Case 231: F7. Exophytic naevus over left trapezious. Grown over a few weeks. Iniitally flat.?spitz naevus,?malignant
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1 Case 231: F7. Exophytic naevus over left trapezious. Grown over a few weeks. Iniitally flat.?spitz naevus,?malignant Dermoscopy: coarse vascular structures. c/o A, B, C RAC7750
2 Case 231: F7. Exophytic naevus over left trapezious. Grown over a few weeks. Iniitally flat.?spitz naevus,?malignant c/o D RAC7750
3 Base
4
5 Necrotic foci
6
7 Atypical mitotic figure
8 Deep mitosis
9 Pie Chart Participants N=74
10 Benign: 9 Spitz 30 Uncertain favour benign 16 Uncertain favour malignant 20 Malignant 27 Spitzoid 30 Nodular 8 SSMM 1
11 Table for Malignant Responses
12 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
13 EQA Participants: Benign N=9 Symmetrical with collarette and maturation with depth. No destructive growth. I'd at least be asking a local colleague for a second opinion, though. Almost symmetrical compound lesion with epithelioid cells having promiennt eosinophilic nucleoli and mitotic activity (9mf/10HPF); focal indvidual cells wrapping around dermal collagen; no definite pagetoid spread. Overall spitzoid lesion, favour spitz naevus with atypia (focal ulceration and high mitoses).
14 EQA Participants: Uncertain favour benign N=16 Atypical Spitz tumour - low score (according to Barnhill), uncertain malignant potential. Needs molecular analysis (HRAS mutation or kinase fusion, PTEN, 9p21 deletion, etc); also BRAF, BAP1. I would treat as malignant, but without SLNB. Bapoma? Several. DD with Epithelioid spitz polypoid tumour of large pleomorphic epitheliod naevus cells with big pink nucleoli, some multinucleated. Some mitoses incl deep ones. Vascular network and lymphocytes present? BAPoma Sheets of mitotically active spitzoid cells forming a wedge shaped but expansile dermal nodule. Given age group of patient, I would categorise as atypical Spitz tumour. Need to ensure complete excision (with more sections) and keep under clinical follow up for 5 years. Difficult case. On balance I favour atypical spitz, considering the age of the patient, otherwise could easily be diagnosed as melanoma
15 EQA Participants: Uncertain favour malignant N=20 I am wary of an outright diagnosis of melanoma in this age group, and would prefer to call STUMP (but clearly very worrying), and advise FISH, etc. Atypical Spitz tumour. STUMP. Favour melanoma, but this is a young patient Spitzoid lesion. Young child. Atypia with pleomorphism and deep mitoses. Do not wish to call MM but worrying features therefore classify atypical spitz tumour and manage as MM. SNB questionable. Looks like a Spitzoid melanoma. STUMP at least. Very mitotic, but well circumscribed and age 7. Would request FISH before calling it melanoma BAPOMA?
16 EQA Participants: Malignant N=27 Spitzoid lesion but without maturation and several deep mitoses seen such that despite the patients young age should be regarded as malignant Difficult case but I think on balance this is a Spitzoid malignant melanoma. Pushing deep border and occasional deep mitotic figures. Symetrical but consumption of epidermis, variable pleomorphism, loss of maturation, increased mitotic activity with deep mitoses.
17 N=24 Pie Chart Slide Club *1 STUMP, NOS assigned to Favour Malignant
18 SLIDE CLUB RESPONSES Uncertain favour malignant, Spitzoid Uncertain favour malignant Spitzoid MM.Highly cellular predominantly dermal tumour with barely any intervening stroma, a complete lack of architectural and cytological maturation and several deep mitoses. Nodular severely atypical epithelioid/spitzoid melanocytic tumor; lots of mitoses superficial and deep, no maturation, no definite ulceration, deep dermal bulky growth. I would prefer a classification as high risk Spitzoid tumor/stump, but melanoma not excluded, based on histological findings alone. I would definitely do additional immunostainings and molecular analysis before signing out such a case. It is a young girl. I have seen such cases in young children with favourable outcome, more than 20 years follow-up without recurrences. AST, high risk (Spatz et al) Age is the obvious confounder here, but despite the patient's age, I suspect this is malignant melanoma, nodular type. While the age definitely prompts consideration of a Spitzoid melanoma, I see few genuinely 'Spitzoid' histopathologic features here. Ancillary testing might help with classification. Spitzoid melanoma of childhood with a comment that these tumours may have a favorable outcome and that LNSB is unnecessary. Epithelioid spitz naevus
19 SLIDE CLUB RESPONSES Uncertain favour benign. Requires molecular correlation with FISH. Atypical Spitzoid tumour, deep and atypical mitotic figures but no necrosis. Malignant rare at this age so more likely benign although uncertain malignant potential Spitzoid tumor of uncertain malignant potential. Cannot rule out Spitz melanoma. Would do HMB45, MelanA/Mart, Ki-67 and p16 stains, also BRAF V600E and available usion genes if BRAF negative. CGH could be a useful next step. Will be interested in results of these studies. clearly spitzoid in type. At low power the lesion has a rather dumbell configuration with focal extension into superficial subcutis. The lesion comprises epithelioid and spindle shaped cells in compact aggregates with little intervening stroma. There is uniform and severe nuclear atypia, mitoses at varying levels and also attenuatuion of the epidermis. This lesion is a spitzoid nodular melanoma. 1 st : High-risk atypical Spitz tumor (inflamed, with necrosis) 2 nd : This is an atypical Spitz tumour with high-risk features. Pleomorphic epithelioid cells with inflammation; cells are larger in the depth than close to the surface; there is a group of apoptotic cells (this is a bad sign). Atypical Spitz tumor with extension into the deep dermis. Would order immunostains (Ki67/MelanA, p16, HMB45). The mitotic activity is worrying but could be related to the initial fast growth phase of the tumor. I would recommend to manage this lesion by complete excision with 5-10 mm margin and clinical surveillance.
20 SLIDE CLUB RESPONSES the combination of deep expansive nodules, pleomorphism and mitoses makes the diagnosis of benignity impossible. This even though the evolution will probably be favourable. In my own limited experience only a small fraction of these lesions kills the patient Very spitzoid in nature, but with severe nuclear atypia with irregular large nucleoli deep, plus mitoses and pushing margin all point to uncertain malignant potential [favour malignant] spitzoid nodular melanoma of childhood In view of the large atypical cell type; massiveness of the dermal architecture associated with epidermal consumption ; mitotic activity at all levels), and add a note that, although regional lymph node involvement may well occur (be detected at SN), distant metastasis is relatively unlikely to occur (though can by no means be ruled out). spitzoid MM with atypical mitoses Spitzoid melanoma. I thought also in polypoid Spitz nevus, but neoplastic melanocytes are confluent, there is no maturation and I think that I have seen some mitotic figures in deeper areas (digital); Polypoid melanoma (glass) [Spitzoid, Uncertain favour malignant] No obvious pagetoid spread but the epidermis is considerably thinned and there are intraepidermal melanocytes. The atypia and mitotic activity are too much to simply ascribe to the young age. However, I would recommend genetic analysis and make a final report in the light of the findings.
21 SLIDE CLUB RESPONSES Melanoma, Spitzoid. Young age gives me a low baseline level of suspicion but histology is very worrying high risk atypical Spitzoid tumour and favour a malignant Spitz tumour (normally for a case like this we would do BRAF & NRAS IHC as well as immunochemistry for assessment of proteins associated with various chromosomal fusions including ALK, ROS1, NTRK1&3, MET & RET, p16 and FISH) (glass) Spitz Tumour of uncertain malignant potential (STUMP) High risk Spitz tumour with numerous mitoses and extends focally into subcutis. Could consider ABBOTT probe set and p16/c-myc or acgh but advise wide local excision. [Spitzoid, Uncertain favour malignant] Exophytic, symmetric prolieration of spitzoid melanocytes extending into the reticular dermis. Lesional melanocytes show prominent nucleoli and pleomorphism. There is associated inflammation. Worrisome features include signficnt mitotic rate of dermal melanocytes and melanocytes with pyknotic nuclei. Little maturation. However, given the patient's young age and history of recent growth, this could be a Spitz nevus in its growth phase.
22 Additional Studies: IHC HMB45 & S100 strong, diffuse p16 widespread loss Ki67: lack of maturation, high superficial & deeper areas ALK1 negative
23 HMB45
24 p16
25 Ki67 Ki67: lack of maturation, high in superficial & deeper areas
26 MICRO REPORT: Case 231 Nov17 AST, high risk features Absent Kamino bodies Pleomorphic, large epithelioid melanocytes Expansile growth, little intervening stroma Extending deep, into the subcutaneous fat with a focal pushing deep margin. Foci of tumour cell necrosis Mitotic activity was moderately high at 8/mm 2 Atypical mitotic figures
27 Dec 17: At post-operative review, a palpable ipsilateral supraclavicular lymph node was noted. A CT PET confirmed an enlarged 10mm markedly FDG avid lymph node that was highly metabolically active and suspicious for metastasis
28 c/o A: Lymph node 1.6cm diameter, grossly involved Dear Y, This girl has now come up with a gross (palpated) lymph node deposit 1.6cm in the neck. Question is whether at this age she should undergo a full neck dissection. I d be tempted to say not if it was my daughter but obviously you might have a view with the results of CGH still pending. She s actually provisionally booked for a neck dissection next Monday. Kind regards, X
29 Initial cytogenetic tests, namely comparative genomic hybridisation showed multiple segmental gains and losses on chromosomes 1, 6, 9, 10, 11 and 17. DLRS = 0,20
30 [Y]: Preliminary RNA sequencing data revealed mutations in PIK3CA p.5733f (c.2318c>t), MTOR p.a2416v (c.7247 C>T) and 3 different mutations on the BRCA 1 gene. A new analysis we have identified an exon 2 G12S mutation in KRAS in this child. There are very few data on KRAS mutated melanocytic tumors to my knowledge. (But I am working on this topic ) It is not very good news on the therapeutic options if they were needed in the future.
31 Discussion with the adult specialist skin cancer MDT (SSMDT) highlighted the difficulty in predicting malignant potential from the clinical, biological and molecular features. Detailed further discussion with the general paediatricians, paediatric head and neck and plastic surgeons resulted in the difficult decision to recommend a therapeutic level 1-3 partial neck dissection in view of the number of severely atypical histopathological and molecular features with lymph node involvement, which suggested a less indolent course despite the age of the patient. Following the radical neck dissection, 56/56 lymph nodes were subsequently negative. The patient made an excellent postoperative recovery, with minor wound infection and mild lymphoedema of the ipsilateral jaw post-operatively only.
32 Discussion: Slide Club Responses Clearly age led a significant proportion of EQA responders to favour benign diagnosis despite worriesome histology Bapoma mentioned by some participants Slide Club Panel: More decisively away from benign/favour benign (<20%) Spitzoid : How can we define today? Spatz et al: Unfortunately grading AST is based on a now quite old paper with relatively few cases and little molecular work-up
33 GENERAL DISCUSSION POINTS This rare case of a paediatric spitzoid melanoma with lymph node involvement highlights the challenges in the clinical, histopathological and molecular diagnosis of atypical spitzoid lesions. Molecular studies can play a key role in the diagnosis of spitzoid melanomas in paediatric patients. KRAS exon 2 mutations, as found in our patient have been rarely described in melanomas to date. In the Cancer Genome Atlas database only 0.9% (6/666) of melanomas displayed a KRAS mutation. G12D mutation was the most frequently found (3/6). Management of atypical spitzoid tumours is variable, with a lack of evidence of prognostic benefit for sentinel lymph node biopsy over wide local excision and regular clinical follow-up (ref). Managing rare paediatric spitzoid lesions within an adult SSMDT is less than ideal / remains a challenge and may impact on the provision of optimal holistic and developmentally appropriate care. Provision of a paediatric-specific SSMDT at a regional or national level may help tailor potentially radical treatment decisions in this group of patients.
34 Melanomas of childhood. Am J Pathol. 1948;24: Sophie Spitz Differentiation histologically between juvenile and adult melanoma could not be made with certainty in most cases
35 Spatz A, Calonje E, Handfield-Jones S, Barnhill RL. Spitz tumors in children: a grading system for risk stratification.arch Dermatol Mar;135(3): Alan Spatz University of McGill Canada Eduardo Calonje St John s Institute UK Raymond Barnhill Institut Curie Paris, France
36 ATYPICAL SPTIZ TUMOUR (AST) SPITZ TUMOUR OF UNCERTAIN MALIGNANT POTENTIAL (STUMP) GRADING for childhood cases May promote better reproducibility for diagnosis between observers Should be born in mind that not all cases of metastasis (especially loco-regional nodes) indicate a long-term adverse outcome But even lesions in low risk category may result in death from metastatic disease Needs validation in a larger dataset
37 SPITZ NAEVUS v ATYPICAL SPTIZ TUMOUR (STUMP) Spatz A, Calonje E, Handfield-Jones S, Barnhill RL. Spitz tumors in children: a grading system for risk stratification.arch Dermatol Mar;135(3):333-5.
38 ...currently no IHC or Molecular that can be used to make an entirely safe diagnosis of Spitz nevus or melanoma in problematic cases. 40% 15y or younger H&N commoner location in children c/w adults Compouned (46%); Junctional (33%); Dermal (21%) Epithelioid and/or spindle cells: 100% Maturation: 72% Inflammation: 70% (rarely dense) Epidermal hyperpalsia: 66% Melanin: 50% Telangiectases: 40% Kamino bodies: 34% Desmoplastic stroma: 26% Mitosis: 23% Note: Polypoid SN looks decidedly uncommon! Pagetoid: 13% Stromal hyalinisation: 8% Am J Dermatopathol Apr;31(2):
39 Ferrara et al Am J Dermatopathol Jun;32(4): Reed / PSCN is recognisable clincally & dermascopically The commonest variant of Spitz naevus in one large series Clinical view of a heavily pigmented asymmetric plaque located on the left arm of a 33-year-old man. B, Dermoscopically, the lesion exhibits a starburst pattern typified by pigmented streaks distributed at the periphery in a regular fashion. Despite the shape, asymmetry, distribution of color, and structure are rather homogenous in dermoscopy. C, Histopathologically, the lesion is slightly raised and sharply circumscribed (hematoxylin eosin 340); D, there is a moderate epidermal hyperplasia with hypergranulosis and a prevailingly nested junctional proliferation of spindle and epithelioid melanocytes (hematoxylin eosin 3250). The overall histopathologic features are quite in between a PSCSN and a RN.
40 pink-red papulonodular lesions, previously considered classical Spitz nevus, could be histopathologically atypical with a great probability than tanblack macules & plaques of PSCSN/RN The previously typical clinical lesions associated with Spitz naevus are probable not infrequently AST (a tumour of intermediate or borderline malignancy) Ferrara et al Am J Dermatopathol Jun;32(4): A, Clinical view of a pink nodule located on the right arm of an 11-year-old girl. B, At a first dermoscopic examination, the lesion exhibits a few red to black hemorrhagic globules over a pink background. C, The second dermoscopic view refers to the same lesion after 15 days when the planned excision was finally performed. The hemorrhagic globules are no more appreciated, and the lesion shows a tan pigmentation at the periphery with a few irregular vessels in the amelanotic central portion. D, Histopathologically, the lesion is nodular and asymmetric (hematoxylin eosin 340); E, despite the absence of any pagetoid spread, there is atrophy of the epidermis, together with some irregular architecture of the dermal nests, which are notably larger in the depth than close to the surface (hematoxylin eosin 3100). The lesion was 4.48 mm in thickness: a sentinel node biopsy showed isolated tumor cells within the subcapsular sinus.
41 18 cases Mean age 35.2 (15 to 56) Mean size 7.27mm Mean Breslow 2.51 High cell density 10/18 Atypia 9/18 (marked in 1) Mitoses 8/18 (atypical & clustered in 4) Absent maturation 9/18 Absent zonation 8/18 SUBTYPES Genuine (7) Uniform (5) Packed (5) Polypoid (3) Pigmented (2) BEST PARAMETERS: cell density, mitosis, zonation, infiltration pattern, consumption of epidermis Requena et al Am J Dermatopathol Jul;34(5): mitoses in Spitz nevus are scarce, typically in the superficial areas of the neoplasm. We consider this criterion very important in the differential diagnosis of Spitz nevus and spitzoid melanoma; thus, the presence of mitoses in the lower portion or many grouped in an area of a spitzoid lesion must be considered highly indicative of melanoma
42 Last follow-up: slight keloid scar at the site of her original surgery and the worrisome moment in April time when she presented with a changing melanocytic lesion on her parietal scalp which we excised and was shown to be a benign melanocytic naevus she has full mobility and dances and acts and is doing fantastically. She has slight swelling on the side of the surgery but not significant lymphoedema. Acknowledgements: All EQA and Slide Club responders Dr Ina Nicklaus Dr Bella Ganatra Dr Emma Howard Dr Claire Bowen Dr Arnaud de la Fouchardiere
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