Lentiginous pattern Melanocytic lesions

 هدف اولیه پاتولوژیست در برخورد با ضایعات مالنوسیتی مشخص نمودن خوشخیم و یابدخیم بودن تومور است  در موارد بدخیم هدف دوم پاتولوژیست ارزیابی صحیح پارامترهای پروگنوستیک میباشد  در برخورد با ضایعه مالنوسیتی توجه به عالئم بالینی، درموسکوپی، Reflectance confocal microscopy، عالوه بر نمای مورفولوژیک ، در تشخیص صحیح مهم میباشند.  در بین تمامی حیطه های پاتولوژی، تشخیص تومورهای مالنوسیتی یکی از مشکلترین موارد است ، که حتی برای یک پاتولوژیست با تجربه نیز میتواند مشکل ساز شود.  تشخیص غلط تومورهای مالنوسیتی مسئول شایعترین موارد ایجاد مشکل قانونی برای پاتولوژیستها میباشد PROBLEMATIC LESIONS

 Dysplastic Nevus vs. Melanoma  Malignant/Atypical Blue Nevus Spectrum: blue nevus–like melanoma , melanoma arising within a preexisting blue nevus, malignant blue nevus  Atypical Spitz Nevi/Tumors and Spitzoid Melanoma  Lentigo Maligna vs. Actinic Melanocytic Hyperplasia  Borderline or ambiguous Melanocytic Lesions : Pigmented epithelioid melanocytoma (PEM) Melanocytic lesions diagnosis

Pattern analysis has been shown to have higher reliability Pattern for melanoma and nevus based classification and have a higher success for diagnosing approach melanoma Algorithmic approach Lentiginous pattern

 Lentiginous melanocytic hyperplasia  Lentiginous nevus and Atypical Lentiginous Nevus  Dysplastic nevus  Lentiginous melanoma  Acral lentiginous melanoma  Lentigo maligna and LMM  Melanoma of conjunctiva, nail and mucosal melanoma  Superficial spreading malignant melanoma Approach to the Diagnosis of Melanocytic Lesions Melanocytic lesions Biopsy

The ideal biopsy : excisional biopsy with narrow (2 mm) clinical margins . Incisional biopsies are not associated with increased risk of metastasis. Partial biopsy (incisional, punch and shave) are subject to sampling error in diagnosis, increased risk for the misdiagnosis of melanoma and increase ambiguous or borderline diagnosis Methods of margin assessment

 Lentigo maligna (LM) and acral lentiginous melanomas demonstrate uninterrupted, contiguous spread into the periphery at the epidermal- dermal junction  Superficial spreading and nodular pattern melanomas show non- continuous, subclinical spread  Transverse (bread-loaf) vertical sections: Sample only a small percentage of the surgical margin. To sample close to 100% of the peripheral margin step sections at intervals of 0.1 mm would be required.  En face vertical sections from the perimeter of the excision specimen: Not useful for melanoma with a discontinuous growth pattern  En Face Oblique Sections (Mohs micrographic surgery) Trotter MJ. Melanoma Margin Assessment. Clin Lab Med 31 (2011) 289– 300.  Embedding and oriantation is more important than cutting for accurate diagnosis: Ensure the laboratory staff are skilled in embedding and cutting skin specimens.  Hematoxylin and eosin sectioning remains the gold standard in evaluating melanocytic lesions.  Examine the entire melanocytic lesion histopathologically.  Levels often helpful: Examine at least 3 levels histopathologically.  Immunohistochemistry, cytogenetic studies, and gene expression assays have emerged as potential adjuncts to improve diagnostic accuracy. Genetic classification of nevi, melanocytomas, and melanomas. Beware of fixation artifacts

 In poorly fixed specimens melanocytes are enlarged and their nuclei may seem to be hyperchromatic.  Artifact simulating melanocytic hyperplasia  Nuclei are surrounded by an empty irregular halo.  Beware of keratinocytes with haloes that resemble pagetoid melanocytes  Halo around nucleus without cytoplasm= keratinocyte  Halo around nucleus with attached cytoplasm= melanocyte  The presence of cellular shrinkage of the keratinocytes and fibroblasts indicates the artifactual nature of the alteration. Histology

The ratio of melanocytes to basal keratinocytes ranges from approximately 1 : 4 on the cheek to 1 : 10 on the limbs and most body site. Sun-exposed skin the mean number of melanocytes is 4 to 16 per 0.5 mm of epidermis CLUES FROM THE REQUEST FORM

 Age : The appearance of a new pigmented lesion in a young person probably signifies a nevus, while in an older person one must suspect a melanoma.  An atypical junctional proliferation in an elderly patient are nearly always an indication of melanoma.  A Spitz nevus occurs commonly up to 50 years of age (or less). After that age a “Spitz nevus” with a mostly junctional distribution of its cells is suspected for being a melanoma.  Pagetoid spread is almost always benign in the first years of life, whereas it should be considered malignant unless proven otherwise after 40 years of age (unless the lesion is in special areas as genital and volar skin or is a persistent or traumatized lesion). CLUES FROM THE REQUEST FORM

Size: The clinicians should be to include size of the lesion and clinical information(color, border, previous biopsy) and clinical impression of lesion But in the absence of size of the lesion, the macroscopic description can be useful. CLUES FROM THE REQUEST FORM

Site: special sites ; acral locations, the genital skin, the milk line (from the axillae over the breast to the genitalia), the umbilicus, the flexural skin, the scalp, the ears, and the back and shoulder of elderly patients. A melanocytic lesion with a significant junctional component in the palate or the anogenital region of an older patient is almost by definition at least a melanoma in situ. CLUES FROM THE REQUEST FORM

 Clinical impression :  Be cautious about diagnosing melanoma when an experienced clinician has made a clinical diagnosis of a nevus.  Conversely, it is not rare to counter a clinical diagnosis of melanoma if the histologic features are those of a benign lesion.  Hormonal states:  Teenagers: some atypia and rare mitotic figures  Pregnancy Pregnancy

1-Increased dermal mitoses, and increased Ki-67 2-Superficial micronodules of pregnancy (SMOPs): Rounded clusters of 3–20 large epithelioid melanocytes with prominent nucleoli, abundant pale eosinophilic cytoplasm, lack of pleomorphism and occasional fine melanosomes distinctive from the deeper nevic melanocytes 3-Cellular atypia. No significant effect of pregnancy on the size of nevi CLUES FROM LOW-POWER EXAMINATION

 Configuration : verrucous, papillomatous, polypoid, Dome-shaped, Plaque or patch (flat).  Pigmentation:Melanotic and Amelanotic lesions  Location of lesion: Intraepidermal(Pagetoid & Lentiginous), Junctional, Compound, Intradermal  Size and depth of lesion.  Symmetry: Junctional component, Dermal component, Pigmentation,  Circumscription  Sun damage: nevi act as a sunscreen (umbrella sign)

Nevoid M Dimension of the Lesion

 The lateral dimension of a lesion can be estimated at the microscope.  Small lesions (less than 4 mm) in which nests predominate at the junction, is probably a nevus.  Small melanomas and metastatic melanoma (smaller than 6 mm) do exist  Clark nevus and congenital nevi can be much broader than 6 mm. Lesion depth

 Lesions that extend deeply should be viewed with some suspicion  Congenital nevi, deep penetrating nevi, cellular blue nevi, and some Spitz nevi may extend deeply into the reticular dermis and subcutis.  Wedge shape (DPN)  Bulbous outline(cellular blue nevus)  Infiltrative growth of melanocytes (nevoid melanoma, melanoma) Circumscription

 Good circumscription: A well-circumscribed lesion is one that ends with an identical nest at both lateral borders. The sharp demarcation within the epidermis parallels the dermal extension of the tumor  Poor lateral circumscription of the lesion : when the epidermal melanocytic proliferation, extending beyond the dermal component of the lesion (shouldering phenomenon), ended with single cells, rather than with a well defined nest (DN and SSMM)  Well circumscription could be seen in nodular melanoma . Heavily pigmented melanocytic lesions

 Heavily pigmented melanoma  Blue nevus  Pigmented Spitzoid lesions  Recurrent nevus  Combined nevus  Pigmented spindle cell nevus (Reed nevus)  Deep-penetrating nevus  Spontaneous regression of melanoma and hyperpigmented scar with abundant melanophages after the surgical treatment of melanoma  Tumoral melanosis: A nodular aggregate of melanophages occupies and expands the papillary dermis. Residual melanoma cells are not evident. Occurrence of such lesions in the deep dermis or subcutaneous fat suggests the regression of a metastasis Hypomelanotic / Amelanotic melanocytic lesions

 Amelanotic cellular blue nevus  Spitz nevus  Amelanotic intramucosal nevus  Amelanotic Melanoma: 2–8% of melanomas  Spindle cell and desmoplastic melanoma: Epidermal component(Nested , Lentiginous and Pagetoid patterns)

Dermal expansile nodules

 Proliferative microndule and macronodule in congenital nevus  Naked Nodules: large intradermal proliferative nodule , without a background of a congenital nevus  Nodular intradermal Spitz nevus  Recurrent nevus  Acquired melanocytic nevi: DPN/Clonal nevus  Intradermal melanoma and melanoma(VGP) Symmetry

 The growth pattern, cellular density, and cytologic features should all be similar, with exception allowed for populations within adventitial dermis.  Pigment is usually distributed evenly in nevi , whereas it is often asymmetrically dispersed in melanoma.  Symmetry of the Lateral Margins: two discrete nests usually bookend each a lateral borders of an ideal nevus (“starts with a nest and ends with a nest)  Symmetry in the Distribution, Size, and Shape of junctional nests Symmetry of Silhouette of the Lesion (Vertical Levels ) is a feature of benign lesions. Asymmetry : when two parts that looked different in shape, in thickness, or in number and position of dermal cells.  Symmetry of Silhouette of the Lesion(Horizontal Levels ) is a feature of benign lesions.  Absence of maturation, defined as failure of the nuclei of melanocytes to become smaller with progressive descent into the dermis Symmetry in Distribution, Size, and Shape of Junctional Nests and lateral margins

 In nevus : numerous, discrete, small and evenly distributed roundish nests without skip areas or interposed lentiginous zones at the junction  The junctional nests at both lateral borders are of the same size, shape, and disposition and have the same cytological details.  Among nevi, only dysplastic nevi have variably sized or confluent junctional nests.  Asymmetry: different morphological details at the two borders may indicate a melanoma. (eg; if cells are in nests at one border and aligned singly on the other) Note

Symmetry : in metastatic melanoma, spitzoid melanomas in children, and Small melanoma(smaller than 3 mm in diameter). Asymmetry and architectural irregularity : in traumatized nevi, combined nevi, some congenital nevi . Solar elastosis(‘‘umbrella sign’’) : the elastosis is diminished under nevi because of presence a solar shield for the underlying dermis. Conversely, invasive melanomas tend to push down the elastotic layer. Epidermal changes

 Symmetry of the Epidermal Pattern: A uniform epidermal hyperplasia in nevus and irregular hyperplasia in melanomas.  Pseudoepitheliomatous hyperplasia : Spitz, Melanoma  Atrophy(epidermal flattening and thinning): melanoma(LMM), in Spitzoid melanoma .  Lichenoid reaction: can occur in melanoma and may cause partial regression  Spongiosis, vesiculation or parakeratosis: in Meyerson nevus Epidermal changes

In melanomas foci of epidermal hyperplasia irregularly alternate with uneven thinning or even ulceration of the epidermis, and the rete ridges are effaced or asymmetrically altered(epidermal consumption) Kamino bodies: a common feature of Spitz nevus and pigmented spindle cell nevus Absent or rare in melanoma, but occasionally more numerous(Spitzoid melanoma) The inflammatory infiltrate

 Lymphocyte:  The inflammatory infiltrate accompanying of melanocytic nevus :Common melanocytic nevi , Duperrat nevus ,Meyerson nevus, Wiesner nevus, BAP1-negative atypical Spitz nevus  Sutton(Halo) nevus : The inflammatory infiltrate is mainly made of T-cells (predominantly CD8+). The CD4:CD8 ratio can vary from 1:1 to 1:3. This contrasts with melanoma regression, in which the number of CD4+ cells overcomes the number of CD8+ T-cells  Tumor infiltrating lymphocytes(TIL): in primary melanomas (Absence of TILs are significantly associated with Epidermotropic/dermal metastatic melanoma) Lymphocytic aggregates

 The presence of lymphocytic aggregates in association with a sclerosing melanocytic proliferation is commonly regarded as a feature in support of a diagnosis of desmoplastic melanoma.  Lymphocytic aggregates is not specific for melanoma, and is seen in a minority of sclerosing melanocytic nevi  The presence of lymphocytic aggregates per se does not prove that a sclerosing melanocytic proliferation is malignant. Patchy perivascular pattern in congenital nevus can resemble a lymphoid aggregate The inflammatory infiltrate, Plasma cells

 Plasma cells can favor a diagnosis of melanocytic malignancy in the appropriate context  A few plasma cells commonly accompany banal common melanocytic nevi.  Plasma cells are very few in halo nevus, but are easy to find in many melanomas  Plasma cells are also useful in the diagnosis of desmoplastic melanoma (with plasma cells) versus desmoplastic Spitz nevus (without plasma cells)  Tumor infiltrating plasma cells(TIP): primary nodular melanoma and Epidermotropic/dermal metastatic melanoma) CLUES FROM MEDIUM TO HIGH-POWER EXAMINATION

 Circumscription  Maturation  Growth pattern:  Epidermal-only or epidermal-predominant (lentiginous growth, junctional nests, pagetoid spread ) / Nested vs. single cells ( Nevus, Melanoma(RGP) , Metastatic melanoma)  Epidermal and dermal: Nevus, Melanoma(VGP)  Dermal: Regular nests vs. irregular nests or confluent(Nodular melanoma, Nevus). “Maturation” (zoning)

 Two form of maturation :  1- Shrinkage of melanocytes whose size diminishes in the deeper part of the lesion.  2- Schwannian metaplasia of the melanocytes, which become achromic and elongated and start to synthesize basement membrane material and fibrillary collagen.  Along with diminished cellular size, smaller nuclei, smaller nucleoli, less cytoplasm, and less pigmentation are all correlates of maturation. Zoning (maturation)

 Neural “maturation” occurs in desmoplastic, neurotropic, and neural differentiated melanomas.  Maturation (diminished size of the melanocytes) present in nevoid melanoma and in metastatic melanomas.  Absent in melanomas: but zoning may be mimicked by presence of small cell melanoma component or by a nevus remnant at the base of lesion.  Absent in blue nevi and variants , deep penetrating nevus, balloon cell nevus, and may not be apparent in thin nevi, including variants such as pigmented spindle cell nevus Adnexotropism

 Neurotropism : a hallmark of desmoplastic melanoma/ neurotropic melanoma.  Syringotropic and folliculotropic melanoma: Involvement of the hair follicle and extension of melanocytes along the eccrine ducts in favor of melanoma  The presence of malignant melanocytes in the hair follicles below the isthmus is one of the significant characteristics of malignant melanoma in situ.  In congenital nevus: Perivascular, perineural, periadnexal pattern and within arrector pili muscle. Architectural patterns

 A. Nevoidal pattern: Nevus, Nevoid melanoma, Metastatic melanoma  The spindle cell melanocytic lesions characterised by a compound nevoidal pattern:  1. Neuroidal naevus/melanocytic naevus with neurotisation  2. Congenital naevus with spindle cell component  3. Naevi of special sites  4. Naevoid melanoma with spindle cell morphology  5. Nodular melanoma with a spindle cell component  6. Spindle cell melanoma Architectural patterns

 B. Spitzoid pattern: are characterised by both architectural and cytological features.  Proliferation of unusual large, spindle or epithelioid melanocytic cells with large nuclei, prominent nucleoli and eosinophilic/amphophilic sometimes ground glass cytoplasm,  Spitz nevus, Atypical Spitz tumour, Spitzoid melanoma, Pigmented spindle cell nevus (of Reed), Atypical pigmented spindle cell nevus Architectural patterns

 C. Intradermal pattern:  Diffuse vs. Nodular pattern and patchy pattern.  Plexifom pattern: DPN, Spitz, Melanoma with a plexiform pattern  Desmoplasia and Hyalinizing: Desmoplastic nevi, Desmoplastic and Hyalinized Spitz nevus, Sclerosing Blue Nevi, Desmoplastic melanoma  Fascicular and storiform pattern  Parallel theque pattern  Indian-file pattern(congenital nevus)  Myxoid alteration  Adenoid (pseudoglandular) pattern  Angiomatoid: Spitz  Palisaded type Parallel theque pattern

 Nevoid melanoma: dermal chords/strands of melanocytes one or more cells thick and disposed as parallel arrays with ropey collagen fibers in between  The parallel nests tend to be longer in nevoid melanoma, and the surrounding connective tissue is compressed or displaced by the nests in contrast to the fine collagen fibers with no evidence of compression seen in nevi with parallel nesting.  Traumatized nevi, recurrent nevi, dysplastic nevi with florid fibroplasia, and nevi in the setting of lichen sclerosus Fascicular and storiform pattern: spindle cell melanoma (collagen content is <10%), mixed spindle/desmoplastic melanoma (collagen content is 10–90%), and desmoplastic melanoma (when the collagen content is >90%) Palisaded metastatic melanoma Dermal fibrosis

 Common acquired nevi at “special” anatomic sites: Scalp and Genital nevus  Sutton(Halo) nevus is characterized by the disappearance of nevus cells without development of fibrotic tissue. In the late stages of regressing nevi, there can be a thin and delicate collagen bundles, randomly disorganized and accompanied by a low density of fibroblasts . In regressing melanoma, the disappearing of melanoma cells is accompanied by fibroplasia and thick collagen bundles .  Dysplastic nevus  Sclerosing melanocytic lesion Sclerosing melanocytic lesions

 Persistent/recurrent nevi , Traumatized nevi  Desmoplastic nevi  Compound nevus with subtotal regression  Desmoplastic(sclerotic) cellular blue nevus and Spitz nevus  Irritated intradermal sclerosing melanocytic nevus  Congenital melanocytic nevus with sclerosis of its dermal component.  Nevi arising against a background of lichen sclerosus or epidermolysis bullosa  Dysplastic nevi with florid fibroplasia and pseudomelanomatous features  Melanomas with regression  Desmoplastic melanomas. Sclerosing melanocytic lesions

 Recurrent/ previously traumatized nevi: This lesion displays the classic trilayered appearance (Trizonal pattern).  An atypical junctional proliferation overlies an area of dermal scarring, below which is a bland intradermal nevus. Compound nevus in cutaneous lichen sclerosus et atrophicus

 The dermal nests are large, irregularly shaped, and deeply situated .  These aspects could induce one to think of a nevoid melanoma or a melanoma in which the intraepidermal portion regressed Regression

 Regression is present when one or more segments within the tumor show a marked reduction or absence of intradermal tumor cells; instead, this area shows a lymphocytic infiltrate and/or fibrosis, melanophages, and telangiectasia  Partial regression: A band-like area of subepidermal fibrosis and some inflammation with scattered melanocytes and remnant of melanoma .  Complete Regression: an intense infiltrate of melanophages with some hemosiderophages were found in a background of fibrosis, mild lymphocytic infiltrate, and neovascularization Morphologic features that are suggestive or diagnostic for a melanoma in sclerosing melanocytic lesions

 Presence of a melanoma in situ adjacent or extending beyond the sclerotic area.  An atypical intraepidermal component that extends outside the area of sclerosis is strongly suggestive of a melanoma in situ. (Atypia above the sclerosis could be attributed to some degree to the sclerotic process in the dermis) .  Prominent full-thickness pagetoid spread above the sclerosis  Absence of maturation in the sclerotic area, with atypical melanocytes, prominent nucleoli an sometimes mitoses and presence of mitotic activity in the sclerotic area. Architectural patterns

D. Horizontally orientated pattern

 Prominent junctional component, presence of a lentiginous or nested pattern. Spindle and epithelioid cytomorphology.  1. Clark’s nevus (‘dysplastic nevus’): a. with spindle cell morphology b. with Spitzoid morphology (‘SPARK nevus’)  2. Disruption phenomena in melanocytic lesions : a. Recurrent nevus phenomenon b. Traumatised or treated nevi, c. Sclerosing nevus with pseudomelanomatous features/nevi with regression, d. Nevi with associated inflammatory dermatoses  3. Melanoma in situ (LM)and melanoma of the solar type (LMM)  4. Melanoma in situ and superficial spreading melanoma with spindled morphology  5. Acral lentiginous melanoma  6- Epidermotropic metastatic melanoma Architectural patterns

E. Nested pattern and junctional location: nested melanoma, junctional nevus F. Lentiginous pattern G. Pagetoid pattern: SSMM, Pagetoid spitz Nested pattern

 In a nevus, junctional melanocytes are arranged in a predominantly nested pattern, with the nests being of even size and regular distribution.  The nests may appear enlarged, uneven, and irregularly distributed in melanoma.  Large nested melanoma: a variant of low-CSD melanoma: predominance of large ‘cannon-ball’ nests within the epidermis.  The bridging growth and lamellar fibroplasia which characterise dysplastic nevus are not features of large nested variant melanoma  A predominance of nested growth can also be seen in high- CSD melanoma  Spitz nevus  Common acquired nevus Nested and dyshesive pattern and retraction artifact

 Nested and dyshesive pattern, in melanocytic nevi of genital and flexural sites (axilla, umbilicus, inguinal creases, pubis, scrotum and perianal area) : characterized by the confluence of enlarged nests with variation in size, shape and diminished cohesion of melanocytes within the nests  Retraction artifact: Atypical genital-type melanocytic nevus , Atypical acral nevus, Spitz nevus “Melanocyte-rich pseudomelanocytic nests” or “melanocytic pseudonests

 Pseudonests or pseudomelanocytic nests represent aggregates of cells and cell fragments that include keratinocytes, macrophages, and lymphocytes, as well as occasional melanocytes.  Aggregates in which some (i.e. >1–2 cells per nest), but not all, cells express numerous melanocytic markers(melan-A, MiTF, Sox-10 staining). These nests showed interspersed cytokeratin- positive staining reminiscent of colloid bodies, as would be expected in a lichenoid dermatitis.  Pseudomelanocytic nests in the setting of lichenoid inflammation can mimic atypical melanocytic proliferations. CLUES FROM MEDIUM TO HIGH-POWER EXAMINATION

 Melanocytes tend to be arranged as single cells in many early melanomas, with nests predominating in most nevi. When nests are present in melanomas, they tend to vary in size, shape, and orientation.  Bridging between adjacent rete ridges: Bridging (the merging of melanocytes between adjacent rete ridges) is a criterion used in the diagnosis of dysplastic naevus.  Confluent bridging involving three or more adjacent rete ridges can be worrying for melanoma.  The confluent growth of a melanoma often extends over the tops of the dermal papillae, rather than solely connecting the bases of adjacent rete ridges Lentiginous pattern

 In actinic melanocytic hyperplasia: the number of melanocytes is ranging from between 10 and 20 melanocytes per 0.5 mm.  Melanocytes are evenly distributed in the basal layer, separated from one another by keratinocytes.  Occasional confluence of a few melanocytes (2-3 melanocyte), but cells neither line up in a row along the dermoepidermal interface(lentiginous pattern)  The ‘lentiginous’ or single cell pattern tends to be continuous between rete in melanomas, while being discontinuous in nevi & dysplastic nevus (confined to the tips and sides of the rete while sparing the suprapapillary plate region Continuous proliferation of melanocytes

In LM: Markedly increased numbers of melanocytes in the epidermis (eg, >25 melanocytes per 0.5 mm of basal layer) Architectural patterns

 H. Congenital pattern:  Perivascular, perineural, and periadnexal pattern and infiltration of arrector pili muscle in congenital nevus and DPN.  Melanocytes have a band-like pattern occupying the entire span of the dermis.  Splaying (Indian filing) or reticular pattern. The cells in the deeper part of a congenital nevus are frequently aligned in long rows between undisturbed collagen fibers(Congenital nevus , Intramucosal nevus, Acquired Nevi with Congenital Features)  Presence of an increased number of terminal hairs.  Widespread neural differentiation Congenital Nevus-Like Acquired Nevi (Acquired Nevi with Congenital Features)

 Herniation of melanocytic nests into dilated lymphovascular structures: True vascular invasion in melanoma, Dermal nevus .  They are deep and have a marked periadnexal and perivascular pattern  Melanocytes are found inside follicular structures and eccrine glands (but not within sebaceous glands and hair arrector muscles)  Splaying of melanocytes among collagen fibers. CLUES FROM MEDIUM TO HIGH-POWER EXAMINATION

Upward (pagetoid) spread Shapes of melanocytes Cytological atypia Epidermal and dermal mitotic activity Suprabasal melanocytes(transepidermal melanocytic migration

 Tangential sectioning  True pagetoid scatter: The cells should not be in continuity with the junctional component, and they should be located above a line parallel to the skin surface located at the basal epidermal layer overlying the most superficial dermal papilla. Melanocytic proliferations with pagetoid spread(Melanocytic ascent)

 In benign naevi with intraepidermal spread of melanocytes the cells are primarily localized to the basal and spinous layers in the central portion of the lesion.  Limited migration of melanocytes into the lower layers of the epidermis is acceptable in dysplastic naevi  The presence of melanocytes scattered within higher levels of the epidermis( granular layer), is a classic clue for melanoma.  Pagetoid melanocytosis of melanoma also present at edge of melanoma, and in epidermotropic metastatic melanoma(indistinguishable from in situ SSM)  May be absent in spitzoid melanoma. Transepidermal elimination of melanocytic nests

 Melanocytic nests of different size which travel as large aggregates through the epidermis to reach the surface and the stratum corneum.  Spitz nevi and pigmented spindle cell nevi  Occasional junctional and compound nevi  Melanoma (acral melanoma) Mitosis

 In epidermal component: Presence of epidermal mitoses and epidermal mitoses density above 0.01/mm correlate with a diagnosis of malignancy.  Inflammation may induce secondary melanocytic activation and proliferation, resulting increased mitoses.  In borderline lesions, inflammation can confound interpretation.  In dermal component: finding a mitotic figure should prompt a search for additional mitoses and a careful evaluation of the architectural and cytomorphological features. Mitosis

 Mitoses in nevi and recurrent nevus: small number mitoses in the upper aspects of lesion, in younger patients, in polypoid lesion, and in pregnant patients. Mitotic figures are never atypical or clustered together.  The presence even of a single mitosis in a neoplasm with conspicuous nuclear pleomorphism or atypia makes melanoma more likely.  The presence of mitoses in significant number (“easily found”) or mitoses gathered in clusters or mitoses in the deep portion of the lesion are findings favoring a melanoma.  In thin melanomas, IHC does not replace the careful search for mitotic figures in H&E stain  Anti-monoclonal mitotic protein-2 (MPM-2) and anti-phosphohistone H3 (PHH3) are more specific than other markers of proliferation such as Ki-67 Necrosis

 Necrosis is absent in nevi, with rare exceptions. These include traumatized nevi, in which cells with pyknotic nuclei can be present in the upper part of a lesion.  Melanoma CLUES FROM HIGH-POWER EXAMINATION

 Cytologic atypia :  Dysplastic nevi  Special site nevi  Halo nevus  Neonatal or childhood nevi  Recurrent naevi and those nevi with recent exposure to ultraviolet irradiation  Melanoma  “Ancient” atypia : atypical nuclei in benign lesions. Mitoses, confluent growth, or an expansile growth pattern (nodule) should never be present CLUES FROM HIGH-POWER EXAMINATION(Shapes of melanocytes)

 Melanoma cells are typically divided into two major types: epithelioid(SSM, NM) and spindled cell(LMM, ALM).  Other cell morphology: small / large round, wavy, balloon, oval, polygonal(epithelioid), spindle, dendritic, pulverocyte, multinucleate and giant cell, plasmacytoid, pseudolipoblastic, rhabdoid, with clear cytoplasm (may be granular or vacuolated (eg, “balloon cell” melanocytes); contain small vacuoles (“sebocyte-like” melanocytes); compress the nuclei (“signet-ring” cell melanocytes); or have pale cytoplasm (“clear-cell” melanocytes) and pleomorphic. Dendritic melanocytes

 Dermal dendritic melanocytic proliferations : characterized by the presence of dermal spindled and dendritic cells resembling melanocytes migrating from the neural crest to the epidermis.  Dermal melanocytoses (nevus of Ota, Ito, Mongolian spot and related conditions),  Blue nevi  Malignant blue nevi Pulverocyte morphology

 Characterized by larger epithelioid melanocytes with nuclear atypia and voluminous cytoplasm with a fine, dusty melanin pigment.  Melanoma  Clonal naevi  Spitzoid lesions Epithelioid melanocytes

 Epithelioid melanoma cells often lack cohesiveness and demonstrate marked pleomorphism, including the formation of multinucleated tumor cells  BAPoma  Pigmented epithelioid melanocytoma: well circumscribed, and the heavy pigmented large epithelioid melanocytes with prominent nucleoli  Spitz and Spitzoid melanoma  Epithelioid blue nevus Spindle melanocytes

 Morphological spectrum of ‘spindle cells’ :  (A) Wavy or ‘comma-shaped’ (neuroidal) spindle cells from the tactoid bodies of a neuroidal nevus.  (B) Slender bipolar spindle cells from a common blue nevus.  (C) Blunted oval spindle cells from a satellitic nodule of a plaque-type cellular blue nevus .  (D) Plump ‘histiocytoid’ spindle cells from a desmoplastic melanoma and Spitzoid lesions .  (E) Fusiform spindle cells from a spindle cell melanoma . Abrupt changes in cell type

 Abrupt changes in cell type from area to area are common in melanoma.  Small cutaneous melanoma metastases often show one cell type only  In combined nevi , balloon cell nevi, DPN/clonal nevus. MALIGNANT FEATURES IN BENIGN LESIONS

 Disordered junctional growth in a traumatized or recurrent nevus  Mitoses in nevi removed during Pregnancy  Pagetoid Spitz Nevi  Combined Nevi: displays asymmetry  Atypical Features in Congenital Nevi  Nevi From Special Sites: The lentiginous patterns with regular rete ridge elongation that characterize dysplastic nevi are not as a rule seen in genital nevi, but often present in vulvar melanoma.  Deep Penetrating Nevi BENIGN FEATURES IN MALIGNANT LESIONS

 Desmoplastic Melanoma  Metastatic Melanoma: small, circumscribed, and symmetrical  Nevoid melanoma  Nested variant of melanoma  Spitzoid melanoma: These lesions can be remarkably symmetrical and circumscribed on low- power examination . Summary

 Clinical features, dermoscopic findings and histology  Clinicopathologic correlation  Do not sign out difficult cases when you are tired.  If the diagnosis is clear, finalise the case.  If the diagnosis is not clear, perform immunohistochemistry  If still uncertain, show cases to colleagues and get consults when necessary  If colleague also uncertain, consider molecular tests.  If molecular tests are not available/unhelpful, be honest and convey the problem to the clinician, the evidence for or against the various differential diagnostic considerations should be presented in the pathology report and a ‘‘most likely’’ or ‘‘favored’’ diagnosis given or diagnose it as a diagnostically ambiguous melanocytic neoplasm . Practical algorithm for use of molecular studies.(Andea A. university of Michigan.) Diagnostic and ambiguous Terms Used to Describe Atypical Melanocytic Lesions

 Atypical intraepidermal melanocytic proliferation” (AIMP),  Borderline melanocytic tumor (BMT): intraepidermal BMT & dermal BMT  De novo intraepidermal melanocytic dysplasia (DNIEMD)  Atypical junctional melanocytic hyperplasia (AJMH)  Pagetoid melanocytic proliferation(PMP)  Atypical Spitz tumor (AST)  “Superficial atypical melanocytic proliferations of uncertain significance” (SAMPUS), and “melanocytic tumors of uncertain malignant potential” (MELTUMP) REFERENCES

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