Michèle Delaunay

Randomised trial of interferon α-2a as adjuvant therapy in resected primary melanoma thicker than 1·5 mm without clinically detectable node metastases

Summary Background Owing to the limited efficacy of therapy on melanoma at the stage of distant metastases, a well-tolerated adjuvant therapy is needed for patients with high-risk primary melanoma. Our hypothesis was that an adjuvant treatment with low doses of interferon a could be effective in patients with localised melanoma. Methods After resection of a primary cutaneous melanoma thicker than 1·5 mm, patients without clinically detectable node metastases were randomly assigned to receive either 3X106 IU interferon α-2a, three-times weekly for 18 months, or no treatment. The primary endpoint was the relapse-free interval. Findings 499 patients were enrolled, of whom 489 were eligible. When used as part of a sequential procedure, interferon α-2a was of significant benefit for relapse-free interval (p=0·038). A long-term analysis, after a median follow-up of 5 years, showed a significant extension of relapse-free interval (p=0·035) and a clear trend towards an increase in overall survival (p=0·059) in interferon α-2a-treated patients compared with controls. There were 100 relapses and 59 deaths among the 244 interferon α-2a-treated patients compared with 119 relapses and 76 deaths among the 245 controls. The estimated 3-year-relapse rates were 32% in the interferon α-2a group and 44% in controls; the 3-year death rates were 15% and 21%, respectively. Only 10% of patients experienced WHO grade 3 or 4 adverse events. Treatment was compatible with normal daily life. Interpretation Adjuvant therapy of high-risk melanoma with low doses of interferon α-2a for 18 months is safe and is beneficial when started before clinically detectable node metastases develop.

Blastic NK-cell lymphomas (agranular CD4+CD56+ hematodermic neoplasms): a review.

Blastic natural killer (NK) cell lymphoma (also termed CD4+CD56+ hematodermic neoplasm) is a recently described entity, with the first case reported in 1994. It was suggested initially that the disease originates from NK cells. Since 1994, single cases and a few small series have been published. In this review, data from the literature and a series of 30 cases from the French and Dutch study groups on cutaneous lymphomas are discussed. The major clinical, histopathologic, and phenotypic aspects of the disease and diagnostic criteria and data suggesting a plasmacytoid dendritic cell origin for the tumor cells are provided.

Delays in diagnosis and melanoma prognosis (I): The role of patients

A prospective survey was conducted to assess the role of patients in the melanoma prognosis. Consecutive patients with primary melanoma were interviewed and examined using a comprehensive questionnaire including a psychological instrument. Main outcome measures were the delay before medical intervention and the tumor thickness. Of 590 melanomas, 70.8% were detected by patients and this proportion was higher in females. Relatives were involved in the detection of half of the cases. Median delays before the patient realized he had a suspicious lesion, before this lesion was seen by a doctor, and before the melanoma was removed were 4 months, 2 months, and 1 week, respectively. Delays up to several years were observed in some cases. The rate of self‐detection tended to be lower, the delays before seeking medical advice to be longer, and the tumor thickness to be higher in old people, in males, in lower‐educated individuals, in those living out of towns, and in people with a low awareness about melanocytic tumors than in other cases. Conversely, individuals with a high number of atypical nevi, those who were aware to be at risk, and those who regularly visited a dermatologist tended to detect their melanoma more rapidly. No specific psychological traits were associated with a late reaction, although negligence and anxiety tended to prolong the delays. Knowledge about melanoma was poor in many patients, especially in males, and wrong beliefs were widespread. This study provides the targets of future education programs. Int. J. Cancer 89:271–279, 2000.

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.

Delays in diagnosis and melanoma prognosis (II): The role of doctors

A prospective survey was conducted to assess physician responsibility in melanoma prognosis. Consecutive patients with primary melanoma were interviewed and examined using a standardized questionnaire. Main outcome measures were medical components of the delay before tumor resection and tumor thickness. Of 590 melanomas, 29.1% were coincidentally detected by physicians and their tumor depth was lower than in melanomas detected by patients (p < 0.001). Physician sensitivity for melanoma diagnosis was evaluated at 86%. Median time intervals to propose resection and to perform removal of melanoma were short: 0 (mean 103) and 7 (mean 68) days, respectively. Melanomas were managed in an inappropriate way in 14.2% of cases. Location on acral areas and absence of pigmentation were associated with longer medical delays and more frequent inappropriate medical attitudes. Melanomas located on hardly visible areas were less frequently detected by physicians than those on visible areas. Medical delays were shorter, doctors attitude was more frequently appropriate, and melanoma thickness was lower (p < 0.001) when the patient visited a dermatologist (54.7%) than when he or she visited a general practitioner (33.4%). Our study shows that doctor responsibility accounts for only a small part of the total delay before melanoma removal. However, systematic total examination and better training of doctors, especially about unusual forms of melanoma, could still improve melanoma detection. Int. J. Cancer 89:280–285, 2000.

Prospective Multicenter Study of Pegylated Liposomal Doxorubicin Treatment in Patients With Advanced or Refractory Mycosis Fungoides or Sézary Syndrome

OBJECTIVE To assess the rate of objective response to pegylated liposomal doxorubicin hydrochloride (Caelyx) in patients with advanced or refractory cutaneous T-cell lymphoma (CTCL). DESIGN Prospective, open, multicenter study. SETTING Thirteen dermatology departments in France. PATIENTS Twenty-five patients with either (1) stage II to stage IV CTCL previously unsuccessfully treated with at least 2 lines of treatments or (2) histologically transformed epidermotropic CTCL requiring chemotherapy. INTERVENTION Administration of Caelyx intravenously once every 4 weeks at a dose of 40 mg/m(2). MAIN OUTCOME MEASURES The response to treatment was evaluated by clinical evaluation. RESULTS At the end of treatment, we observed an objective response (primary end point) in 56% of the patients (14 of 25): 5 complete responses and 9 partial responses. The median overall survival time was 43.7 months. For the 14 patients who experienced an objective response, the median progression-free survival time after the end of treatment was 5 months. CONCLUSIONS This prospective study demonstrates the effectiveness of Caelyx in treating CTCL, with an overall response rate of 56% in spite of the high proportion of patients with advanced-stage disease. Responses were observed in 2 subpopulations of patients in which the prognosis is known to be poorer: Sézary syndrome (overall response rate, 60%) and transformed CTCL (overall response rate, 50%). Moreover, this study shows that dose escalation to 40 mg/m(2) does not seem to improve the effectiveness but increases toxic effects (especially hematologic toxic effects) compared with the dose previously tested of 20 mg/m(2).

Brain magnetic resonance imaging in patients with Cowden syndrome.

Abstract: Cowden syndrome (CS) is a rare autosomal dominant genodermatosis, characterized by multiple hamartomas, particularly of the skin, associated with high frequencies of breast, thyroid, and genitourinary malignancies. Although Lhermitte-Duclos disease (LDD) or dysplastic gangliocytoma of the cerebellum, a slowly progressive unilateral tumor, is a major criterion of CS, its frequency in patients with CS is unknown. Other cerebral abnormalities, especially meningioma and vascular malformations, have also been described, albeit rarely, in these patients. The aim of the current study was to use cerebral magnetic resonance imaging (MRI) to evaluate LDD frequency and to investigate other brain abnormalities in CS patients recruited by dermatologists. A multicenter study was conducted in 8 hospital dermatology departments between January 2000 and December 2003. Twenty patients with CS were included; specific cerebral MRI abnormalities were found in 35% (7/20) of them. Cerebral MRI revealed LDD in 3 patients, a meningioma in 1, and numerous vascular malformations in 6 patients. Five patients had venous angiomas (3 associated with LDD) and 2 patients had cavernous angiomas (1 associated with LDD and a venous angioma). The discovery of asymptomatic LDD in 3 patients and a cavernous angioma in another prompted us to perform neurologic examinations regularly and MRI to estimate the size and the extension of the tumor, and to assess the need for surgery. CS similarities with Bannayan-Riley-Ruvalcaba (BRR) are discussed because some patients could also have the BRR phenotype (for example, genital lentigines, macrocephaly, multiple lipomas) and because BRR seems to have more central nervous system vascular anomalies. Because CS signs can involve numerous systems, all physicians who might encounter this disease should be aware of its neurologic manifestations. Our findings confirm the contribution of brain MRI to detecting asymptomatic LDD, vascular malformations, and meningiomas in patients with CS. Abbreviations: BRR = Bannayan-Riley-Ruvalcaba, CNS = central nervous system, CS = Cowden syndrome, CT = computed tomography, LDD = Lhermitte-Duclos disease, MRI = magnetic resonance imaging, PTEN = phosphatase and tensin homolog deleted on chromosome 10.

The kinetics of the visible growth of a primary melanoma reflects the tumor aggressiveness and is an independent prognostic marker: a prospective study.

Primary melanoma (MM) could be a good model to test an intuitive concept: a cancer that is growing fast in its early phase is likely to have a high aggressiveness. Since MMs are visible tumors, many patients can provide information to indirectly assess the kinetics of their lesion. A prospective study was designed to assess if the kinetics of the visible growth of a primary MM, as described by the patient, could be a noninvasive prognostic marker. The ratio of MM thickness to delay between MM appearance and MM removal was used as a surrogate value for the kinetics of the MM growth. To assess the delay between MM appearance and removal, 362 patients with self‐detected invasive MM fulfilled a detailed questionnaire, which provided 2 types of estimations of this delay and thus 2 melanoma kinetics indexes (MKI and MKI*). After a median follow‐up of 4 years, univariate and multivariate analyses assessed whether relapse‐free survival was linked to MKI or MKI*. MKI was significantly predictive of relapse‐free survival (HR = 1.84 [1.51–2.25]) and relapse at 1 year (RR = 2.93 [1.84–4.69]), independently from Breslow thickness. MKI was retained in multivariate prognostic models, just after thickness and before other usual markers. MKI* was also a significant independent risk marker, although less predictive. In this model, the initial growth kinetics of a cancer reflects its aggressiveness and a high index predicts a short‐term relapse. The “subjective” data obtained from patients about their MM history, although usually neglected, can thus provide a better prognostic marker than many “objective” tests.

Relevance of vertical growth pattern in thin level II cutaneous superficial spreading melanomas.

Thin (≤0.76 mm) level II cutaneous superficial spreading melanomas (SSMs) are known to be of excellent prognosis and very few recur, metastasize, or are lethal. Although many prognostic features at this stage have been studied, none appears to be statistically significant. The concept of tumor growth phase is correlated with Clarks level except for level II. SSM level II show either an invasive vertical growth phase or an invasive radial growth phase. The aim of our study (retrospective, multicenter, and case–control type) was to investigate the prognostic impact of vertical growth phase in thin level II cutaneous SSM. We identified 12 patients of poor outcome with complete initial excision. Each case was matched with three controls for gender, age, location, tumor thickness, and follow-up period since diagnosis. Independent pathologists studied all cases and controls. Univariate analyses were performed with a conditional logistic regression method. A kappa test was used to assess reproducibility between pathologists. Our study is the first and largest that shows that vertical growth phase is the only statistically significant prognostic factor for thin level II cutaneous SSM. We propose that growth phase evaluation (a minimum of eight serial sections being mandatory not to underdiagnose vertical growth phase) should be added to the recommendations for melanoma histologic report, at least for level II SSM.

Bone Marrow Histopathologic and Molecular Staging in Epidermotropic T-Cell Lymphomas

This study was undertaken to determine the prognostic value of bone marrow histopathologic and molecular analyses in 53 patients with mycosis fungoides and 7 with Sézary syndrome. Bone marrow was involved in only 1 patient with Sézary syndrome, clinical stage IVA, before bone marrow biopsy. An ambiguous T-cell infiltrate was observed in 8 patients but was not associated with disease progression. The bone marrow specimen was normal in 51 patients. Monoclonality was detected in the skin specimen in 44 cases; an identical T-cell clone in the blood specimen was found in 21 of them and, in 16 of the 21 patients, in bone marrow specimens without histologic correlation. Multivariate analysis confirmed that clinical stage and detection by polymerase chain reaction of an identical T-cell clone in skin and blood specimens had an independent prognostic value. No further prognostic value was observed for the presence of a T-cell clone in bone marrow specimens. Our data do not support the need for bone marrow examination in patients with mycosis fungoides/Sézary syndrome.