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Spitz nevus - Humpath.com - Human pathology

Home > E. Pathology by systems > Skin > Spitz nevus

Spitz nevus

Wednesday 16 June 2004

- spindle and epithelioid cell nevus, spitz tumor, spitz’s nevus, spindle cell nevus, juvenile melanoma, benign juvenile melanoma, epitheliod junctional nevus; Spitz tumor

Images

- Spitz nevus: Melanocytes with ample cytoplasm. Note the collagenous stroma which adds desmoplastic part of the name.

Digital cases

- UI:337 - Spitz nevus

- JRC:10786 : Spitz nevus

References

- Clinical, Histopathologic, and Genomic Features of Spitz Tumors With ALK Fusions. Yeh I, de la Fouchardiere A, Pissaloux D, Mully TW, Garrido MC, Vemula SS, Busam KJ, LeBoit PE, McCalmont TH, Bastian BC. Am J Surg Pathol. 2015 Jan 19. PMID: 25602801

Variants

- desmoplastic Spitz nevus

Differential diagnosis

- malignant melanoma
- dysplastic nevi with features of Spitz nevus
- pigmented spindle cell nevus
- desmoplastic Spitz nevus
- plexiform spindle cell nevus - deep-penetrating nevus
- cellular blue nevus
- combined nevus
- epithelioid cell histiocytoma
- reticulohistiocytoma
- cellular neurothekeoma

IHC

- high expression of p16 (15111324)

Molecular biology

- tyrosine kinase fusions

- HRAS mutations

  • HRAS-mutated Spitz tumor (20871217)
  • HRAS belongs to the family of ras genes, which contains the two additional members KRAS and NRAS.
  • HRAS maps to the distal end of chromosome 11p, and cancers with mutations in ras gene frequently amplify the mutated allele.
  • Sequencing of the two hot spots for mutations in HRAS, codons 12, 13, and 61, and found that about 70% of the Spitz nevi with 11p copy number increases showed oncogenic mutations (Bastian et al., 2000b).
  • In a study, one out of 21 Spitz nevi with a normal copy number of 11p that had a mutation of HRAS. These findings suggest that HRAS is at least one target of the selection forces that lead to increasing copy numbers.
  • HRAS mutations have been described in Spitz naevi, but thus far never in melanoma.
  • Thus far no HRAS mutations have been reported in spitzoid melanomas.
  • There is no evidence that cases with HRAS mutations were at risk to progress to melanoma.

- NRAS mutations

  • NRAS mutations are found in about 25% of primary cutaneous melanomas (see Herlyn and Satyamoorthy, 1996 for a review).
  • Interestingly, HRAS itself is rarely mutated in melanoma (van Elsas et al., 1996; Jiveskog et al., 1998).

Molecular biology

- ALK fusion

  • Activating kinase fusions have been described as early oncogenic events that are mutually exclusive with HRAS and BRAF mutations in Spitz tumors.
  • Spitz tumors with ALK rearrangement show distinct histopathologic features that should aid in improving classification of these diagnostically challenging tumors.
  • Spitz tumors with ALK fusions demonstrated unique histopathologic features.
  • Clefts and small vesicle-like spaces are arrayed between plump spindled melanocytes with fibrillar cytoplasm and enlarged nuclei.
  • These melanocytes are typically arrayed in elongated and fusiform nests with radial orientation.
  • The tumors often have extension into the dermis or subcutis with a wedge-shaped or bulbous lower border (45% and 17%, respectively).
  • An infiltrative growth pattern was often present at the periphery of the tumor and was highlighted by ALK immunohistochemistry.

Cytogenetics

add(6)(q12-13) 9566288

CNV - CGH (15163005)

- copy number increases of chromosome 11p paralleled by mutations in the HRAS oncogene

The isolated copy number increases of chromosome 11p in Spitz nevi raised the question as to which gene on 11p drives the selection forces that led to the accumulation of extra copies of that chromosomal arm.

Gains 1q
Losses Ch.9

LOH

Ch.9
Ch.10

Differential diagnosis

- Mutation analysis to differentiate between Spitz naevus and spitzoid melanoma

- A minor part of the Spitz naevi is unique among melanocytic tumours for having a single gain of 11p (26%) and/or HRAS mutations, the latter occurring in up to 29% of cases.

- Demonstration of either a HRAS mutation or a single 11p gain therefore seems indicative of benign behaviour.

- In difficult to diagnose spitzoid lesions, so-called Spitzoid tumours of uncertain malignant potential, assessment of one of these cytogenetic aberrations could be of help in making a more accurate diagnosis.

- The observation that the 11p copy number increase indicating an isochromosome 11p was not seen in over 300 melanomas, and melanoma cell lines studied so far further argues against the possibility that these Spitz nevi are precursors to melanoma. (Bastian, 2003; 12789284)

See also

- melanocytic tumors

References

- HRAS-mutated Spitz tumors: A subtype of Spitz tumors with distinct features. van Engen-van Grunsven AC, van Dijk MC, Ruiter DJ, Klaasen A, Mooi WJ, Blokx WA. Am J Surg Pathol. 2010 Oct;34(10):1436-41. PMID: 20871217

- Harvell JD, Kohler S, Zhu S, Hernandez-Boussard T, Pollack JR, van de Rijn M. High-resolution array-based comparative genomic hybridization for distinguishing paraffin-embedded Spitz nevi and melanomas. Diagn Mol Pathol. 2004 Mar;13(1):22-5. PMID: 15163005

- Maldonado JL, Timmerman L, Fridlyand J, Bastian BC. Mechanisms of cell-cycle arrest in Spitz nevi with constitutive activation of the MAP-kinase pathway. Am J Pathol. 2004 May;164(5):1783-7. PMID: 15111324

- Bogdan I, Burg G, Boni R. Spitz nevi display allelic deletions. Arch Dermatol. 2001 Nov;137(11):1417-20. PMID: 11708943

Portfolio

  • Spitz nevus