Case RAC7783. M46. Ear. Mole. r/o MM. ?Blue naevus

RAC7783

Pie Chart Participants

N=74

Benign: 48

Blue naevus: 38

Intradermal: 12

DPN: 10

Compound 3

Clonal: 3;

Spitz 2; Special Site: 1; Congenital: 1

Benign unclassifiable: 1

Uncertain favour benign 10

Uncertain favour malignant 4

Malignant 11 Nodular: 5

Malignant blue: 3

SSMM: 1, Naevoid: 1

N=74

Table for Malignant Responses

MPathDx*

*I: Leave as is even if incompletely excised; II: Complete excision <5mm; III: 5mm; IV:

as pT1a, pT1b; 1cm +/-; V: as pT2 or greater e.g. >1cm

EQA Participants: Benign N=49

Combined naevus - intradermal naevus and cellular blue naevus

– several

Combined naevus with naevocellular and DPN like elements

Differential diagnosis is deep penetrating naevus or blue naevus

Sub 5mm reasonably symmetrical combined lesion with

conventional nevus and deep penetrating nevus like

components. Mitotically active, but DPN component cells

uniform and I see no atypical mitoses. Patient on edge of age

range for new presentations of this lesion, so worth getting

history of lesional behaviour at MDT prior to sign out.

Epithelioid cellular blue naevus – x4

Depending on Beta-Catenin and Cyclin D1; DPN or Cellular blue

naevus

EQA Participants: Uncertain favour benign N=10

A pigmented melanocytic lesion which is very cellulra and dual

cell population in keeping with cellular blue naevus. However

there are clearly some cells that show atypia and some mitoses

are located in the deep part of the lesion.I do not think the

features are of melanoma arising in blue naevus or a blue

naevus -like melanoma. On balance I favour cellular bleu

naevus with atypia

Need BAP1 staining

DPN-like but with reverse wedge shape and slightly older age

than usual.

A combined naevus with superficial ordinary intradermal naevus

and deeper DPN component. Could do Beta-catenin to help

confirm this. One mitosis identified in DPN component but no

atypical forms seen.

EQA Participants: Uncertain favour malignant N=4

Combined naevus - compound melanocytic and epithelioid blue.

The blue component is atypical with deep mitoses and extends

into subcutis. Unceratin malignant potential, but would treat as

malignant.

EQA Participants: Malignant N=11

Superficial spreading melanoma arising on intradermal naevus

spitzoid, but several mid/deep mitoses, 2 very close together ( 3

in 1mm2.some atypical junctional nests

Deep mitotic figures (up to 2/mm2 ), infiltrating edge. No

necrosis. ?nevoid melanoma ?atypical CBN

Mitoses: “Can’t see on digital slide”

Pie Chart Slide Club

N=23

SLIDE CLUB RESPONSES

combined banal and epithelioid blue

Combined naevus with a cellular blue naevus component.

Heavily pigmented compound melanocytic proliferation which I think is benign and belongs to the

deep penetrating naevus / combined naevus spectrum. I would recommend conservative re-

excision given the very close deep margin.

Combined melanocytic dermal tumor with a common nevus component at the sides and

superficially. Centrally a DPN-like component but growing less nested than usual and with a

more compact/expansile base. I do not see mitoses or necrosis. Fat cells in the deeper part. I

would prefer a benign lesion, in the spectrum of combined nevus, common & DPN. I would

perform additional MIB, HMB,beta-catenin and BAP1 stain. I would comment on the unusual

growth and I would like clear margins (seems very close to the margin), otherwise advise a (small)

re-excision.

Combined congenital-like cellular naevus with deep penetrating-like pigmented clone. The

latter shows mild cellular pleomorphic and scanty mitotic activity.Given the diagnosis challenges in

these cases, excision with clear margins may be advisable.

Favor benign based on silhouette, absence of junctional component, and relatively regular

distribution of melanin pigment / melanophages. Biphenotypic pattern with smaller nevus cell

aggregates at periphery of larger DPN-like lesion is common presentation of a combined nevus,

however, given patient age, ctyologic atypia, and a possible (deep) mitotic figure, re-excision

seems warranted.

Cellular blue naevus, benign.

SLIDE CLUB RESPONSES

Uncertain favour benign. Combined naevus with intradermal naevus and component with some

features of deep penetrating naevus

Combined common acquired naevus which merges with a more cellular, pigmented clone of larger

melanoytes.Differential diangosis deep penetrating naevus (so do beta catenin), and an atypical

cellular blue naevus - would do FISH..

Combined nevus with components of congenital pattern nevus and melanocytoma c/w deep

penetrating nevus with atypical features (confluence of nests and fascicles but without severe

atypia or mitoses)

compound melanocytic lesion with modest component of usual type naevus. Admixed and

dominating the coventional naevus is a heavily pigmented and cellular component of short spindle

cells. It is difficult to define mitotic activity (I have found just one in the lower third). There is no

thinning of the epidermis and although the lesion pushes out into subcutis it stops rather abruptly.

On balance I favour a combined naevus with usual and cellular blue types although a combined

lesion with DPN component is a further consideration but one I think less likely.

Atypical DPN ( with some worrying features such as the patients age, few mitotic figures,

asymmetry, increased cellularity and somewhat unusual location on the ear which is a special and

UV exposed site). There are remnants of the conventional dermal naevus in papillary dermis.

Complete excision with 5 mm margin and surveillance should be a sufficient treatment. BRAF and

Beta catenin immunostains could confirm the diagnosis.

SLIDE CLUB RESPONSES

1st: [Uncertain favour benign] This is a very difficult-to-diagnose case. There is a fascicular and

sheet-like growth of pigmented spindle melanocytes which merge with a banal-appearing

naevocytic component close to the surface. The tumor bulges into the subcutis more or less like a

cellular blue naevus; I see no relevant mitotic activity and no foci of necrosis (on the digital slide). I

would sign out a provisional diagnosis of atypical (cellular blue naevus-like) dendritic cell

melanocytic tumor. My gut feeling is that this lesion will behave in a benign fashion. PS - Funny

that the ear is considered as a special site for naevi, because melanomas are even commoner

than naevi in such a location

2nd: This is a combined tumor with a good merging between a banal nevus and a cellular blue

nevus-like melanocytic tumor. I don't know how to correctly call the latter if not 'atypical cellular

blue [nevus-like] tumour' (a kind of dendritic cell counterpart of atypical Spitz tumour). In my

experience, the rule of 'merging' as a criterion for benignity has some exceptions. And this case

may be an exception. I think that this tumour is a low-grade melanocytic malignancy.

a peculiar form of blue nevus of the face. I suggest serial sections to rule out intralesional

malignant evolution. I saw 3 similar lesions with limited follow up of the patients (all consultation

cases). All lesions were on the face of adults or elderly. Two had negative 4-6 years long follow-up.

The third lesion had an obvious melanoma nodule in the middle (but without metastasis, at least

until I could follow up the case).

Two types of cell in the dermis. One ordinary type naevus, the other lager pigmented plump

spindle cell. Mininal junctional component. Minimal variation in cell size/ shape. No mitoses.

Favour Deep penetrating naevus. Would be interesting to see Beta-catenin

benign compound with deep penetrating component

SLIDE CLUB RESPONSES

favour the idea of a combined naevus, with a small superficial / peripheral common acquired

naevus component, and a rather massively cellular but monomorphic plump-spindle cell

component that does not ‘mature’ and is and apparently devoid of mitotic figures. I wonder

whether that component could be related to DPN, even though it looks rather different; I would

ask for a beta-catenin stain all the same. Of course, if I could lay may hands on the materials, I

would study it more extensively for absence of mitotic figures &c.

Combined nevus: Conventional intradermal melanocytic nevus + cellular blue nevus (digital).

Combined melanocytic nevus (glass)

[Uncertain favour malignant] A blue/cellular blue lesion, albeit with an admixed common

acquired component, arising on sun-damaged skin, with readily identifiable mitoses. No necrosis,

but there is some cytological atypia. Recommend NGS.

[Uncertain favour benign] Common naevus and spindle and epithelioid cells but low mitotic rate

and little pleomorphism, some form of combined phenotype. Worrying size and close margin, so

would like wider excision because of uncertainty

favour a combined melanocytic naevus with dysplastic compound naevus and (atypical) deep

penetrating naevus components (glass).

Combined naevus: classic acquired and cellular blue

Deep penetrating naevus; to confirm with Beta-Catenin stain. Advise complete excision

There are nests of small round melanocytes in the superficial dermis. The cytologic features of the

melanocytes are reminiscent of those in deep penetrating nevus, or tumors with PRKCA fusion.

Original Report [Y]:

Combined naevocellular and deep penetrating naevus.

Mitotic rate = low (<1/50hpf).

Depth 4mm

Close to deep (0.5 mm) and focally abutting deep radial margin.

Comment: In view of known challenge for diagnosis in such

cases complete excision with a clear margin may be advisable.

Dear X,

1. ?worth using for slide club

2. Would you recommend a re-excision for a DPN abutting the

margin on someone’s ear?

MICRO REPORT: [X]

That lesion is combined with a superficial common component especially visible in

the junction that it is associated with a deep penetrating component underneath

but that latter presents atypia with hyperdensity and confluent nests into large

sheets. The melanocytes are of large size with enucleated ovular nuclei.

Mitotic activity reaches 2/mm2. There is no inflammatory phenomenon

associated.

The IHC study found a strong nuclear staining with Beta-Catenin and negativity

of antibodies against BRAF V600E. In the deep part, proliferation rate

reaches 20% of stained nuclei.

Mutation by NGS shows the presence of a canonical HRAS mutation and an exon

Beta-Catenine mutation.

The array-CGH could not be performed because of the depletion of

material.

Excision of the ear: Combined melanocytic tumour associating a common nevus

and deep penetrating nevus in the latter atypia with high density and a high

proliferation rate. A complementary resection is advised for this lesion which

reaches 4 mm in depth. These aspects suggest a transformed malignant DPN

component. The resection should be decided in a multidisciplinary meeting

(personal suggestions: complementary resection of at least 1 cm).

The French version of this text prevails.

Lame 10082

1_3

BM18002822 (ABRA)

DLRS = 0,18

Repeat Array CGH: Flat profile

Comment from [X]:

Paper from C Magro described DPN with flat CGH that went malignant if I recall

[Y] Given overwhelming weight of opinion for benign/favour benign would you alter you

opinion of “atypical” and “suggests transformed malignant DPN component”?

Obviously the CGH was a different block but I think it had the DPN component.

I appreciate the lesion could have in the future taken another step.

RAC

[X] I agree this would tend to have me downstage from favor malignant to atypical with

unknown prognosis.

ATYPICAL/”BORDERLINE” DPN

• A small subset of DPN

• Cytologic atypia

• Architectural atypia

• Mitotic activity

SUMMARY: BORDERLINE DPN

• SLN+ve in 1/3

• Cases treated aggressively were free

of dis.

• All 6 examined by CGH showed no

abnormalities

• 7/9 normal by FISH

• 3 cases of progression from

borderline DPN to overt melanoma

SUMMARY: PLEXIFORM MELANOMA

• 4/6 died of disease

CONCLUSION: BORDERLINE

DPN

• Incidence of regional LN

involvement

• Potential progression to over

melanoma

• Management: at least local re-

excision & consideration of SLN

regardless of cytogenetic data

RAC3172

M21. History not available

Diagnosis?

DEEP PENETRATING NAEVUS

DEEP PENETRATING NAEVUS

• Fairly symmetrical wedge-shaped

• Extension in to deep dermis or

subcutis

• Adnexal and neurovascular tropism

• Variable focal junctional component

• Finely pigmented epithelioid cells

• Clear cells, multinucleate cells,

• Spindle cells in deeper areas

• Conspicuous macrophages

• Elongated pigmented dendritic cells

• Mild cytological atypia

• Occassional normal mitotic figures

• Lymphocytic infiltrate

• Often component of combined naevus

RAC3163

M18. Congenital naevus with darker area

Diagnosis?

CONGENTIAL NAEVUS, PIGMENTED

EPITHELIOID CLONE

(possibly DPN-type)

Courtesy of Dr. Pauline Guyot

c/o Dr Arnaud de la Fouchardiere

Combined activation of -catenin signaling and MAP

kinase pathway define DPN

Yeh, Iwei et al. “Combined

Activation of MAP Kinase

Pathway and β-Catenin

Signaling Cause Deep

Penetrating Nevi.” Nature

Communications 8, no. 1

(September 21, 2017): 644.

c/o Arnaud de la Fouchardiere. Recent tumour referred as ?Pigmented

epithelioid melanocytoma ?atypical cellular BN

• Atypical Deep

penetrating nevus

• Cellularity (density)

• Inflammatory features

• Mitotic activity: 3/mm²

• Breslow: 5mm

• Diffuse HMB45 positivity

• P16 slightly heterogeneous

• Ki67: 10-20% nuclear

positivity in some areas

• BRAF V600E: negative

• Beta-catenin staining: strong

nuclear staining

• Array CGH

• Exon 3 CTNNB1 G34E

mutation

• No hotspot mutations in

BRAF, NRAS, KIT

Beta-catenin IHC

DEEP PENETRATING NAEVUS MESSAGES

• Recent clarification of genetics: 2 alternations

• 1: MAPK pathway – BRAF, MAPK2, HRAS

• 2: βCatenin pathway – CTNNB1, APC

• «Intermediate tumor» that can progress

towards malignancy

• Beta-catenin IHC is useful in recognizing DPN

c/o Dr Arnaud de la Fouchardiere

Combined PEM: More

Pigment, Low cellularity,

Numerous melanophages

Combined DPN: Less

Pigment, High Cellularity

CTNNB1

PRKAR1A

c/o Arnaud de la Fouchardiere

Many EQA participants and a few panel members (8) did not appreciate

unlikely to be “naevocellular” combined with “blue” as they are mutually

exclusive

Greater proportion of panel favoured DPN (13)

Interesting the MAPK abnormality is in HRAS (present in a proportion of

Spitz, particularly desmoplastic type) but the naevus is naevocellular in

Case 232

However N. spilus is characterised by HRAS mutation (and these lesions

are usually naevocellular)

Of concern 8/17 EQA MPathDx responses were happy to leave a

challening case such as this without re-excision

Even typical DPN should probably be regarded as a “difficult” case for

diagnosis and given possibility for malignant transformation complete

excision with clear margins recommended as for a “melanocytoma”

Discussion

Dutch Master? Without Title, 1986

Prof Wolter Mooi Amsterdam, NL

www.melanocytepathology.com

PS: this might be my last contribution to your excellent

slide club... I plan to quit pathology by the end of this

year, in order to devote my time entirely to some of ‘the

humanities’ (at a modest level of achievement, no

doubt).

THANK YOU WOLTER!

Thank You

Arnaud de la Fouchardiere

All responding EQA members and

panel members

Cases 231 & 232 are dedicated to

Professor Wolter Mooi

REFERENCE

Eur J Dermatol. 2014 Sep-Oct;24(5):594-602. doi: 10.1684/ejd.2014.2393.

Deep penetrating nevus-like borderline tumors: A unique subset of ambiguous melanocytic

tumors with malignant potential and normal cytogenetics.

Magro CM1, Abraham RM2, Guo R3, Li S4, Wang X1, Proper S5, Crowson AN6, Mihm M7.

Author information BACKGROUND:

Deep penetrating nevi (DPN) are a relatively uncommon subtype of melanocytic nevi. A small subset of these lesions exhibit atypical

features (cytologic and architectural atypia, mitotic activity) seen in melanoma. These lesions we term the deep penetrating nevus-

like borderline tumor. Unequivocal melanomas can show overlapping morphologic features of DPN, which have been termed

plexiform melanomas.

PATIENTS AND METHODS:

40 cases of DPN-like borderline tumor were identified along with 6 cases of plexiform melanoma. Clinical follow up was obtained,

along with cytogenetic analysis in the form of fluorescent in situ hybridization (FISH) and/or comparative genomic hybridization

(CGH).

RESULTS:

The DPN-like borderline tumor cases included 24 females and 16 males. Of sentinel lymph node biopsies performed, 1/3 of cases

showed lymph node involvement. All patients where an aggressive clinical approach was adopted remain free of disease. All 6 DPN-

like borderline tumor cases tested by CGH showed normal cytogenetics, as did 7 of 9 cases tested by FISH. Of the plexiform

melanomas, 4/6 patients died of disease. In 3 cases there was morphologic progression from a DPN-like borderline tumor to overt

melanoma. In one case of progression, cytogenetics was normal in the DPN-like borderline tumor and then abnormal in the

progressed melanoma.

CONCLUSION:

DPN-like borderline tumors are melanocytic tumors associated with a high incidence of regional lymph node disease and exhibiting

the potential for melanoma progression despite a normal cytogenetic profile. Patients with these lesions should be aggressively

managed, with at least complete re-excision and consideration of sentinel node biopsy, regardless of cytogenetic data.