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

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

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8 Pie Chart Participants N=74

9 Benign: 48 N=74 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

10 Table for Malignant Responses

11 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

12 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

13 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.

14 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.

15 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

16 Pie Chart Slide Club N=23

17 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 reexcision 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.

18 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.

19 SLIDE CLUB RESPONSES 1 st : [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 2 nd : 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

20 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.

21 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?

22 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.

23 Repeat Array CGH: Flat profile Lame _3 DLRS = 0,18 BM (ABRA) 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.

24 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 reexcision & consideration of SLN regardless of cytogenetic data

25 M21. History not available RAC3172

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28 Diagnosis? DEEP PENETRATING NAEVUS

29 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

30 M18. Congenital naevus with darker area RAC3163

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32 Diagnosis? CONGENTIAL NAEVUS, PIGMENTED EPITHELIOID CLONE (possibly DPN-type)

33 Combined activation of -catenin signaling and MAP kinase pathway define DPN Courtesy of Dr. Pauline Guyot 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 Dr Arnaud de la Fouchardiere

34 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

35 Beta-catenin IHC 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 c/o Dr Arnaud de la Fouchardiere 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

36 Combined DPN: Less Pigment, High Cellularity Combined PEM: More Pigment, Low cellularity, Numerous melanophages CTNNB1 PRKAR1A c/o Arnaud de la Fouchardiere

37 Discussion 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

38 Dutch Master? Without Title, 1986 Prof Wolter Mooi Amsterdam, NL Thank You Arnaud de la Fouchardiere All responding EQA members and panel members Cases 231 & 232 are dedicated to Professor Wolter Mooi 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!

39 REFERENCE Eur J Dermatol Sep-Oct;24(5): doi: /ejd Deep penetrating nevus-like borderline tumors: A unique subset of ambiguous melanocytic tumors with malignant potential and normal cytogenetics. Magro CM 1, Abraham RM 2, Guo R 3, Li S 4, Wang X 1, Proper S 5, Crowson AN 6, Mihm M 7. 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 nevuslike 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 DPNlike 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.