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Lentigo Maligna Melanoma

LMM

Lentigo maligna melanoma (LMM) is a type of skin cancer arising in chronically sun-exposed areas like the face, neck, forearms, and hands. It develops from a precursor lesion called lentigo maligna (LM) and usually corresponds to a pigmented plaque or nodule. The surgical removal of the tumor is the mainstay of therapy. Even though wide surgical margins may be difficult to achieve, LMM is associated with a favorable prognosis.


Presentation

LMM arises from LM, a slowly growing and variably pigmented macule that almost exclusively develops on chronically sun-damaged skin of the head and neck region [1]. LM may be present for years before transforming into LMM; it is an indolent, rather small lesion that may not overly concern the patient [2]. There are no macroscopic features that would unequivocally confirm the transition from LM to LMM, although the loss of symmetry and regular borders, changes in pigmentation, the progressive elevation above surrounding skin, and an acceleration in growth may provide valuable hints to this end. Vertical growth giving rise to nodularity is a sign of dermal invasion. It is not to be expected in mere LM, but should neither be considered an exclusion criterion for LMM: The latter may remain in the radial growth phase for years. What's more, LMM may simultaneously grow and regress in a pattern that makes the lesion appear to move across the skin [3]. The spectrum of colors ranges from light to darker brown to black, though pink and amelanotic LMM have also been described [4].

Loss of Appetite
  • […] therefore lead to a build-up of lymph causing swelling (lymphedema) Chemotherapy: Drugs are used to kill the tumor cells, which may be given as oral pills, or injected into veins Side effects of chemotherapy may include nausea, vomiting, hair loss, loss[dovemed.com]
Hypopigmented Macule
  • ALMM requires early clinical suspicion and histopathologic confirmation of diagnosis in every patient presenting with a slowly enlarging erythematous or hypopigmented macule, especially when located on the face of an older woman with a light complexion[ncbi.nlm.nih.gov]

Workup

The distinction of LMM, LM, and other lesions on sun-damaged skin may pose a major challenge. The presurgical diagnosis is based on a thorough clinical, dermoscopic, and confocal evaluation and the histopathological analysis of biopsy samples [1] [5] [6]. With regard to the latter, incisional biopsies involving more or less extensive parts of the lesions and a margin of clinically normal-appearing skin are most commonly performed. Complete excisional biopsies may provide even more reliable information as to the presence and distribution of atypical melanocytes, but they are more difficult to obtain. In the presence of high-risk features, additional biopsies of sentinel lymph nodes may be realized to detect subclinical metastases [2].

With regards to skin biopsies, the following may be expected [2] [7]:

  • LMM consist of large atypical melanocytes initially proliferating along the lower layers of the epidermis and up to the hair follicles, but eventually invading the dermis. Melanocytic markers such as S100, MITF, Melan A, and HMB45 may be used to confirm the origin of degenerated cells.
  • The abnormally high density of melanocytes, which tend to group in nests, may help to demarcate the tumor and to distinguish LM and LMM from non-malignant actinic lesions. This is particularly important because most LMM are embedded in chronically sun-damaged skin, which shares many features with the neoplasm. Increased pigmentation of basal keratinocytes, atrophy of the epidermis, and solar elastosis are frequent background features related to chronic sun exposure and skin damage.
  • Both melanocytes and keratinocytes may contain giant granules filled with melanin, which are called macromelanosomes.
  • Desmoplasia may be noted in adjacent regions.

Treatment

Radical surgical removal is the first choice of treatment but may be impeded by the location of the tumor. Staged excision is thus preferred in many cases, i.e., the tumor is removed in two or more sessions [7]. After each surgery, the excision specimen is histopathologically examined. If surgical margins are not free of tumor cells, another intervention is scheduled for the following day. This procedure is associated with optimum preservation of healthy tissues and high rates of cure. Alternatively, Mohs micrographic surgery may be performed. The idea is similar, but instead of taking longer breaks between multiple interventions, the patient awaits for the results of tissue processing and evaluation, and the excision of LMM is concluded in a single procedure. A potential pitfall of this approach is the difficulty of identifying LMM using en face frozen sections [2]. Most studies show low rates of recurrence after Mohs micrographic surgery, in the range of 0.5 to 6.3% [7]. Once margins are histologically clear, both staged excision and Mohs micrographic surgery must be followed by skin reconstruction. Methods include healing by secondary intention, primary repair, skin grafts, local flaps, and distant flap.

Due to the advanced age of many LMM patients, non-surgical management is frequently considered. In this context, topical imiquimod may be combined with cryosurgery, laser ablation, or radiotherapy. Topical imiquimod has been shown to induce clinical and histological clearance in up to 74% of patients with LM [8], but the prognosis is likely to be less favorable in case of LMM - even if combined with additional therapeutic procedures. Recurrence rates in the range of 20 to 100% have been reported for non-surgical LMM therapy, and thus, it should be carefully revised whether or not a patient is truly "unfit for surgery" [7].

In any case, monitoring for disease clearance and recurrence is paramount and can be achieved using dermoscopy and confocal microscopy [2]. The mean time to local recurrence has been reported to be almost five years for LM and thin LMM, but more than a decade may pass until the relapse [9]. Hence, lifelong surveillance is recommended. Follow-ups should take place every 3 to 6 months for the first two years after therapy and annually thereafter [3].

Prognosis

LMM is a slowly-growing type of skin cancer, and most patients are diagnosed with in situ melanoma or stage 0 disease, which has an extremely positive effect on the outcome. Post-surgical recurrence rates are low, and cosmetic issues can generally be resolved. Even in case of recurrence, the incidence of invasive disease is low among patients who previously underwent surgery, and their prognosis remains favorable [9].

Notwithstanding, LMM may grow invasively and has metastatic potential [10] [11]. Advanced-stage LMM is associated with the same detrimental prognosis as other malignant melanoma, with maximum Breslow thickness being one of the most important prognostic factors [1].

Etiology

The development of LM involves the proliferation of atypical melanocytes along the basal layer of the epidermis. Its transformation into LMM is characterized by the progression of degenerated cells beyond the epidermis, i.e., by the invasion of adjacent tissues [1]. The lifetime risk of LM patients to develop LMM decreases with age and ranges between 2-5% [8].

The molecular mechanisms behind LM and LMM development could not yet be clarified. Mutations, as induced by ultraviolet radiation, of stem cells in the hair follicle have recently been suggested as a possible starting point of tumorigenesis [12]. Other hypotheses refer to primitive melanoblasts as the cells of origin.

Epidemiology

LMM accounts for 4–15% of cutaneous melanomas [7]. At the time of diagnosis, the vast majority of patients is older than 65 years, and the individual risk of developing LMM augments with age [2]. Rising life expectancy and the more frequent relocation of retirees to warmer locations with higher cumulative ultraviolet light exposure have been named as possible causes of the global increase of LMM incidence rates [7]. In detail, the annual incidence of LMM has recently been estimated at 1.2 and 4.7 per 100,000 inhabitants of the Netherlands and Australia, respectively [13] [14]. LMM incidence rates have been observed to increase by as much as 12.4% per year among the Dutch population [13]. Gender preference varies between distinct countries; in Australia, males are affected up to three times as often as females, while no differences between sexes were observed in Holland [13] [14].

Sex distribution
Age distribution

Pathophysiology

Little is known about the pathogenesis of LMM. The study of differences in gene-expression patterns of LM and LMM revealed a downregulation of p53, p16, and Bax, which are all involved in the cellular stress response. At the same time, an upregulation of Bcl-2 may be observed. These changes imply a progressive loss of the cell's ability to respond to stress and reduced sensitivity towards apoptosis. Loss of function of PTEN may further disturb the regulation of cell proliferation and survival, but the triggers of these changes remain unclear. In sum, tumor cells may accumulate more than 100,000 somatic mutations, and primary oncogenic mutations tend to affect proto-oncogenes NRAS and KIT instead of BRAF [15].

Prevention

Sun exposure, light skin with freckles, and propensity towards the development of lentigines have been identified as risk factors for LM and LMM [2]. Beyond that, LMM patients are more likely to have a history of non-melanoma skin cancers than comparable patient populations [7]. Among these factors, sun exposure is the easiest target of preventive actions. The general population should be educated accordingly, should be encouraged to use sunscreen, wear sunglasses and hats as well as long-sleeved clothes, and to avoid sunlight exposure during the peak hours of ultraviolet radiation. Such measures should be taken throughout life.

Summary

LMM is the most common presentation of cutaneous melanomas with cumulative sun-induced damage [15]. Here, a pigmented macule comprising a subtle proliferation of single intraepidermal melanocytes transforms into invasive melanoma with accelerated radial and vertical growth. It may take years or even decades until this transformation occurs. The primary lesion is LM, and both environmental and genetic factors may trigger profound changes in the tumor's growth characteristics. Further research is required to identify these factors and to understand their interactions, with current knowledge not allowing for reliable conclusions as to the individual risk and time of transformation, or the likelihood of aggressive growth and the formation of metastasis. Accordingly, close monitoring is recommended for all LM and LMM patients, both before and after treatment. If at all possible, the tumor should be removed in its entirety, and the clearance of excision margins should be confirmed histologically.

Patient Information

Lentigo maligna melanoma (LMM) is a type of skin cancer. It arises from lentigo maligna, a non-invasive lesion almost exclusively developing on chronically sun-damaged skin. Lentigo maligna typically corresponds to an indolent, pigmented macule in the head and neck region and is related to a favorable prognosis. It may be present for decades before transforming into invasive LMM, a tumor with metastatic potential. This transformation may be associated with evident changes of the lesion, e.g., more pronounced pigmentation, the progressive elevation above surrounding skin or invasion of deeper layers, and an acceleration in growth - or it may go unnoticed. Indeed, the distinction of lentigo maligna and LMM poses a major challenge even to experienced dermatologists. It is thus of major importance to seek medical advice and a thorough evaluation of anomalies of the skin, especially if their appearance is changing.

The surgical removal of LMM is the mainstay of therapy. Because it may be difficult to establish the margins of LMM, it is usually resected in multiple operations. After each intervention, the excision specimen is microscopically examined for the presence of tumor cells in the peripheral regions. This procedure is repeated until all margins are found to be clear from tumor cells. The post-surgical management of LMM involves measures of skin reconstruction and regular evaluations for possible recurrence. It is important to note that recurrence may occur years after the initial diagnosis and surgery, so patients and physicians need to remain alert to any changes of the scar or adjacent skin.

The causes of LMM are incompletely understood. Notwithstanding, prolonged exposure to sunlight is known to be a major risk factor for this type of skin cancer and a variety of other diseases. The best way to prevent the development of lentigo maligna and LMM thus is the consistent use of sun protection and the avoidance of sunlight exposure during the peak hours of ultraviolet radiation.

References

Article

  1. Star P, Guitera P. Lentigo Maligna, Macules of the Face, and Lesions on Sun-Damaged Skin: Confocal Makes the Difference. Dermatol Clin. 2016; 34(4):421-429.
  2. Connolly KL, Nehal KS, Busam KJ. Lentigo maligna and lentigo maligna melanoma: contemporary issues in diagnosis and management. Melanoma Manag. 2015; 2(2):171-178.
  3. Juhász ML, Marmur ES. Reviewing Challenges in the Diagnosis and Treatment of Lentigo Maligna and Lentigo-Maligna Melanoma. Rare Cancers Ther. 2015; 3:133-145.
  4. Ponzo MG, Crawford RI, Kossintseva I. Amelanotic Lentigo Maligna Melanoma: Mohs Surgery as the Definitive Treatment of an Invisible Tumour. J Cutan Med Surg. 2018; 22(1):51-57.
  5. Pralong P, Bathelier E, Dalle S, Poulalhon N, Debarbieux S, Thomas L. Dermoscopy of lentigo maligna melanoma: report of 125 cases. Br J Dermatol. 2012; 167(2):280-287.
  6. Zoutendijk J, Tio D, Koljenovic S, van den Bos RR. Nine percent of biopsy proven lentigo maligna are reclassified as lentigo maligna melanoma after surgery. Br J Dermatol. 2019.
  7. McGuire LK, Disa JJ, Lee EH, Busam KJ, Nehal KS. Melanoma of the lentigo maligna subtype: diagnostic challenges and current treatment paradigms. Plast Reconstr Surg. 2012; 129(2):288e-299e.
  8. Tio D, van der Woude J, Prinsen CAC, Jansma EP, Hoekzema R, van Montfrans C. A systematic review on the role of imiquimod in lentigo maligna and lentigo maligna melanoma: need for standardization of treatment schedule and outcome measures. J Eur Acad Dermatol Venereol. 2017; 31(4):616-624.
  9. Connolly KL, Hibler BP, Lee EH, Rossi AM, Busam KJ, Nehal KS. Locally Recurrent Lentigo Maligna and Lentigo Maligna Melanoma: Characteristics and Time to Recurrence After Surgery. Dermatol Surg. 2017; 43(6):792-797.
  10. Abdaal A, Price RD, Durrani AJ. Rapid recurrence of Lentigo Maligna Melanoma – A case report. JPRAS Open. 2017; 13:106-110.
  11. Albert LS, Fewkes J, Sober AJ. Metastatic lentigo maligna melanoma. J Dermatol Surg Oncol. 1990; 16(1):56-58.
  12. Bongiorno MR, Doukaki S, Malleo F, Arico M. Identification of progenitor cancer stem cell in lentigo maligna melanoma. Dermatol Ther. 2008; 21 Suppl 1:S1-5.
  13. Greveling K, Wakkee M, Nijsten T, van den Bos RR, Hollestein LM. Epidemiology of Lentigo Maligna and Lentigo Maligna Melanoma in the Netherlands, 1989-2013. J Invest Dermatol. 2016; 136(10):1955-1960.
  14. Guitera P, Collgros H, Madronio CM, et al. The steadily growing problem of lentigo maligna and lentigo maligna melanoma in Australia: Population-based data on diagnosis and management. Australas J Dermatol. 2018.
  15. Bastian BC. The molecular pathology of melanoma: an integrated taxonomy of melanocytic neoplasia. Annu Rev Pathol. 2014; 9:239-271.

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Last updated: 2019-07-11 20:38