. Six patients presented at least one WHO grade 3 side-effect: hypotension (5 patients), dyspnoea (two patients), fever (one patient), fatigue (one patient), chills (two patients), diarrhoea (one patient), agitation (one patient), locoregional pain (two patients). Hypotension was constantly seen in patients who were given TILs every week. Two cases of minor pericarditis were recorded. No objective response to treatment was observed; 1 stable disease occurred in one patient and progression in eight. However, five patients presented a partial response on a tumour site for 1-4 months. Three patients presented signs of inflammation or softening at one tumour site. Plasma tumour necrosis factor alpha (TNF-alpha) levels were increased 1.2- to 22-fold after TIL infusion. TILs could be produced in sufficient quantity to perform this study, so repetitive infusions of TIL became possible on a weekly basis. However, no objective response was observed even when TIL infusions were performed weekly. An increase in circulating TNF-alpha was noted after TIL infusion.

[Paraneoplastic retinopathy associated with cutaneous melanoma. An update apropos of a case]. / Rétinopathie paranéoplasique associée au mélanome cutané. Mise au point à propos d'un cas.

BACKGROUND: Ocular paraneoplastic syndromes are rare, and consist of optic neuropathy or retinopathy. Classically, these syndromes are related to carcinoma. Melanoma-associated retinopathy is extremely rare, and unrecognized. METHODS: A patient with metastatic cutaneous melanoma discovered and operated 18 months before. Visual complains consisted of xanthopsia and shimmering light vision, then hemeralopia, which dramatically worsened. Classical clinical examination, visual field and electroretinogram were performed. RESULTS: Visual acuity was 20/25, and fundus examination was normal. The visual field showed a tubular aspect, with V4 isopter remained, like an advanced retinitis pigmentosa. The photopic electroretinogram was negative, and the scotopic one was flat. CONCLUSION: This recent hemeralopia with normal fundus and "negative" electroretinogram, ruled out congenital stationary night blindness diagnosis, and suggested the diagnosis of melanoma-associated retinopathy. This is a rare paraneoplastic syndrome since to date only 7 cases have been reported. Immunochemistry studies, that show antibodies directed against bipolar cells, are consistent with selective reduction of the electroretinogram b wave.

[Melanoma of the ORL mucosa]. / Mélanome des muqueuses O.R.L.

The study of ENT mucous melanomas (ENT MM) was performed retrospectively, based on 20 patients treated in Bordeaux and 156 detailed files taken from the international literature. Each paragraph is followed by a review of the general literature. The ENT MM, a rare form of melanomas, presents a majority of nasal locations. The mean age is 63 years old. The sex ratio trend is towards one. The aspecific call signs partially explain the delayed diagnosis. The difficult pathological examination is assisted by tumoral markers. Mean survival is two and a half years without any clear prognostic factors as for cutaneous melanomas. Treatment is essentially surgical, but adjuvant radiotherapy may have a significant effect. The other treatments are palliative.

[Surgery of pulmonary metastasis from malignant melanoma. Results and criteria of surgical excision]. / Chirurgie des métastases pulmonaires du mélanome malin. Résultats et critères d'opérabilité.

Lung metastases from malignant melanoma are frequent and they often inaugurate the metastatic stage. Exceptionally, they present as one or a few nodules, and in the absence of any other secondary lesion these cases raise the problem of surgical eradication. A retrospective multicentre study was carried out in a series of 38 patients and its results were compared to the data obtained from a review of 435 published cases in order to assess the value of surgery in terms of survival and to delimit its indications as closely as possible. Our series of 38 patients comprised 20 men and 18 women aged from 22 to 93 years (mean 51 years, median 55 years). The primary tumour was located in the trunk in 47 p. 100 of the cases; it was nodular in 33 p. 100 and superficial but extensive in 37.5 p. 100. The time elapsed before the metastases appeared varied from 0 to 108 months (median 40 months). Surgery had been radical in 70 p. 100 of the patients and usually limited, tumorectomies and segmentectomies accounting for 51 p. 100 of the operations. RESULTS. In this series the duration of survival varied between 2 and 144 months (mean 26 months, median close to 15 months), with a 20 p. 100 probability of survival at 5 years (fig. 1). Disease free survival varied from 0 to 144 months (mean 22.5 months, median 10.5 months) (fig. 2, curve 1). The parameters of response as regards patients, primary tumour, metastases and treatment were analysed. Response was uninfluenced by sex and slightly influenced by age, with a difference of borderline significance between subjects under and over 50. The primary tumour characteristics did not affect survival, and the features of metastases were of extremely varied importance. The number of operable metastases was not determinant. On the other hand, the presence of mediastinal lesions, either isolated or associated with lung lesions, worsened the prognosis of terms of survival and much more significantly so in terms of remission (fig. 3 and 4). The evaluation of evolutive characteristics, such as date of appearance and tumour doubling time, was inconclusive. Survival was of the same duration after wide and limited surgery, so that tumorectomy or segmentectomy should preferably be performed. The results of surgical treatment were determinant, with a highly significant difference in survival between radical and incomplete surgery (fig. 5 and fig. 2, curve 2). DISCUSSION. The median survival of patients operated upon for lung metastases is diversely evaluated in the literature as 8 to 29 months (table V), the mean figure of 16 months being virtually the same as that of our series. In this, as in most of the previously published series, the maximum duration of survival was beyond 8 to 10 years. The mean survival rate at 5 years is very close to the one we have recorded (20 p. 100) (table V). Compared with other treatments of lung metastases, surgery may be considered as capable of prolonging survival by 6 months; this is not much unless we add the possibility of a 5-year survival in 1 out of 5 operated patients and the possibility of a survival exceeding 8 or 10 years in 2 to 5 p. 100 of the cases. Some prognostic factors seem to constitute positive or negative criteria of operability. This is the case with mediastinal lesions which may consist of a metastasis of metastasis or of a lymph node invasion associated or not with the lung lesion, but in any case correspond to the involvement of more than one site. Mediastinal lesions must be systematically looked for and treated as contraindications of surgery, as shown by the differences in survival recorded in our series. Opinions differ as regards the value of evolutive parameters of the metastasis. For some authors, a more than 5 years interval before the metastasis appears is associated with a good chance of prolonged survival, whereas a less than 6 months or 1 year interval reflects a steadily high progressiveness and in practice precludes surgery. The value of the