Mark H. Greene

A study of tumor progression: The precursor lesions of superficial spreading and nodular melanoma

Six evident lesional steps of tumor progression form the neoplastic system that affects the human epidermal melanocyte: 1) the common acquired melanocytic nevus; 2) a melanocytic nevus with lentiginous melanocytic hyperplasia, i.e., aberrant differentiation; 3) a melanocytic nevus with aberrant differentiation and melanocytic nuclear atypia, i.e., melanocytic dysplasia; 4) the radial growth phase of primary melanoma; 5) the vertical growth phase of primary melanoma; and 6) metastatic melanoma. The common acquired melanocytic nevus is viewed as a focal proliferation of melanocytes, destined in most instances to follow a programmed pathway of differentiation that leads to disappearance of the nevus. If the pathway of differentiation is not followed, characteristic lesions result, and such lesions are regarded as the formal histogenetic precursors of melanoma. Such a developmental flaw is termed aberrant differentiation, and the resultant precursor lesion is designated melanocytic dysplasia. The vast majority of melanocytic nevi showing melanocytic dysplasia are terminal lesions that do not progress to melanoma. If melanoma is to develop via a precursor lesion, however, the nevus with melanocytic dysplasia is that precursor. When melanomas do develop, they develop focally within the precursor. The resultant primary melanoma itself does not follow a pathway of inexorable expansion of a population of melanoma cells in space and time. Rather, primary melanomas, with the exception of nodular melanoma, also evolve in a stepwise fashion. The first step, termed the radial growth phase, is characterized by the net enlargement of the tumor at its periphery, along the radii of an imperfect circle. Tumors in this stage of development show a characteristic pattern of growth within the epidermis and a distinctive form of invasion of the papillary dermis. Such melanomas are not associated with metastasis, and it is hypothesized that such tumors do not have competence for metastasis. For a melanoma to acquire competence for metastasis it must progress to the next step of tumor progression--the vertical growth phase. This lesional step is characterized by the appearance of a new population of cells within the melanoma, not an expansion of the cells forming the pre-existing radial growth phase. The net growth of the cells of the vertical growth phase is perpendicular to the directional growth of the radial growth phase. As a rule, the cells of the vertical growth phase grow in an expansile fashion, expansile as a balloon expands: a growth form characteristic of metastases.(ABSTRACT TRUNCATED AT 400 WORDS)

High Risk of Malignant Melanoma in Melanoma-Prone Families with Dysplastic Nevi

The risk of hereditary cutaneous malignant melanoma was evaluated in 401 members of 14 families with an autosomal dominant form of melanoma. We documented 127 primary melanomas in 69 family members, including 39 new melanomas diagnosed in 22 study participants from the time of first examination through a maximum of 8 years of follow-up. The 39 newly diagnosed melanomas occurred only in family members with dysplastic nevi, a known precursor of familial melanoma. Of 77 patients with dysplastic nevus syndrome without prior melanomas, 4 developed their first melanoma during prospective follow-up, as compared with 0.03 cases expected. The prospective age-adjusted incidence for melanoma was 14.3/1000 patients with dysplastic nevus per year, with a cumulative melanoma risk (+/- SE) of 7.2% (+/- 3.6) at 8 years. The actuarial probability of melanoma developing in family members with dysplastic nevi was 56.0% (+/- 10.1) from age 20 to age 59. This study confirms that dysplastic nevi are clinical markers of high risk for, and precursors of, hereditary melanoma.

Dysplastic nevus syndrome: a phenotypic association of sporadic cutaneous melanoma.

Clinical photographs of 79 prospectively studied cases of non‐familial cutaneous malignant melanoma were reviewed; special attention was directed to the distribution pattern of coexistent melanocytic lesions. A group of 15 patients had moles on the covered buttock area. Seven of these patients had large clinically atypical nevi, and biopsies of these nevi showed severe melanocytic dysplasia. Residual elements of melanocytic dysplasia were identified in five of the primary melanomas in this group of patients. It is suggested that these patients represent a distinctive syndrome, the Dysplastic Nevus Syndrome (DNS) and that they are at increased risk for development of primary cutaneous malignant melanoma. The clinically and histologically distinctive dysplastic nevi of these patients are identical to the precursor lesion for melanoma that we have previously described in a familial context, the B‐K mole syndrome. This paper represents the first description of this form of dysplasia in non‐familial melanoma.

Acquired precursors of cutaneous malignant melanoma: the familial dysplastic nevus syndrome

THE incidence of cutaneous malignant melanoma is rising rapidly throughout the world.1 The most current data from the National Cancer Institutes Surveillance Epidemiology and End Results (SEER) sy...

Mapping the gene for hereditary cutaneous malignant melanoma-dysplastic nevus to chromosome 1p

We used molecular genetic techniques and multipoint linkage analyses to locate the gene responsible for cutaneous malignant melanoma-dysplastic nevus. We evaluated 99 relatives and 26 spouses in six families with a predisposition to melanoma. Thirty-four family members had cutaneous malignant melanoma, and 31 of these 34 also had histologically confirmed dysplastic nevi. Twenty-four family members had dysplastic nevi alone. An analysis of the cosegregation of the cutaneous malignant melanoma-dysplastic nevus trait with 26 polymorphic DNA markers on the short arm of chromosome 1 demonstrated the presence of a gene for susceptibility to melanoma. The gene was located between an anonymous DNA marker (D1S47) and the gene locus for pronatrodilatin, a commonly used reference gene (PND), in chromosome band 1p36. The odds were greater than 260,000:1 in favor of linkage at this location.

Association between BRCA1 and BRCA2 mutations and survival in women with invasive epithelial ovarian cancer

CONTEXT Approximately 10% of women with invasive epithelial ovarian cancer (EOC) carry deleterious germline mutations in BRCA1 or BRCA2. A recent article suggested that BRCA2-related EOC was associated with an improved prognosis, but the effect of BRCA1 remains unclear. OBJECTIVE To characterize the survival of BRCA carriers with EOC compared with noncarriers and to determine whether BRCA1 and BRCA2 carriers show similar survival patterns. DESIGN, SETTING, AND PARTICIPANTS A pooled analysis of 26 observational studies on the survival of women with ovarian cancer, which included data from 1213 EOC cases with pathogenic germline mutations in BRCA1 (n = 909) or BRCA2 (n = 304) and from 2666 noncarriers recruited and followed up at variable times between 1987 and 2010 (the median year of diagnosis was 1998). MAIN OUTCOME MEASURE Five-year overall mortality. RESULTS The 5-year overall survival was 36% (95% CI, 34%-38%) for noncarriers, 44% (95% CI, 40%-48%) for BRCA1 carriers, and 52% (95% CI, 46%-58%) for BRCA2 carriers. After adjusting for study and year of diagnosis, BRCA1 and BRCA2 mutation carriers showed a more favorable survival than noncarriers (for BRCA1: hazard ratio [HR], 0.78; 95% CI, 0.68-0.89; P < .001; and for BRCA2: HR, 0.61; 95% CI, 0.50-0.76; P < .001). These survival differences remained after additional adjustment for stage, grade, histology, and age at diagnosis (for BRCA1: HR, 0.73; 95% CI, 0.64-0.84; P < .001; and for BRCA2: HR, 0.49; 95% CI, 0.39-0.61; P < .001). The BRCA1 HR estimate was significantly different from the HR estimated in the adjusted model (P for heterogeneity = .003). CONCLUSION Among patients with invasive EOC, having a germline mutation in BRCA1 or BRCA2 was associated with improved 5-year overall survival. BRCA2 carriers had the best prognosis.

Common Breast Cancer-Predisposition Alleles Are Associated with Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Germline mutations in BRCA1 and BRCA2 confer high risks of breast cancer. However, evidence suggests that these risks are modified by other genetic or environmental factors that cluster in families. A recent genome-wide association study has shown that common alleles at single nucleotide polymorphisms (SNPs) in FGFR2 (rs2981582), TNRC9 (rs3803662), and MAP3K1 (rs889312) are associated with increased breast cancer risks in the general population. To investigate whether these loci are also associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers, we genotyped these SNPs in a sample of 10,358 mutation carriers from 23 studies. The minor alleles of SNP rs2981582 and rs889312 were each associated with increased breast cancer risk in BRCA2 mutation carriers (per-allele hazard ratio [HR] = 1.32, 95% CI: 1.20-1.45, p(trend) = 1.7 x 10(-8) and HR = 1.12, 95% CI: 1.02-1.24, p(trend) = 0.02) but not in BRCA1 carriers. rs3803662 was associated with increased breast cancer risk in both BRCA1 and BRCA2 mutation carriers (per-allele HR = 1.13, 95% CI: 1.06-1.20, p(trend) = 5 x 10(-5) in BRCA1 and BRCA2 combined). These loci appear to interact multiplicatively on breast cancer risk in BRCA2 mutation carriers. The differences in the effects of the FGFR2 and MAP3K1 SNPs between BRCA1 and BRCA2 carriers point to differences in the biology of BRCA1 and BRCA2 breast cancer tumors and confirm the distinct nature of breast cancer in BRCA1 mutation carriers.

Acute nonlymphocytic leukemia after therapy with alkylating agents for ovarian cancer: a study of five randomized clinical trials.

We evaluated the occurrence of acute nonlymphocytic leukemia (ANL) among 1399 women with ovarian cancer who were treated in five randomized clinical trials. Of the 1399 women, 998 had been treated with alkylating agents, and among these, 12 cases of ANL were observed; the expected number was 0.11. Ten patients with ANL had received melphalan, and two chlorambucil. ANL was not observed in 401 women who had been treated with surgery or radiation or both, without alkylating agents. The excess risk of ANL that was associated with alkylating-agent therapy was 5.8 cases per 1000 women per year, and the cumulative seven-year risk of ANL among patients who were treated with chemotherapy alone was indistinguishable from that observed in patients receiving both radiation and chemotherapy. A positive correlation between initial drug dose and the risk of ANL was suggested. These data underscore the need to assess other cytotoxic agents and regimens of drug administration to identify those that do not have harmful late effects.

Decreasing Risk of Leukemia with Prolonged Follow-up after Chemotherapy and Radiotherapy for Hodgkin's Disease

Acute nonlymphocytic leukemia is a recognized complication of combined chemotherapy and radiation treatment of patients with Hodgkins disease. Previous studies have suggested that the risk of leukemia in these patients increases with time after treatment. We analyzed the occurrence of second neoplasms among 192 patients with Hodgkins disease who were followed for a median of over 15 years. We originally planned to identify prospectively the morphologic changes in bone marrow that precede the development of acute leukemia. All 63 patients consenting to bone marrow aspiration had normal marrow morphology, and no case of acute leukemia occurred more than 11 years after treatment. Actuarial analysis revealed that the peak onset of leukemia-related complications was between three and nine years after first treatment. We conclude that there appears to be a period of increased risk in patients treated with chemotherapy and radiation, after which the risk of secondary leukemia decreases. Patients surviving for more than 11 years after treatment appear to be at no increased risk of acute leukemia.

Malignancies and survival patterns in the National Cancer Institute inherited bone marrow failure syndromes cohort study.

Fanconi anaemia (FA), dyskeratosis congenita (DC), Diamond‐Blackfan anaemia (DBA), and Shwachman‐Diamond syndrome (SDS) comprise major inherited bone marrow failure syndromes (IBMFS). Adverse events include severe bone marrow failure (BMF), myelodysplastic syndrome (MDS), acute myeloid leukaemia (AML), and solid tumours (ST). The natural history of FA is well characterised; hazard rates in the other syndromes have not yet been quantified. An open cohort was established at the National Cancer Institute (NCI) in 2002. Patients enrolled prior to December, 2007 were followed up to December, 2008. Diagnoses were confirmed with standard tests. Age‐associated risks of adverse events were calculated. Most patients in each syndrome survived to young adulthood. Patients with FA had earlier onset of cancers, need for stem cell transplant, and death; followed by DC; DBA and SDS were mildest. While FA and DC patients had markedly increased risks of cancer, AML and MDS, there were no cases of leukaemia in DBA or SDS patients. The NCI cohort provides the first direct quantitative comparison of timing and magnitude of cancer risk in the IBMFS. The findings demonstrate that both FA and DC are major cancer susceptibility syndromes. The IBMFS, historically considered paediatric disorders, have important management implications for physicians treating adult patients.