Key points

Introduction

Pink lesions are a large, heterogeneous group of skin lesions of neoplastic and/or inflammatory origin that are characterized by a conspicuous absence of pigmentation. They often constitute a difficult diagnostic challenge because of the lack of unique observable features using conventional techniques, for example, dermoscopy. Dermoscopy and other related techniques, despite offering advantages over visual inspection of the lesion, have an elevated rate of misdiagnosis. Rapid accurate diagnosis is particularly crucial in the case of amelanotic melanoma, which requires early diagnosis to increase the probability of therapeutic success.

The gold standard in the assessment of dermatologic disease is histologic analysis of a sample of the lesion. However, this implies the collection of a biopsy specimen, which is invasive and can be aesthetically damaging. Dermoscopy is closer to this standard than visual inspection, but it is still far from it in the case of pink lesions. Other techniques, however, offer better resolution while preserving the noninvasive nature of dermoscopy. One of such techniques is reflectance confocal microscopy (RCM), which takes advantage of light scattering by endogenous skin structures, for example, melanin granules, architectural differences between the skin layers. The differential reflection of the light together with sampling and analysis of the affected area in a noninvasive manner underlies the great promise of RCM in the assessment and management of pink lesions.

In this review, the state-of-the-art regarding the use of RCM for the assessment of pink lesions in the dermatology office is summarized.

Introduction

Pink lesions are a large, heterogeneous group of skin lesions of neoplastic and/or inflammatory origin that are characterized by a conspicuous absence of pigmentation. They often constitute a difficult diagnostic challenge because of the lack of unique observable features using conventional techniques, for example, dermoscopy. Dermoscopy and other related techniques, despite offering advantages over visual inspection of the lesion, have an elevated rate of misdiagnosis. Rapid accurate diagnosis is particularly crucial in the case of amelanotic melanoma, which requires early diagnosis to increase the probability of therapeutic success.

The gold standard in the assessment of dermatologic disease is histologic analysis of a sample of the lesion. However, this implies the collection of a biopsy specimen, which is invasive and can be aesthetically damaging. Dermoscopy is closer to this standard than visual inspection, but it is still far from it in the case of pink lesions. Other techniques, however, offer better resolution while preserving the noninvasive nature of dermoscopy. One of such techniques is reflectance confocal microscopy (RCM), which takes advantage of light scattering by endogenous skin structures, for example, melanin granules, architectural differences between the skin layers. The differential reflection of the light together with sampling and analysis of the affected area in a noninvasive manner underlies the great promise of RCM in the assessment and management of pink lesions.

In this review, the state-of-the-art regarding the use of RCM for the assessment of pink lesions in the dermatology office is summarized.

A brief classification of pink lesions

Pink lesions can be inflammatory in origin or neoplastic. In general, inflammatory pink lesions are clustered or widespread, unlike amelanotic tumors, which are usually solitary and can be either benign or malignant. Examples of benign pink tumors include amelanotic benign nevi, sebaceous hyperplasia (SH), sebaceous adenoma/sebaceoma, trichoepithelioma, seborrheic keratosis (SK), clear cell acanthoma (CCA), dermatofibroma (DF), angioma, and pyogenic granuloma (PG). Examples of malignant pink tumors include amelanotic/hypomelanotic melanoma, mammary and extramammary Paget disease, basal cell carcinoma (BCC), and squamous neoplasia (actinic keratosis [AK], squamous cell carcinoma in situ [SCCIS]/Bowen disease, invasive squamous cell carcinoma [SCC]). Other pink lesions, such as but not limited to, angiosarcoma, Merkel cell carcinoma, and lymphoma as yet have not been well described on dermoscopy or RCM; therefore, these lesions will not be discussed further, but should be considered in lesions that lack features described in this article.

Diagnostic flow of skin lesions at the dermatologist office

The evolution of imaging techniques such as dermoscopy and RCM has altered the decision and diagnostic trees in the dermatologist’s office. Primary visual inspection reveals whether the lesion is inflammatory (usually multifocal) or neoplastic (often solitary), melanotic (contains melanin), or amelanotic/hypomelanotic (not obviously pigmented). Most melanotic lesions are benign nevi, as revealed by dermoscopy and/or RCM. This approach also reveals unique features of malignant melanoma (reviewed elsewhere in this issue); hence, diagnosis has the potential to be efficient and decisive. However, amelanotic/hypomelanotic (pink) lesions are often less easy to distinguish; thus, visual aids and information are required to establish an initial diagnosis. Although the gold standard is histology, a desirable goal (particularly from the patient’s point of view) is to obtain information close to the gold standard without resorting to invasive biopsy specimen collection.

The limits of dermoscopy in the diagnosis of solitary pink lesions

Dermoscopy represents a leap over mere visual inspection of solitary pink lesions, particularly in terms of sensitivity. However, it also has severe limitations regarding specificity, which is crucial to determine the course of action to treat the disease. In the following paragraphs, the major dermoscopic observations of a wide range of nonmalignant and malignant pink tumors are outlined with an emphasis on the lack of distinguishing features in many cases.

Dermoscopic findings of noninflammatory benign pink tumors

Dermoscopy confers a significant advantage over visual inspection alone in the clinical diagnosis of several nonpigmented lesions. Variants of amelanotic nevi include Miescher facial, Unna, Clark (red), and Spitz nevi. The main dermatoscopic feature of Miescher and Unna nevi is the presence of comma-shaped blood vessels, which have great predictive value. Additional features include keratinized crypts. On the other hand, Clark nevi display dotted and comma-shaped vessels arranged regularly against a pink background. Spitz nevi display dotted vessels in a relatively regular arrangement and reticular depigmentation.

Dermoscopy varies in its utility for the diagnosis of adnexal tumors. SH is often confused with superficial BCC by visual inspection due to its appearance, which includes yellowish smooth papules on the face. Dermoscopy reveals wreathed and blurred blood vessels and radial telangiectasia. Such radial arrangements are the defining feature that distinguishes SH from BCC, in which telangiectasia are treelike, intense, and very sharp. Sebaceous adenoma and sebaceoma show opaque structureless yellow areas surrounded by elongated, radially arranged crown vessels or branching arborizing vessels and a few loosely arranged arborizing vessels. Trichoepithelioma can be very difficult to distinguish from papular variants of BCC clinically and dermoscopically because it also presents as a papule with arborizing telangiectasias. However, because of the characteristic stroma of trichoepithelioma, the tumor lacks the pearliness seen in BCC and has a shiny white background on dermoscopy. Desmoplastic trichoepithelioma closely mimics morpheaform BCC on dermoscopy, appearing as an ivory-white plaque with prominent arborizing telangiectasias.

SK and CCA are benign epithelial tumors that can be confused with SCC or BCC. Dermoscopy of SK reveals lobulated vessels (capillary loops) arranged regularly, but surrounded by whitish halos consistent with keratinized structures. A major distinguishing feature of SK from SCC is that lobulated vessels are irregularly shaped and do not form a pattern in the latter. An exception to this is trauma to the lesion, which may turn the regular distribution of lobulated vessels into an irregular pattern, confusing diagnosis. Regarding CCA, dermoscopy reveals a pattern of coiled vessels forming a necklacelike distribution, which can be reticulated at times. These vessels also display whitish halos, unlike malignant tumors.

Dermoscopy can assist in the diagnosis of nonpigmented DF, which usually shows a subtly pigmented area surrounding a whitish scarlike center. However, the vascular tree around the lesion is often not complete, which can lead to confusion with melanoma.

Vascular lesions vary from being fairly straightforward to extremely difficult to distinguish using visual inspection and dermoscopy. Angiomas show variably sized red, purple, or blue lacunae and, if not thrombosed, blanch with contact dermoscopy. PG, however, is more complicated to distinguish from malignancies on dermoscopy, usually showing homogeneous red regions with white collars. The information added by dermoscopy, unfortunately, is not sufficient to exclude nodular amelanotic/hypomelanotic melanoma.

Dermoscopy findings of malignant pink lesions

Dermoscopy clearly reveals several findings of amelanotic skin tumors, particularly amelanotic and hypomelanotic melanoma. Some dermoscopy observations include dotted vessels forming an irregular pattern, whitish shiny areas, and ulceration in bona fide amelanotic melanoma. Hypomelanotic melanoma can be subdivided into streaked (<30% of the tumor bears 100% pigmentation) and light colored (100% melanoma is lightly pigmented). These melanoma also display irregularly shaped vascularization with scarce pigmentation (peppering) and whitish depigmented areas. Furthermore, the existence of pink (poorly melanotic) regions is a recent novel tool for the dermoscopic identification of melanoma. However, these features are also present in other malignancies; hence, disambiguation often requires histologic examination.

Mammary and extramammary Paget disease commonly show milky red areas, surface scales, and a prominent vascular pattern (most commonly dotted vessels, to a lesser extent glomerular vessels, or polymorphous vessels and rarely linear irregular vessels). Many also show erosions or ulcerations, and a minority shows shiny white lines and/or white structureless areas.

Regarding the more frequently encountered BCC, these tumors can be divided into nodular, superficial, infiltrating, and fibroepithelioma of Pinkus variants. Common features of these lesions as observed using dermoscopy include leafing and ulceration. Specific features are as follows: in nodular BCC, bright red arborized vasculature enveloping the lesion; in superficial BCC, thin vascular trees. Infiltrating BCC is scarcely described, but one study describes finely arborized trees and scattered telangiectasias. A unique type of BCC is fibroepithelial BCC, or fibroepithelioma of Pinkus. Histologically, Pinkus tumors are characterized by thin branches of atypical basaloid cells extending from the epidermis into the dermis. Dermoscopy reveals bright striae and fine arborized blood vesicles, but less branched than those in other abnormalities. Also, slightly pigmented ulcerations are not uncommon.

AK is considered together with SCC, which is the most common type of skin tumor. Dermoscopic observation of the lesion often reveals a pink erythematous network that encircles keratotic hair follicles and abundant yellowish scaling. The vascular system is often twisted in the region of the lesion, appearing as coils in the case of facial AK. On the other hand, SCCIS (Bowen disease) reveals scaly pink plaques quite similar to psoriasis plaques and clusters of glomerular vessels, similar to the dermoscopic observation of invasive SCC, except the latter displays white halos around the glomerular vessels and the background is white, not pink.

Reflectance confocal microscopy: less (penetration) is sometimes more (information)

RCM is rapidly becoming a useful tool to widen the knowledge of the dermatologist regarding a specific lesion. Although the actual z penetrance limit of RCM is set around 200 μm, right under the superficial dermis, its xyz resolution is much higher than that of dermoscopy at this level, and its noninvasive nature (shared with dermoscopy) allows the consecutive examination of the lesion using both techniques, which is very useful to disambiguate equivocal lesions. This approach: dermatoscopy first, followed by RCM to disambiguate, enables us to obtain specific data when dermatoscopy does not reveal specific features or the findings are ambiguous. As detailed in later discussion, reports on RCM findings of different skin diseases, including pink lesions, have been increasing in number in recent years (reviewed recently in Ref. ), enabling the elaboration of several formal atlases of RCM findings.

Reflectance confocal microscopy: the stepwise approach to solitary pink tumors

A stepwise approach is helpful when examining an ambiguous solitary (presumably tumoral) pink lesion on RCM. Initially, one must establish whether the lesion is melanocytic or nonmelanocytic in nature, and then whether specific features of malignancy are present. Thereafter, one can attempt to further achieve a specific diagnosis using the established criteria ( Box 1 , Fig. 1 ).

A stepwise approach to solitary pink tumors.

In order to establish that a melanocytic neoplasm is present, one looks closely for junctional nests, junctional thickenings, and/or widespread atypical nucleated cells at the dermal-epidermal junction (DEJ) and/or nests in the dermis. If one finds features suggestive of a melanocytic neoplasm, one then must assess the lesion for features of melanoma, such as (on nonfacial lesions) widespread round Pagetoid cells, widespread atypical cells along the basal layer, greater than 10% of DEJ showing nonedge papillae, individual nucleated cells in the dermal papillae, and cerebriform nests. Differentiating melanoma from nevus or other benign macules is described in detail elsewhere in this issue. Step 2 is to look for widespread round Pagetoid cells. If these are identified, the lesion is probably either amelanotic superficial spreading melanoma or Paget disease, mammary or extramammary.

Once it is established that there is no evidence of a melanocytic tumor or Pagets disease, one must rule out squamous neoplasia and BCC. First, one looks for evidence of squamous neoplasia (pleomorphic keratinocytes and an atypical or disarranged epidermal honeycomb pattern). If present, one then must look for evidence of an underlying tumor because both invasive SCC and BCC can show overlying features of AK or SCCIS. If no underlying tumor is present and the changes of squamous neoplasia are partial thickness or patchy and mild, AK is likely. If the changes are full thickness, SCCIS is likely. If there is evidence of an underlying tumor and a keratin pearl is identified, invasive SCC should be suspected. If no keratin pearl is seen, one proceeds to the next step, which is to evaluate for features of BCC (streaming, tumor nodules with peripheral palisading of nuclei, and tumor nodules with peritumoral dark spaces).

Once melanocytic neoplasms, Paget disease, squamous neoplasms, and BCC have been excluded, one can then begin searching for constellations of features that suggest specific benign diagnoses (see Box 1 ). If no specific features are identified or if the lesion appears too deep for visualization using confocal, biopsy for histopathology is needed to allow for diagnosis to steer appropriate management. In the following paragraphs the RCM features of several benign and malignant pink tumors are described in detail.