Melanoma: the Morphological Dimension I.4 Lorenzo Cerroni

Home , Benign melanocytic nevus, Nevoid melanoma, Nodular melanoma

ChapterMelanoma: I.4 the Morphological Dimension Melanoma: the Morphological Dimension I.4 Lorenzo Cerroni

Contents

I.4.1 introduction...... 23 I.4.4.7 Melanocytic Proliferations with “Spitzoid” Morphology...... 33 I.4.2 General Remarks...... 25 I.4.2.1 Morphological Observations...... 25 I.4.5 Conclusion ...... 34 I.4.2.2 ancillary Techniques ...... 25 References...... 35 I.4.2.3 Particular Morphological Types of Melanoma...... 25 I.4.3 Special Settings...... 26 I.4.3.1 Melanocytic Tumors Biopsied I.4.1 Introduction in Newborns or Shortly After Birth...... 26 I.4.3.2 Proliferations of Melanocytes Within Chronic Sun-Damaged Skin...... 27 The histopathological diagnosis of melanocytic I.4.3.3 Proliferations of Melanocytes Biopsied tumors, including malignant melanoma (hence Shortly After Sun Exposure...... 28 referred to as melanoma) and benign melano- I.4.3.4 Proliferations of Melanocytes cytic nevi, has been the subject of countless Within Mucosal Epithelium studies published in the literature. Although (Genital and Oral Mucosa)...... 28 precise histopathological criteria for distinction I.4.3.5 Melanocytic Proliferations of benign from malignant melanocytic prolif- at Other Special Skin Sites...... 29 erations have been established, in some instanc- I.4.3.6 Proliferations of Melanocytes at Sites es a precise diagnosis is not possible, a problem of Inflammatory Skin Disorders...... 30 that is reflected by the use of various terms coined during the years, including “melanocytic I.4.4 Particular Histopathological Problems. . . . 30 tumors of uncertain malignant potential I.4.4.1 Melanocytic Nevi with Several Cell (MELTUMP)” or “superficial atypical melano- Populations (“Combined” Nevi)...... 30 cytic proliferation of uncertain significance I.4.4.2 Nodular Proliferations of Melanocytes Within Congenital Nevi...... 30 (SAMPUS)” among others. Despite uncertainty I.4.4.3 Superficial Proliferations of Melanocytes in given cases, however, histological examina- with Prominent Pigmentation...... 31 tion of a tissue specimen is still the gold stan- I.4.4.4 Proliferations of Melanocytes Associated dard in diagnosis of melanocytic tumors, and with Prominent Inflammatory Response the most important prognostic criteria for pri- and/or Regression ...... 31 mary melanoma (tumor thickness, ulceration) I.4.4.5 recurrence (Persistence) are established by the observation of the histo- of Melanocytic Lesions at the Site pathological specimens as well. Sharing unusual of a Previous Incomplete Excision or controversial cases in consultation with der- (Recurrent Nevi, Recurrent Melanoma). . . 32 matopathologists with special expertise in me- I.4.4.6 atypical Melanocytic Nevi lanocytic tumors is helpful in minimizing the with Degenerative Changes risk of misdiagnoses that may be potentially (“Ancient” Melanocytic Nevi)...... 32 fatal for the patients. 24 L. Cerroni

It is crucial to remember that under the mi- croscope each single melanocytic lesion should first be analyzed at scanning magnification in order to evaluate properly overall symmetry and lateral circumscription. It is also important to emphasize that a proper biopsy is a pre-requisite for a specific diagnosis. This is true in dermatopathology in general, and even more so in I.4 the evaluation of melanocytic lesions. Incom- plete biopsies (e.g., punch biopsies, shave biopsies) often do not allow a precise classification of the cases. In a similar manner, biopsies with surgical artifacts (crush artifacts) often cannot Fig. I.4.1. Melanoma shows scatter of melanocytes in be interpreted properly. Finally, optimal prepa- small nests and as solitary units at all level of the epi ration of the specimens in the dermatopatho- dermis logical laboratory is crucial as well. All too often we receive specimens in consultation that are Table I.4.1. Histopathological features of melanoma either badly cut, or badly stained, or both. A precise diagnosis in these cases is often impos- Asymmetry of the lesion sible. overall asymmetry A good practice in the histopathological asymmetry of pigment distribution evaluation of melanocytic tumors is to study asymmetry of inflammatory infiltrate more than a single section of tissue. Step sec- Unsharp lateral circumscription tions should be prepared routinely, particularly Presence of ulceration in cases that are controversial histopathologically, or that showed atypical features clinically. “Consumption” of the epidermis In this context, communication between clini- (thinning of the epidermis with attenuation cians and dermatopathologists is crucial. In ad- of the basal and suprabasal layers and loss of the rete ridges adjacent to collections of melanocytes) dition, photographic documentation of each lesion deemed to be suspicious clinically should Solitary melanocytes predominate over melanocytes be attached to the referral sheet, in order to in nests within the epidermis avoid mistakes in the grossing of the specimens. Pagetoid spread of melanocytes within the In fact, in melanomas arising within melano- epidermis (melanocytes distributed in all layers cytic nevi the specific histopathological changes of the epidermis) may be found only focally, and a clinical picture Incohesive melanocytes within nests with remarks by the clinicians allows precise identification of the suspicious areas before Sheets of melanocytes within the dermis grossing. The occurrence of melanoma within “Pushing” lower margin of dermal complexes pre-existing melanocytic nevi is probably un- of melanocytes derestimated [46]. Obliteration and/or destruction of adnexal The histopathological criteria for the diagno- structures sis of melanoma are listed in Table I.4.1. They Presence of intravascular complexes of melanocytes include general architectural criteria, features of the intraepidermal and dermal components, Perineural growth and/or neurotropism and cytomorphological features of the melano- Presence of atypical melanocytes cytes (Fig. I.4.1) [1, 2]. No single criterion is spe- Presence of several mitoses, especially at the base cific for benign or malignant proliferations of of the lesion melanocytes, and exceptions to any of these criteria exist; thus, only integration of all criteria can be helpful in establishing the correct diag- Melanoma: the Morphological Dimension Chapter I.4 25 nosis. In this context, it is important to under- stand that in most cases application of the histopathological criteria listed in Table I.4.1 allows a precise diagnosis of melanoma, and that exceptions are relatively rare; however, exceptions do exist, and their recognition and precise classification is crucial in order to manage patients ad- equately. We discuss herein the general aspects of the histopathological diagnosis of melanoma and nevi, as well as some of the histopathological problems that may be encountered in the microscopic evaluation of pigmented lesions of the skin. Fig. I.4.2. Melanoma growing along a hair follicle within the dermis is shown. Breslow tumor thickness should not be measured in the proximity of adnexal structures (adventitial dermis) I.4.2 General Remarks I.4.2.1 Morphological Observations I.4.2.2 Ancillary Techniques In recent years, many different studies have addressed specific aspects of melanoma diagnosis The diagnosis of melanoma rests upon careful and prognosis, and many different suggestions examination of sections of tissue stained with have been proposed as to what information a hematoxylin and eosin. Although many studies histopathological report should include. Exam- addressed the value of immunohistochemical ples are, among others, presence/absence of tu- stainings in the diagnosis and classification of mor-infiltrating lymphocytes, vertical or hori- melanocytic tumors, there are no compelling zontal growth phase, number of mitoses per data showing that any immunohistochemical unit area, presence of regression, presence of marker provides informations that go beyond neo-angiogenesis, and details on histopatho- those already provided by routine histological logical classification according to the categories examination of the specimen. Genetic studies of superficial spreading melanoma, nodular may provide in the near future additional valu- melanoma, lentigo maligna melanoma, or acral able informations, especially in controversial le- melanoma [17, 19, 27, 28, 34, 43, 60, 73]. This last sions. At present, however, careful examination classification, in our opinion, is obsolete, and of routine histopathological sections and accu- does not convey any meaningful information to rate clinicopathological correlation are the gold physicians and/or patients. In addition, the standard in the histopathological diagnosis of prognostic value of most of the histopathologi- benign and malignant melanocytic tumors, and cal features listed above have yet to be validated in the assessment of prognostic parameters in in large studies, and at present the only accepted primary melanoma [38, 55, 93]. prognostic features for TNM classification of the tumors are the maximal thickness and the presence of ulceration [6, 7]. The Clark level I.4.2.3 Particular Morphological Types needs to be mentioned only in the rare cases of of Melanoma thin melanoma (<1 mm) of levels IV or V. For a precise TNM classification of each case it is cru- In some cases, melanoma deviates from the cial that prognostic criteria be evaluated prop- conventional histopathological features listed in erly (Fig. I.4.2). Table I.4.1, and is characterized by peculiar aspects that may render the diagnosis difficult. It is important to be familiar with the different morphological presentations of melanoma in 26 L. Cerroni

I.4

Fig. I.4.3. Desmoplastic melanoma. Note patchy lympho Fig. I.4.4. Balloon-cell melanoma. Note atypical nuclei cytic infiltrate of the balloon cells and a mitotic figure

order to avoid misdiagnosis in such cases. One I.4.3 Special Settings relatively common problem is the presence of spindled melanocytes in the context of desmo- I.4.3.1 Melanocytic Tumors Biopsied plasia (desmoplastic melanoma) [2, 20, 84]. Use- in Newborns or Shortly After ful diagnostic clues are the presence of features Birth of melanoma in situ in the overlying epidermis, of patchy lymphoid infiltrates within the der- Melanocytic tumors biopsied shortly after birth mal component, of atypical cells and mitoses, show frequently histopathological criteria of and of neurotropism (Fig. I.4.3). Staining for S- melanoma, but behave almost invariably in a 100 may be helpful in verifying the lateral and benign fashion, and thus are considered to be deep extension of the tumor, but other melano- benign simulators of melanoma [2, 5, 24, 33, 44, cytic markers may be negative in this type of 47, 78]. Two main groups are recognized: the melanoma. Another peculiar variant of mela- first is characterized by a pagetoid intraepider- noma is characterized by the presence of abun- mal growth of melanocytes which is virtually dant myxoid stroma (myxoid melanoma), a indistinguishable from that observed in mela- variant that is found more frequently in cutane- noma (Fig. I.4.5). These lesions usually present ous metastases of the disease but that can be clinically with plaques characterized by irregu- observed in primary cutaneous cases as well lar pigmentation. Histopathologically, melano- [2]. In addition, sporadic reports of melanomas cytes arranged in nests or as solitary units are with other peculiar histopathological features present within the entire thickness of the epi- have been published (balloon cell, signet-ring, dermis including the horny layer. Although it spindle cell, melanophagic/animal type, pseu- has been frequently reported that a helpful cri- dolipoblastic, schwannoid, ganglioneuroblastic, terion for differentiation of these cases from plasmacytoid, Merkel cell-like, etc.; Fig. I.4.4) melanoma is the monomorphism of intraepi- [2, 9, 40, 41, 51, 56, 57, 58, 94]. In some cases, dermal melanocytes, in our experience the me- melanoma may be characterized by the absence lanocytes can be polymorphous and display of prominent cellular atypia and by predo atypical morphological aspects (hyperchroma- minance of small cells (nevoid cells) [75, 91, tism, large nuclei). The presence of melanocytes 95]. These cases have been termed “nevoid of a congenital nevus without atypical features melanoma” or “small cell melanoma,” and in the dermis is helpful in establishing the cor- represent yet another potential pitfall in the rect diagnosis. The second group is character- differential diagnosis of cutaneous melanocytic ized by so-called proliferative nodules in con- tumors. genital nevi in newborns [2, 3, 21, 24, 78]. These Melanoma: the Morphological Dimension Chapter I.4 27

Fig. I.4.6. Congenital pseudomelanoma (proliferating nodules within congenital nevi in newborns). Note monomorphous population of large, atypical melanocytes

melanocytes. Children presenting with such lesions, however, should be closely and carefully followed.

I.4.3.2 Proliferations of Melanocytes Within Chronic Sun-Damaged Skin Chronic sun-damaged-skin presents two main Fig. I.4.5. Melanocytic nevus biopsied shortly after birth. problems in diagnosis and differential diagnosis a Note complexes of a congenital melanocytic nevus in the dermis and prominent intraepidermal component. of melanocytic tumors. The first problem is due b Scatter of pleomorphic melanocytes within all layers of to the presence in “normal” chronic sun-dam- the epidermis aged skin of melanocytes at the dermo-epidermal junction that have enlarged nuclei with atypical morphological features, thus being a lesions simulate a melanoma clinically as well as possible cause of misdiagnosis of melanoma [2, histopathologically, and are one of the most 24]. In chronic sun-damaged skin melanocytes vexing problems in the realm of melanocytic le- are seated only at the dermo-epidermal junc- sions in newborns. Clinically, there is a nodule tion, are equidistant from one another, do not within a giant congenital nevus, which may be show prominent dendritic processes, never form more or less pigmented than the neighboring nests, and are relatively monomorphous, that is, nevus. Histopathologically there are sheets of all melanocytes have similar morphological fea- melanocytes larger than those in the surround- tures. On the other hand, any junctional or ing nevus, and there can be mitoses and necrot- compound melanocytic lesion that develops on ic melanocytes (Fig. I.4.6). Although the epider- severely sun-damaged skin must be considered mis usually lacks features of melanoma in situ, as a probable melanoma [58]. Melanoma in situ it is often impossible to distinguish these lesions in chronic sun-damaged skin is characterized from a so-called dermal melanoma developing in the early stages by a slight increase in the in a giant congenital nevus. Features that are number of melanocytes arranged as solitary helpful in the diagnosis are the sharp circum- units at the dermo-epidermal junction and only scription and the superficial location of the focally above it. The nuclei are enlarged, but so nodule, and the monomorphism of the large are the nuclei of “normal” melanocytes in 28 L. Cerroni

chronic sun-damaged skin, and at times the diagnosis may be extremely difficult, especially when only small punch biopsies are available. Of course, benign nevi may be observed in chronic sun-damaged skin; however, such a diagnosis should be made only when the evidence for a benign lesion is compelling (sharp circumscription, absence of increased number of soli- I.4 tary intraepidermal melanocytes at the lateral margins, no pagetoid spread, and, more gener- ally, absence of any criteria suggestive of melanoma). Fig. I.4.7. Genital melanosis. Note hyperpigmentation of the epidermis without increase in number of melanocytes I.4.3.3 Proliferations of Melanocytes Biopsied Shortly After Sun Exposure Benign melanocytic nevi exposed to UV radia- tion may show intraepidermal features simulating melanoma in situ (e.g., solitary melanocytes disposed not only at the dermo-epidermal junction but also in upper epidermal layers) [24, 87]; however, intraepidermal melanocytes do not show atypical features, and the dermal component does not reveal any aspect of malignancy. Architectural features return to normality in a few weeks after UV irradiation.

I.4.3.4 Proliferations of Melanocytes Fig. I.4.8. Genital melanoma in situ. Note slight increase Within Mucosal Epithelium of solitary melanocytes with long dendrites above the dermo-epidermal junction (Genital and Oral Mucosa) Two conditions may create diagnostic problems in pigmented lesions within mucosal epitheli- junction, nor nests of melanocytes [2]. A few um, namely, so-called melanosis (oral or geni- melanophages, but no melanocytes, are found tal) and melanocytic nevi arising within the in the dermis. Reports of melanoma arising in genital skin. Melanosis may occur on the geni- the background of melanosis most likely repre- tal, labial, or oral mucosa [10, 24, 79]. Clinically, sented cases of melanoma misdiagnosed from lesions are often similar to those of melanoma the beginning. Genital nevi can be located on in situ in these regions, being asymmetrical, the vulva, the penis, and the perianal region [2, poorly circumscribed, and irregularly pigment- 24, 26, 41, 44]. Clinically, they can simulate mel- ed. Histopathologically, the diagnosis of mela- anoma by showing asymmetry and poor cir- nosis can be accepted only if there is no increase cumscription. Histopathologically, there is an of melanocytes at the dermo-epidermal junc- intraepidermal proliferation of melanocytes tion, and if there are no melanocytes with long that can be mistaken for melanoma in situ, with dendrites (Figs. I.4.7, I.4.8). In addition, in gen- some melanocytes and nests located in the up- uine melanosis there are neither cellular atypia, per layers of the epidermis. Features that allow nor melanocytes above the dermo-epidermal classification of genital nevi as benign are the Melanoma: the Morphological Dimension Chapter I.4 29 predominance of nests over solitary melano- Table I.4.2. Special skin sites for melanocytic nevi cytes within the epidermis, the presence of an Acral skin (palms and soles, finger, toes, nails) intradermal component showing discrete nests of melanocytes with maturation with progres- Knees, elbows (extensor surfaces) sive descent into the dermis, and the absence of Ears atypical melanocytes and mitoses [4, 24, 36, 61, Mucosal regions (oral and genital mucosa, 72]. perianal region) Flexural/intertriginous areas I.4.3.5 Melanocytic Proliferations Nipple at Other Special Skin Sites Navel Melanocytic nevi located on palms and soles Milk-line may simulate melanoma clinically by being asymmetrical and showing irregular pigmentation. Histopathologically, they often reveal me- 30]. In fact, longitudinal melanonychia may be lanocytes arranged in solitary units or small due to a lentigo simplex, a benign melanocytic nests within the entire thickness of the epider- nevus, or a melanoma (besides other non-mela- mis including the horny layer (Table I.4.2) [18, nocytic, inflammatory, and neoplastic condi- 24, 44, 49]. Features allowing the correct histo- tions). It is characterized clinically by a brown pathological diagnosis are the sharp circum- or black longitudinal streak within the nail scription and symmetry of the lesion, the matu- plate. Benign forms can be very difficult to dis- ration of melanocytes with progressive descent tinguish from melanoma in situ of the nail ma- into the dermis, and the absence of atypical me- trix. A helpful clinical clue is the presence in lanocytes and mitoses. A helpful clue in distin- melanoma of the so-called Hutchinson’s sign, guishing benign from malignant melanocytic characterized by periungual spread of the pig- lesions on acral regions is the columnar disposi- mentation on the proximal or lateral nail fold. tion of melanocytes and melanin within the epi- Histopathology of benign lesions may show ei- dermis and horny layer in nevi, as opposed to ther features of a benign melanocytic nevus, or the diffuse pattern seen in melanoma [49]. This just an hyperpigmentation of the epidermis peculiar architectural feature may be explained with no increase of melanocytes. By contrast, by the particular anatomical location. In fact, it melanoma in situ shows intraepidermal spread has been demonstrated that acral nevi cut per- of atypical melanocytes arranged in nests or as pendicular to the skin marks show involvement solitary units. Finally, atypical clinicopathologi- of upper layers of the epidermis restricted to the cal features may be observed in melanocytic site of the skin marks (that is, columnar ar- nevi arising at other skin sites such as the nipple, rangement of melanocytes and melanin within navel, ears, knee, and elbows (extensor surfac- the epidermis and horny layer), whereas those es), intertriginous or flexural areas, and the cut parallel to skin marks present melanocytes milkline [2, 13, 24, 31, 53, 54, 58, 74]. A slight in the epidermis and horny layer throughout the degree of architectural atypia (some melano- entire length of the lesion [77]. This finding sug- cytes may be present above the basal layer) may gests a role of the peculiar anatomy of these re- be accepted at these locations, and a diagnosis of gions in the genesis of the atypical histopatho- melanoma should be rendered only when com- logical features of acral melanocytic nevi. pelling evidence is present. Pagetoid spread in Pigmented lesions located on the nail may also these lesions, if present, is confined only to the represent a problem in differential diagnosis be- center of them and does not extend to the mar- tween benign and malignant processes [8, 16, gins. 30 L. Cerroni

I.4.3.6 Proliferations of Melanocytes sion of congenital and/or acquired nevi. A typi- at Sites of Inflammatory cal variant presents with epithelioid and spindle Skin Disorders cells of a Spitz’s nevus together with a dysplastic nevus. Another type features small melanocytes Melanocytic nevi arising at sites of inflamma- admixed with large balloon cells, simulating tory skin disorders can display atypical mor- balloon cell melanoma. Combined nevi can be phological features induced by the associated distinguished from melanoma by the absence of disease [58]. In particular, melanocytic nevi features of melanoma in situ in the intraepider- I.4 arising at sites of lichen sclerosus are often mis- mal portion of the neoplasm, the maturation of diagnosed as melanoma because of atypical ar- melanocytes with progressive descent into the chitectural and cytological changes due to the dermis, and the absence of nuclear atypia (with lichen sclerosus [37]. Melanocytic nevi arising the exception of cells of Spitz’s nevi). Combined in patients with epidermolysis bullosa (at sites of nevi show overlapping features with many other scarring) or at sites of burns’ scars, too, may be variants of benign nevi, including proliferating misinterpreted as melanoma both clinically and nodules in congenital nevi and cellular blue nevi histopathologically. Any inflammatory skin among others. A particular variant of combined condition may alter the normal architecture of a nevus is represented by the so-called deep pen- melanocytic nevus conferring some degree of etrating nevus [24, 59, 76]. This melanocytic ne- atypia to it, thus representing a diagnostic pit- vus can simulate melanoma histopathologically fall. Finally, both melanocytic nevi and mela- by virtue of a dense nodular proliferation of me- noma arising in patients with mycosis fungoides lanocytes extending into the subcutaneous fat or other cutaneous T-cell lymphomas may dis- and showing some atypical features and rare play intraepidermal lymphocytes arranged as mitoses; however, the neoplasm is sharply cir- solitary units or in collections (Pautrier’s micro- cumscribed, top-heavy, and lacks intraepider- abscesses), thus complicating the histopatho- mal features of melanoma in situ. Deep pene- logical diagnosis. trating nevi may be characterized by a plexiform pattern with populations of melanocytes with different morphological features. Difficulties in I.4.4 Particular Histopathological the correct interpretation of these lesions are Problems well illustrated by the description of deep penetrating nevus-like melanocytic tumors with I.4.4.1 Melanocytic Nevi metastases [42]. with Several Cell Populations (“Combined” Nevi) I.4.4.2 Nodular Proliferations Combined nevi are characterized either by the of Melanocytes combination of histopathological features of Within Congenital Nevi two different benign melanocytic nevi, or by the presence of more than one population of mela- This is a variation on the theme of combined nocytes within a single lesion [2, 24, 32, 39, 66, melanocytic nevi. Some congenital nevi display 71]. They may simulate melanoma clinically by nodular aggregates of large melanocytes within being asymmetric and revealing markedly ir- the dermal component [24, 45, 92]. The overly- regular pigmentation. Features that allow dis- ing epidermis does not show any sign of mela- tinction from melanoma are the sharp circum- noma in situ. Differentiation between benign scription and the overall appearance of the nevi (proliferative nodules in melanocytic nevi) lesion, showing a well-circumscribed hyperpig- and occurrence of melanoma within a pre-exis- mented spot surrounded usually by a less-pig- tent melanocytic nevus (so-called dermal mela- mented area. Histopathologically, there are sev- noma) is one of the most vexing problems in eral types of combined nevi, characterized by pathology of melanocytic tumors [15, 62, 86]. the combination of any morphological expres- Histopathological features that favor a diagno- Melanoma: the Morphological Dimension Chapter I.4 31 sis of benignancy are the blending of the two components of the lesions, the absence of prominent necrosis within the nodular component, and the presence of only a few mitoses; however, in given cases a precise diagnosis may be impossible.

I.4.4.3 Superficial Proliferations of Melanocytes with Prominent Pigmentation A variant of melanocytic nevi is characterized clinically by small lesions with prominent pig- Fig. I.4.9. Melanoma shows architectural features of mentation, located mostly on skin exposed in- melanocytic nevi. Note scatter of melanocytes above the termittently to the sun (“hypermelanotic nevi”) dermo-epidermal junction and normal architecture of [28, 29]. Histopathologically, there is marked the rete ridges with concentric fibroplasia elimination of melanin through the epidermis and the horny layer (so-called pigmented para- keratosis), thus mimicking melanoma; however, I.4.4.4 Proliferations of Melanocytes lesions are small, symmetrical, and sharply cir- Associated with Prominent cumscribed. Melanocytes are arranged mostly Inflammatory Response and/or at the dermo-epidermal junction, and there are Regression neither atypical features nor mitoses. Hyper- melanotic nevi have been termed in the past Halo nevi are defined as melanocytic nevi sur- also “new nevi of midlife” and “nevoid lentigo.” rounded by an area of depigmentation caused Besides benign hypermelanotic nevi, in the past by an immunological reaction directed against years we have come across several specimens of the melanocytes of the nevus [2, 24, 90]. Clini- melanoma simulating histopathologically the cally, they are easily diagnosed as benign. Histo- picture of the “hypermelanotic nevi” (Fig. I.4.9). pathology, however, may pose problems in the These lesions are larger and less well circum- classification of such lesions. The presence of a scribed than the benign counterpart, and fo- dense infiltrate of inflammatory cells in a mela- cally melanocytes above the dermo-epidermal nocytic lesion, in fact, may be confused with the junction can be observed. Evaluation of cyto- immune response caused by a melanoma (a morphological features is often problematic due “halo nevus” variant of so-called minimal de- to the prominent pigmentation, but in most in- viation melanoma has been described in 1990 stances melanocytes with large nuclei can be by Reed and coworkers) [69]. The inflammatory observed. In these cases clinicians made invari- cells may at times obscure completely the nests ably a confident clinical diagnosis of melanoma, of melanocytes, and atypical nuclear features and review of clinical images taken prior to the can be observed in single cells. Features that fa- surgical excision, when available, confirmed the vor benignancy are the distribution of lympho- diagnosis. These tumors represent a subset of cytes throughout the entire neoplasms in a sym- melanomas in which the clinical diagnosis is metrical fashion (in melanoma, by contrast, much easier than the histopathological diagno- there is a tendency for focal aggregation of reac- sis, and in which accurate clinicopathological tive lymphocytes), and the benign aspect of me- correlation is crucial for a precise diagnosis [50]. lanocytes with nests situated mainly at the der- Dermatopathologists should be alert when a mo-epidermal junction and predominating over confident diagnosis of melanoma is made by a solitary melanocytes. Once completely re- reliable clinician. gressed, halo nevi can be very difficult to differentiate from completely regressed melanoma. 32 L. Cerroni

Features that favor benignancy in completely pathological verification of the clinical diagno- regressed pigmented lesions are the size (i.e., re- sis). In such cases, the diagnosis relies only on gressed melanoma are larger as a rule) and the histopathological features discussed above, shape, halo nevi being usually dome-shaped in and a note should be added in the report men- contrast to melanoma, which presents with flat tioning that an accurate diagnosis is hindered macules. by the lack of correlation with the primary lesion. I.4 A particular type of melanocytic nevus with I.4.4.5 Recurrence (Persistence) dermal fibrosis and epidermal changes similar of Melanocytic Lesions at the to those observed in persistent/recurrent nevi is Site of a Previous Incomplete characterized by the absence of history of previ- Excision (Recurrent Nevi, ous surgical excision. The dermatopathological Recurrent Melanoma) features, which at times may be mistaken for melanoma, most likely are caused by chronic ir- Recurrent (persistent) nevi may simulate mela- ritation and/or repeated traumatic events. Diag- noma clinically by being asymmetric, poorly nostic clues are the presence at the lateral edges circumscribed, and irregularly pigmented [2, of the lesion of conventional complexes of ne- 24, 35, 44, 52 ,64]. They occur after incomplete void melanocytes, the restriction of the fibrotic excision of a benign melanocytic nevus, usually changes to the center of it, and the absence of after “shaving” biopsies that fail to remove cells prominent pagetoid spread. These particular in the deeper part of the lesion. Complete clini- nevi are often located on the back of young cal history and review of the original sections adults. are crucial for the diagnosis, in order to rule out the possibility of a melanoma recurring after incomplete excision. Recurrent nevi are charac- I.4.4.6 Atypical Melanocytic Nevi terized histopathologically by the proliferation with Degenerative Changes of melanocytes above a scar. Intraepidermal (“Ancient” Melanocytic Nevi) melanocytes are arranged mainly as solitary units disposed in all levels of the epidermis, thus Ancient nevi have been described recently as simulating melanoma; however, the atypical benign histopathological simulators of melano- growth of melanocytes is strictly confined to ma [24, 48]. They are characterized by the pres- the area where scar tissue is present in the der- ence of dilated, sometimes thrombosized blood mis (by contrast, melanocytes of recurrent mel- vessels, hyalinized collagen, fibrosis and sclero- anoma extend beyond the lateral margins of the sis, and by the finding of atypical melanocytes scar). Complexes of the pre-existing nevus are and the presence of mitotic figures. The term often detectable below the scar and/or at the “ancient nevus” has been derived from the so- side of the lesion. In contrast, in recurrent mela- called ancient schwannoma, which shows simi- noma atypical intraepidermal complexes of me- lar degenerative aspects and atypical features. lanocytes are observed also beyond the dermal Criteria that favor benignancy in ancient nevi margins of the scar, and complexes of a dermal are the absence of changes of melanoma in situ melanocytic nevus are not found. In addition, within the epidermis, and the presence of mela- intraepidermal pagetoid spread of melanocytes nocytes of a conventional melanocytic nevus is usually more pronounced. As already men- beneath the atypical melanocytes. Due to the tioned, in all cases review of the original section presence of different populations of melano- is crucial for the final diagnosis. In this context, cytes, ancient nevi show overlapping histopath- a particular pitfall is represented by melanocyt- ological features with combined melanocytic ic tumors recurring after laser vaporization (or nevi. other types of surgical treatment without histo- Melanoma: the Morphological Dimension Chapter I.4 33

I.4.4.7 Melanocytic Proliferations with “Spitzoid” Morphology Since the original description by Sophie Spitz [83], spitzoid melanocytic tumors (that is, melanocytic proliferations characterized by predominance of large spindle and/or epithelioid melanocytes) have been one of the most commonly discussed problems in dermatopathology [2, 9, 24, 31, 41, 54, 57, 58, 63, 71]. Although one of the patients described originally by Spitz died of metastatic melanoma, it has been clearly demonstrated that most Spitz nevi are completely benign. “Conventional” Spitz nevi are symmetrical, sharply circumscribed, superficial proliferations of large spindle and/or epithelioid melanocytes, commonly associated with epithelial hyperplasia, some scatter of melanocytes above the dermo-epidermal junction (usually confined to the center of the lesion), and presence of dull pink intraepidermal globules that have been termed “Kamino bodies.” A melanocytic nevus with predominance of pigmented spindle cells has been termed “pigmented spindle cell nevus” or “Reed nevus,” and its relationship to Spitz nevi has been debated [12, 67, 70, 81]. Besides “conventional” Spitz nevi and variants, in the past years several publications have addressed the problem of atypical melanocytic tumors with spitzoid morphology [11, 14, 65, 68, 80, 82, 89]. These tumors arise often in children or adolescents, are usually mainly dermal and asymmetrical, lack a prominent pagetoid spread within the epidermis, and in a distinct propor- tion of cases are associated with the presence of deposits of melanocytes within the parenchyma of regional lymph nodes (Fig. I.4.10). Terminol- ogy of these lesions is a matter of debate, and Fig. I.4.10. Atypical Spitz tumor. a Note asymmetrical, mainly dermal melanocytic tumor. b Spitzoid melano- different terms have been used, including atypi- cytes admixed with inflammatory infiltrates cal spitzoid tumors, malignant Spitz nevi, Spitz nevi with lymph node metastases, and Spitz tumors with uncertain malignant potential, dermis. In some cases lymph node deposits of among others. Atypical Spitz tumors are differ- melanocytes have been found by diagnostic sen- ent from “conventional” Spitz’s nevi, which are tinel lymph node biopsy [35, 85], and a few of characterized by a symmetrical, dome-shaped these patients have died of metastatic melano- architecture, a prominent junctional compo- ma. The vast majority of patients, though, seem nent, and a superficial dermal component. In- to have a good prognosis without further mani- stead, they are tumors characterized often by festations of the disease, in spite of the presence only focal involvement of the epidermis, and by of clusters of cells within the lymph nodes. The confluent nests and sheets of melanocytes in the exact classification of these cases is still a matter 34 L. Cerroni

of debate, and it has been recently proposed that approach to the evaluation of controversial me- they may represent a type of low-grade melano- lanocytic lesions is provided in Table I.4.3. Some ma with better prognosis than conventional melanocytic tumors with particular morpho- melanoma of similar thickness [22, 23, 88]. In logical features (so-called atypical spitzoid tu- fact, there are no criteria that allow to distin- mors) may represent a special variant of mela- guish cases with lymph node involvement and/ noma with better prognosis than conventional or progression to systemic disease from those melanoma. that do not show any evidence of extracutane- I.4 ous spread [25]. Whatever the personal interpre-

tation of these intriguing tumors, in our opinion C Core Messages the patients should be carefully followed, as the unlucky possibility of a melanoma cannot be ■ accurate examination of routinely ruled out on morphological grounds alone. stained sections of tissue and clinicopathological correlation represent the gold standard in histopathological I.4.5 Conclusion diagnosis of benign and malignant melanocytic tumors. Histopathological examination is the gold stan- ■ optimal biopsies are a pre-requisite for dard for diagnosis and classifications of benign accurate histopathological diagnoses; and malignant melanocytic tumors. Differenti- punch biopsies and shave biopsies often ation of specific entities is usually easily achieved cannot be interpreted accurately. on morphological grounds, but occasionally Sections should be carefully processed histopathological criteria alone may not allow a and stained, as poor quality of the precise categorization of a given tumor. Derma- histopathological specimens hinders a topathologists should pay special attention to precise diagnosis. particular settings such as lesions biopsied in ■ Besides paying attention to histopatho- newborns, or arising at special body sites, or as- logical criteria for diagnosis, dermato- sociated with inflammatory diseases, or pre- pathologists should be aware of special senting with particular morphological aspects settings and particular histopathologi- (e.g., prominent pigmentation, presence of sev- cal presentations that may have an eral population of melanocytes, etc.). A rational influence on the diagnosis (e.g., specific skin site, age, association with other skin disorders, etc.). Table I.4.3. Stepwise evaluation of controversial/atypical ■ although precise criteria for histopath- melanocytic tumors ological diagnosis allow a correct Clinicopathological correlation (including clinical diagnosis and classification of the vast features of the lesion, age, personal and/or familial majority of melanocytic tumors, a history of melanoma, skin type and/or other small number of lesions defies precise predisposing factors, previous surgery, trauma, interpretation and cannot be classified recent exposure to UV light, etc.) with certainty histopathologically (e.g., Evaluation of conventional histopathological benign nevi simulating melanoma, and criteria melanoma mimicking a benign nevus). ■ Presence/absence of signs of chronic sun damage Sharing cases in consultation with dermatopathologists with special Anatomical location (special skin site?) expertise in melanocytic tumors allows Expert consultation minimization of the number of cases Uncertainty should be clearly documented in the that cannot be classified with certainty. histopathological report

Melanoma: the Morphological Dimension Chapter I.4 35

References 14. Bastian BC, LeBoit PE, Pinkel D (2000) Mutations and copy number increase of HRAS in Spitz nevi 1. ackerman AB (1987) The concept of malignant with distinctive histopathological features. Am J melanoma in situ. In: Elder DE (ed) Pathobiology of Pathol 157:967–972 malignant melanoma. Basel, Karger, pp 205–210 15. Benisch B, Peison B, Kannerstein M, Spivack J 2. ackerman AB, Cerroni L, Kerl H (1994) Pitfalls in (1980) Malignant melanoma originating from in- the histopathologic diagnosis of malignant mela- tradermal nevi. A clinicopathologic entity. Arch noma. Lea and Febiger, Philadelphia Dermatol 116:696–698 3. angelucci D, Natali PG, Amerio PL, Ramenghi M, 16. Blessing K, Kernohan NM, Park KGM (1991) Sub- Musiani P (1991) Rapid perinatal growth mimick- ungual malignant melanoma: clinicopathological ing malignant transformation in a giant congenital features of 100 cases. Histopathology 19:425–429 melanocytic nevus. Hum Pathol 22:297–301 17. Blessing K, McLaren KM (1992) Histological re- 4. ariel IM (1981) Malignant melanoma of the female gression in primary cutaneous melanoma: recogni- genital system: a report of 48 patients and review of tion, prevalence and significance. Histopathology the literature. J Surg Oncol 16:371–383 20:315–322 5. Baas J, Bergfeld WF (1986) Melanoma-like changes 18. Botet MV, Caro FR, Sanchez JL (1981) Congenital ac- in benign congenital nevi. J Cut Pathol 13:436 ral melanocytic nevi clinically simulating acral len- 6. Balch CM, Buzaid AC, Soong SJ, Atkins MB, Cas- tiginous melanoma. J Am Acad Dermatol 5:406–410 cinelli N, Coit DG, Fleming ID, Gershenwald JE, 19. Breslow A (1970) Thickness, cross-sectional areas Houghton A Jr, Kirkwood JM, McMasters KM, and depth of invasion in the prognosis of cutaneous Mihm MF, Morton DL, Reintgen DS, Ross MI, melanoma. Ann Surg 172:902–908 Sober A, Thompson AJ , Thompson JF (2001) Final 20. Busam KJ, Mujumdar U, Hummer AJ, Nobrega J, version of the American Joint Committee on Can- Hawkins WG, Coit DG, Brady MS (2004) Cutane- cer Staging System for cutaneous melanoma. J Clin ous desmoplastic melanoma. Reappraisal of mor- Oncol 19:3635–3648 phologic heterogeneity and prognostic factors. Am 7. Balch CM, Soong SJ, Gershenwald JE, Thompson J Surg Pathol 28:1518–1525 JF, Reintgen DS, Cascinelli N, Urist M, McMasters 21. Carroll CB, Ceballos P, Perry AE, Mihm MC, Jr., KM, Ross MI, Kirkwood JM, Atkins MB, Thompson Spencer SK (1994) Severely atypical medium-sized JA, Coit DG, Byrd D, Desmond R, Zhang Y, Liu PY, congenital nevus with widespread satellitosis and Lyman GH, Morabito A (2001) Prognostic factors placental deposits in a neonate: the problem of con- analysis of 17,600 melanoma patients: validation of genital melanoma and its simulants. J Am Acad the American Joint Committee on Cancer Mela- Dermatol 30:825–828 noma Staging System. J Clin Oncol 19:3622–3634 22. Cerroni L (2004) Spitzoid tumors. A matter of per- 8. Baran R, Haneke E (1994) Longitudinal melano- spective? Am J Dermatopathol 26:1–3 nychia. In: Baran R, Dawber RPR (eds) Diseases of 23. Cerroni L (2005) A new perspective for Spitz tu- the nails and their management. London, Blackwell, mors? Am J Dermatopathol 27:366–367 pp 485–492 24. Cerroni L, Kerl H (1998) Simulators of malignant 9. Barnhill RL (1995) Pathology of melanocytic nevi melanoma of the skin. Eur J Dermatol 8:388–396 and malignant melanoma. Boston, Butterworth- 25. Cerroni L, Kerl H (2001) Tutorial on melanocytic Heinemann lesions. Am J Dermatopathol 23:237–241 10. Barnhill RL, Albert LS, Shama SK, Goldenhersh 26. Christensen WN, Friedman KJ, Woodruff JD, Hood MA, Rhodes AR, Sober AJ (1990) Genital lentigino- AF (1987) Histologic characteristics of vulvar nevo- sis: a clinical and histopathologic study. J Am Acad cellular nevi. J Cut Pathol 14:87–91 Dermatol 22:453–460 27. Clark WH (1967) A classification of malignant 11. Barnhill RL, Argenyi ZB, From L, Glass LF, Maize melanoma in man correlated with histogenesis and JC, Mihm MC Jr, Rabkin MS, Ronan SG, White WL, biological behaviour. In: Montagna W, Hu F (eds) Piepkorn M (1999) Atypical Spitz nevi/tumors: lack Advances in biology of the skin. Oxford, Pergamon of consensus for diagnosis, discrimination from Press, pp. 621–647 melanoma, and prediction of outcome. Hum Pathol 28. Clark WH Jr, Elder DE, Guerry D IV, Epstein MN, 30:513–520 Greene MH, Van Horn M (1984) A study of tumor 12. Barnhill RL, Barnhill MA, Berwick M, Mihm MC progression: the precursor lesions of superficial Jr (1991) The histologic spectrum of pigmented spreading and nodular melanoma. Hum Pathol spindle cell nevus. Hum Pathol 22:52–58 15:1147–1165 13. Barnhill RL, Rous GC (1990) Histopathological 29. Cohen L, Bennion S, Johnson T, Golitz L (1995) Be- spectrum of clinically atypical melanocytic nevi. nign black nevus: clinical, histopathologic and ultra- Arch Dermatol 126:1315–1318 structural features in 316 cases. J Cut Pathol 22:55 36 L. Cerroni

30. Colver GB, Beveridge GW (1991) Familial acquired 44. Haupt HM, Stern JB (1995) Pagetoid melanocyto- pigmented streaks in the nail. Clin Exp Dermatol sis. Histologic features in benign and malignant le- 16:158–159 sions. Am J Surg Pathol 19:792–797 31. Connors RC, Ackerman AB (1976) Histologic 45. Herron MD, Vanderhooft SL, Smock K, Zhou H, pseudomalignancies of the skin. Arch Dermatol Leachman SA, Coffin C (2004) Proliferative nodules 112:1767–1780 in congenital melanocytic nevi. A clinicopathologic 32. Cooper PH (1992) Deep penetrating (plexiform and immunohistochemical analysis. Am J Surg spindle cell) nevus: a frequent participant in com- Pathol 28:1017–1025 bined nevus. J Cut Pathol 19:172–180 46. Kaddu S, Smolle J, Zenahlik P, Hofmann-Wellenhof I.4 33. Cullity G (1984) Intra-epithelial changes in child- R, Kerl H (2002) Melanoma with benign melano- hood nevi simulating malignant melanoma. Pathol- cytic naevus components: reappraisal of clinico- ogy 16:307–311 pathological features and prognosis. Melanoma Res 34. Dadras SS, Lange-Asschenfeldt B, Velasco P, Nguy- 12:271–278 en L, Vora A, Muzikansky A, Jahnke K, Hauschild 47. Kamino H, Ackerman AB (1981) The problems of A, Hirakawa S, Mihm MC, Detmar M (2005) Tu- interpreting the meanings of atypical melanocytes mor lymphangiogenesis predicts melanoma metas- and unusual pattern of melanocytes within the epi- tasis to sentinel lymph nodes. Mod Pathol 18:1–11 dermis. In: Ackerman AB (ed) Pathology of malig- 35. Dwyer CM, Kerr RE, Knight SL, Walker E (1993) nant melanoma. New York, Masson, pp 129–157 Pseudomelanoma after dermabrasion. J Am Acad 48. Kerl H, Soyer HP, Cerroni L, Wolf IH, Ackerman Dermatol 28:263–264 AB (1998) Ancient melanocytic nevus. Semin Di- 36. Eisen D, Voorhees JJ (1991) Oral melanoma and agn Pathol 15:210–215 other pigmented lesions of the oral cavity. J Am 49. Kerl H, Trau H, Ackerman AB (1984) Differentia- Acad Dermatol 24:527–537 tion of melanocytic nevi from malignant melano- 37. El Shabrawi-Caelen L, Soyer HP, Schaeppi H, Cer- mas in palms, soles, and nail beds solely by signs in roni L, Schirren CG, Rudolph C, Kerl H (2004) the cornified layer of the epidermis.A m J Dermato- Genital lentigines and melanocytic nevi with super- pathol 6 (Suppl):159–161 imposed lichen sclerosus: a diagnostic challenge. J 50. King R, Page RN, Googe PB, Mihm Jr MC (2005) Am Acad Dermatol 50:690–694 Lentiginous melanoma: a histologic pattern of mel- 38. Ferrara G, Argenziano G, Soyer HP, Corona R, Sera anoma to be distinguished from lentiginous nevus. F, Brunetti B, Cerroni L, Chimenti S, El-Shabrawi- Mod Pathol 18:1397–1401 Calelen L, Ferrari A, Hofmann-Wellenhof R, Kaddu 51. Koch H, Zelger B, Cerroni L, Soyer HP, Kerl H S, Piccolo D, Scalvenzi M, Staibano S, Wolf IH, De (1996) Malignant blue nevus: malignant melano- Rosa G (2002) Dermoscopic and histopathologic ma in association with blue nevus. Eur J Dermatol diagnosis of equivocal melanocytic skin lesions. 6:335–338 An interdisciplinary study on 107 cases. Cancer 52. Kornberg R, Ackerman AB (1975) Pseudomelano- 95:1094–1100 ma. Arch Dermatol 111:1588–1590 39. Fletcher V, Sagebiel RW (1981) The combined ne- 53. lazova R, Lester B, Glusac EJ, Handerson T, Mc- vus: mixed pattern of benign melanocytic lesions Niff J (2005) The characteristic histopathologic fea- that must be differentiated from malignant melano- tures of nevi on and around the ear. J Cutan Pathol mas. In: Ackerman AB (ed) Pathology of malignant 32:40–44 melanoma. New York, Masson, pp 273–283 54. leBoit PE (1994) Simulants of malignant mela- 40. Garbe C, Cerroni L, Kerl H (2003) Melanozytäre noma: a rogue’s gallery of melanocytic and non- Nävi und malignes Melanom. In: Kerl H, Garbe melanocytic imposters. Pathology: state of the art C, Cerroni L, Wolff HH (eds) Histopathologie der reviews 2:195–258 Haut. Berlin, Heidelberg, New York, Springer, pp. 55. lohmann CM, Iversen K, Jungbluth AA, Berwick 593–649 M, Busam KJ (2002) Expression of melanocyte dif- 41. Gonzalez SB (1991) Histopathologic diagnosis ferentiation antigens and ki-67 in nodal nevi and of pigmented lesions of the skin. Path Res Pract comparison of ki-67 expression with metastatic 187:387–431 melanoma. Am J Surg Pathol 26:1351–1357 42.Graham J (1996) Malignant deep penetrating nevus. 56. Magro CM, Crowson AN, Mihm MC (2006) Un- J Cut Pathol 23:76 usual variants of malignant melanoma. Mod Pathol 43. Hantschke M, Bastian BC, LeBoit PE (2004) Con- 19 (Suppl 2):S41–S70 sumption of the Epidermis. A diagnostic criterion 57. Maize JC, Ackerman AB (1987) Pigmented lesions for the differential diagnosis of melanoma and Spitz of the skin. Lea and Febiger, Philadelphia nevus. Am J Surg Pathol 28:1621–1625 58. Massi G, LeBoit PE (2004) Histological diagnosis of nevi and melanoma. Steinkopff Verlag and Spring- er, Darmstadt Melanoma: the Morphological Dimension Chapter I.4 37

59. Mehregan DA, Mehregan AH (1993) Deep penetrat- 76. Seab JA, Graham JH, Helwig EB (1989) Deep pen- ing nevus. Arch Dermatol 129:328–331 etrating nevus. Am J Surg Pathol 13:39–44 60. Mihm MC Jr, Clark WH Jr, From L (1971) The clini- 77. Signoretti S, Annessi G, Puddu P, Faraggiana T cal diagnosis, classification and histogenetic con- (1999) Melanocytic nevi of palms and soles: a histo- cepts of the early stages of cutaneous malignant logical study according to the plane of section. Am J melanomas. N Engl J Med 284:1078–1082 Surg Pathol 23:283–287 61. Mihm MC Jr, Googe PB (1990) Problematic pig- 78. Silvers DN, Helwig EB (1981) Melanocytic nevi in mented lesions. Lea and Febiger, Philadelphia neonates. J Am Acad Dermatol 4:166–175 62. okun MR, Mattia A di, Thompson J, Pearson H 79. Sison-Torre EQ, Ackerman AB (1985) Melanosis of (1974) Malignant melanoma developing from intra- the vulva. A clinical simulator of malignant mela- dermal nevi. Arch Dermatol 110:599–601 noma. Am J Dermatopathol 7 (Suppl):51–60 63. Paniago-Pereira C, Maize JC, Ackerman AB (1978) 80. Smith KJ, Barrett TL, Skelton HG III, Lupton GP, Nevus of large spindle and/or epithelioid cells Graham JH (1989) Spindle cell and epithelioid cell (Spitz’s nevus). Arch Dermatol 114:1811–1823 nevi with atypia and metastasis (malignant Spitz 64. Park HK, Leonard DD, Arrington JH; Lund HZ nevus). Am J Surg Pathol 13:931–939 (1987) Recurrent melanocytic nevi: clinical and 81. Smith NP (1987) The pigmented spindle cell tu- histologic review of 175 cases. J Am Acad Dermatol mour of Reed: an underdiagnosed lesion. Semin 17:285–292 Diag Pathol 4:75–87 65. Piepkorn M (1995) On the nature of histologic ob- 82. Spatz A, Calonje E, Handfield-Jones S, Barnhill RL servations: the case of the Spitz nevus. J Am Acad (1999) Spitz tumors in children: a grading system Dermatol 32:248–254 for risk stratification. Arch Dermatol 135:282–285 66. Pulitzer DR, Martin PC, Cohen AP, Reed RJ (1991) 83. Spitz S (1948) Melanoma of childhood. Am J Pathol Histologic classification of the combined nevus: 24:591–609 analysis of the variable expression of melanocytic 84. Su LD, Fullen DR, Lowe L, Wang TS, Schwartz JL, nevi. Am J Surg Pathol 15:1111–1122 Cimmino VM, Sondak VK, Johnson TM (2004) 67. reed RJ (1985) The histological variance of malig- Desmoplastic and neurotropic melanoma. Cancer nant melanoma: the interrelationship of histologi- 100:598–604 cal subtype, neoplastic progression, and biological 85. Su LD, Fullen DR, Sondak VK, Johnson TM, Lowe L behaviour. Pathology 17:301–312 (2003) Sentinel lymph node biopsy for patients with 68. reed RJ (1999) Atypical spitz nevus/tumor. Hum problematic spitzoid melanocytic lesions: a report Pathol 30:1523–1526 on 18 patients. Cancer 97:499–507 69. reed RJ, Webb SV, Clark WH, Jr (1990) Minimal 86. Swetter SM, Ecker PM, Johnson DL, Harvell JD deviation melanoma (halo nevus variant). Am J (2004) Primary dermal melanoma: a distinct sub- Surg Pathol 14:53–68 type of melanoma. Arch Dermatol 140:99–103 70. requena L, Sanchez Yus E (1990) Pigmented spindle 87. Tronnier M, Wolff HH (1995) UV-irradiated me- cell nevus. Br J Dermatol 123:757–763 lanocytic nevi simulating melanoma in situ. Am J 71. rogers GS, Advani H, Ackerman AB (1985) A com- Dermatopathol 17:1–6 bined variant of Spitz’s nevus. How to differentiate 88. Urso C (2005) A new perspective for Spitz tumors? them from malignant melanomas. Am J Dermato- Am J Dermatopathol 27:364–366 pathol 7 (Suppl):61–78 89. Walsh N, Crotty K, Palmer A, McCarthy S (1998) 72. ronan SG, Eng AM, Briele HA, Walker MJ, Gupta Spitz nevus versus spitzoid malignant melanoma: TK (1990) Malignant melanoma of the female geni- an evaluation of the current distinguishing histo- talia. J Am Acad Dermatol 22:428–435 pathologic criteria. Hum Pathol 29:1105–1112 73. rongioletti F, Smoller BR (2005) Unusual histologi- 90. Wayte DM, Helwig EB (1968) Halo nevi. Cancer cal variants of cutaneous malignant melanoma with 22:69–90 some clinical and possible prognostic correlations. J 91. Wong TY, Suster S, Duncan LM, Mihm MC Jr Cutan Pathol 32:589–603 (1995) Nevoid melanoma: a clinicopathological 74. Saad AG, Patel S, Mutasim DF (2005) Melanocytic study of seven cases of malignant melanoma mim- nevi of the auricular region. Histologic character- icking spindle and epithelioid cell nevus and ver- istics and diagnostic difficulties. Am J Dermatopa- rucous dermal nevus. Hum Pathol 26:171–179 thol 27:111–115 92. Xu X, Bellucci KSW, Elenitsas R, Elder DE (2004) 75. Schmoeckel C, Castro CE, Braun-Falco O (1985) Cellular nodules in congenital pattern nevi. J Cutan Nevoid malignant melanoma. Arch Dermatol Res Pathol 31:153–159 277:362–369 38 L. Cerroni

93. Zalaudek I, Argenziano G, Ferrara G, Soyer HP, Co- 95. Zembowicz A, McCusker M, Chiarelli C, Dei Tos rona R, Sera F, Cerroni L, Carbone A, Chiominto A, AP, Granter SR, Calonje E, McKee PH (2001) Mor- Cicale L, Rosa G de, Ferrari A, Hofmann-Wellen- phological analysis of nevoid melanoma: a study of hof R, Malvehy J, Peris K, Pizzichetta MA, Puig S, 20 cases with a review of the literature. Am J Der- Scalvenzi M, Staibano S, Ruocco V (2004) Clinically matopathol 23:167–175 equivocal melanocytic skin lesions with features of regression: a dermoscopic-pathological study. Br J Dermatol 150:64–71 94. Zembowicz A, Carney JA, Mihm MC (2004) Pig- I.4 mented epithelioid melanocytoma. A low-grade melanocytic tumor with metastatic potential indistinguishable from animal-type melanoma and epithelioid blue nevus. Am J Surg Pathol 28:31–40