Distinguishing lentigo maligna (LM) and lentigo maligna melanoma (LMM) from background pigmented non-melanoma lesions is challenging. The field of solar damage can obscure clinical assessment, and diagnostic ambiguities are created due to the overlap of the clinical features of LM with other benign lesions. Moreover, margin assessment on histology is limited by the resemblance between melanocytic hyperplasia of actinically damaged skin and scattered atypical melanocytes of LM/LMM. Dermoscopy has made a significant contribution but is often not sufficient for diagnosis and margin assessment. Confocal microscopy has become an important complementary tool in enhancing the management of these complex lesions.
Key points
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Lentigo maligna (LM) and lentigo maligna melanoma (LMM) often resemble one another and are difficult to distinguish from solar-induced macules of the face, clinically, and on dermoscopy and histopathology.
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LM/LMM has the highest recurrence rate of all melanoma subtypes despite treatment, reflecting the diagnostic and treatment ambiguities this lesion presents.
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In vivo reflectance confocal microscopy addresses many of the complexities and challenges of LM/LMM, enhancing patient care at all stages of diagnosis and management.
Introduction
Lentigo maligna (LM) is defined as a form of melanoma in situ that presents as a slowly growing variably pigmented macule typically on the sun-damaged skin of the elderly, most commonly on the head and neck. LM involves the proliferation of atypical malignant melanocytes along the basal layer of the epidermis. Lentigo maligna melanoma (LMM) is defined as the invasive progression of LM, whereby atypical melanocytes are no longer confined to the epidermis.
The incidence of LM is estimated to be approximately 13.7 per 100,000 person-years but is difficult to confirm due to incomplete data collection for in situ melanoma in most cancer registries. Evidence suggests that LM/LMM is underestimated, and LM rates are likely to increase with an aging population in most high-income countries. Although LM grows slowly, once invasive, it has the same prognosis as other malignant melanoma in terms of metastatic potential, when adjusted for Breslow thickness.
Due to shared aetiology of UV exposure and age, LM typically copresents with general solar and aged-induced macules and lesions, which include solar lentigines (SL), pigmented actinic keratosis (PAK), seborrheic keratosis (SK), lichen planus-like keratosis (LPLK), as well as freckles and generalized UV-induced pigmentation. The borders of LM are frequently obscured by their collision with these lesions and emergence on photo-damaged skin.
Distinguishing melanocytic hyperplasia in actinically damaged skin from atypical melanocytes, especially in the peripheries of LM, is difficult on histopathology. There is significant controversy about what constitutes a negative margin. This controversy is reflected in high discordance rates between pathologists in interpreting excision margins. The high recurrence rate of LM after conventional surgery, estimated to be between 8% and 31%, indicates more accurate margin assessment is needed.
Dermoscopy has made significant progress in distinguishing LM/LMM from benign pigmented macules of the face. Schiffner and colleagues demonstrated the 4 main dermatoscopic criteria enabling 93% of lesions to be correctly identified as LM (sensitivity of 89% and specificity of 96%), while the vascular features on dermoscopy added by Pralong and colleagues are particularly beneficial in assessing amelanotic LM/LMM peripheries, devoid of pigment.
There are several other studies producing dermatoscopic criteria against which the ability to distinguish LM from pigmented macules of the face are tested. However, dermoscopy is limited by the overlap of features between benign and malignant lesions. For example, the dermatoscopic features including gray color, gray circles, and annular granular structures can be seen in PAK and LM. Similarly, the hyperpigmented rim of follicular openings of LM/LMM can be mistaken for pseudofollicular openings of SK.
There are multiple controversial issues with the time line of the disease and its progression from benign solar damage to fully invasive LMM. Early LM is extremely subtle and may involve a gradual increase in the number of individual melanocytes at the dermoepidermal junction (DEJ). Some atypical cells may be present. However, these features are also seen in severely sun-damaged skin. Reflectance confocal microscopy (RCM) is well suited to assessing the morphology and subtle or complex features of a macule such as LM. It also enables the visualization of cellular features that differentiate LM/LMM from its pigmented counterparts. RCM generates a horizontal (enface) view of at least 8 × 8 mm from stratum corneum to the level of the upper dermis at cellular resolution, an approximate depth of 250 μm, which is appropriate for assessing the radial spread of LM throughout the epidermis, often over very large areas.
Introduction
Lentigo maligna (LM) is defined as a form of melanoma in situ that presents as a slowly growing variably pigmented macule typically on the sun-damaged skin of the elderly, most commonly on the head and neck. LM involves the proliferation of atypical malignant melanocytes along the basal layer of the epidermis. Lentigo maligna melanoma (LMM) is defined as the invasive progression of LM, whereby atypical melanocytes are no longer confined to the epidermis.
The incidence of LM is estimated to be approximately 13.7 per 100,000 person-years but is difficult to confirm due to incomplete data collection for in situ melanoma in most cancer registries. Evidence suggests that LM/LMM is underestimated, and LM rates are likely to increase with an aging population in most high-income countries. Although LM grows slowly, once invasive, it has the same prognosis as other malignant melanoma in terms of metastatic potential, when adjusted for Breslow thickness.
Due to shared aetiology of UV exposure and age, LM typically copresents with general solar and aged-induced macules and lesions, which include solar lentigines (SL), pigmented actinic keratosis (PAK), seborrheic keratosis (SK), lichen planus-like keratosis (LPLK), as well as freckles and generalized UV-induced pigmentation. The borders of LM are frequently obscured by their collision with these lesions and emergence on photo-damaged skin.
Distinguishing melanocytic hyperplasia in actinically damaged skin from atypical melanocytes, especially in the peripheries of LM, is difficult on histopathology. There is significant controversy about what constitutes a negative margin. This controversy is reflected in high discordance rates between pathologists in interpreting excision margins. The high recurrence rate of LM after conventional surgery, estimated to be between 8% and 31%, indicates more accurate margin assessment is needed.
Dermoscopy has made significant progress in distinguishing LM/LMM from benign pigmented macules of the face. Schiffner and colleagues demonstrated the 4 main dermatoscopic criteria enabling 93% of lesions to be correctly identified as LM (sensitivity of 89% and specificity of 96%), while the vascular features on dermoscopy added by Pralong and colleagues are particularly beneficial in assessing amelanotic LM/LMM peripheries, devoid of pigment.
There are several other studies producing dermatoscopic criteria against which the ability to distinguish LM from pigmented macules of the face are tested. However, dermoscopy is limited by the overlap of features between benign and malignant lesions. For example, the dermatoscopic features including gray color, gray circles, and annular granular structures can be seen in PAK and LM. Similarly, the hyperpigmented rim of follicular openings of LM/LMM can be mistaken for pseudofollicular openings of SK.
There are multiple controversial issues with the time line of the disease and its progression from benign solar damage to fully invasive LMM. Early LM is extremely subtle and may involve a gradual increase in the number of individual melanocytes at the dermoepidermal junction (DEJ). Some atypical cells may be present. However, these features are also seen in severely sun-damaged skin. Reflectance confocal microscopy (RCM) is well suited to assessing the morphology and subtle or complex features of a macule such as LM. It also enables the visualization of cellular features that differentiate LM/LMM from its pigmented counterparts. RCM generates a horizontal (enface) view of at least 8 × 8 mm from stratum corneum to the level of the upper dermis at cellular resolution, an approximate depth of 250 μm, which is appropriate for assessing the radial spread of LM throughout the epidermis, often over very large areas.
Confocal makes the difference through several applications
Differentiating Lentigo Maligna from Benign Macules of the Face and Solar Damage
It is important to differentiate LM/LMM from benign macules and solar damage. Diagnostic ambiguities can lead to unnecessary excisions of LM-like benign macules, which can carry surgical morbidly in the elderly patient and cosmetic issues on sensitive areas of the face. Similarly, erroneous diagnosis of LM as a benign macule can lead to inappropriate management and delayed melanoma diagnosis.
There are numerous case series examining the RCM features of benign lesions and solar damage in correlation with histopathology and/or dermoscopy, including the following:
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SK ( Fig. 1 )
Fig. 1
Seborrheic keratosis. ( A ) Confocal image, 0.5 × 0.5 mm, of a SK with broadened honeycomb pattern in the epidermis. ( B ) Confocal images in a 4 × 4-mm mosaic of a SK in the epidermis showing cysts ( red arrows ), crypts ( green arrows ), and bulbous projections ( circle ). ( C ) Confocal images in a 2 × 2-mm mosaic of a SK in the DEJ showing a ringed pattern ( red arrow ).
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Actinic keratosis (AK) ( Fig. 2 )
Fig. 2
Actinic keratosis. ( A ) Confocal images in a 0.5 × 0.5 mm mosaic of an actinic keratinocyte showing detached corneocytes ( red arrow ) and parakeratosis ( green arrow ) in the stratum corneum. ( B ) Confocal images in a 0.5 × 0.5 mm mosaic of an actinic keratinocyte showing architectural disarray and atypical honeycomb pattern at the level of the stratum granulosum. ( C ) Confocal images of 0.5 × 0.5 mm at the DEJ, showing irregularly shaped keratinocytes ( red arrow ) around hair follicles ( green arrow ).
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SL ( Fig. 3 )
Fig. 3
Solar lentigo. ( A ) Confocal images in a 0.5 × 0.5 mm mosaic of small regular bright cells in the epidermis ( arrows ). ( B ) Confocal images in a 0.5 × 0.5 mm mosaic of bright cells forming a polycyclic pattern at DEJ. ( C ) Confocal images in a 0.5 × 0.5 mm mosaic of small regular bright cells (basal keratinocytes) arranged in clumps rather than polycyclic pattern at DEJ.
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LPLK
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Chronic UV-induced changes ( Fig. 4 )
Fig. 4
Photoageing. ( A ) Confocal image of 0.5 × 0.5 mm showing large skin furrows ( red arrow ) in the epidermis. ( B ) Confocal image of 0.5 × 0.5 mm showing irregularly distributed keratinocytes at the granular layer. ( C ) Confocal image of 0.5 × 0.5 mm showing bright collagen bundles in upper dermis: coarse collagen ( red arrow ) and dense collagen ( green arrow ).
Similarly, the features of LM/LMM have been elucidated on RCM ( Fig. 5 ). The proliferation of atypical melanocytes at the DEJ may be visualized on RCM as atypical pleomorphic cells, both round and/or dendritic. These atypical cells are twice the size of the adjacent keratinocytes. As LM becomes more extensive, pagetoid spread of large pleomorphic cells with prominent dendritic processes are seen through all layers of the epidermis, causing epidermal disarray. The often asymmetrical periadnexal extension is also striking on horizontal section. LMM is typified by pagetoid cells, confluence of cells, and formation of nests in the dermis, resulting in global disruption of the junction.
Preliminary reports showed that RCM could be used to differentiate LM from other pigmentations of the face. Guitera and colleagues assessed the sensitivity and specificity of 64 RCM features of LM in a series of clinically equivocal macules of the face (81 LM and 203 benign macules) and developed an LM score to distinguish LM from benign lesions. The score consists of 2 major and 4 minor criteria ( Table 1 ). An LM score of greater than 2 resulted in a sensitivity of 85% and specificity of 76% for the diagnosis of LM (odds ratio [OR] for LM 18.6; 95% confidence interval [CI] 9.3 to 37.1). The algorithm was equally effective in the diagnosis of amelanotic lesions and demonstrated good interobserver reproducibility (87%). In a test set of 29 LMs and 44 benign macules, the OR for LM was 60.7 (CI: 11.9–309) (93% sensitivity, 82% specificity). However, the score cannot be applied to margin assessment, such as in staged excision procedures, where the subtle presence of atypical melanocytes may be the only clue.
| Criteria | Points | |
|---|---|---|
| Major | Nonedged papillae | +2 |
| Round pagetoid cells >20 μm | +2 | |
| Minor | Three or more atypical cells at the DEJ in five 0.5 × 0.5-mm 2 fields | +1 |
| Follicular localization of pagetoid cells and/or atypical junctional cells | +1 | |
| Nucleated cells within the dermal papillae | +1 | |
| Broadened honeycomb pattern | −1 | |
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