Spindle cell melanocytic lesions—part I: an approach to compound naevoidal pattern lesions with spindle cell morphology and Spitzoid pattern lesions
- Correspondence to Dr Danny Ghazarian, Department of Pathology, Toronto General Hospital, 190 Elizabeth St, Toronto, Ontario M5G2C4, Canada;
- Accepted 3 January 2010
Melanocytic lesions show great morphological diversity in their architecture and the cytomorphological appearance of their composite cells. Whereas functional melanocytes reveal a dendritic cytomorphology and territorial isolation, lesional naevomelanocytes and melanoma cells typically show epithelioid, spindled or mixed cytomorphologies and a range of architectural arrangements. Spindling is common to melanocytic lesions, and may be either a characteristic feature or a divergent appearance. The presence of spindle cells may mask the melanocytic nature of a lesion, and is often disconcerting, either because of its infrequent appearance in a particular lesion or its interpretation as a dedifferentiated phenotype. Spindle cell melanocytic lesions follow the full spectrum of potential biological outcomes, and difficulty may be experienced judging the nature of a lesion because of a lack of consistently reliable features to predict biological behaviour. Over time, recognition of numerous histomorphological features that may portend a more aggressive lesion have been identified. However, the translation of these features into a diagnostic entity requires a gestalt approach. Although most spindle cell melanocytic lesions can reliably be resolved with this standard approach, problem areas do exist and cause no end of grief to the surgical pathologist or dermatopathologist. In this review, the authors present their algorithmic approach to spindle cell melanocytic lesions and discuss each entity in turn, in order to (1) model a systematic approach to such lesions, and (2) provide familiarity with those melanocytic lesions that either typically or occasionally display a spindled cytomorphology.
Melanocytic lesions of the skin can be a notorious challenge for the pathologist.1–5 This is due in part to the lack of consistent and reliable features differentiating benign from malignant melanocytic proliferations, but also to the great morphological variability that melanocytes can exhibit.6 7 The former point is illustrated by the vast array of features that a pathologist must evaluate when confronted with a melanocytic entity, features that, when considered on their own, exhibit limited diagnostic utility. The general approach to diagnosing a melanocytic lesion is through a gestalt impression which incorporates: clinical parameters; architectural parameters including size, silhouette, pattern of growth and degree of maturation; cytological parameters including cytomorphology, extent of atypia and mitotic activity; and often ancillary studies as well. The morphological variability of melanocytic lesions is exhibited by both architectural and cytological variations.6 8 Particular difficulty arises when melanocytes express cytomorphological features that create uncertainty about the cell of origin, as may be seen with spindled melanocytic lesions.7 9 This difficulty is compounded when the architectural features most typical of melanocytic lesions are poorly developed or absent. This architectural and cytomorphological variability of melanocytes, in addition to the diagnostic challenges of differentiating benign from malignant lesions, accounts for the vast array of terms applied to melanocytic lesions—a list that can be intimidating. Numerous publications discuss selected challenges and pitfalls that may be encountered in the diagnosis of specific melanocytic entities.10–21 This review will focus specifically on spindle cell melanocytic lesions, with itemisation of those melanocytic entities that characteristically or occasionally show a spindled cytomorphology, with particular reference to diagnostically challenging situations and pitfalls. We also provide the algorithmic approach to these lesions that we use. The review is structured according to this approach. Part I deals with our algorithmic approach to spindle cell melanocytic lesions and includes their initial categorisation into compound naevoidal pattern lesions, Spitzoid lesions, intradermal proliferations and horizontally oriented lesions.21a Part I further covers the compound naevoidal pattern lesions and the Spitzoid lesions. Part II continues with a discussion of intradermal melanocytic proliferations, horizontally oriented lesions and combined lesions.
Before embarking upon the hefty task of cataloguing a list of cutaneous spindle cell lesions, it is worthwhile attempting a definition for the widely used but fairly loosely defined ‘spindle cell’. The term is one that is quite malleable to the needs of the pathologist and as such is rather freely used in cytological description of cellular morphology (figure 1). Perhaps, in its purest sense, spindling refers to cells with elongated fusiform nuclei. Such cells are best appreciated when they are present in a fascicular arrangement, imparting a streaming quality to the lesion. Fusiform spindled cells may be further qualified as: having rounded ends or being ‘cigar-shaped’ (eg, leiomyoma, many spindle cell melanomas); showing waviness or being ‘comma-shaped’ (eg, neuroma, neurofibroma, neuroidal naevus); or with tapered ends (eg, myofibroblasts, nodular fasciitis). Intermediate forms can also be seen and may appear blunted (eg, dermatofibroma, desmoplastic melanoma). Spindle cells may also vary in their thickness, appearing either plump (leiomyoma, melanoma) or thin (neurofibroma, fibromatosis, common blue naevi). Oval nuclei also impart a vague spindled quality, and many lesions with oval nuclei are classically listed as spindle cell lesions (eg, perineurioma, desmoplastic naevi, cellular blue naevi). The overall pattern of arrangement or other formations may offer further histogenetic clues (slit-like spaces in Kaposi sarcoma; storiform pattern in dermatofibrosarcoma protuberans; herringbone pattern in fibrosarcoma or malignant peripheral nerve sheath tumour (MPNST); palisading in neural lesions), as may other characteristic features (presence of nucleoli (eg, nodular fasciitis, melanoma), intranuclear inclusions (melanocytic lesions), subnuclear vacuoles (smooth muscle)). Spindle cells also encompass lesions with intermediate epithelioid and spindled morphologies, as may often be seen in histiocytic disorders such as Langerhans cell histiocytosis, dermatofibromas and atypical fibroxanthomas. Many melanocytic lesions offer further examples, such as frequent desmoplastic melanomas and Spitz naevi. Cellular–stromal interactions may further impart a spindling phenotype either by direct compressive effects or through chemical interaction.22–24 In general, interstitial infiltrating lesions may take on an oval or spindled morphology due to partial distortion as they infiltrate between collagen bundles. Given the standard option of describing a cell as either spindled or epithelioid, other cytomorphologies such as dendritic or stellate may thus also fall under the somewhat inappropriate label of spindled, including the common blue naevus, fibrous papules and dendritic cell tumours, particularly when the finer details may not be well appreciated on light microscopy. Finally, most epithelioid tumours also have spindle cell variants (and vice versa) (eg, epithelioid sarcoma, carcinoma). Clearly, the task of outlining spindle cell lesions becomes a laborious one when, by convention and practice, the term spindle cell: (1) encompasses a range of differing cytomorphologies; (2) may arise by nature of the histogenetic origin of the lesion, the nature of the lesional cells or the effects of the surrounding stroma; or (3) may be applied in intermediate, admixed or even inappropriate settings to satisfy convention or simplicity. Nevertheless, in this article, we try to consider all the possible applications of the term spindle cell to melanocytic lesions, but also try to put the term in appropriate context with respect to finer cytomorphological descriptions that offer diagnostic utility. After all, even though a neuroidal naevus, a cellular blue naevus and a pigmented spindle cell naevus of Reed are all spindle cell melanocytic lesions, they can still be distinguished from each other on the basis of cytomorphology alone.
Algorithmic approach to melanocytic spindle cell tumours (figure 2)
Establishing the histogenetic origin of a cutaneous spindle cell lesion: histopathological assessment, ancillary testing and clinical correlation
When first confronted with a spindle cell tumour of the skin, the first step is to classify the histogenetic origin of the lesional cells before proceeding with further diagnostic categorisation. Although for many cell types, a spindled morphology often equates with a lack of differentiation or metaplastic differentiation (eg, epithelia), for other cell types, spindling represents the appropriate differentiated morphology of the cells (eg, peripheral nerve sheath, smooth muscle, fibroblasts/myofibroblasts). Evaluating the histomorphological features of spindled tumours is an essential step in establishing the histogenetic origin of many spindled lesions. Although non-melanocytic spindled lesions are not the focus of this review, an approach to cutaneous spindle cell melanocytic lesions cannot proceed without consideration of the potential non-melanocytic mimics that often arise in the differential diagnosis; therefore we have listed some useful clinical, histological and immunohistochemical features of non-melanocytic spindle cell lesions in table 1. Suffice it to say that for certain non-melanocytic spindle cell tumours, histomorphology alone is generally sufficient for confident diagnosis, whereas, in others, ancillary methods (usually immunohistochemistry) are required in the diagnostic work-up. The reader is also referred to other excellent publications for consideration of non-melanocytic cutaneous spindle cell lesions.25–32 For melanocytes, spindling is a common and, even occasionally, a definitive feature in certain types of melanocytic lesions (eg, blue naevi, Spitz naevi, melanoma). Spindling in melanocytes does not necessarily reflect a lack of differentiation, and, in fact, the epithelioid morphology of naevomelanocytes seen in most common melanocytic naevi reflects a deviation from the functional dendritic morphology of intraepidermal melanocytes.21 33 Even nesting, the characteristic organisational pattern of melanocytic lesions, represents a deviation from the isolated and territorial behaviour of functional melanocytes. Furthermore, type C (‘Schwannian’) melanocytes represent a maturation phenomenon that may occasionally be seen in aged melanocytic naevi (‘neuroidal naevi’, ‘naevi with neurotisation’).34 Alternatively, high-grade melanomas often take on a spindled morphology, reflecting a metaplastic or dedifferentiation phenomenon.6 9 31 35 36 Nonetheless, in most cases of spindle cell melanocytic lesions, melanocytic differentiation may be determined/inferred through evaluation of the histomorphological features of the lesion (box 1), whereas in others further ancillary testing is required (table 2).6 21 26 37–54
Box 1 Histomorphological features suggestive of melanocytic differentiation in a spindle cell lesion
Cytomorphological features suggestive of melanocytic differentiation
consider other pigments: haemosiderin, exogenous pigment, lipofuscin
consider melanin production in non-melanocytic lesions
consider melanin incontinence in non-melanocytic lesions
Intranuclear cytoplasmic inclusions
Nucleoli (typically prominent in melanoma)
Cytoplasm variable in terms of quantity and character
Architectural features suggestive of melanocytic differentiation
Congenital pattern (including growth along adnexal and neurovascular structures; herniation of melanocytic nests into dilated lymphovascular structures)
Other patterns may also be seen (diffuse, trabecular, pseudovascular)
Evidence of dermal maturation
Stromal response may be evident
Presence of melanophages
Other regressive features (irregular scattering of lesional cells, vascular proliferation)
Other features consistent with a melanocytic lesion
Look for background/admixed clear-cut melanocytic lesion
Presence of solar elastosis (for certain entities)
Macroscopic ‘gross’ features (pigmentation, ABCD criteria)
Lack of features to suggest non-melanocytic origin (table 1)
Fontana–Masson or Schmorl staining for melanin pigment
DOPA reaction to demonstrate tyrosinase activity
Immunohistochemical phenotype (table 2)
Ultrastructural demonstration of melanosomes/pre-melanosomes
Assessing the biological potential of melanocytic spindle cell tumours
Having optimally established the histogenetic origin of a lesion through clinical parameters and histomorphology with or without ancillary studies, the next step in the algorithmic approach to a spindle cell melanocytic lesion is to assess the lesion's biological/malignant potential. Classic pathological tenets teach us that such potential generally correlates very closely with cytological atypia/anaplasia (ie, cytological features) and invasive/destructive growth (ie, architectural features). Unfortunately, in the realm of melanocytic lesions, this approach may be misleading in a number of settings. For instance, Spitz naevi and naevoid melanomas are two examples where the degree of cytological atypia fails to reflect the true biological potential of the lesion. Spitz naevi, deep penetrating naevi and cellular blue naevi are examples of benign spindle cell melanocytic lesions that typically show infiltrative patterns that disguise their benign nature. Desmoplastic melanomas on the other hand are infiltrative lesions with full malignant potential. Furthermore, invasion is a difficult concept to appreciate in melanocytic lesions because precursor melanocytic cells/melanoblasts migrate from the neural crest through the dermis to reach their ultimate ‘supposed’ epidermal location (as well as other sites of normal melanocyte migration).21 55 56 Hamartomatous malmigration may occur, resulting in a variety of dermal or combined lesions. Furthermore, naevic aggregates that have successfully completed upward migration through the dermis into the epidermis still undergo a normal maturation pattern of ‘falling off’ from their initial intraepidermal location with descent into the dermis. Thus there are no reliable tissue barriers available to evaluate definitive invasive growth. Rather, through the determination of malignant cytological and architectural features, a melanoma is considered ‘invasive’ (or perhaps more accurately, capable of local invasive behaviour and distant spread), once it is present within the dermis and thus potentially accessible to nerves, lymphatics and other vascular spaces. This, of course, presumes a junctional origin for melanoma; however, rare examples of completely intradermal melanomas are known (eg, malignant blue naevus, malignancy arising within the dermal component of a congenital naevus, primary dermal melanoma). Thus, in many respects, determination of the biological/malignant potential of a melanocytic lesion must rely on other evaluated features.
Owing to the high clinical detectability of cutaneous melanocytic lesions, their relative commonality, and their general ease of excision, there has accumulated a general wealth of experience that has permitted the correlation of histopathological features with biological behaviour. Unfortunately, no single feature (except in extreme cases) allows reliable discrimination of benignancy from malignancy. Rather, a gestalt impression is formed by weighing the relative value of numerous clinical and histopathological features with or without immunohistochemical features in order to predict the biological behaviour (and thus achieve a diagnosis) of a given lesion. It is this generalised understanding of the correlation between a host of histopathological features and biological outcomes that outlines the standard approach to melanocytic lesions (table 3). However, owing to the significant morphological variability of melanocytic lesions, there exist numerous examples of lesions that violate these generalised rules (eg, deep expansile cellular nodules in cellular blue naevi; cytological atypia and pagetoid activity in Spitz naevi), and so, phenotypic categories are created that permit a more precise assessment of the biological potential associated with each histological feature. It is with this objective that an initial pattern approach offers clinical value.
Architectural patterns of melanocytic spindle cell lesions
Recognising that a dogmatic cytomorphological and generalised architectural approach applied universally to spindle cell melanocytic lesions may be misleading, an architectural patterns approach may be used to categorise melanocytic lesions into specific recognised patterns for which generalised rules may be applied in a more reliable manner in order to qualitatively assess the biological potential of a given lesion. Four general architectural families can be defined (figure 3):
Compound naevoidal pattern
Horizontal orientation pattern
Assessment of biological potential follows somewhat differently for lesions in each pattern category. Ultimately it is the clinicopathological experience with different lesions that guides thresholds for diagnostic terminology. Each category will be discussed further in the following section with a focus on highlighting the features that allow most precise assessment of biological potential. Table 3 lists the features that should be evaluated when a melanocytic lesion is encountered and states in a general way the impact that each has upon the estimated biological potential of the lesion. Of course, consideration must be given to the lesion being dealt with before applying relative weight to the findings (eg, pagetoid spread is of significant concern in a Clark's naevus but a well-established finding in benign acral naevi; perineural location of lesional cells may be seen in blue naevi but is otherwise generally indicative of malignancy).
Reaching a diagnosis
Outside of a few well-recognised melanocytic entities, the pathological diagnosis of melanocytic lesions is daunting for many. This is, in part, due to the great array of diagnostic terms available. The long list of existing melanocytic lesions reflects two aspects of melanocyte pathobiology:
The cytomorphological and architectural diversity of melanocytic lesions
The difficulty in recognising universally reliable histomorphological features to accurately reflect the biological potential of melanocytic lesions.
The first point reflects the traditional morphologist's view, in which diagnostic entities are defined by their histomorphological appearance (eg, neuroidal naevus, desmoplastic naevus, pigmented spindle cell naevus). The second point reflects the utilitarian need to communicate in a diagnostic term the clinical potential of a lesion (eg, naevi of special sites, atypical Spitz tumour, melanoma). Despite this great range of lesional names in melanocytic pathology, it should be remembered that the ultimate aim of diagnosis is to guide clinical management of a lesion, and so should reflect the biological potential of the lesion. Ultimately, this means that, despite the terminology used, a lesion fundamentally falls into one of three categories:
Benign—essentially no risk of aggressive/malignant biological potential (eg, compound naevus)
Atypical lesions—lesions that are overall consistent with a benign lesion but which display unsettling atypical features that may portend a more aggressive course (eg, atypical blue naevus, common or cellular)
Lesions of uncertain biological potential—lesions that generally behave in a benign manner but with exceptions common enough to warrant conservative management (eg, cutaneous neurocristic hamartoma), or rare lesions for which the natural history is not confidently known (eg, plaque-type cellular blue naevi with satellitic nodules)
Borderline lesions—lesions with pathological features that overlap with those of malignant entities to the point that assurance that the lesion is not in fact its malignant mimic cannot be reliably made (eg, Clark's naevus with high-grade atypia; junctional Clark's naevus bordering on melanoma in situ)
Malignant—malignant biological behaviour is predicted (or a significant risk to progress to such for in situ lesions) (eg, nodular melanoma)
In making diagnoses, one should thus concern oneself with the application of diagnostic terminology that relays precise transmission of the lesion's histogenetic origin and its risk of aggressive/malignant biological behaviour, thus facilitating appropriate clinical management decisions. Often melanocytic lesions may not fall neatly into any predefined category, and a descriptive diagnosis or qualifying statement may best accomplish this task. On occasion, we do find it acceptable to use the term ‘melanocytic lesion of undetermined malignant potential’ (MELTUMP) for lesions that exhibit features that raise concern about their biological potential, and also fail to satisfactorily show clinical, architectural and cytomorphological features to define them as an established entity. Such a diagnosis should not be ashamedly felt as a failing of the pathologist's diagnostic ability, but rather the final deduction that the biological potential of the lesion in question simply cannot be accurately predicted on the basis of clinical, histological and cytological data with or without other ancillary information, despite a diligent attempt to do so. In addition, there should be no better diagnostic term to reflect the histology of the lesion in a way that still communicates its uncertain biological potential (eg, atypical Spitz naevus, atypical cellular blue naevus, Clark's naevus with high-grade features). On such occasions, a comment is warranted to more precisely describe the pathological difficulty, estimate the biological risk of the lesion, and provide management recommendations. Nevertheless, optimal communication is best achieved when terminology is well defined and strongly established, and so, when possible, the most established and simplest diagnostic terms should be used. Thus, whenever possible, we do avoid terms, such as MELTUMP, that do not effectively communicate a lesion's biological potential or its architectural pattern. Towards this end, we begin our discussion of the most established and useful diagnostic entities within the spindle cell melanocytic spectrum (table 4) with a focus on the diagnostic features and potential pitfalls.
Spindle cell melanocytic lesions
Compound naevoidal pattern lesions (figure 4)
The first architectural pattern is the ‘compound naevoidal pattern’, which exhibits underlying architectural features reminiscent of an ordinary naevocellular naevus, prototypically with both a junctional and an intradermal component (see box 2 for notable pitfalls). This is the most common melanocytic pattern encountered. Naevoidal pattern lesions are generally circumscribed and symmetric compound melanocytic lesions. They tend to present as macules or papules, but may also be dome-shaped, papillomatous or occasionally polypoid. Benign naevoidal lesions show organised growth that is often nested and lacking confluence or irregularity in pattern. Junctional shouldering should not be prominent. With age, compound naevoidal lesions tend to mature via descent into the dermis, and some lesions may thus lack an appreciable junctional component. Such lesions still maintain the remaining naevoidal features, and so are still considered consistent with an overall ‘naevoidal’ pattern, albeit intradermal rather than compound. Malignant lesions may preserve a naevoidal appearance, but generally show superimposed features of concern to varying degrees (eg, large size, dense confluent growth, deep expansile growth, pagetoid spread, dermal mitoses). Papillomatous or verruciform epidermal changes occasionally accompany both benign and malignant ‘naevoidal’ lesions. Cytomorphology may vary from bland and quiescent to overtly malignant. Distinguishing benign from malignant lesions exhibiting this pattern is generally not challenging, with the notable exception of naevoid melanoma, which is often a challenging diagnosis that may be revealed when there are subtle or pronounced deviations from the standard naevoidal architecture or bland cytomorphology in an otherwise naevoidal pattern lesion. In certain cases, the diagnosis may only be made in retrospect following clinically evident malignant behaviour of a lesion. The spindle cell melanocytic lesions characterised by a compound naevoidal pattern are discussed in turn as follows:
Box 2 Notable challenges/pitfalls in the evaluation of naevoidal pattern spindle cell melanocytic lesions
Atypical spindle cell proliferation in a congenital naevus versus spindle cell melanoma arising within a congenital naevus.
Naevi of special sites exhibiting pseudomelanomatous features versus melanoma arising in special sites.
Diagnosis of naevoid melanoma with spindle cell morphology.
Spindle cell melanoma versus other spindle cell lesions.
Neuroidal naevus/melanocytic naevus with neurotisation
Congenital naevus with spindle cell component
Naevi of special sites
Naevoid melanoma with spindle cell morphology
Nodular melanoma with a spindle cell component
Spindle cell melanoma
Neuroidal naevus/melanocytic naevus with neurotisation
Over time, certain melanocytic naevi may undergo a form of cytological maturation where they transform into Schwannian cells (ie, type C naevomelanocytes)34 57 (figure 4A,B). These cells have bland wavy nuclei surrounded by a pale loose, occasionally mucinous or fibrotic stroma reminiscent of neural structures. Furthermore, the cells may be arranged in tactoid formations (‘Wagner–Meissner corpuscles’) further suggestive of a neural origin.21 31 Mast cells may also be increased in these areas. Often these changes are only focal in the overall lesion with more characteristic type A or type B naevomelanocytes also present, often more superficially. Occasionally, the neurotisation may be complete or near-complete, making differentiation of the lesion from a neurofibroma difficult.30 31 Nerve fascicle-like or even Verocay body-like structures may be observed in occasional cases.58 Immunohistochemical staining for myelin basic protein, CD57 or glial fibrillary acid protein may be discriminating features in uncertain cases, with positivity favouring neurofibroma or possibly another neural lesion.21 58 Pigment is rarely expressed in such lesions and S100 is non-discriminatory. More specific melanocytic markers are generally not preserved in type C naevomelanocytes, as they typically do not exhibit melanosomes or tyrosinase activity.35 Ultrastructurally, neurotised naevic cells do not show true Schwannian differentiation because of a lack of axonal or mesaxonal structures, and may reveal the rare melanosome.34 57 58 Overall, neuroidal naevi generally are not clinically concerning, and show an overall naevoidal pattern lacking any atypical cytological or architectural features, and so are easily recognised as benign. A junctional component to the lesion may be lacking, in contrast with the prototypical naevoidal pattern. Histopathological consideration of this form of melanocytic maturation is generally sufficient to make the diagnosis, and careful inspection for type A or B naevomelanocytic areas or a residual junctional component should be used to achieve greater certainty. Finally, there is no clinical utility in noting this phenomenon in the diagnostic report, and the lesion may be simply reported as ‘compound naevus’ or ‘intradermal naevus’.
Congenital naevi with spindle cell component
Congenital melanocytic naevi may be evident in one of two ways: (1) clinical history of a congenital (or tardive congenital) pigmented lesion which may be stable or changing; (2) recognisable architectural features suggestive of a congenital naevus in the absence of a clinical history (ie, ‘melanocytic naevus with congenital pattern’). Activated areas or proliferative nodules may account for the clinical history of a ‘changing naevus’, but, of course, so can the development of a melanoma arising within a congenital naevus.59 60 Architectural features that are suggestive of a congenital naevus include larger size (although congenital naevi may also be small), a diffusely infiltrative horizontal component of naevomelanocytes, a deeply penetrating component involving the lower third of the reticular dermis or even the subcutis, and prominent extension of lesional cells along adnexal and neurovascular structures.30 31 56 Often, congenital naevi show lesional cells herniating into dilated lymphovascular spaces simulating vascular invasion. Congenital naevi also have a great capacity for heterologous morphology, including neuroidal differentiation and spindle cell morphology31 35 (figure 4C,D). Variants of congenital naevi may be entirely spindled, may show prominent neurotisation suggestive of a neural lesion (as per the neuroidal naevus phenomenon—see above), may show blue naevus-like morphology, or may show cellular proliferative nodules or clonal areas with a spindle cell morphology.31 59 Melanisation may be preserved in the spindle cell component of a congenital naevus, aiding histogenetic determination. Assessing the biological potential of congenital melanocytic naevi may be difficult because of the possible presence of mild cytological atypia, nucleoli, architectural irregularities and limited mitotic activity which may be seen in some cases, either diffusely within the lesion or focally within a proliferative nodule.16 59 61 Compounding the difficulty is the potential preanalytical bias that may exist with the clinical picture of, often, a large lesion that is potentially changing and the knowledge that congenital naevi (especially giant congenital naevi) are relatively fertile ground for the development of melanoma.61 Confound this further with the presence of a heterologous spindle cell morphology, either in part or whole, and the lesion may just be too disconcerting. Nevertheless, it should be recognised that all of these features are acceptable benign features of a congenital naevus which lacks aggressive/malignant potential. Assessment of biological potential must therefore rely on more established features of atypicality: uniform moderate–severe cytological atypia with prominent macronucleoli, confluent and irregular growth, destructive expansile or infiltrative growth including surface ulceration and necrosis, pagetoid activity (except in infants), lack of maturation, prominent dermal mitotic activity especially in the deeper portions of the lesion, etc. Proliferative nodules in congenital naevi are recognised by the relative rarity of mitoses (and the low proliferative index), evidence of maturational blending with surrounding naevic cells, and the lack of necrosis or destructive expansile growth.16 59 61 Cytological atypia is variable but usually low grade, although significant pleomorphism can be seen. Nevertheless, the biological potential of proliferative nodules, although seemingly benign, is not fully known, and we do recommend excision of such lesions when clinically feasible. Melanoma may arise in small–medium-sized congenital naevi (as well as acquired naevi), but typically does so in the junctional component, recapitulating the pattern of a superficial spreading or nodular melanoma with overt malignant features.30 Large congenital naevi may occasionally demonstrate malignant degeneration in the form of a dermal nodule. The malignant nature of melanomas arising within congenital naevi may be inferred from an expansile and destructive nodule, with abrupt demarcation from the surrounding lesion and often extension into the subcutaneous tissue with or without prominent tumoural necrosis, and a marked increase in mitotic activity.59 61
Naevi of special sites
Part of the appreciation of the biological diversity of melanocytic lesions has occurred as a result of the recognition that certain histopathologically disturbing melanocytic lesions may predictably behave in a benign manner (see figure 8 of Part II).21a Such clinicopathological correlation led to the recognition that benign naevi present in certain sites may exhibit histological features that normally connote an aggressive biological potential. The most classic and well defined of these special sites are acral locations16 62–65 and the vulva.16 62 66 67 The male genitalia, anorectal region and perineum may also be considered ‘genital sites’, with features akin to vulvar naevi; however, these sites are not as well studied. Other recognised special sites include the breast,68 flexural sites69 (ie, axilla, umbilicus, inguinal region, popliteal fossa or any other site that exists in a tissue fold such as the neck skin or abdominal folds), the ear70 71 and scalp.72 For most of these regions, chronic irritation of the lesion appears to be the most theoretically consistent explanation for the unusual features. Alternatively, hormonal factors have also been put forward as a possible explanation, albeit with some scepticism. The conjunctiva represents a non-cutaneous special site.62 73 74 Spindling may be seen in naevi from special sites, and, in particular, is notably a feature of vulvar naevi.62 Spindling on its own is not a feature that raises the potential risk of a lesion. Such an analysis requires evaluation of standard features with an understanding of the permissible site-related atypia (table 5).
Clinically, naevi of special sites are generally small with a banal appearance, but may occasionally show some heterogeneity in coloration, an asymmetrical profile and lack of good circumscription. Lesions tend to be stable, often over a long period of time. Spontaneous ulceration, pruritic change or a change in size or coloration may herald more ominous clinical events, warranting excision and pathological assessment. The histology of naevi removed from special sites is indistinguishable from naevi removed from other sites in most cases. However, occasional cases do show a range of architectural and histological features that deviate from the norm, features that are generally associated with melanoma (table 5). The most well recognised of these features is the possible presence of pagetoid ascension of cells. This is a well-established phenomenon in acral naevi, probably due to chronic irritation of lesions in such sites. In fact, the term ‘MANIAC’ (melanocytic acral naevus with intraepithelial ascent of cells) has been proposed to raise awareness of the possible occurrence of pagetoid activity in an otherwise benign acral naevus.75 Clues as to the benign nature of the pagetoid activity in naevi from special sites are the concurrent presence of melanocytic nests undergoing transepidermal elimination, a preferential syringotropic localisation of the pagetoid activity, and the presence of pigment in the stratum corneum.62 Pagetoid cells should be banal and should not show mitotic activity. Architecturally, naevi from special sites are small and have a symmetrical and well-circumscribed silhouette; however, this may not be appreciated depending on the completeness of excision and the sectioning of the lesion. Lesions generally show bland cytology, a lack of mitotic activity and evidence of maturation; however, irritative effects may induce changes in all three of these parameters. In cases where such features are present, they need to be interpreted within the context of the remainder of the lesion. As always, multiple dermal mitoses (especially when located deeply), high-grade cytological atypia and a complete lack of maturation are all concerning features that should trigger complete excision of a lesion. A rare mitosis or mild cytological atypia may be acceptable within an otherwise small and symmetrical lesion with no evidence of confluent growth. Vulvar naevi, however, may notably show cytological atypia, and often an alarming degree of dermal growth including occasional mitoses. Clark et al76 originally described three abnormal architectural patterns of vulvar naevi: (1) the ‘nested’ pattern; (2) the ‘dyshesive nest’ pattern; and (3) the ‘crowded’ pattern. However, lesions often show overlapping patterns. Clinical parameters are crucial in such cases, as the threshold for diagnosing a melanoma in a young patient should be very high because of its extreme rarity. In contrast, a vulvar melanocytic lesion should be eyed suspiciously in an older patient if it has worrisome clinical or histological features. Vulvar melanomas tend to present as clinically evolving lesions in postmenopausal women, with a histological picture of a crowded lentiginous proliferation of atypical melanocytes.66 This is in contrast with the more typical dermal proliferation and young patient age for vulvar naevi. Prominent lentiginous growth is, however, a feature that may be seen in naevi from special sites, even to the point of apparent confluence. A stromal response is also commonly encountered in naevi from special sites and includes papillary dermal fibroplasias (both lamellar and concentric), and occasionally a unique diffuse pattern of dermal fibrosis which may be confused with desmoplasia or regression.62 66 Recognition and proper assessment of the site-related deviant cytological and architectural features, particularly when taken in the context of the patient's age and other clinical parameters, is crucial in order to avoid the systematic overcalling of biologically inert lesions biopsied from such sites. Conversely, recognition of the site-related atypia phenomenon may also lead to undercalling of truly atypical lesions.
Naevoid melanoma with spindle cell morphology
Naevoid melanoma is a challenging diagnosis in melanocytic pathology. The term is relatively poorly defined, but may be used to encompasses a heterogeneous histological spectrum of malignant melanocytic lesions ranging from those histologically unrecognisable as malignant but which subsequently behave in a malignant manner77 to those atypical melanocytic lesions composed of small (albeit atypical) ‘naevoidal’ melanocytes arranged in an overall pattern suggestive of a naevus but which display features that are concerning enough to warrant the label of melanoma78–80 (figure 4E,F). Naevoid melanomas may be encountered in both young and old patients, often as a moderately sized tan nodule which may be verruciform in some cases (verruciform pseudonaevoid melanoma81). Although classically epithelioid in morphology, spindle cell naevoid melanomas may also be encountered.78 Such lesions may often be recognised by the presence, albeit subtle, of cytological atypia, mitotic activity and irregular, often somewhat confluent, growth.16 17 Commonly, the most telling feature is a large nodule with an expansile front that may reach or extend into the subcutis. In addition, there is generally no evidence of maturation. Ancillary immunohistochemical staining with HMB-45 and MIB-1 may further highlight the atypicality, increased proliferative rate, and lack of maturation of these lesions.78 80 Needless to say, any melanocytic lesion, particularly in the setting of a new or changing lesion or one in an older patient, should be carefully scrutinised for malignant features. Although low-power examination reveals a variable degree of distortion of an underlying benign-appearing silhouette as well as a variable degree of cytological enlargement, hyperchromasia and nuclear atypia, close high-power scrutiny is generally the key to recognition and ultimate diagnosis. Evaluation of the biological potential of a naevoidal lesion should follow a standard approach to melanocytic lesions (table 3). Intradepartmental or external consultative opinions may be sought in challenging cases.
Nodular melanoma with a spindle cell component
By definition, nodular melanoma is a neoplastic proliferation of malignant melanocytes exhibiting a vertical growth phase in the absence of a horizontal growth phase.82 A horizontal growth phase is considered to be present when the intraepidermal/junctional component of the lesion does not extend peripherally more than three adjacent rete ridges beyond the dermal component of the nodule. Such lesions probably arise from the rapid development of a melanoma into an invasive phenotype thereby avoiding a prolonged precursor horizontal growth phase. Clinically, nodular melanomas are a relatively common subtype of melanoma seen more often in older people. Lesions are characteristically rapid-growing dark nodules or polyps that commonly ulcerate and crust. Amelanotic forms are also known. Histologically, nodular melanomas preserve a compound naevoidal pattern, although, not uncommonly, ulceration obliterates the majority of the epidermal component. When preserved, the epidermis reveals an in situ component, which may reveal pagetoid activity. By definition, lesions are circumscribed (in the horizontal plane) and also generally maintain a relatively symmetrical silhouette. The lesions are often of moderate–large size, with destructive expansile growth, dense confluence of cells, lack of dermal maturation and variable cytological atypia. Mitotic activity is generally appreciable and often high. This may further be highlighted by Ki67 or MIB-1 labelling. Spindling can be seen, and may even be the prominent cytomorphology. However, epithelioid areas are generally also present to varying extents.8 Uniform spindling in an otherwise nodular melanoma overlaps with the generic term ‘spindle cell melanoma’ (see below). Spindle cell nodular melanomas are generally not difficult to diagnose. Deviant clinical, architectural and cytological features generally allow easy recognition of its malignant nature. Occasional cases may exhibit less pronounced aggressive features, but careful scrutiny usually will reveal sufficient dermal mitoses, appreciable cytological atypia or other features to permit diagnosis. In such cases, an increased proliferative fraction or immunohistochemical demonstration of a lack of maturation (eg, diffuse HMB-45 staining) may offer some assistance in diagnosis. A careful search for residual epithelioid areas, particularly in the junctional/superficial areas, helps eliminate consideration of non-melanocytic entities in challenging cases. Efforts to develop other antibodies in the diagnosis of melanoma are ongoing, with WT-143 47 54 83 and nestin51–53 84 offering two potential aids in the determination of melanomas. However, the reliable utility of these antibodies has not yet been fully established.
Spindle cell melanoma
The generic term ‘spindle cell melanoma’ refers to a malignant melanocytic lesion with a uniform spindle cell cytomorphology. In many cases, such lesions are, in fact, nodular melanomas with complete spindled morphology. Both acral melanomas and melanomas of the solar type (‘lentigo maligna melanoma’) also often exhibit a spindled morphology. Both of these are generally easily recognised despite their cytomorphology on clinical and other histopathological grounds. In such cases, these terms are preferred, and we generally do not use the diagnostic term ‘spindle cell melanoma’ except when more precise resolution cannot be attained. The true challenge in most cases is in distinguishing such lesions from non-melanocytic spindle cell lesions (table 1). This requires careful histological scrutiny of the lesions for evidence of melanocytic differentiation (box 1) or evidence of another form of differentiation, as well as immunohistochemical confirmation (S100, other melanocytic markers, negativity for markers suggestive of other entities in the differential diagnosis). Challenging cases may arise, particularly since the more specific melanocytic immunostains are often negative in spindle cell melanomas. Multiple antibodies should be used, as occasionally MiTF or tyrosinase will show positivity despite the absence of staining with HMB-45 and Melan-A. WT-1 expression may offer some support to a presumptive diagnosis of melanoma, although its specificity is lower than that of the aforementioned stains. We do not consider S100 positivity alone to be definitive evidence of melanoma in cases that lack other evidence of melanocytic differentiation (nesting pattern, melanin production, junctional component, other immunohistochemical evidence, background melanocytic lesion). S100 positivity is also seen in neural lesions (although MPNSTs are generally only focally S100 positive and often negative). Langerhans cell lesions are also S100-positive lesions and may reveal misleading pagetoid spread.14 85 Atypical fibroxanthomas and cellular dermatofibromas may show scattered S100-positive Langerhans cells.29 We have also seen three cases of interdigitating dendritic sarcomas misdiagnosed as melanomas on the basis of their diffuse S100 positivity. Clinical correlation is often crucial in resolving such issues. Ultrastructural studies may also provide additional support for or against spindle cell melanoma in challenging situations (box 1).
The next group of recognisable spindle cell melanocytic lesions is the Spitzoid family (refer to Box 3 for notable pitfalls). The name ‘Spitzoid’ represents a distinct architectural and cytological pattern, which, when present in the classical form, is readily identifiable (figures 3B and 5 and table 6). Spitzoid lesions are classically well-circumscribed, symmetrical lesions that may be junctional, compound or, rarely, intradermal.30 31 86 Compound lesions may extend deep into the dermis often in a subtly infiltrative manner, and often with discrete isolated cells or small nests present deep to the main body of the tumour (‘outlier cells’).30 Spitzoid lesions by definition are composed of enlarged spindled and/or epithelioid melanocytes that typically show nucleoli and a variable degree of cytological atypia.87 88 Multinucleation is commonly encountered in Spitzoid lesions, and nuclei characteristically show angulations and geometric forms. Cells may also fit together creating geometrical patterns. Significant eosinophilic cytoplasmic substance generally preserves a low N/C ratio in lesional cells, and may reveal a bluish tinge. Classically, Spitzoid lesions are amelanotic or hypopigmented, although hyperpigmented variants do exist. Architecturally, Spitzoid lesions may show pagetoid activity even when benign. As well, limited superficial dermal mitotic activity is permissible in benign Spitzoid lesions, although deep dermal mitoses, atypical mitoses or clustering of mitotic figures remain atypical features.86 Spitzoid lesions are notorious for their histological overlap with melanoma, highlighted by the historic use of the outdated term ‘benign juvenile melanoma’ for classic Spitz naevi. The fact that Spitzoid lesions are more commonly encountered in younger populations (<20 years) compounds the need for caution in the pathological interpretation of these lesions. Fortunately, recognition of Spitzoid lesions may be aided by additional characteristic histological features including epidermal hyperplasia surrounding the junctional nests, a vertical (‘raining down’) orientation of junctional nests, the presence of intraepidermal eosinophilic globules (‘Kamino bodies’), and artifactual stromal retraction around junctional nests (‘semilunar clefts’).30 31 86 89–91 The utility of identifying Spitzoid morphology is in the recognition that certain otherwise concerning histological features may not be indicative of aggressive biological potential.
Box 3 Notable challenges/pitfalls in the evaluation of Spitzoid melanocytic lesions
Spitz tumours versus melanoma.
Placement of Spitzoid lesions on the Spitz naevus–atypical Spitz naevus–Spitzoid melanoma spectrum.
Pigmented spindle cell naevus of Reed versus Clark's naevus.
Pigmented spindle cell naevus of Reed versus melanoma in situ/superficial spreading melanoma.
On the other hand, there are persistent concerns regarding Spitzoid lesions, in particular, the lack of pathological criteria to assuredly determine benignancy in a Spitzoid lesion.92–98 Clinical follow-up of classic lesions in most cases reveals a benign course. Yet rare cases, particularly with the accumulation of atypical features, still have unexpected clinical outcomes, from the presence of sentinel node deposits but an otherwise benign course to disseminated metastases and death.96 97 99–105 This uncertainty has led some to prefer usage of the term ‘Spitz tumour’ to ‘Spitz naevi’ for all except perhaps only the most classic cases of Spitz naevi.96 As a result, Spitz naevi are ideally completely excised when it is clinically feasible.21 92 96 This is also required since proper pathological evaluation must assess a lesion in its entirety because of the extreme importance of assessing the lesion's silhouette to identify its Spitzoid nature and form an estimate of its biological potential. Atypical lesions must be managed more conservatively. Furthermore, there has been some evolution of the concept of the Spitz naevus from a mainly paediatric melanocytic tumour, with histological features overlapping those of adult melanoma, but with an almost certain benign course when showing classical features, to a morphological entity recognised not only in children but also in adults, in which the concern for mistaken identity becomes more significant, particularly when there is partial deviation from the classical phenotype. Appropriate evaluation of Spitzoid lesions thus needs to proceed in two parallel ways (figure 6):
Histopathological assessment of the lesion in order to assess atypical features and thus grade the degree of atypia, placing the lesion on a poorly defined spectrum of Spitzoid lesions (ie, is it an atypical lesion?)
Clinical assessment of the lesion (ie, age, location, colour, size, silhouette) in order to best predict the pretest probability that the lesion is, in fact, a melanoma, regardless of histological features (ie, is it a borderline lesion?)
Assessment of the clinical parameters adjusts the thresholds for translating the extent of deviation from a classical Spitz phenotype to a specific diagnosis. For example, there should be great resistance to diagnosing a Spitz naevus in an older patient because of the significant risk that the lesion is a melanoma with Spitzoid features.86 In contrast, in a child, one should be wary before diagnosing a Spitzoid lesion with highly deviant features as a melanoma unless truly convincing malignant features are present. Needless to say, such a lesion should certainly be diagnosed in a manner that reflects its atypicality, its potential for aggressive behaviour, and the histopathological limits to ruling out a melanoma. Juvenile melanomas do certainly exist, and many tragic cases attest to the potential malignant behaviour of atypical melanocytic lesions in the paediatric population. Furthermore, it should be emphasised that the ultimate diagnosis should not be based on the pretest probability of the lesion representing a melanoma (ie, essentially the relative incidence of the lesions in the differential diagnosis) but rather the post-test probability that the lesion will behave in a biologically aggressive manner (ie, the probability that the lesion is a melanoma or other aggressive lesion based on histopathological assessment and accounting for the pretest probability).
Efforts to resolve these issues are ongoing, with promising cytogenetic work that may allow differentiation of Spitz naevi from Spitzoid melanoma based on the extent and types of chromosomal abnormalities observed.106–109 Spitz naevi may reveal a normal karyotype, but, not uncommonly, reveal a unique copy number increase of the small arm of chromosome 11. Melanomas tend to show complex cytogenetic anomalies including chromosomal losses of 6p, 8p, 9p and 10q, as well as copy number increases in chromosomes 1q, 6p, 7, 8q, 17q and 20q. Thus the unique nature of the 11p gain in Spitz naevi, which is not typically seen in melanoma, as well as the complex chromosomal aberrations seen in melanoma as opposed to the absent or minimal chromosomal aberrations seen in Spitz naevi (or other naevi for that matter) offer new cytogenetic features that may be exploited to differentiate challenging cases, or even as a standard test in the work-up of Spitzoid lesions. Clearly, clinical validation is required, but such a test would be of great value in that it would allow more accurate study of the true biological basis of such lesions and a prediction of their biological potential based on their molecular make-up. Such ancillary tests are clearly enticing given the challenge inherent to predicting the biological potential of Spitzoid lesions based on morphology alone.
The spectrum of Spitzoid lesions used in our practice include:
Spitz naevus (and variants) (may be junctional, compound, dermal)
Atypical Spitz tumour (low-grade, high-grade)
Spitzoid melanoma/melanoma with Spitzoid morphology
Pigmented spindle cell naevus (of Reed) (may be junctional or compound)
Atypical pigmented spindle cell naevus
Spitz naevi (may be junctional, compound or intradermal)
Spitz naevi are uncommon melanocytic lesions (although often encountered in dermatopathology practice4), which most commonly occur on the extremities or trunk, although the head and neck region, in particular the face, is also a site of predilection in children.32 56 110 A general rule is that one third of cases occur in children (<10 years), one third in adolescents/teenagers (10–20 years), and one third in adults (>20 years), although some studies suggest a higher proportion in adults.111 Most appear as amelanotic/hypopigmented red or red–brown macules, papules or nodules of limited size with most <6 mm and almost all <10 mm. Rare lesions may extend up to 2 cm. Spitz naevi are usually acquired lesions that have an initial rapid growth phase, which reaches permanent stability after about 6 months.86 Polypoid and pigmented variants do exist and are not criteria for considering the lesion atypical or for rendering an alternative diagnosis. Another clinical pattern is the agminate (multifocal) Spitz naevus. Spitz naevi may become pruritic when there is an inflammatory infiltrate, but should not ulcerate unless traumatised. Critical to the diagnosis of a Spitz naevus is its symmetry and sharp circumscription. The dermatoscopic appearance of Spitz naevi often shows a characteristic ‘sun-burst’ pattern.
Spitz naevi may be entirely junctional, compound (majority of cases) or intradermal. An intraepidermal pagetoid variant is also known.86 Most lesions tend to show either a papillomatous or a dome-shaped pattern with preservation of the symmetrical and circumscribed silhouette histologically. There should be no shouldering phenomenon. Spitz naevi may grow deeply, and, in such cases, typically show an infiltrating, but non-destructive pattern of growth, often with small groups of cells or single cells isolated from the main body of the tumour at its advancing edge (‘outlier cells’).30 Mild–moderate pagetoid activity is acceptable in Spitz naevi, although it should be located centrally within the lesion and should not reach the granular cell layer. True pagetoid activity must be distinguished from transepidermal elimination of melanocytic nests, however, since the latter may also be present and may extend through the stratum granulosum/corneum. Moderate mitotic activity is acceptable (up to six mitoses per 10 hpf) within otherwise classical Spitz naevi, although deep dermal mitoses, atypical mitoses, clustering of dermal mitoses, and mitoses in pagetoid cells remain features of concern. Rare cases of classical Spitz naevi in young children may reveal profuse mitotic activity.96 We may tolerate up to 20 mitoses per 10 hpf provided that no further atypical features are appreciated and a classic silhouette is maintained, and have termed such lesions ‘proliferating Spitz naevi’. The natural history of such lesions is unknown, but it is likely that they represent sampling of classic Spitz naevi during a proliferative phase of the lesion. Cytological and architectural maturation are important reassuring features in Spitz naevi, and a lack of maturation should be considered an alarming feature. In particular, a large deep dermal nest (ie, significantly larger than the more superficial nests) with an expansile border and no evidence of cytological maturation is of significant concern. The density of the cellular proliferation in Spitz naevi may vary; however, dense confluent growth, particularly if it is irregular or destructive, is an atypical feature. In addition to these characteristic cytological and architectural features, Spitz naevi classically show epidermal hyperplasia with elongation of the rete ridges, which give a ‘clutching’ appearance around the junctional nests, which often contain spindled cells in a vertical orientation likened to a bunch of bananas or imparting a ‘raining down’ effect. Furthermore, there is typically evidence of stromal retraction around these nests, at least in part producing the so-called ‘semilunar clefts’. This appearance should be contrasted with the appearance of dyscohesive melanocytic nests, which may also give the appearance of stromal separation but with an otherwise loose dyscohesive arrangement. Dyscohesion is an atypical feature and may raise concern for a melanoma. Kamino bodies89 90 are a characteristic and fairly specific histological feature of Spitz naevi which represent amorphous PAS-positive, diastase-resistant eosinophilic globules composed of basement membrane material located at the dermo–epidermal junction.112 113 Only rarely are they found in melanomas. Kamino bodies may be absent in Spitz naevi, especially when there is limited sampling/levels. Vascular ectasia and an inflammatory component may also be seen in Spitz naevi. Spitz naevi may be present as the following histological variants: desmoplastic (refer to part II: intradermal proliferations);21a pigmented (pigmented spindle cell naevus; discussed below); angiomatoid (Spitz naevus with halo phenomenon); plexiform; hyalinised; myxoid; pagetoid; as a component of a combined naevus (refer to part II: combined lesions).21a
Of paramount importance to the diagnosis of Spitz naevi is the presence of large spindled and/or epithelioid melanocytes with Spitzoid nuclear features (nucleoli, pleomorphism, angulated/geometric nuclei, multinucleation).19 30 31 86–88 Hyperchromasia and coarsening of chromatin are not features of benign Spitz naevi. The cytoplasm of Spitz naevi is also characteristic because of its abundance, typical lack of pigmentation, and its glassy pale eosinophilic quality often with a bluish tinge. Spindled cells tend to predominate, and epithelioid variants should be viewed with suspicion when found in adult patients.
The classic cytological and architectural Spitzoid features are critical to the diagnosis (figure 4 and table 6), and thus light microscopy remains the ‘gold standard’ of diagnosis. Spitz naevi stain diffusely for S100 and generally show a stratified maturation pattern of staining with other melanocytic markers (eg, HMB-45).92 Proliferation index markers (eg, Ki67, MIB-1) also show greater labelling towards the surface. Numerous other immunohistochemical markers (CD99,50 92 cyclin D1,38 45 p16,46 92, c-kit,49 92 bcl-2,45 others45 92) have shown positive expression in Spitz naevi, but none have reproducibly been shown to differentiate benign from malignant Spitzoid lesions. Spitz naevi tend to show limited cytogenetic abnormalities in contrast with melanomas, which tend to show a multitude of changes106–109 (discussed above). Comparative genomic hybridisation may be used to assess the cytogenetic status of lesional cells, and, if reliable discriminating cytogenetic foci are determined, routine fluorescence in situ hybridisation assays may be developed.
Atypical spitz tumour
The label ‘atypical Spitz tumour’ (also known as ‘Spitz tumour of undetermined malignant potential’ or STUMP) serves two purposes in the pathological reporting of Spitzoid lesions: (1) it highlights the significant grey zone in Spitzoid lesions in which the pathologist no longer feels comfortable promising benign biological behaviour based on clinical and pathological parameters; (2) it allows categorical placement of such lesions so that established management protocols may be followed by clinicians and for future studies on the true nature of these lesions. Compromising the latter point is the fact that this category is almost certainly a heterogeneous group of lesions, which we would ultimately wish to resolve into more appropriate diagnoses. Thus the atypical Spitz tumour category probably consists of lesions that are Spitzoid in nature as well as many lesions that are not fundamentally Spitzoid but exhibit features suggestive of a Spitzoid lesion (which, if recognised more precisely, are preferably termed ‘the underlying melanocytic lesion … with Spitzoid morphology’). Furthermore, the atypical nature may be based on deviation from architectural features (eg, loss of the classic Spitzoid silhouette, lack of architectural maturation, ulceration, confluent growth with an expansile front, extension into the subcutaneous tissue), cytological features (eg, severe cytological atypia beyond the acceptable limits for Spitz naevi, increased/abnormal/deep mitoses), clinical features (eg, large size), or any combination of the above (eg, epithelioid morphology in an adult, prominent pagetoid activity in an adult). These features have mainly been discussed above (see Spitz naevus) and are also summarised in table 6. Confounding this category even further is the fact that, despite much effort, there are no reliable criteria to guide the placement of entities into this category, and, in essence, the task is largely left up to the individual thresholds tolerated by each pathologist.96 114 115 Almost certainly, significant interobserver and potentially intraobserver variation must exist.97 However, it is certain that no effective criteria could be put forward, as, by nature, the entity is a diagnosis by exclusion (ie, not certainly a Spitz naevus and not certainly a melanoma). This highlights the final concern about the heterogeneous population of lesions within the atypical Spitz tumour group: it contains both lesions considered in the differential diagnosis of a Spitz naevus (ie, with low-grade features or considered low risk for malignant behaviour) and lesions considered in the differential diagnosis of a melanoma (ie, with high-grade features or considered at high risk for malignant behaviour). This assessment of risk is again a gestalt of the clinical and pathological attributes of the lesion without clear defining lines of separation. Nevertheless, we do use this separation to help communicate our best estimate of malignant potential for a lesion falling in the wide gap between a Spitz naevus and a melanoma. Thus we use the terms atypical Spitz tumour (low grade) and atypical Spitz tumour (high grade). Such a division is used by other groups as well.19 93 In general, severe cytological atypia particularly in prominently epithelioid tumours, multiple deep dermal mitoses, surface ulceration and loss of the classic Spitzoid silhouette, particularly if it is by a dense confluent proliferation that shows a bulging margin, are considered high-grade features. Clinical management may vary on the basis of this delineation in select cases (eg, Spitzoid lesion on the face of a young child). However, only a minority of cases of Spitzoid lesions should fall into the category of atypical Spitz tumour, with resolution of Spitz naevi and Spitzoid melanomas possible in most instances. Immunohistochemistry may be of some help in the evaluation of atypical Spitzoid lesions.92 Proliferation markers such as Ki67 or MIB-1 may highlight an increased proliferation rate and/or a lack of diminished activity in the deeper components of the lesion. HMB-45 may highlight a stratified staining pattern suggestive of maturation, although diffuse staining is not incompatible with a benign compound Spitz naevus.
Atypical Spitz tumours in children, with or without sentinel lymph node (SLN) metastases, show almost universal survival,114 116 with paediatric mortality from Spitzoid lesions occurring essentially only in cases in which the primary tumour is histologically clearly malignant (see Spitzoid melanoma below). This is at the centre of the debate whether or not SLN positivity is a criterion for a diagnosis of Spitzoid melanoma. Owing to the favourable outcome of paediatric patients whose primary Spitzoid lesions are indefinite for malignancy but whose SLNs are subsequently found to contain deposits/metastases, we consider such a finding compatible with a diagnosis of atypical Spitz tumour, provided that the deposit is not highly malignant appearing and does not exhibit appreciable destructive infiltration of the lymph node. Such studies also beg the question whether or not SLN biopsies are warranted for atypical Spitz tumours, particularly because of the high rate of positivity (up to 50%).100–102 104 105 However, until further study is carried out, we will continue to recommend SLN biopsy (in addition to complete excision with conservative margins of at least 1 cm) for cases of Spitzoid lesions equivocal for malignancy. Atypical Spitz tumours in adult patients are not as well studied, and a more guarded prognosis is warranted.
The end of the Spitzoid spectrum is Spitzoid melanoma. Spitzoid melanomas share many of the general clinical features of melanoma except that they are more common in younger patients including children.92 95 117 Spitzoid melanomas may be clinically suspected in cases of Spitzoid lesions that spontaneously ulcerate or enlarge, often with disruption of the symmetrical silhouette. Large Spitzoid lesions (ie, >10 mm) are also suspect. As opposed to the termination of the initial growth phase of Spitz naevi, Spitzoid melanomas do not attain stability but continually grow and change.86 Overt signs of malignancy may include regional adenopathy or other evidence of metastatic disease. Occasionally, one or multiple Spitz naevi may arise near the place of a prior excision of a classic Spitz naevus, raising concern for satellitic metastases of a missed Spitzoid melanoma. However, such a phenomenon, when histologically benign, should be appreciated as satellitic Spitz naevi, akin to an agminated Spitz naevus, with no increased potential for malignant behaviour.118 Recurrent Spitz naevi119 may also be confused with a malignant process, and features of a recurrent naevus phenomenon should be appreciated (see part II: horizontally oriented lesions; naevi with disruption phenomena).21a
Histological evaluation of a Spitzoid melanoma follows as per the evaluation of any other melanocytic lesion, with attention also paid to the special features of a Spitzoid lesion (eg, presence of Kamino bodies, characteristics of the deep border, pattern of pagetoid activity) (tables 3 and 6). As previously discussed, the threshold for calling a lesion melanoma will depend on the clinical setting (ie, pretest probability). Spitzoid lesions that prompt serious consideration for a melanoma but which ultimately fall short of meeting the minimal criteria for a diagnosis of melanoma should be diagnosed as atypical Spitz tumour (high grade). Typically, a Spitzoid melanoma will exhibit an irregular pattern of growth which either disrupts or over-runs an existing organised Spitzoid silhouette or which appears completely irregular with no underlying organisation.86 95 120 Occasionally, the disruption may occur as an expansile dermal nodule which often shows a different cytomorphology and mitotic rate compared with the background lesion. Extension of a Spitzoid lesion into the subcutaneous tissue is also an unusual feature, but not unheard of for Spitz naevi. Numerous mitoses including deep dermal forms and severe cytological atypia with macronucleoli are features favouring a Spitzoid melanoma. A clear-cut lack of architectural and cytological maturation is a more reliable feature for Spitzoid melanoma. Spitzoid melanomas should exhibit underlying characteristic Spitzoid architectural and/or cytomorphologcal features that define Spitzoid lesions in general.
Two paths generally lead a pathologist into the differential diagnosis of a Spitzoid melanoma: (1) removal of a lesion suspected to be a Spitzoid lesion (eg, red–brown nodule from the face of a child), which subsequently shows high-grade features; (2) histopathological appreciation of Spitzoid architectural and cytological features in a lesion in the absence of a suggestive clinical history (eg, often the manner in which Spitz naevi in adults come to light). In the former setting, the burden of diagnosis is typically on assessing the atypicality of the lesion (ie, placement of the lesion on the Spitzoid spectrum), and thus proceeds in a manner that identifies and grades atypical features with appreciation of what is permitted in Spitzoid lesions. In the latter setting, the burden of diagnosis is often placed on ensuring that one is dealing with a Spitzoid lesion (ie, not a melanoma with potentially misleading Spitzoid features), and so features such as pagetoid spread, cytological atypia and occasional superficial mitoses, which may be acceptable in a classic Spitzoid lesion taken from a child, may be more reflective of a malignant lesion in an adult, calling into question the true Spitzoid nature of the lesion. This is not a trivial distinction, since Spitzoid melanomas removed from children show a more favourable outcome even in the presence of SLN metastases.114 116 117 This favourable outcome has not been noted for melanomas with Spitzoid morphology in adults. This difference in behaviour probably reflects a difference between the accurate recognition of what is probably a relatively indolent malignant tumour (Spitzoid melanoma), which overlaps significantly with lesions essentially lacking true malignant potential (atypical Spitz tumours), and a group mainly comprising fully malignant melanomas that are mistaken for Spitzoid melanomas because of suggestive histological features. For this reason, we prefer to reserve the term ‘Spitzoid melanoma’ for patients 20 years or under, and use the term ‘melanoma with Spitzoid morphology’ for older patients.
As previously mentioned, there are currently no established ancillary tests that definitively differentiate benign from malignant Spitzoid lesions. An increased proliferative index (Ki67 or MIB1 labelling) and a lack of maturation, as evidenced by diffuse HMB-45 staining, support a diagnosis of melanoma, but are not reliable92 120 121—a relatively low proliferative fraction (5–15%) does not exclude a melanoma, and diffuse HMB-45 staining may occasionally be seen in benign lesions. Cytogenetic demonstration of multiple chromosomal abnormalities is consistent with a diagnosis of melanoma,106 108 109 but such testing does not have strong clinical validation and is not widespread.
Pigmented spindle cell naevus (of Reed)
A characteristic subtype of Spitz naevus is the pigmented spindle cell naevus (also known as ‘pigmented spindle cell naevus of Reed’ or ‘Reed naevus’) (figure 7). Clinically, pigmented spindle cell naevi of Reed are recognised by their deep coloration, often appearing pitch black.32 56 Lesions are uniform in appearance, typically small (<6 mm), well-circumscribed and symmetrical. Classically, lesions occur in young adults, although children may be affected, with females affected more commonly than males. Typical location is the thigh followed by shoulder and upper arms, although lesions may be located on any skin site. Dermoscopy shows the characteristic Spitzoid sun-burst pattern. Histologically, the lesion is characteristic for its Spitzoid morphology (figure 5 and table 6), prominent pigmentation with numerous melanophages, and its horizontal orientation, often being entirely junctional, although most do reveal a limited dermal component. The benign nature of the lesion is assured through recognition of the Spitzoid nature of the lesion in conjunction with its benign silhouette (small size, sharp circumscription and good symmetry), and a lack of atypical features30 31 122 (see below). In addition, pigmented spindle cell naevi reveal uniformity in the size and distribution of nests. As with any Spitzoid lesion, pigmented spindle cell naevi exhibit large nuclei with nucleoli often vertically oriented with epidermal hyperplasia and possible Kamino bodies. Occasional mitoses including rare dermal forms are acceptable. Pagetoid ascent of cells is often seen and, classically, in a nested rather than single cell pattern. Pigmented spindle cell naevi may show an apparent lack of maturation due to their thin nature. Lesions may also appear concerning because of their cellularity and typical rete bridging, although prominent fibroplasia is unusual. The major risk of misdiagnosis is with a superficial spreading melanoma/melanoma in situ or a Clark's naevus with high-grade features. The focus on the differential rests on recognition of the Spitzoid nature of the lesion, its small size and benign silhouette with a lack of shouldering, the uniformity of the lesion, and the lack of truly concerning features suggestive of melanoma outside of those permissible in Spitzoid lesions (tables 3 and 6). Our practice is to consider lesions consisting of more than a small minority of epithelioid cells with features otherwise consistent with a pigmented spindle cell naevus as a pigmented variant of a Spitz naevus, granting that this differentiation is somewhat semantic.
Atypical pigmented spindle cell naevus is a term used to raise clinical concern about the biological potential of a lesion consistent with a pigmented spindle cell naevus but which demonstrates further features that are not acceptable as strictly benign. Abnormal clinical parameters (older age, changing lesion, spontaneous ulceration), larger lesions (>1 cm), loss of the reassuring benign silhouette, severe cytological atypia, increased mitotic activity with deep dermal or atypical forms, and expansile dermal growth represent atypical features warranting some caution in the biological potential of the lesion, and a diagnosis of atypical pigmented spindle cell naevus is appropriate.31 122 Such lesions require complete excision with conservative margins and continued patient follow-up.
In part I, we have presented our algorithmic approach to spindle cell melanocytic lesions, one which begins with the need to recognise a spindle cell lesion as melanocytic in nature. Cytological, architectural and immunohistochemical features of melanocytic lesions are discussed to facilitate such recognition. To this end, we have also included table 1, which lists diagnostic features of non-melanocytic spindle cell cutaneous lesions that may enter into the differential diagnosis of certain spindle cell melanocytic lesions. The algorithm proceeds with a categorical subdivision of spindle cell melanocytic lesions based primarily on architectural pattern. This initial step aims to provide greater acuity when proceeding with the subsequent detailed assessment of histopathological features in an effort to predict the potential biological behaviour of the lesion. A generalised approach to grading the biological potential of melanocytic lesions is also provided. The final step is the application of diagnostic terminology. We strive to use established and communicative diagnostic terms that describe the histogenesis of the lesion, and at the same time optimally facilitating subsequent clinical management by reflecting an estimate of the biological risk posed by the lesion based on the assessment of the pathological and clinical parameters. Finally, we have begun our discussion of spindle cell melanocytic entities by covering those entities that fall under our first two categories: compound naevoidal pattern lesions and Spitzoid lesions. Continuing in part II, we proceed with a discussion of spindle cell melanocytic entities that fall under the final two categories: intradermal proliferations and horizontally oriented lesions. We also discuss combined lesions and provide summary thoughts.
Spindling, in its many forms, is a common phenomenon (partial or complete) that may be seen in most melanocytic lesions.
A spindle cell morphology does not necessarily connote an aggressive biological potential and must be interpreted within the context of the type of melanocytic lesion (ie, architectural pattern) as well other histopathological and clinical features.
Spindle cell melanocytic lesions commonly show loss of melanocyte-specific immunohistochemical markers—use of multiple specific melanotic markers increases sensitivity.
Commonly, the histogenetic origin of a spindle cell melanocytic lesion may be determined histologically by the presence of a more recognisable junctional component, by characteristic nesting, or by an admixed pigmented/epithelioid component.
Optimal assessment of the biological capacity of spindle cell melanocytic lesions requires a gestalt impression of numerous features (clinical, histological, ancillary studies), which should proceed in a standard way but with acceptances made for lesional patterns that characteristically express certain, otherwise, concerning features.
The pathology report should relay to the clinician information about the histogenetic nature of the lesion as well as its potential for aggressive biological behaviour in a manner that facilitates optimal management decisions.
Interactive multiple choice questions
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Competing interests None.
Provenance and peer review Not commissioned; not externally peer reviewed.