Vulvar melanoma, biologically different from other cutaneous melanomas

faecium, appropriate use of quinupristin/dalfopristin will require identification of enterococci to the species level, which is not routinely done in many microbiology laboratories. A further problem may be the reduced bactericidal activity of quinupristin/dalfopristin against strains of S aureus that have acquired the erm gene and express it constitutively (MLSB/C strains). These strains are resistant to both erythromycin and clindamycin, and their resistance to chemically diverse drugs reflects the overlapping ribosomal target sites of macrolides, lincosamides, and group B streptogramins (including quinupristin).11 This pattern of multiresistance has implications for dosing regimens, in that although the manufacturer’s product summary states that quinupristin/dalfopristin may be used twice daily for most skin or soft-tissue infections, it should be given three times a day for those due to MRSA resistant to erythromycin and clindamycin, and thus inferred to be MLSB/C strains. An additional concern is that resistance to quinupristin/dalfopristin has already been reported, both in E faecium and in staphylococci. Several mechanisms of resistance have been identified, including acetylation or efflux of dalfopristin and hydrolysis of quinupristin.12 Although streptogramin resistance is currently rare, reservoirs may have been preselected through use of the related drug virginiamycin as a growth promoter in farm animals, and the resistance may become more prevalent under the selective pressure of increasing quinupristin/ dalfopristin use. Despite these caveats, the effectiveness of quinupristin/dalfopristin against multiresistant grampositive pathogens, including MRSA and vancomycinresistant E faecium, is good news giving clinicians an additional agent against serious gram-positive infections. The availability of quinupristin/dalfopristin, and the likely licensing, within 1–5 years, of other agents active against gram-positive organisms give grounds for cautious optimism. Agents in the pipeline include oxazolidinones (linezolid), everninomicins (Ziracin), ketolides, anti-MRSA cephalosporins, daptomycin, and glycylcyclines. *Alan P Johnson, David M Liver more Antibiotic Resistance Monitoring and Reference Laboratory, Public Health Laboratory, Colindale, London NW9 5HT, UK 1

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Tomasz A. Multiple-antibiotic-resistant pathogenic bacteria: a report on the Rockefeller University Workshop. N Engl J Med 1994; 330: 1247–51. 2 Leclercq R, Courvalin P. Streptogramins: an answer to antibiotic resistance in gram-positive bacteria. Lancet 1998; 352: 591–92. 3 Nadler H, Dowzicky MJ, Feger C, Pease MR, Prokocimer P. Quinupristin/dalfopristin: a novel selective-spectrum antibiotic for the treatment of multi-resistant and other gram-positive pathogens. Clin Microbiol Newslett 1999; 13: 103–12. 4 Tenover FC, Lancaster MV, Hill BC, et al. Characterization of staphylococci with reduced susceptibilities to vancomycin and other glycopeptides. J Clin Microbiol 1998; 36: 1020–27. 5 Ploy MC, Grélaud C, Martin C, de Lumley L, Denis F. First clinical isolate of vancomycin-intermediate Staphylococcus aureus in a French hospital. Lancet 1998; 351: 1212. 6 Nichols RL, Graham DR, Barriere SL, et al. Treatment of hospitalised patients with complicated gram-positive skin and skin structure infections: two randomised, multicentre studies of quinupristin/dalfopristin versus cefazolin, oxacillin or vancomycin. J Antimicrob Chemother 1999; 44: 263–73. 7 Nichols RL. Optimal treatment of complicated skin and skin structure infections. J Antimicrob Chemother 1999; 44 (suppl A): 19–23. 8 Moellering RC, Linden PK, Reinhardt J, Blumberg EA, Bompart F, Talbot GH. The efficacy and safety of quinupristin/dalfopristin for

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the treatment of infections caused by vancomycin-resistant Enterococcus faecium. J Antimicrob Chemother 1999; 44: 251–61. 9 Moellering RC. Quinupristin/dalfopristin: therapeutic potential for vancomycin-resistant enterococcal infections. J Antimicrob Chemother 1999; 44 (suppl A): 25–30. 10 Rubinstein E, Prokocimer P, Talbot GH. Safety and tolerability of quinupristin/dalfopristin:administration guidelines. J Antimicrob Chemother 1999; 44 (suppl A): 37–46. 11 Low DE, Nadler HL. A review of in-vitro antibacterial activity of quinupristin/dalfopristin against methicillin-susceptible and resistant Staphylococcus aureus. J Antimicrob Chemother 1997; 39 (suppl A): 53–58. 12 Thal LA, Zervos MJ. Occurrence and epidemiology of resistance to virginiamycin and streptogramins. J Antimicrob Chemother 1997; 43: 171–76.

Vulvar melanoma, biologically different from other cutaneous melanomas Malignant melanoma may show a predisposition for vulvar skin. Although 3–7% of all melanomas in women affect the vulva, the skin in this area accounts for only 1–2% of the total surface area of the body.1 The unusual nature of vulvar melanoma and how it differs biologically from other cutaneous melanomas are highlighted in reports of a nationwide 25-year follow-up study of 219 Swedish women with primary melanoma of the vulva.2,3 The reports confirm previous data and add insight to the natural history of this rare tumour. In the Swedish cohort, there were 2·5 times as many vulvar melanomas as other cutaneous melanomas. During the period of the study, the incidence of cutaneous melanomas in women in Sweden increased by about 5% annually, whereas that of vulvar melanoma declined by about 3% annually. However, the prognosis of vulvar melanoma (47% 5-year survival) remained poorer than that for other cutaneous melanomas (80% 5year survival). Vulvar melanomas have been classified pathologically into superficial spreading melanomas, nodular melanomas, and mucosal lentiginous melanomas (MLM). MLM is histologically similar to acral lentiginous melanoma (ALM). In the Swedish series, MLM was the commonest type, followed by nodular melanoma. Superficial spreading melanoma was least common. This order is opposite to that for cutaneous melanoma in most series. The contrasting patterns of change in incidence of vulva melanomas and other cutaneous melanomas have been thought to indicate that MLM/ALM differ biologically from other cutaneous melanomas and that their pathogenesis is less dependent on DNA damage induced by ultraviolet light. Vulvar melanoma seems to have a stronger resemblance to primary anal melanoma disease; they are similar in clinical presentation and prognosis.4 Vulvar melanoma is generally a disease of older patients, with most studies recording a mean age of over 60 years at diagnosis.5 Likewise, in the Swedish study only 19 of the 219 patients were aged under 54 years. By contrast, the average age of female patients with cutaneous melanoma is younger.6 The Swedish study revealed several important clinical and histopathological findings. Malignant melanoma of the vulva presented as polypoid tumours in 35% of patients. Of special clinical note is that 27% of the tumours were macroscopically amelanotic. The commonest sites of disease were the clitoral area and the labia majora, which accounted for more than 60% of all lesions. Only 15% of tumours were located primarily in 2013

hair-bearing areas. The commonest symptoms of vulvar melanomas are similar to those of other vulvar neoplasias—a lump or mass that later bleeds and becomes itchy.7 The staging system most commonly used is the clinical one (stage I for tumour localised to the primary organ, stage II when spread is limited to regional nodes, and stage III when there is distant metastasis). Howe ve r ,t h e r e are at least three other staging systems—Clark’s original staging system for cutaneous melanomas based on five anatomical levels; Breslow’s, based on depth of invasion; and Chung’s based on level of histological involvement. Chung’s system may be the best on which to base management because it incorporates indicators that are prognostically significant for vulvar melanoma. FIGO staging, which is based on size and location of the lesion, and which is used for other neoplasias of the vulva, is of little prognostic value for melanomas in this area.8–11 Because of the retrospective nature of the Swedish data, only the clinical staging system could be analysed. 60% of patients had stage I disease. Univariate analysis for stage I disease showed that tumour thickness, ulceration, number of mitoses, amelanosis, pre-existing naevi, and age are significant predictors of survival. However, multivariate analysis showed that only tumour thickness, ulceration, and clinical amelanosis predict survival. The investigators correctly point out that these observations may have clinical implications on surgical excision for vulvar melanoma, since variables such as ulceration and amelanosis had not been considered in the past. There are no good comparative data on treatment for vulvar melanoma because of the rarity of this tumour. Over the past few decades, the trend in surgical management has been to become less radical. Because of the high recurrence rates and the possibility of distant metastases, radical vulvectomy with lymph-node dissection, once thought appropriate treatment, has been superseded by wide local excision, which gives the same survival benefits with less morbidity.12 In patients with superficial lesions, several studies showed a difference in effect between wide excision and more radical treatments. Because it is associated with a high risk of recurrence, radical surgery is recommended for patients with deeply invasive lesions only as a means of controlling local symptoms.12–15 The Swedish investigators had difficulty in drawing strong conclusions from their study because various treatment strategies were adopted. Howe ve r ,u n i va ri ate analysis did not reveal any significant differences in recurrence or survival between the three largest treatment subgroups (hemivulvectomy plus wide excision, partial or total vulvectomy, or vulvectomy plus elective lymphadenectomy). Although melanoma is an unusual cancer of the vulva, early diagnosis can certainly improve survival.6 Any new vulvar lesion should thus be confirmed histologically. The tumour does not always arise in a naevus, but any pigmented lesion in the vulva that undergoes a change should be biopsied. Many vulvar melanomas may be polyploid and a high percentage are amelanotic. Although the Swedish study has highlighted several important differences between vulvar melanoma and cutaneous melanoma that should help to direct surgical care, other approaches should not be neglected. Judged against historical controls, immunotherapy increased median survival in patients with recurrent and advanced 2014

cutaneous melanoma.16 Phase III trials of vaccine therapy are in progress. Patients with vulvar melanoma could be considered candidates for such trials. *Charles J Dunton, David Berd Divisions of *Gynecologic Oncology and Medical Oncology at Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA 1

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Tasseron EWK, van der Esch EP, Hart A A M ,B rutel de la Riviere G, Aartsen EJ. A clinicopathological study of 30 melanomas of the vulva. Gynecol Oncol 1992; 46: 170–75. Ragnarsson-Olding BK, Nilsson BR, Kanter-Lewensohn LR, Lagerlöf B, Ringborg UK. Malignant melanoma of the vulva in a nationwide,25-year study of 219 Swedish females. Cancer 1999; 86: 1285–93. Ragnarsson-Olding BK, Kanter-Lewensohn LR, Lagerlöf B, Nilsson BR, Ringborg UK. Malignant melanoma of the vulvar in a nationwide,25-year study of 219 Swedish females. Cancer 1999; 86: 1273–84. Cagir B, Whiteford MH, Topham A, Rakinic J, Fry RD. Changing epidemiology of anorectal melanoma. Dis Colon Rectum 1999; 42: 1203–08. Piura B, Egan M, Lopes, Monagham JM. Malignant melanoma of the vulva: a clinicopathologic study of 18 cases. J Surg Oncol 1992; 50: 234–40. Mastrangelo MJ, Bellet RE, Berd D. Prognostic factors. I n :C l a r k WH, Goldman LI, Mastrangelo JM, eds. Human malignant melanoma. New Yo r k :G rune and Strat t o n ,1 9 7 9 . Bacchi CE, Goldfogel GA, Greer BE, Gown AM. Paget’s disease and melanoma of the vulva. Gynecol Oncol 1992; 46: 216–21. Clark WH, From L, Bernardino EA, Mihm MC. The histogenesis and biologic behavior of primary human malignant melanomas of the skin. Cancer Res 1969; 29: 705–27. Breslow A.Thickness, cross-sectional areas, and depth of invasion in the prognosis of cutaneous melanoma. Ann Surg 1970; 172: 902–06. Chung AF, Woodruff JM, Lewis JL. Malignant melanoma of the vulva. Obstet Gynecol 1975; 45: 638–46. Rogo KO, Andersson R, Edbom G, Stendahl U. Conservative surgery for vulvovaginal melanoma. Eur J Gynaecol Oncol 1991; 12: 113–19. Rose PG, Piver MS, Tsukada Y, Lau T. Conservative therapy for melanoma of the vulva. Am J Obstet Gynecol 1988; 159: 52–55. Look KY, Roth LM, Sutton GP. Vulvar melanoma reconsidered. Cancer 1 9 9 3 ;7 2 :1 4 3 – 4 6 . Trimble EL, Lewis JL Jr, Williams LL, et al. Management of vulvar melanoma. Gynecol Oncol 1992; 45: 254–58. Davidson T, Kissin M, Westbury G. Vulvo-vaginal melanoma: should radical surgery be abandoned? Br J Obstet Gynaecol 1987; 94: 473–76. Berd D, Maguire HC, Schuchter LM, et al. Autologous,haptenmodified melanoma vaccine as post-surgical adjuvant treatment after resection of nodal metastases. J Clin Oncol 1 9 9 7 ;1 5 :2 3 5 9 – 7 0 .

Second thoughts about safety of St John’s wort St John’s wort (Hypericum perforatum) has been phenomenally successful as a herbal antidepressant. In the USA sales increased by 2800% in 1 year,1 and in Europe total sales figures were around US$6 billion in 1998.2 There are few doubts about the efficacy of hypericum extracts. In 1996, a meta-analysis of 15 placebo-controlled trials reported an odds ratio of 2·7 (95%CI 1·8–4·0) in favour of hypericum extracts, and six equivalence trials suggested that hypericum extracts are as effective as conventional antidepressants.3 The mode of action for hypericum extracts is thought to be similar to that of conventional serotonin-reuptake inhibitors; in various biological depression models hypericum extracts weakly inhibit the activities of A and B monoamine oxidases but strongly inhibit serotonin reuptake into the synapse.4 The meta-analysis3 and another comprehensive analysis5 strongly implied that hypericum extracts are associated with substantially fewer adverse effects than synthetic antidepressants. However, their safety has recently been questioned. Several reports have raised the

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