HISTOLOGY OF ATYPICAL MELANOCYTIC LESIONS

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Abbreviations used:   Atypical Actinic Lentigo (AAL), Acral Lentiginous Melanoma (ALM), Acral Nevus (AN),  Atypical Spitz (AS), Blue Nevus (BN), Cellular Blue Nevus (CBN),  Compound  Melanocytic Nevus (CMN), Congenital Nevus (CN), Congenital Nevus with cellular Nodules (CNwCN), Deep Penetrating Nevus (DPN), Intradermal Melanocytic Nevus (IMN), Desmoplastic Melanoma (DM), Epithelioid Blue Nevus (EBN), Flexural Nevus (FN), Genital Nevus (GN), Halo Nevus (HN), Junctional Melanocytic Nevus (JMN), Dysplastic Nevus with Low Grade Dysplasia (DNLG), Dysplastic Nevus with High Grade Dysplasia (DNHG), Lentigo Maligna (LM), Malignant Blue Nevus (MBN),  Melanocytic Hyperplasia (MH), Melanoma arising in Nevus (MAN), Melanoma in Situ (MS),  Mitotically Active Nevus (MAN), Pigmented Epithelioid Melanocytoma (PEM), Pigmented Spindle Cell Nevus (PSCN), Proliferative dermal nodule in Congenital Nevus (PDNCN), Radial Growth Phase Melanoma or nontumorigenic melanoma (RGPM), Recurrent Melanocytic Nevus (RMN),  Spitz Nevus (SN) , Vertical Growth Melanoma or Nodular Melanoma (VGM), Vulvar Melanoma (VM), Metastatic Malignant Melanoma (MMM).

References
Wikipedia
eMedicine
AFIP Atlas of Tumor Pathology Series 4. Melanocytic Tumros of the Skin. Elder and Murphy.
Ackerman's Surgical Pathology: Rosai
Diagnostic Surgical Pathology: Sternberg
Robbins Review of Pathology
Lever. Tenth edition. Histopathology of the skin Textbook. David E Elder
Dermatology Online Journal http://dermatology.cdlib.org
Multiple other sources
 

AGE OF ONSET

-SN common in kids and young, generally < 40y/o. Favor benign melanocytic lesions in people < 30.  Favor Spitzoid melanoma in >30, if > 2 mit/HPF,  sheet formation, mixture of small and large cells. VM more common in older.

CLINICAL PRESENTATION:

-Location: LM head and neck.  ALM acral.  VGM and RGPM in intermitent sun exposure like back and limbs. SN common in thigh and rare in head and neck.  Be careful with melanocytic lesions or possible Spitz in back of adults or leg (calf) of a woman, it may be a melanoma.  PSCN common young woman in thigh.
-Rapid growth: Suggest malignant.
-Macular component: RGPM.  Asimetry, color variation blue black and irregularity favor melanoma.
-Papular component: SN, VGM. 
-Color: SN and VGM pink,  RGPM intense black macule
-Border of lesion: Irregular favor melanoma
-Multiple lesions: think in DNLG and DNHG. Risk for melanoma is important in DNLG and DNHG if multiple lesions or family history (not in solitary dysplastic nevus).

SIZE:

-Horizonatal size : <5mm: central nevus in HN, DNLG.  >5mm: DNHG, most VGM, many CBN, DPN, CMN, IMN.   <1cm: PSCN, DPN, GN, CNwCN, most SN, most DNLG and DNHG   >1cm:  RPGM, VGM, VM, AS
-Clark:  I (no invasion dermis/melanoma in situ), II ( in papillary dermis, not filling the papillary dermis), III (expand and fill the papillary dermis), IV (reticular dermis), V (fat) . Most nontumorigenic RPGM clark II or less. Most tumorigenic and VGP clark III or more.
- Breslow:  More than 1 mm in most VGM or tumorigenic. Less than 1 mm in most RPGM, non tumorigenic.

MICROSCOPIC FINDINGS

 

ARCHITECTURE /PATTERN/TISSUE ARRANGEMENT

Confined to dermis with no junctional nests: PSCN (papillary), BN (all variants), PEM, MMM

Simetry of dermoepidermal and dermal growth present (two halves of the lesion similar):  Most: CMN, GN, SN, PSCN, DNLG, DNHG

Asimetry of junctional and/or dermal component (two halves of lesion disparate) with asymetry of nests, inflammation, pigment etc :  Most:   VGM, RPGM, VM  Some: DPN  Rare: GN

Extension around skin appendages: Most:  Pagetoid extension in MS, LM, ALM.  AN also extends to eccrine seat ducts.

Storiform like whorls with or without hemosiderin laden macrophages:  CBN, similar to dermatofibroma. Order IHC.

Focality of nodules: Unifocal:   VGM   Multifocal: Some CNwCN,  

Verrucous surface: Nevoid and verrucous melanomas sometimes simulate nevus with congential pattern and are classified as MELTUMP.

Mixed biphasic pattern with clusters of plump or cubical clear cells (without melanin) surrounded by heavily pigmented spindle cells. Lesion reach reticular dermis and fat with bulbous extensions: CBN. CBN also is biphasic because nested and plexiform nests predominated in lower dermis and it is less dense and dendritic in the surface of lesion.

Variants of Melanoma in Radial Growth:   RGPM, LM, ALM, Mucosal lentigionous. All  may be classified as MS if  if invasion not identified and only macule present. When invasion present commonly nodules (tumorigenic). 

Variants of Melanoma in Vertical  Growth:   VGPM, DM, MBN and variants (desmoplastic, neurotropic and nevoid/spitzoid). The in situ component and radial phase may not be identified in VGM. ALM may grow  tumorigenic.  
Invasion of dermis in Melanoma: 

-Non tumorigenic or microinvasive RPGM: invasive nests smaller than junctional or epidermal nests (most clark II and less than 1mm)
-Early tumorigenic RPGM: invasive nests in papillary dermis larger than junctional nests  (most Clark II, but may be III or IV if individual tumoral cells invading dermis)
-VGM: dermal tumor nodule gross and microscopic. Invasive nests in papillary dermis larger than junctional nests

Melanomas commonly associated with nevus: Common: RPGM   Occasional: VGM, LM   Rare: ALM

Growth borders of the melanocytic lesion:
-Destructive expansile or infiltrative (invasive) growth with poorly demarcated borders: Most: VGM, MBN.  Some:  CBN, CMN, SN (only deep border with well demarcated lateral border). Some VGM  pushing border rather than infiltrative. Rare: DPN  Comment: Circumscription is not a good criteria for melanoma. Many benign lesions are not well circumscribed.
-Fat involvement: Some: DPN, VGM, AS, CBN (nodules in fat connect with nodules in reticular dermis),   Rare: SN

Shape of lesion:  Piramidal with apex in deep reticular dermis: DPN,  Dome shaped: SN, PEM (resembles blue nevus but intensely pigmented).   Dumbbell: CBN

Lesions with associated nevus:
Look for residual dermal nevus below and above the scar in RMN. If maturation present in melanoma is probably arising in nevus.   

EPIDERMIS

-Single atypical  melanocytes along basal layer or dermoepidermal junction: AAL. Dx MH if melanocytes equidistant from one another, not atypical, uniformly pigmented,  not located around appendages or above junction and no nest formation.  Dx  evolving LM/MS  if atrophy of rete and solar change, melanocytes not equidistant from one another,  atypical, not uniformly pigmented, located around appendages or above junction or nests in epidermis. The last lesion is considered for some as a dysplastic lesion in transformation but many considere this lesion a MS. Generally shows abundant melanocytes (> 15 /0.5 mm)

-Contiguous melanocytes  along basal layer or dermoepidermal junction:  If solar change + atrophy + linear continuous proliferation demostrated with Melan A along basal layer or between irregularly elongated rete ridges think in LM/MS (melanoma in situ lentigo maligna type).  A linear or continuous proliferation demostrated with Melan A in acral region, without pagetoid extension  or nested proliferation is diagnosed as Melanoma in Situ, acral lentiginosus type.

-Shoulder within epidermis or junctional shoulder: defined as disorganized intraepidermal component beyond the dermal component: Common:  RGPM, VGM, VM  Some: DNLG and DNHG.  None: CMN, GN

-Lesional cells at lateral border of epidermis:  Nests: Nests between rete and suprapapillary present in shoulder of DNLG, DNHG and AN.   Single cells in pagetoid pattern: RGPM

-Pagetoid spread  as single or solitary non confluent cells low in epidermis (basal or suprabasal not beyond mid spinous layer):  Common:  RMN, VM, MS, ALM  Some: AN (not prominent and limited to central part of nevus), Focal: LM/MS ( (melanoma in situ lentigo maligna type)   Very rare or minimal: CMN, CN, HN, RMN, DPN, GN,  SN (pagetoid or AS), PSCN (pagetoid), CN, DNLG, DNHG. All these conditions  show epidermal cells banal in cytology without macronucleoli and tend to be localized towards the central portion of the lesion, not towards periphery. None: AAL

-Pagetoid spread with contiguous proliferation above basal layer into all levels of the epidermis including stratum corneum or spread of large number of melanocytes:  Common: Extensive and high in epidermis in RPGM and VGM. Also VM , ALM or MS. It is always a dx clue for melanoma.  Rare: AS, pagetoid SN, pagetoid PSCN,  RMN, AS, MS, ALM  None: AN, BN and variants. 

-Pigmented keratinocytes:  RMN, ALM

-Ulceration:  Common: VGM, MBN  Some: AS, PEM  Rare: SN, CBN. Ulceration is not a feature of SN  None: DPN, CNwCN. Comment: ulceration is possible after trauma in any benign lesion showing hemorrhage, crust and parakeratosis. 

-Epidermal hyperplasia: Common: SN  Rare: VGM

-Hyperkeratosis: Common: RPGM, VGM over the nodule   None: DNLG, DNHG

-Hypergranulosis: SN

-Areas of irregular epidermal thickening or acanthosis combined with thin areas of consumption of epidermis with no rete: Common: VGM, RGPM.

-Pseudoepitelliomatosis hyperplasia: Some VGM.

RETE PATTERN:
-Rete pattern elongated (Lentiginous elongation of rete ridges):  Elongation short: JMN  Delicated elongation long and narrow : DNLG, DNHG (more irregular than DNLG), some  LM and ALM.  Elongation of rete possible:  CN, GN, AN, PSCN, VM. Nevus with lentigionous changes  without cytologic atypia are called lentiginous nevi.
-Rete pattern effaced: AAL, RPGM, GN, RMN, MS, LM. Lentigo maligna look like Melanoma in situ with effacement of the rete and solar changes.  Focally effaced: DNHG (discontinuous lentiginous proliferation)
-Anastomosis between rete ridges (bridging):
 criteria for DNLG and DNHG. Confluent bridging in more than 3 rete ridges is concerning for RPGM

JUNCTIONAL NESTS:
-Absent: BN and all variants and PEM are both dermal lesions without junctional nests.  No nests in AAL
-Discontinuos nests or junctional proliferation: Most: JMN, DNLG, SN, CMN, Focal: LM/MS
-Confluent nests with continuous proliferation in dermis: Most: VGM, RPGM, DPN, RMN, GN, DNHG (focally or discontinuous)  Some: VM
-Bridging nests between elongated rete ridges: DNLG, DNHG.
-Sheet like growth or dense expansile growth: Common: VGM  Rare: SN
-Single cells in epidermis between junctional nests: Nest predominate over single cells: JMN, DNLG, DNHG, Late phase of RGPM  Single cells predominate over nests: RPGM.
-Dishesive cells in nests: Common: VM, VGM, DNLG, DNHG  Some: FN, Nevus in children. 
-Location of nests: Tips and sides or edges of elongated rete ridges: DNLG, DNHG, RPGM, ALM   Tips only: JMN , AN,
-Shape of nests:  round: JMN   Ovoid: SN, AN, PSCN, DNLG, DNHG. 
- Uniformity of nests:  Nest regular in size and shape: SN, PSCN, DNLG, DNHG   Nest irregular in size and shape: VGM, RPGM, VM. Irregular nests also common in RMN, GN
-Orientation of the nests: Vertically oriented (raining down): SN, PSCN, AN  Random or horizontally oriented: VGM, DNHG, DNLG
-Size of nests: Large nests : GN, AN, VGM. In vertical growth melanoma dermal nests are larger than dermoepidermal and epidermal nests.  Small nests : DNLG, DNHG. In RPGM superficial spreading with microinvasion or Clark II, the dermal nevus are small, no larger than 10 cells in width and no larger than the dermoepidermal or epidermal nests.
-Clefting artifact or retraction artefact around nests: Common: AN, FN, SN, PSCN  None: DNLG, DNHG. 

-Comments: In recurrent SN or PSCN nests identified above the scar.

 

DERMIS
-Always sun damage skin: LM
-
Coalescent or confluent nests: Most: DPN, RMN.
-Expansile nodule formation present: Most: VGM, CBN, CNwCN  None: CMN.
-Size of nests: Variation in size of nests favor melanoma.
-Formation of sheetlike:  Sheets are unusual for SN and favor the dx of VGM.
-Maturation or zonation (enlarged cells at surface with small single cells at base): Most: CMN, HN, GN, AN, SN, PSCN, DNLG. Incomplete: DNHG   Rare: DPN  None: VGM, RPGM, VM.  Exception: rare CMN shows inverted maturation (smaller cells superficial and larger at base). Very rare cases of VGM show pseudomaturation.
-Full thickness dermis: Most: CBN.  Some: VGM, DPN, AN.  Rare: SN and variants.
-Nests at the base:   VGM generally deep dermal nests larger than epidermal nests.   Rare:  SN show small individual nests  at the base, no large nests.
-Single cells at the base of lesion, highlighted with reticulin: Most: CMN  Rare: SN, PSCN   None: No single cells in base of VGM (only compact ill defined nests and fascicles at the base)
-Morphology of cells at the base of lesion: Resemble cells at epidermis: RGPM  Cells different to cells at epidermis: In VGM deep dermal nests larger than epidermal nests and cells do not become smaller (no maturation). If they become smaller, they remain large comapared to nevus cells.

TYPE OF CELLS
-Epithelioid cells: very common in VGM, RPGM, LM, PEM. At least some atypical epithelioid nevoid cells required for dx of DNLG and DNHG. Also present in: EBN (plump), SN (see comments), PSCN, DPN,  RMN (junctional above the scar only), AN. Some DM have lentiginous radial growht with superficial epithelioid cells. Clonal nevus described a nevus with a well circumscribed clonal aggregate of epithelioid cells in upper reticular dermis with mild atypia and rare mitosis, surrounded by melanophages.  Same tipe of aggregate may occur in deep dermis  in DPN.
-Dendritic melanocytes: Common: DPN, BN, CBN, ALM, PEM  Rare: DPN
-Spindle cells: SN, PSCN, DPN, BN, CBN, some AN, some nodules in CNwCN, LM, ALM. Common in dermal component of mucosal melanomas and VM. Individual spindle wavy cells with subtle atypia infiltrate collagen in dermis in DM.
-Small nevoid cell: Common: CMN,  ALM  Some: VGM nevoid type  show cells with minor atypia and some evidence of maturation. To document melanoma order Melan A to see contiguous dermoepidermal proliferation , pagetoid extension, confluence of dermal nests and sheets or any dermal mitosis.  
-Comments:
 SN  combines spindle and eosinophilic epithelioid cells. They may be large and bizarre but mitosis < 2/mm2
Spindle cells predominate in SN and PSCN and epithelioid cells predominate in RGPM and VGM.
Spindle cell melanoma are common in older with sun damaged skin.
When spindle cell infiltrate at the base of melanocytic lesion think in VGM or BN, not common in SN or PSCN.
In BN spindle and dentritic cells are identified among reticular dermis collagen, sometimes in contiguity with one another in CBN.

 

OTHER TYPE OF CELLS
-Lymphoplasmocytic infiltrate: Common clue for dx of melanomas.  RGPM and VGM is brisk, band like with most lymphocytes asymetrically distributed peripheral and across the base.  Lichenoid pattern or abundnat lymphos mixed with tumoral cells and melanophages is common in RPGM in regression,  HN, SN with halo reaction.  Perivascular lymphocytes and dermal clusters of lymphocytes are  common in DM. Sprinkling of lymphocytes between dermal tumoral cells common in MMM and VM.
-Lymphoplasmocytic inflammation mild or absent:  CMN, CN, RMN, SN, sclerosing SN, BN and variants.

-Admixed melanophages: Most: DPN, all variants of BN.    Common: VGM  and RPGM (very common in areas of regression), DNHG, PSCN. Comment: melanophages of postinflammatory hyperpigmentation are not seen in deep reticular dermis.  
-Multinucleated Giant Cells: Some: CMN, SN, CBN
-Wagner  Meisnner corpuscles deep dermis: Some: CMN

TUMOR STROMA:

-Fibrosis: Common and diffuse: HN, VGM, RPGM (if regresive fibroplasia scar + occasional melanophages seen), sclerosing SN, desmoplastic SN, desmoplastic BN  Eosinophilic and lamellar fibroplasia only in papillary dermis: DNLG, DNHG. Fibrosis rare: CMN. 
-Reticulin pattern: Surrounds single cells: CMN   Surrounds clusters of cells: VGM
-Necrosis: Common: VGM, VM, MBN.  Absent: CMN, DPN, RMN, GN, SN, PSCN, BN and variants, CNwCN.  
-Regresion: Absent: DNLG, DNHG   Common: Melanoma.
-Perineural Invasion: Common: DM  and most recurrent melanomas are neurotropic.   Some: PSCN, CBN, BN, AS, DPN, VGM, some congenital nevus

VASCULAR PATTERN:

-Proliferation of vessels and/or endothelial hypertrophy: DNLG, DNHG. Vascular proliferation and angiomatoid pattern with abundant vascular proliferation seen in some lentigo maligna melanoma with desmoplasia in face of older patients.
-Nevic cells mixed with vessels, not endothelial proliferation: Some CMN and SN are mixed with vascular spaces.  
-Lymphovascular involvement: VGM. Easily detected in MMM. 
-Pseudovascular invasion: AS
-Perivascular involvement:  BN and variants

NUCLEUS:
-Chromatin: Coarse:  VGM, MMM  Delicate: CMN, JMN, AN, SN, PSCN.

-Nuclear membrane: Thin and uniform: CMN, JMN, SN, PSCN.,  Thickened and angular:  VGM.

-Nucleoli: Large, sometimes eosinophilic:  VGM, RPGM,  some SN, some PSCN, CBN, minority of cells in DNHG and DNLG  Small commonly basophilic  nucleoli CMN, AN, DPN, AN, most cells in DNHG and DNLG.  

-Severe pleomorphism or high nuclear atypia: VGM most cells (more than random atypia), LM/MS, RPGM, DPN, MMM, MBN. In DNHG  >10% of cells show atypia but is random, most cells not atypical.  If a dysplastic nevus presents severe atypia and is a patient over 30 years old, recommend complete excision with 5 mm margin and follow up.  

-Mild to moderate pleomorphism: AAL, CBN, GN, SN, PSCN, PEM, CNwCN, DNLG (rare atypical epithelioid cells), very early or evolving LM.   Rare: CMN  and CN (ancient change), RMN, AN, BN other than CBN.  Comment: The individual cells in the nests in PSCN appear atypical but they have nuclear morphology similar to those of nearby keratinocytes.

-Bizarre  cells or obvious anaplasia: Some VGM, MMM, MBN

-Intraepidermal mitosis: Common: PSCN, SN, RGPM (30% cases), VGM  Rare but possible: All other benign lesions, including DNLG and DNHG.

-Dermal Mitosis: Common: MMM, MBN, VGM,  VM, PSCN, AS. If abundant mitosi in RGPM suspect early tumorigenic phase or early vertical growth phase.  Rare:  DNLG, DNHG, RPGM, CMN, PSCN, CN, CNwCN, HN, DPN, RMN, GN, AN, BN and all variants, most SN including sclerosing variant (located to epidermis or upper dermis and < 2 mitosis/HPF or 2 mitosis/mm2).  Deep dermal mitosis, atypical mitosis or more than 2 mit/mm2  or growth in sheets are unusual for Spitz and favor the diagnosis of VGM rather than atypical spitz.  DM very rare mitosis in the dermal spindle component (if present look for mitosis in superficial lentigionous epithelioid component).  Comment:  All melanomas with dermal mitosis are considered tomorigenic by definition. Any melanoncytic lesion with frequent mitosis or atypical mitosis is suggestive of melanoma or have at least uncertain biologic potential. If concerned recommend complete excision with 5 mm margin and follow up.
  
-Apoptosis: Suggest melanoma. Rare in benign melanocytic lesions. They may resemble Kamino bodies in melanoma in regression

-Comments: some nevus in special locations like vulva, breast, skin flexures, acral and neonatal nevus may show important atypia with pleomorphism and prominent nucleoli with difficult differential with DNHG or MS and may be classified as SAMPUS (Superficial atypical melanocytic proliferation of uncertain significance). However cytologic atypia is minimal in most cases and maturation present. If questionable dx recommend complete excision with 5 mm margin and follow up.

PIGMENTS
-Location: Within epidermis and stratum corneum: RGPM, PSCN, RMN  Superficial: CMN, RMN, DNLG, DNHG, RGPM, PSCN, postinflammatory hyperpigmentation. Superficial and deep: VGM, DPN, BN and variants.  Not beyond lateral border of scar: RMN
-Quality: Coarse: CMN, HN, SN, PSCN, BN, CBN, MH  Fine (dusty): VGM, DNLG, DNHG, MS  
-Ammount:  Heavily Pigmented: PSCN, PEM, BN (most pigmented BN is plaque type BN in superficial dermis), CBN, some nodules in CNwCN, some RPGM  Scant or none: SN, Desmoplastic or Olygomelanotic BN, DM
-Distribution: Patchy, asymetric, irregular distribution: VGM.   Diffuse: DNLG, DNHG. Comment: RPGM more pigment than VGM.

Comment: lesions like solar lentigo shows solar elastosis and increase melanin pigment within keratinocytes with transepidermal elimination, but proliferation of melanocytes is not identified.

INCLUSIONS
-Globoid eosinophilic Kamino bodies at junction: Common: AN, SN  Rare: RPGM and VGM

REGRESION : HN, some VGM and other.

IMMUNOHISTOCHEMISTRY AND CYTOCHEMISTRY

-S-100:  highlight spindle and reticular cells inside dermis in BN and variants, sometimes in contiguity with one another in CBN. Stain PEM, a lesion similar to CBN but intensely pigmented that may concern about the possibility of Melanoma (commonly associated to Carney).  S-100 is positive in melanomas and also stain DM throughout the dermis and epidermis.

-Melan A: Positive:  In MS and ALM highlight the continuous layer of cells along dermoepidermal junction (in situ melanoma). Continuous melanocytic proliferation  is a potential indicator of MS. In LM highlight the continuous layer of cells along the dermoepidermal junction + confluent junctional asymetric nests. Diffuse positivity in all variants of BN and MMM. VGM shows patchy or diffuse staining throughout the lesion.  It is important to highlight residual nevus cells in HN (differential with lichenoid keratosis). Superficial epithelioid cells as well as pagetoid or lentiginous nests stain positive for  Melan A in DM, but spindel cell population at the base do not stain.  Negative: PEM , DM

-HMB-45: Positive: Diffuse positivity in all variants of BN and MMM. VGM shows patchy or diffuse staining throughout the lesion. CMN and SN present only positive cells in junctional and superficial dermis, decreasing with depth and absent in deeper cells. Rare cases of Spitz stain throughout the lesion. VGM present in deeper cells or deeper dermis. In nevoid melanoma simulating nevus dermal component is stronger than junctional component (inverse pattern expected in benign nevi). In CNwCN highlight the cellular nodules.  Negative: DM in dermal spindle cell population (generally positive in surface of the lesion but spindle cells at the base do not stain. PEM is HMB45 neg.
Cyclin D1:
Nuclear positivity. In nevoid melanoma simulating nevus, dermal component stronger than junctional component, similar to HMB-45 (inverse pattern expected in benign nevi and SN)
Ki-67 in dermis:  Negative:
Most benign by definition commonly negative or <1%  Low: Most RPGM, SN, DNLG, DNHG and benign nevi Ki67 < 5% and cells in mitosis or proliferation are superficial in dermis.  High: Most VGM > 10% . Ki-67  is important if high proliferation in the diagnosis of nevoid melanoma and it is  specific for melanoma if > 30%. MIB+ cells tend to be dispersed in all dermis thickness including base of the lesion in VGM. Be careful when reactivity is only present in reactive lymphos.
-p16:
 Commonly high in CMN.  Commonly low in VGM.
-p53: Commonly nuclear positivity in VGM. Negative in SN.

Other stains useful in differential diagnosis.
-Use CD1a + for histiocytosis X, Giemsa for mastocytosis, CD68 + for histiocytoma, XIIIa + for dermatofibroma.

MOLECULAR/CYTOGENETICS

-A FISH pannel using probes 6p25, 6q23, 6 centromere and 11q13 shows specific gains and looses in Melanoma and is negative in CMN, IMN, SN or melanocytic lesions of uncertain malignant potential without metastatic potential.
-Comparative Genome Hybridization with chromosomal gain or losses favor melanoma over benign.

DIFFERENTIAL DIAGNOSIS

-PSCN vs SN: Probable PSCN is a pigmented variation of SN with intense coarse pigment and nest blending more with epidermis and having not very good vertical orientation as SN and some  relation with sebaceous glands. 
-PSCN vs  Melanoma:  In cases of PSCN showing regular elongated spindle cell nevus and nevoid maturation with some mitosis in dermis, it is difficult to rule out PSCN vs Melanoma. Best dx for these cases is MELTUMP
-Pagetoid SN vs MS: Pagetoid SN smaller size, symmetry, not marked atypia. If questionable recommend complete excision with 5mm margin and follw up.
-Nevus with marked atypia: Sometimes nevus in special locations like vulva, breast, skin flexures or acral may show important atypia with pleomorphism and prominent nucleoli, difficult differential dx with DNHG or MS and may be classified as SAMPUS (Superficial atypical melanocytic proliferation of uncertain significance). However cytologic atypia is minimal in most cases and maturation present. If concerned recommend complete excision with 5 mm margin and follow up.
- DNHG vs MS: Use the term SAMPUS if: 1) focal thickening and thinning of epidermis with epithelioid melanocytes in tips and sides of rete with mild random atypia   2) focal continuous proliferation of single cells between the rete with confluent nests and solar damage (nevoid lentigo maligna)  3) mild pagetoid extension in lower epidermis (proved with MART) may be a dysplastic nevus evolving to MS.  4) lesions without rete elongation, continuous proliferation or Pagetoid extension but with severe nuclear atypia. For SAMPUS strong recommendation for complete excision with 5 mm margin and follow up. 
-RPGM vs LM: continuous basal proliferation with nests composed of epithelioid cells and absence of pagetoid reaction favor RPGM.

- AS vs Spitzoid Melanoma: If difficult dx use MelTump (Melanocytic tumor of uncertain malignant potential). > 1cm, ulceration, fat involvement, > 6 mit/mm2 and inflammation present favor Spitzoid Melanoma. Difficult to differentiate from DPN or CBN. Recommend reexcision for MelTump.
-DM vs sclerosing SN: If mitosis, lymphocytes around melanocytic cells or lymphocytes clusters or junctional component in radial growth favor DM.
-SN vs DPN: SN more superficial, more cellular and less pigmented in dermis than DPN.
-MS vs MH, differential in sun damaged skin: MH common in r solar damage skin, shows few single clear melanocytic cells in dermoepidermal junction, not contiguos proliferation, evenly or simetrically dispersed.   Benign Atypical Junctional melanocytic Hyperplasia may be used if melanocytes with large nuclei, unevenly dispersed, pigmented melanocytes with coarse melanin,  no mitosis, no lymphocytic proliferation, no dermal fibrosis, no melanophages in dermis (some call this lesions actinic lentigo when rete well preserved).  Be careful with possibility of MS if nests in dermoepidermal or aggregates of melanocytes, if melanocytes around adnexa, if pagetoid extension, high number of lymphocytes, lymphoid infiltrate, flattening rete.
-Nevus cells vs small melanoma cells (Nevoid Melanoma):  Finding only one mitosis in a nevus without pleomorphic cells or nucleoli that appear symetric and matures may be ignored. Nevoid melanomas appear to mature and simulate nevus, but cells at the base aare similar in size to surface cells, nucleoli is prominent and mitosis or necrosis may be present.
-RPGM vs RMN:  Always review previous excised shave biopsy of nevus to rule out RMN vs RPGM. Remember that RMN nevus nevic cells do not extend beyond scar. In RPGM they extends beyond scar.
-Malignant blue vs benign:  Malignant more cellular, asymetric, necrosis, expansile or infiltrative growth, more density, sheet like dermal architecture, subcutis involved.
BCN vs Spitz: spitz large nuclei, eosinophilic cyto, prominent nucleoli, no pigmented melanocytes or melanophages, maturation with dermal descent.
-Clear Cell Sarcoma vs Cellular blue Nevus: CBN centered in subcutis, oval or spindle cells with clear cyto, atypia, mitosis, deeper planes, translo EWS/ATF-1 by FISH
- Common case of Combined Nevi:  Spitz or Blue Nevus + CMN or congential nevus
-remember: SAMPUS (superficial atypical melanocytip proliferation of uncertain significance) and MELTUMP (melanocytic tumor of uncertain malignant potential) require wide excision. They may persist or regrowth after complete excision and some cases of MELTUMP even metastasize after complete excision.
 
 

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