Superficial Atypical Melanocytic Proliferations...Differential diagnosis could include severe dermal and epidermal melanocytic dysplasia, however, dermal (or even epidermal) mitotic

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Disclosures

Consulting:Myriad Genetics

SciBase

Superficial Atypical Melanocytic Proliferations

SSM, LMM and (some of) their Simulants

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Melanomas and Nevi.

• Nevi are important mainly in relation to melanoma– Precursors – but risk for individual lesions is low

– Risk markers – important mainly in high risk situations

– Simulants – important in everyday clinical decision-making

• Makes sense to consider attributes of melanomas before discussing nevi

Low UV

Pathway I

Low-CSD MelanomaSupertpficial Spreading Melanoma

Banal Acquired Nevus (junctional, compound, dermal)

Low Grade Dysplasia Bap-1

Deficiency Melanocytoma

Deep penetrating

nevus (DPN)/ Melanocytoma

PigmentedEpithelioid

Melanocytoma (PEM)High Grade

Dysplasia

Superficial Spreading Melanoma

Melanoma in BPDM (rare)

Melanoma in DPN (rare)

Melanoma in PEM (rare)

BRAF V600E, NRAS

(BRAF or NRAS)+BAP1

(BRAF, MEK1, or NRAS) +(CBNN1 or APC)

(BRAF+PRKAR1A) or PRKCA

TERT, CDKN2A, TP53, PTEN

Lentiginous junctional nevus

Compound dysplastic nevus

Superficial spreading or “pagetoid” melanoma

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Criteria for Melanoma vs. NeviFeature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed nevoid

Poor circumscription common less common uncommon

Nested variable predominant predominant

Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous discontinuous

Pagetoid high, extensive low, focal, minimal minimal

Nuclear atypia uniform, moderate- random, mild- minimal

severe (size > 1.5x) moderate (1-1.5x) (1x)

Mitoses - junctional about 1/3 of cases almost always absent absent

Pyknosis/necrosis common uncommon uncommon

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike, lichenoid patchy, perivascular minimal

Regression frequent, extensive rare, minimal absent

Dermal Cells uniform atypia random atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Superficial Melanoma and Mimics in Low CSD Skin

• Superficial Spreading (“Pagetoid”) Melanoma

• Junctional and superficial Compound nevi

• Dysplastic Nevi

• Recurrent and Traumatized Nevi

• Pagetoid Spitz and other pagetoid proliferatons

• Superficial Atypical Melanocytic Proliferations (SAMPUS)

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Case 1.

DEE-10253

History: M50, Lesion of BackReason for Consultation: Is this a melanoma or a severely dysplastic nevus?

• Broad, moderately to highly cellular, asymmetric.

• Cells at periphery of lesion- predominantly in nests- predominantly near the DEJ - some nests bridging between adjacent elongated rete ridges

• Pattern of melanocytic dysplasia, with severe cytologic atypia and moderate architectural disorder.

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• Adjacent component more highly cellular.

• More severe uniform atypia

• Pagetoid scatter• Diffuse fibroplasia• Bandlike

lymphocytic infiltrate

• Few clusters of immature cells in dermis

• Adjacent component more highly cellular.

• More severe uniform atypia

• Pagetoid scatter• Diffuse fibroplasia• Bandlike lymphocytic

infiltrate• Few clusters of

immature cells in dermis

• Localized clusters of mature nevoid cells (precursor/associated nevus)

Your Diagnosis?

Melanoma?

Nevus?

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Distribution of Nests variable, irregular predominant predominant, regular

Pattern of Nests coalescent (confluent) bridging discrete


Lentiginous (single cells) continuous discontinuous discontinuous


Nuclear atypia uniform atypia, random atypia, minimal

severe (>1.5x) mild-moderate









Diagnosis, Case 1, M50.

• Malignant melanoma, superficial spreading type, nonulcerated, non-tumorigenic and nonmitogenic invasive radial growth phase only, Clark level II, greatest Breslow thickness 0.28 mm, see comment.

Comment– Dermal mitotic rate is zero, tumor infiltrating lymphocytes are absent (with

moderate noninfiltrating lymphocytes), there is no radial growth phase regression, there is no ulcer, there are no microscopic satellites, and there is no evidence of vascular, lymphatic or neural invasion.

– Age < 56– Associated compound dysplastic nevus. – Appears to be minimally excised. – MPATH-Dx 4. – 100% 5 year survival

Case 2.

Clinical Information.Lesion of left shin with a mottled color in a 26-year-old woman.

Reason for Consultation.I am enclosing for your consultation a melanocytic lesion

present for many years from the right shin of a 27-year-old woman. Though the lesion had not changed (according to the patient), her clinician decided to remove it because he “didn’t

like the mottled color”.

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Description.

A relatively broad moderately cellular plaque-like lesion.

Comprised mainly of nested large epithelioid melanocytes with abundant cytoplasm that contains finely divided “dusty” melanin pigment.

Some bridging nests between adjacent rete - possible junctional melanocytic dysplasia of the epithelioid type.

• Nests somewhat haphazardly distributed along the interface

• Poor circumscription

• Patchy to bandlike lymphocytic infiltrate

• Diffuse fibroplasia


• Poor circumscription



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• Tendency to confluence of nests




• Nests in dermis not larger than largest in epidermis

• Tendency to confluence of nests

• Focal pagetoid scatter

Your Diagnosis?

Melanoma?

Nevus?

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1.1.2.5. Dermal mitotic activity in atypical cells that resemble those in epidermis.

The mitosis on the right could be considered junctional; however there seems to be a wisp of collagen between the nest which is predominantly located in the dermis, and the overlying junctional nest.

Non tumorigenic mitogenic VGP:

Nests in the dermis are smaller than the largest nests in the epidermis.Count dermal mitoses in 1 sq. mm even if not fully occupied by tumor, express rate as a whole number







Distribution of Nests variable, irregular predominant, regular predominant, regular

Distribution of Nests coalescent (confluent) bridging discrete


Lentiginous (single cells) continuous discontinuous minimal



severe (>1.5x) mild-moderate

Mitoses – junctional/dermal about 1/3 of cases almost always absent absent

Pyknosis/necrosis common uncommon none







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Diagnosis, Case 2 F26

• Skin, right shin: Malignant melanoma, superficial spreading type, nonulcerated, with non-tumorigenic but mitogenic early vertical growth phase, Clark’s level II, greatest Breslow thickness 0.51 mm, see description and comment.

• Comment. Differential diagnosis could include severe dermal and epidermal melanocytic dysplasia, however, dermal (or even epidermal) mitotic activity essentially rules out this diagnosis. The lesion is not a Spitz nevus/tumor because it is not comprised of large spindle and/or epithelioid cells.

• Dermal mitotic rate: 2 per square millimeter• Tumor-infiltrating lymphocytes essentially absent in the invasive component, with brisk

noninfiltrating lymphocytes nearby• Focal radial growth phase regression present• No ulcer, no microscopic satellites, and no evidence of vascular, lymphatic, or neural invasion.• Associated junctional dysplastic nevus of the epithelioid subtype• Actinic elastosis in the adjacent dermis is present and mild. • Lesion is completely excised with a closest border of approximately 1 mm.

Superficial Melanoma and Mimics in Low CSD Skin

• Superficial Spreading (“Pagetoid”) Melanoma

• Junctional and superficial Compound nevi

• Dysplastic Nevi

• Recurrent and Traumatized Nevi

• Pagetoid Spitz and other pagetoid proliferations

• Superficial Atypical Melanocytic Proliferations (SAMPUS)

Case 3.

Clinical Information.A macular slightly variegated lesion from the back of a 37-year-old

woman.Reason for Consultation.Is this a dysplastic nevus?

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• 25451• Clinical Information.• A 3 mm macular slightly variegated lesion from the back of a 37-year-old

woman.• Reason for Consultation.• Is this a dysplastic nevus?

• Small• Poorly circumscribed• Nest predominate, discrete• Patchy lymphocytes, scant fibroplasia, numerous melanophages (clinically

atypical)

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• Slight/absent cytologic atypia

• No mitoses

Your Diagnosis?

Melanoma?

Nevus?

Your Diagnosis?

Dysplastic?

Nondysplastic?

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Poor circumscription cannot assess less common uncommon













Dermal Cells uniform atypia random or no atypia no atypia



Diagnosis, Case 2-1, F37.

• Diagnosis.• Skin, abdomen: • Lentiginous junctional nevus, with mild dysplasia, see description and comment.• OR Lentiginous junctional nevus

• Comment. • Mild dysplasia is not an independent risk factor for melanoma however if this patient should

have other clinically atypical nevi and/or a family or personal history of melanoma, or other melanoma risk factors, consideration of periodic surveillance may be appropriate.

• The lesion appears to be excised however even if this were not the case, reexcision might not be necessary if this biopsy was considered representative of the lesion and especially if the patient were to be followed.

• Since mild dysplasia is not an independent risk factor for melanoma, lesions of this type might be better given a descriptive name such as “lentiginous junctional nevus”.

• It is important to distinguish these lesions from nevoid lentigo maligna, which can also be characterized by slight degrees of cytologic atypia.

• This is an MPATH Category 1 lesion (no need for reexcision even if margins are positive).

Superficial Atypical Nevi.

• Nevi are important mainly in relation to melanoma

– Precursors – but risk for individual lesions is low (one in thousands)

– Risk markers – important mainly in high risk situations (patients with multiple atypical nevi, family history, high CSD etc.)

– Simulants – important in everyday clinical decision-making.

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Grading of atypia in nevi: correlation with melanoma risk Arumi-Uria, McNutt, Finnerty, 2003

• Grading of nevi with architectural disorder (dysplastic nevi) involves architectural and cytological features.

• Grades of atypia are related to patient history of melanoma: – personal history of melanoma present in 5.7% of 2,504 patients with mild,

8.1% of 1657 with moderate, and 19.7% of 320 patients with severe atypia.

• Odds ratio as a measure of association between NAD and history of melanoma:– 4.08 for severe versus mild, – 2.81 for severe versus moderate and – 1.45 for moderate versus mild dysplasia.

• “Melanoma risk is greater in persons whose nevi have higher grade histological atypia”

Dysplasia Grading Criteria ……. Arumi-Uria et al, Mod Pathol, 2003

Mild Moderate Severe

• The clinically most atypical macular nevus was biopsied from 80 newly incident cases of melanoma and spouse controls.

• Histological dysplasia was assigned on a subjective 0-4 point scale by a 13-member panel of dermatopathologists (International Melanoma Pathology Group)

• Subjects with panel ratings > 1 had increased relative risk of melanoma:

• Odds ratio after adjustment for confounders = 3.99, 95% CI 1.02-15.71.

• kappa statistic was 0.28 for the panel histological diagnoses, indicating poor interobserver reproducibility.– Repeating study agreed but found size to be a good surrogate/correlate for

atypia– Evidence-based criteria for histologic dysplasia as a risk marker

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Xiong, Rabkin, Piepkorn, Barnhill et al, JAAD, 2014

“Given that measuring diameter tends to be more objective than grading dysplasia, these results could provide increased consistency when assessing risk of melanoma among patients with dysplastic nevi”

Rabkin, Piepkorn, Barnhill et al JAAD

Mild Dysplasia

• Poorly reproducible diagnosis (vs. nevus)• Not associated with melanoma risk• Not a high risk precursor• Not a strong simulant of melanoma• UNCERTAINTY vs. Moderate dysplasia, No dysplasia

• Should be considered in the spectrum of banal nevi (junctional or compound nevus, e.g. lentiginous junctional nevus)

• Complete excision is not necessary even when margins are positive

• TERM “MILD DYSPLASIA” SHOULD NO LONGER BE USED

• (Lentiginous) Junctional Nevus

< 4 mm diameter

minimal cytologic atypia

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Moderate Dysplasia

• Controversial• Poorly reproducible diagnosis (vs mild, severe)• UNCERTAINTY vs. Mild dysplasia, MIS• Associated with melanoma risk• Probably not a high risk precursor• A weak simulant of melanoma (at least

histologically)

• Complete excision is a consideration; observation is an option

Severe Dysplasia

• Reasonably reproducible diagnosis

• UNCERTAINTY vs. MIS

• Associated with melanoma risk

• Probably a high risk precursor

• A strong simulant of melanoma (at least histologically)

• Should be managed by complete excision and consideration of follow-up, similar to MIS

Proposal for Grading Dysplasia

• Junctional/compound nevus

– Includes former mild dysplasia and “Clark’s nevus”

• Low Grade Dysplasia (LGD)

– Former moderate dysplasia

• High Grade Dysplasia (HGD)

– Former severe dysplasia

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Case 4.

Part 2-2. 5475Clinical Information.

Please find enclosed slides on a 36-year-old male with multiple dysplastic nevi removed. Reason for Consultation.

I have also enclosed a prior pathology report of other lesions removed. My diagnosis is compound melanocytic nevus with architectural disorder and moderate cytologic atypia. However,

I am concerned that this lesion may be severely dysplastic. Would you recommend a reexcision procedure?

• Broad• Symmetric• Moderately cellular • Poorly circumscribed

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• Broad• Symmetric• Moderately

cellular • Poorly

circumscribed• Slight low

level pagetoid scatter

• Moderate random atypia

• Nuclear size 1-1.5x

Your Diagnosis?

Melanoma?

Nevus?

Your Diagnosis?

Dysplastic?

Nondysplastic?

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Your Diagnosis?

Low Grade?

High Grade?





Junctional Melanocytes epithelioid mixed (nevoid to epithelioid) nevoid

Poor circumscription cannot assess less common uncommon
















Diagnosis (Part 2, Case 3).

Skin, back (M36): Compound nevus with moderate dysplasia, completely excised, see description and comment.

OR Compound dysplastic nevus, low grade

Comment. • Patient presents with multiple lesions, some of which are

dysplastic nevi with moderate dysplasia. • Benign lesions with little or no potential for recurrence and no

potential for metastasis. • Periodic follow-up may be appropriate for this patient,

especially if there are other clinically atypical nevi and/or a family or personal history of melanoma.

• Although the lesion extends close to the specimen margin, there is no essential indication for reexcision, especially if the patient is to be followed.

This is an MPATH DX Category 1 or perhaps Category 2 lesion, depending on clinical correlation and preference.

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Case 5.

Part 2-3.Clinical Information:

A lesion from the back of a 54 year old manReason for consultation:

The clinician was concerned about a melanoma but I favor a dysplastic nevus.

Description:

Very broad

Moderately cellular

Reasonably symmetrical

Uniformly elongated rete

Patchy infiltrate in dermis

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• Description:• Very broad Moderate pagetoid scatter, low

level• Moderately cellular Mild to moderate cytologic atypia• Reasonably symmetrical Mild to moderate solar elastosis• Uniformly elongated rete• Patchy infiltrate in dermis

Your Diagnosis?

Melanoma?

Nevus?

Your Diagnosis?

Dysplastic?

Nondysplastic?

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Your Diagnosis?

Low Grade?

High Grade?

Compound nevus with severe dysplasia(Severe architectural disorder, moderate cytological atypia)

Feature Melanoma Dysplastic Nevus Nevus


Cellularity high intermediate lower










Nuclear atypia uniform atypia, random atypia, minimal,

moderate-severe mild-moderate (1-1.5X) mild






Dermal Cells Absent uniform atypia random or no atypia no atypia



Diagnosis, Case 5

• Junctional nevus with severe melanocytic dysplasia, completely excised, see note

• vs. Junctional dysplastic nevus, high grade

• vs Intraepidermal atypical melanocytic proliferation (IAMPUS), cannot r/o MIS– Diagnosis is based on “severe” architectural features

(single cell predominance, low level pagetoid scatter), with mild to moderate cytologic atypia.

– MPATH-Dx Category III (consider excision with up to 5 mm margins, if present at the margin)

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Next Case.


An irregular pigmented lesion on the back of a 59 year old manReason for Consultation.

Is this a nevoid melanoma?

Broad, focally highly cellular, asymmetric diffuse fibroplasia and variably sized nests in dermis

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• Only minimal pagetoid scatter

• Moderate cytologic atypia

• No mitoses• Cells in dermal

nests are small, nevoid

• No confluent sheetlike growth

HMB46 staining is “top-heavy”(stratified)

• Ki-67 proliferation is minimal in dermis

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• p16 staining is positive in a checkerboard pattern, with nuclear and cytoplasmic positivity

Helpful Markers in Nevus vs. Melanoma

• HM45 stratification– J Invest Dermatol. 1993 Mar;100(3):313S-317S. Immunophenotyping of compound and spitz nevi and vertical growth-phase

melanomas using a panel of monoclonal antibodies reactive in paraffin sections.Lazzaro B1, Elder DE, Rebers A, Power L, Herlyn M, Menrad A, Johnson B.

• Low Ki-67 proliferation rate– A zonal comparison of MIB1-Ki67 immunoreactivity in benign and malignant melanocytic lesions.

Li LX, Crotty KA, McCarthy SW, Palmer AA, Kril JJ.Am J Dermatopathol. 2000 Dec;22(6):489-95.

• Preservation of p16 protein expression– More problematical; presence in an atypical tumor at

least precludes homozygous loss of 9p21 and is therefore reassuring but does not preclude diagnosis of melanoma

9p21 Locus

• Contains p16, p14 and p15, all suppressor genes

• Presumably all lost together in cases of homozygous 9p21 loss

• Appears to have special significance in Spitzoid lesions

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Your Diagnosis?

Melanoma?

Nevus?

Your Diagnosis?

Dysplastic?

Nondysplastic?

Your Diagnosis?

High Grade?

Low Grade?

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Case 5, M59, backFeature Melanoma Dysplastic Nevus Nevus


Cellularity high intermediate lower





Nested variable predominantpredominant



Lentiginous continuous discontinuousdiscontinuous


Nuclear atypia uniform atypia, random atypia, minimal,

moderate-severe mild-moderate (1-1.5X) mild





Regression frequent, extensive or focal rare, minimal absent

Dermal Cells Absent uniform atypia random atypia no atypia



Diagnosis. Case 6, M59.

• Skin, right, mid back: Compound nevus with severe dermal and epidermal dysplasia and dermal fibrosis (“sclerosing atypical nevus”, “fibrosing dysplastic nevus"), extending close or to specimen base and margins, see description and final comment.

• OR - Dysplastic nevus, high grade, with a sclerosing dermal component

• Overall Comment.

• The presence of p16 staining rules out the possibility of 9P21 loss, which has been associated with aggressive behavior in a recent fluorescence in situ hybridization (FISH) study of atypical lesions, most of which were variants of Spitz tumors.

• Despite reassuring findings from special stains (and lack of mitoses), this is objectively an atypical lesion, and complete excision would be recommended, or perhaps alternatively, careful follow-up of the lesional site (MPATH DX Category 2 or 3).

• Especially if this patient should have other clinically atypical nevi and/or a family or personal history of melanoma, consideration of periodic surveillance of his skin would also be appropriate.

19 Lesions with no recurrence (all completely excised)

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Papillomatous naevoid melanoma• Papillomatous epithelial strands; dense proliferation; lack of

maturation; atypia; mitoses

• In-transit or lymph node metastases occurred in 33% of patients

Maturing naevoid melanoma• “Change from epithelioid, pleomorphic melanocytes in the

junctional component to … smaller but still atypical cells arranged in nests surrounded by dense collagen”

• “…no disease progression was seen in those with maturing naevoid melanomas (including two with measured thicknesses of 3.0 and 3.5 mm, respectively)”

Significance of Nevi.


– Precursors – but risk for individual lesions is low



Case 7.

Clinical Information.Pigmented lesion on the back of a 40 year old

womanReason for Consultation.

Rule out melanoma?

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A Lesion of the Back in a 40 Year Old Woman

• “shave biopsy under the left arm … has caused consternation … two of us believing that we are dealing with a … melanoma… two others believing that although worrisome … not yet melanoma”

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Your Diagnosis?

Melanoma?

Nevus?

Your Diagnosis?

Dysplastic?

Nondysplastic?

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Your Diagnosis?

High Grade?

Low Grade?

Clark’s Dysplastic Nevus vs. Melanoma in Situ vs. Nevus

Feature Melanoma Dysplastic Nevus Nevus

Size tend to be larger intermediate smaller


Keratinocytes irregular uniform elongated rete uniform

Melanocytes epithelioid mixed nevoid


Nests coalescent bridging discrete




severe (> 1.5x) mild-moderate

Mitoses about 1/3 of cases almost always absent absent




Diagnosis Rendered

• “malignant melanoma, probably lentigo maligna type, showing Clark level III invasion with early tumorigenic but nonmitogenic vertical growth phase, at a greatest Breslow thickness of 0.30 mm … associated nevus with congenital pattern features”

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New Information!

“I received a call from the primary care physician of this patient asking me to review a biopsy from June of 2004, which I had signed out as a compound congenital melanocytic nevus. She told me that the lesion had developed re-pigmentation in the previous biopsy site … ”

• “I think it is almost certain that the subsequent biopsy is a pseudomelanoma based on the fact that there was no atypia in the original shave biopsy specimen, the interval between biopsy and re-pigmentation is only three months, and the re-pigmentation is in the previous biopsy site. The lack of this additional information at the time you received the biopsy was a handicap”

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New Report!

“superficial atypical melanocytic proliferation, c/w recurrent nevus phenomenon, extending to specimen margins” … “I would make only one reservation, and that is that this lesion should be re-excised again with a margin of normal skin around the scar and any residual lesion …”

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RECURRENT MELANOCYTIC NEVUS

Pseudomelanoma (Ackerman)

– pigmented patch at site of prior shave biopsy of a benign compound or dermal nevus

– repigmentation occurs quickly (6 weeks)

– pigment does not extend beyond scar's borders

RECURRENT MELANOCYTIC NEVUS

Histology

• variably sized and shaped sometimes confluent nests

• single cells & nests above DEJ usually not beyond mid-spinous layer

• occasional lesional cells or nests in dermis

• slight cytologic atypia (“reactive?”), rare mitoses

• proliferation does not extend beyond scar

• original nevus should be reviewed

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Lessons

• Atypia in recurrent nevi can be severe, yet is “reactive”.

– Mitoses can be present

– Dermal atypia can be present

• A superficial scar can mimic diffuse fibroplasia seen in many melanomas

• Keep a high index of suspicion

– Consider a full differential diagnosis

– Call for history if necessary

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Significance of Nevi.


– Precursors – but risk for individual lesions is low



Conclusions

• Former mild dysplasia is a benign lentiginous nevus (the commonest type of nevus)

• Low grade dysplasia (former moderate dysplasia) can be observed clinically or by patients, looking for evidence of changing lesions

• High grade dysplasia is difficult to distinguish from melanoma in situ (UNCERTAINTY), may have competence for local persistence, recurrence and progression, and should be completely excised

• All of these are “melanocytic neoplasms of low (or no) malignant potential” which have little or no competence for metastasis

Lake Wakatipu and Queenstown, New Zealand, from the Top of “The Remarkables”(Mountains of Mordor in the distance)

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Session II. High CSD Melanomas and Simulants.

Lentigo maligna melanoma

Atypical lentiginous nevi/proliferations

High CSD: Lentiginous Nevi and Lentigo Maligna

Melanoma and Simulant(s)

• Lentiginous Melanoma of Sun-Damaged Skin

– LMM in situ

– LMM invasive

– Distinction from Dysplastic Nevi (Dysplastic Nevus-like Melanoma/Nevoid Lentigo Maligna

• Lentiginous Nevi of the “Elderly” (i.e. CSD Skin)

• Solar (actinic) lentigo, pigmented AK, SK …

High UV

Pathway II Pathway III

High-CSD Melanoma (LMM)

Desmoplastic Melanoma

? IMP ? IMP

? IAMP ? IAMP

Lentigo maligna melanoma in situ

Melanoma in situ

Lentigo Maligna Melanoma

Desmoplastic Melanoma

NRAS, BRAFnon-V600E, KIT, NF1

NF1, ERBB2, MAP2K1, MAP3K1, BRAF, EGFR, MET,

TERT, CDKN2A, TP53, PTEN, RAC1

TERT, NFKBIE, NRAS PIK3CA PTPN11

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Case 1

12438

F64 Lesion of back

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Your Diagnosis?

Dysplastic Nevus - IAMP?

Melanoma?

Criteria for Melanoma vs. NeviFeature Melanoma Dysplastic Nevus Superficial Nevus



Elastosis moderate-severe mild-moderate minimal- mild


Junctional Melanocytes epithelioid mixed (nevoid /epithelioid) nevoid

Poor circumscription often less common uncommon




Lentiginous continuous discontinuous minimal



severe ( > 1.5x) mild-moderate

Mitoses – junctional about 1/3 of cases almost always absent absent








Our Diagnosis

Case 1 12438

Lentigo maligna melanoma in situ

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Case 2.


A large pigmented lesion of the back in a 74-year-old man.Reason for Consultation.

I called this lesion a dysplastic nevus. The clinician then calls back to inform us that this is a 2.2 cm irregular pigmented lesion. Now looking at the deepers we think this

might be a “lentiginous melanoma”.

Description

• Shave biopsy of a broad lesion with a dermal component and a moderately cellular junctional component.

• Lesion is ill-defined (poorly circumscribed) at each periphery, with features overlapping with those of actinic lentigo.

• Subtle increase of melanocytes along the dermal-epidermal junction, with mild to moderate but relatively uniform cytologic atypia.

• Pagetoid scatter is minimal.

• Focally there are elongated rete ridges, overlapping with features of dysplastic nevus, however these changes are focal within the lesion rather than being symmetrically distributed at shoulders adjacent to a dermal component.

Lentiginous nevus versus lentiginous melanoma

• Poorly circumscribed at each periphery

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• JunctionaIIAMP

• Patchy lymphocytic infiltrate

• Solar elastosis

Bridging rete

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Your Diagnosis?

Melanoma?

Nevus?

Criteria for Melanoma vs. NeviFeature Melanoma Dysplastic Nevus Superficial Nevus



Elastosis moderate-severe mild-moderate minimal- mild


Junctional Melanocytes epithelioid mixed (nevoid /epithelioid) nevoid

Poor circumscription often less common uncommon




Lentiginous continuous discontinuous minimal



moderate-severe mild-moderate

Mitoses – junctional about 1/3 of cases almost always absent absent








Lentiginous nevus versus lentiginous melanomaDiagnosis. Case 2, M74

Skin, mid back: Superficial atypical melanocytic proliferation of uncertain significance, most consistent with melanoma in situ, lentiginous type (nevoid lentigo maligna), versus atypical lentiginous nevus of the elderly, see comment.

(i.e. “SAMPUS”)

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Diagnosis. Case 2, M74

• Overall Comment.• There are overlapping features among atypical actinic

lentigines, lentiginous junctional nevi with and without atypia, and lentiginous or “nevoid” lentigo maligna.

• Lesions in a high CSD environment must be interpreted with circumspection.

• Overdiagnosis should be avoided as even atypical lentiginous junctional nevi of the elderly seem to be biologically low grade (non-metastasizing but perhaps locally recurring potential).

• It is judicious to completely excise these lesions in order to be sure that they have been completely examined histologically and also to minimize any possibility of local persistence, recurrence or future progression.

Nevoid Lentigo Maligna/Lentiginous Melanoma(Lentiginous Nevus)

• Kossard 1997. Aust J Dermatol Nevoid lentigo malignaKing, Page, Googe & Mihm. Modern Pathology 2005 Lentiginous melanomaFerrahi, Egbert & Swetter J Cutan Pathol 2005 Dysplastic nevus-like LMM

• Clinical diagnosis may vary– e.g. lentigo maligna, atypical nevus, pigmented basal cell carcinoma, seborrheic keratosis and

lentigo.

• Biopsies may mimic junctional nevus or dysplastic nevus, at least focally– Lentiginous proliferation of melanocytes at the dermo-epidermal junction both as single cells

and as small nests with areas of confluent growth, extending to the edges of the biopsy. – Rete ridges maintained– Pagetoid spread of melanocytes was not prominent in H&E - stained sections.

• Diagnosis of melanoma more easily recognized in the complete excision specimens; similar atypical melanocytic proliferation occurring over a broad area flanking the prior biopsy sites.

• Stains for MITF and Mart-1 highlight continuous basal melanocytic proliferation as well as foci of pagetoid scatter.

Lentiginous MelanomaKing, Page, Googe, Mihm. Mod Pathol 2005

• Initial biopsies mimicked lentiginous nevus or dysplastic nevus

• Lentiginous proliferation of melanocytes at DEJ both as single cells and as small nests with areas of confluent growth, extending to the edges of the biopsy.

• Retiform epidermis was maintained and pagetoid spread of melanocytes was not prominent in H&E sections.

• Immunohistochemical stains for MITF and Mart-1 highlighted the extent of the basalar melanocytic proliferation as well as foci of pagetoid spread by melanocytes.

• UNCERTAINTY IS COMMON!• PROGNOSIS IS GOOD IF LESION IS SUPERFICIAL• IMPORTANT TO COMPLETELY EXCISE

• FOR FULL EXAMINATION AND TO MINIMIZE ANY POTENTIAL FOR LOCAL PERSISTENCE, RECURRENCE AND PROGRESSION

Mart 1

MITF

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Case 3.

Part 2-3. 14474

Clinical Information.Left posterior shoulder, F81.

Reason for Consultation.Favor a junctional Clark’s nevus (see enclosed report).

• Broad lesion, poorly circumscribed, sparse cellularity, single and nested melanocytes.• Mainly near the dermal-epidermal junction, focal pagetoid scatter• Moderate chronic CSD. • Some bridging, few nests that hang down in a droplet-like pattern. • Cytologic atypia mild but relatively uniform.

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Your Diagnosis?

Melanoma?

Nevus?

Diagnosis Case 3, F81

• “Difficult to interpret”. • Cytologic atypia is mild to moderate rather than

severe, with somewhat concerning architectural changes

• “One is somewhat more concerned about a lesion in chronically sun-damaged skin of older subjects”.

• Skin, left posterior shoulder, shave biopsy: Intraepidermal atypical melanocytic proliferation of uncertain significance (IAMPUS), most consistent with atypical lentiginous junctional nevus (of the elderly/CSD skin), cannot r/o evolving or early established melanoma in situ.

• Complete excision recommended (MPATH-Dx 2 or 3)

Case 4.

Part 2-3. 14474

Clinical Information.Left posterior shoulder, F84.

Reason for Consultation.Favor a junctional Clark’s (mildly dysplastic) melanocytic nevus (see

enclosed report). There is mild melanocytic atypia, and that the peripheral and deep margins of the specimen were negative in the

plane of sectioning.

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Your Diagnosis?

Melanoma?

Nevus?

Diagnosis Case 4, F81

• Recurrence of Case 8

• Shave biopsy of similar sun-damaged skin• Somewhat more cellular proliferation of nevoid and

nevoid to epithelioid melanocytes, focally exhibiting severe and uniform cytologic atypia.

• Some of these cells are confined to the epidermis above the scar, while others appear to extend some distance beyond the periphery of the scar.

• This latter feature raises some concern for evolving melanoma in situ extending beyond the scar.

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• Skin, left posterior shoulder, shave biopsy (recurrence): Intraepidermal atypical melanocytic proliferation of uncertain significance, extending to specimen margins, see description and comment.

– Comment: Cannot rule out an evolving more significant lesion, suggest complete excision

Case 5.

Part 2-3. 14474

Clinical Information.Biopsy from posterior shoulder of an 85 year old female.

Reason for Consultation.This specimen, in my opinion, has histologic features concerning for

melanoma because of the architectural symmetry, ill-defined borders, contiguous proliferation of atypical solitary melanocytes, and some pagetoid spread of melanocytes within the epidermis. I do not see

definitive features of a scar consistent with a prior biopsy site.

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• Broad• Moderately

cellular• Moderate to

severe CSD• Poorly

circumscribed• Few bridging

nests• Diffuse

fibroplasia• Cells in dermis

• Moderately cellular

• Moderate to severe CSD

• Nests hanging down

• Diffuse fibroplasia (not a scar)


• Moderate to severe CSD


• Diffuse fibroplasia (not a scar)

• Nests in dermis

• No maturation

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Melan-A Stain


• Continuous basal proliferation


• Low level pagetoid scatter

• Nests in dermis

• No maturation

Your Diagnosis?

Melanoma?

Nevus?

Our Diagnosis

Malignant melanoma, lentigo maligna type (“lentiginous melanoma”, Clark level II, Breslow thickness 0.85 mm

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Updated History Cases 3-5.

• Clinical Information.

• Three separate biopsies from left posterior shoulder of an 85-year-old female over a period of three years. The biopsies were performed 4 years and 1 year ago, and recently.

• The original biopsy was called a junctional Clark’s (mildly dysplastic) melanocytic nevus, might have been better interpreted as a lentiginous nevus of the elderly/sundamaged skin, with mild to moderate atypia. – The peripheral and deep margins of the specimen were said to be negative in the plane

of sectioning.

• The next biopsy at presumably the same anatomic location was signed out as an atypical melanocytic proliferation consistent with a persistent/recurrent Clark’s (dysplastic) nevus, involving the peripheral edge of the biopsy. – It was mentioned that the differential diagnosis included early melanoma in situ

evolving within a pre-existing nevus, and a reexcision was recommended.

• The most recent specimen was concerning for melanoma because of the architectural symmetry, ill-defined borders, contiguous proliferation of atypical solitary melanocytes, and some pagetoid spread of melanocytes within the epidermis.

• Additional procedure warranted to ensure that the lesion has been completely removed.`

• Broad lesion, poorly circumscribed, sparse cellularity, single and nested melanocytes.• Mainly near the dermal-epidermal junction, focal pagetoid scatter• Moderate chronic CSD. • Cytologic atypia mild but relatively uniform. • POTENTIAL PRECURSOR (low risk) VS ACTUAL PRECURSOR (hindsight bias)• Manage by excision or follow-up

• Case 5

• Second recurrence of a lesion that originally had only “mild” atypia (but moderate to severe architectural disorder)

• Diagnosis of dysplastic nevus should be made with caution in elderly/CSD skin

• Complete excision is appropriate for “atypical lentiginous nevus of elderly/sundamaged skin”.

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Last Case.

Part 2-7. 12150

Clinical Information.Lesion of right shoulder, r/o melanoma versus nevus in a 76 y.o. man

Reason for Consultation.Is this anything other than a moderately atypical neurotized compound nevus?

• A relatively broad lesion with irregular thickening and thinning of rete ridges and a sparsely cellular infiltrate in the dermis.

• Generally sparsely cellular• Moderate to severe CSD

Poorly circumscribed

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• Pigmented melanophages in the dermis

• Increased number of melanocytes in the epidermis, many of them suprabasal

• Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

• Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

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S100 stain highlights the increased cellularity in the epidermis and also labels the spindle cells in the papillary dermis

• Melan-A stain highlights the junctional component but the dermal spindle cells are negative.

Case 6

• Skin, right superior shoulder: Malignant melanoma, lentigo maligna type, nonulcerated, with pure desmoplastic vertical growth phase, Clark level IV, Breslow thickness not < 0.64 mm, extending close to the specimen base, see Comment 3.

• Comment• Changes extend close to the base and to a peripheral margin of the

specimen.• It is unusual to see a small desmoplastic melanoma at this early stage of

its evolution. S• Should be excised locally in order to prevent any possibility of persistence,

recurrence, or future progression of it. • Based on its microstaging attributes, the prognosis for this lesion should

be excellent. The prognosis for “pure” desmoplastic melanoma is if anything better than that for melanomas of similar thickness.

• This lesion could be managed with a relatively generous wide local excision – MPATH DX Category 4 (or 5).

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Take Home Messages

• Early/evolving LMM IS can be subtle

• Changes at periphery and at margins can be subtle– Confluence or continuous proliferation of uniformly

atypical cells

– Nests in epidermis overlying elastotic dermis (LeBoit)

• Focal areas in LMM IS can mimic dysplastic nevus– Diagnosis of dysplastic nevus in sun-damaged skin of

elderly is fraught with hazard

• Diagnosis is often based more on architectural disorder(including size) than on severe cytologic atypia.

High CSD Lesions

• Cautious approach – beware of nests of melanocytes in epidermis above solar elastosis

• Caution in diagnosis of dysplastic nevus in CSD skin

• Do not overcall actinic atypia in re-excision specimens (more of a risk marker than a precursor)

• Beware of subtle spindle cells in dermal component of CSD melanomas

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2 Melanocytic Tumours2-0 Introduction to melanocytic tumours

2-1A Pathway concept

2-1B Genomic landscape of melanoma

2-1 Nodular, nevoid, and metastatic melanomas

2-2A Nodular melanoma

2-2B Nevoid melanoma

2-2C Metastatic melanoma

2-2 Melanoma in Intermittently sun-exposed skin, and simulants/precursors

2-3A Superficial spreading melanoma

2-3B Simple lentigo, junctional naevus, compound naevus, dermal naevus

2-3C Speckled lentiginous naevus and naevus spilus

2-3D Dysplastic nevi

2-3E Special site nevi – breast, axilla, scalp, ear

2-3F Halo naevus

2-3G Meyerson nevus

2-3H Deep penetrating naevus

2-3I Recurrent naevus

2-3 Melanoma in chronically sun-exposed skin, and simulants/precursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2-4 Melanoma in acral skin and simulants/precursors

2-5A Acral melanoma

2-5B Acral naevus

2-5 Melanoma arising from blue naevus, and simulants/precursors

2-6A Melanoma arising from blue naevus

2-6B Blue naevus, cellular blue naevus

2-6C Pigmented epithelioid melanocytoma

2-6D Mongolian spot

2-6E Naevus of Ito and Ota

2-6F Combined naevus

2-6 Melanoma arising in congenital naevi and simulants/precursors

2-7A Melanoma arising in a giant congenital naevus

2-7B Congenital melanocytic naevus, junctional naevus, compound naevus

2-7C Proliferative nodules in congenital naevi

2-7 Spitz Tumours

2-8A Malignant Spitz tumour

2-8B Spitz naevus / tumour

2-8C Pigmented spindle cell naevus/tumour (Reed)

2-8 Genital and mucosal melanomas, and precursors/simulants

2-9A Mucosal melanoma (genital, oral, sinonasal)

2-9B Genital naevi

2-9 Ocular melanoma

2-10A Uveal melanoma

2-10B Conjunctival melanoma

2018 Proposed Classification of Melanoma, Precursors and Simulants

2 Melanocytic Tumours

2-3 Melanoma in chronically sun-exposed skin, and simulants/precursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2018 Proposed Classification of Melanoma, Precursors and Simulants

Benign

Borderline

Malignant

Site

Epithelium associated

High UV

CSDDesmopl.

melanoma

Glabrous Mucosa

Acralmelanoma

Mucosal melanoma

Low UV

Acquired nevus

Dysplastic nevus

Non-CSDmelanoma

Spitz nevus

Atypical Spitz tumor

Spitzoid melanoma

NRAS

HRAS

BRAF

KIT

Fusions

Bastian 2014

Documents

Superficial Atypical Melanocytic Proliferations...Differential diagnosis could include severe dermal and epidermal melanocytic dysplasia, however, dermal (or even epidermal) mitotic