Society for Pediatric Pathology Spring Meeting Joint Symposium with American Society of Dermatopathology

Transcription

1 Society for Pediatric Pathology 2013 Spring Meeting Joint Symposium with American Society of Dermatopathology Update on Cutaneous Melanocytic, Mesenchymal and Lymphoproliferative Lesions in Children Melanocytic Lesions in Children: Clinico-Pathologic Features Victor G. Prieto, MD, PhD UT MD Anderson Cancer Center Houston, TX In accordance with the Accreditation Council for Continuing Medical Education (ACCME) guidelines, all planners and faculty (speakers, authors and presenters) who participate in the planning and execution of an SPP educational activity are required to disclose whether they or their spouses/partners have any significant financial interest or other relationship with a commercial company, entity or service (which would be discussed in this education program) to disclose. This applies to current relationships as well as any within the past twelve months. The SPP also has required that the speakers disclose any products that are not labeled for the use under discussion and that the disclosure is made to the audience at the time of presentation. The planners and faculty for this symposium have nothing to disclose.

2 Symposium Objectives Melanocytic Lesions in Children: Clinico-Pathologic Features Victor G. Prieto, MD, PhD UT MD Anderson Cancer Center Houston, TX Upon completion of this presentation, participants should be able to: Interpret and incorporate specific histologic features applied to the differential diagnosis of melanocytic lesions in children Select and analyze the appropriate immunohistochemical studies that aid in the differential diagnosis of melanocytic lesions in children Identify the histologic and clinical criteria employed to recommend sentinel lymph node examination in melanocytic lesions in children Discuss the histologic and clinical features predictive of clinical behavior in malignant melanocytic lesions in children PLEASE NOTE: Several presenters have included proprietary materials in these submissions. You are asked to honor the scholarly proprietary nature of these materials, herein. Symposium SAMs Credit Hours and ABMS-MOC Core Competencies The Self-Assessment Module (SAM) for this lecture, Melanocytic Lesions in Children: Clinico- Pathologic Features, qualifies for 1.0 SAMs credit hour. This SAM addresses the following ABMS- MOC core competencies (see below): 1, 2, K 5, 6, Six Core Competencies American Board of Pathology ABMS Maintenance of Certification Certification Matters 1, Patient Care-Provide care that is compassionate, appropriate and effective treatment for health problems and to promote health. 2, K Medical Knowledge-Demonstrate knowledge about established and evolving biomedical, clinical and cognate sciences and their application in patient care. 3, Interpersonal and Communication Skills-Demonstrate skills that result in effective information exchange and teaming with patients, their families and professional associates (e.g. fostering a therapeutic relationship that is ethically sounds, uses effective listening skills with nonverbal and verbal communication; working as both a team member and at times as a leader). 4, P Professionalism-Demonstrate a commitment to carrying out professional responsibilities, adherence to ethical principles and sensitivity to diverse patient populations. 5, Systems-based Practice-Demonstrate awareness of and responsibility to larger context and systems of healthcare. Be able to call on system resources to provide optimal care (e.g. coordinating care across sites or serving as the primary case manager when care involves multiple specialties, professions or sites). 6, Practice-based Learning and Improvement-Able to investigate and evaluate their patient care practices, appraise and assimilate scientific evidence and improve their practice of medicine.

3 HANDOUT Clinical, histologic, and immunohistochemical features in melanomas of childhood and adolescence. SPP and ASDP Companion Meeting. Baltimore. USCAP 2013 Victor G. Prieto, MD, PhD. Departments of Pathology and Dermatology. The University of Texas M.D. Anderson Cancer Center, Houston, TX (USA). This companion meeting will be focused on neoplastic lesions in children and adolescents. On the field of melanocytic lesions, this first lecture will focus on the clinical, histological, and immunohistochemical findings of melanocytic lesions, and it will be followed by two lectures describing the most recent developments in the fields of molecular pathology (CGH, FISH, and proteomics). Cutaneous melanoma in childhood is rare, particularly before puberty. The incidence under 15 years of age is approximately 1 per million (7% of cancers among patients aged years vs. 1.2% in patients younger than 15 years of age). As with adult population, childhood melanoma mainly affects Caucasian individuals; some series have indicated that white race is associated with an impaired prognosis, although that is not our experience. Some studies have suggested that there is a slight female predominance and that male sex is associated with worse prognosis. However our experience, of the data from cancer registry show equal sex distribution and prognosis. The extremities and the trunk are the most common anatomic locations for cutaneous melanomas in children. On the other hand it has been suggested that childhood melanomas arising from the head and neck may have worse prognosis. Like in the adult population, the most likely reason to suspect melanoma is the detection of changes in the appearance of a mole. Changes described in decreasing order of frequency are: rapid size increase, bleeding, color change, itch, lymph node enlargement, subcutaneous mass, pain and distant metastases. Another common presentation is that of an amelanotic lesion. Approximately 10% of melanomas develop in association with a pre-existing nevus are asymptomatic. Since a diagnosis of melanoma is only rarely included in the differential diagnosis of cutaneous lesions in children, some studies have reported that up to 50-60% of cases have had a significant delay in the diagnosis. Only a minority of childhood melanoma in children may also occur in mucosal surfaces. Primary melanomas of mucosal sites (oral and nasal cavity, genitourinary, gastrointestinal and conjunctiva) account for only 3-4% of all melanomas. Many of known risk factors associated with melanoma in adults (e.g., large congenital nevi, dysplastic nevus syndrome, numerous nevi) may be also identified during childhood. Such conditions were demonstrated in about 50% of cases. As in adults, a large number of melanocytic nevi in children are associated with increased risk of melanoma and a number of childhood melanomas arise in either congenital or acquired nevi. There is some controversy about the risk for progression of congenital nevi to melanoma. Historical estimates of melanoma risk were likely exaggerated due to diagnosis of proliferative nodules as developing in congenital nevi as melanoma. Regarding malignant transformation of congenital nevi, approximately 10% of childhood melanoma arises from congenital nevi, including 3.5% from giant nevi. In our experience, approximately half of all childhood melanomas arise in children with sporadic dysplastic nevi and around 10% in children with dysplastic nevus syndrome. In general, familial cases account for approximately 5-10% of melanomas. This antecedent greatly increases risk of melanoma, both for patients with

4 dysplastic and benign nevi. Familial melanoma is associated with a lower age at diagnosis than sporadic melanoma, presence of dysplastic nevi and the development of multiple primary melanomas. The pattern of heredity is consistent with an autosomal dominant inheritance with incomplete penetrance. Inactivating mutations of the CDKN2A gene (for p16 and p14arf) are present in 20-40% of such families and in 15% of individuals with multiple primary melanomas but only rarely (less than 5%) of childhood melanomas. IN our series 15 (22.4%) patients had 3 or more first-degree relatives with melanoma, but none of them had multiple melanomas during the follow-up. Another phenotype associated with melanoma is the presence of large number of melanocytic nevi. In a study of 201 adolescents with melanoma, they reported a 34-fold increased risk in patients with more than 100 nevi and 15-fold in those with 10 or more large nevi. In our series we found such association only in 21% of patients. A precursor nevus has been reported in up to 47% of childhood melanomas although it appears that the percentage is much lower (15%). Small congenital nevi occur in 1% of newborns, and rarely develop melanoma before the second decade of life. In our large series, we only found small nevi in 2/137 patients (3%). On the other hand, it is interesting that we have shown that children in whom the melanoma is associated with a benign melanocytic nevus have a significantly lower risk of metastases. Other risk factors include inherited and acquired immunodeficiency. In pediatric population, melanoma account for up to 15% of all post-transplantation skin cancers. Regarding sun exposure, unless the patient suffers from inherited conditions that increase sensitivity to ultraviolet light, such as xeroderma pigmentosum, it is unlikely that sun-exposure will be associated with childhood melanoma. Survivors of childhood cancer have increased risk for a second neoplasm, including melanoma. Such lesions tend to be deeper and have poor prognosis, possibly associated with tumor-related immunodeficiency mechanisms mediated by the neoplasm itself. The most important finding regarding prognosis is age. In most studies, older age, likely after puberty, is associated with worse survival. In several series, the large majority patients who died from melanoma were older than 10 years at time of diagnosis. For example, Sander et al reviewed 126 cases of melanoma in young patients, and found that all 13 deceased patients were older than 12 years of age. It is also our experience, since in our series all our patients who died from melanoma were older than 10 years at time of diagnosis. Thus it seems that postpuberal age is one of the main factors determining death risk. Histology: In general, it seems that the same histopathologic criteria developed for adult melanoma should be used for diagnosis of childhood melanoma: size >10 mm, asymmetry, lateral borders poorly demarcated, intraepidermal pagetoid spread of single cells prominent in the center or else present at the periphery of the lesion, irregular intraepidermal nest formation, consumption /atrophy or ulceration of the epidermis, absence of maturation, deep extension in dermis/subcutaneous tissue, expansive deep border, expansive / diffuse sheets of cohesive cells in the dermis, cellular atypia, and deeply located or atypical mitotic figures. However, these features should be evaluated together since none of them is sufficient for a diagnosis of melanoma. Regarding histologic subtypes, several series have reported a predominance of nodular lesions, but more recent series indicate that most childhood melanomas are of superficial spreading type. It is possible that some of the cases in prior series were actually superficial spreading melanomas with large, dermal, nodular component. It is interesting that some 2

5 studies have indicated that true nodular morphology is associated with impaired prognosis. Interestingly, in contrast with melanomas in adults, in whom histologic subtype is not related to prognosis, nodular melanomas appear to show poor survival in children. There appear to be higher rate of metastases in melanomas with fusiform or spitzoid cytology. Also, some studies have indicated impaired prognosis of lesions with melanomas of small cell type, similar to small round cell tumors. A high percentage of reported childhood and adolescent melanomas are relatively thick, possibly due to delay in suspicion of malignancy. When comparing adult and pediatric melanomas, the latter show significantly thicker tumors and such thicker lesions appear to have poor prognosis. Nodal metastases have been detected in up to 2/3 of children with Clark level IV-V or Breslow >1.5 mm melanomas. Conversely, metastases or recurrence are unusual in patients with melanoma <1.5 mm thick. As in adults, ulceration, VGP, vascular invasion and high mitotic activity are also associated with higher recurrence rate, although in our experience it did not correlate with decreased survival. Brisk lymphocytic infiltrate and regression do not appear to have significant correlation with survival. The most challenging diagnosis is the subtype spitzoid melanoma. There appears to be a spectrum of lesions from obvious benign (i.e., Spitz nevus) to obvious malignant (spitzoid melanoma), with a group of lesions falling in between the two poles of the spectrum. It has been reported that up to 40% of melanomas originally diagnosed as nevi actually correspond to these spitzoid melanomas. Classic Spitz nevus is considered as a benign lesion with some nuclear and cytological pleomorphism but absence of deep/atypical mitotic figures, expansile pattern of growth, etc. (see above). In contrast, spitzoid melanoma is a malignant melanocytic lesion with some cytological attributes of Spitz nevus (spindle and/or epithelioid melanocytic cells) but with a preponderance of the atypical features summarized above. Patients with lesions sharing some classic features of Spitz nevus and some of these abnormal pathology features, in which a definite diagnosis of nevus or melanoma is not firmly established, may be described as atypical spitzoid lesions or atypical Spitz tumors (of unknown biological potential). The term nevoid melanoma applies to lesions in which there is little proliferation of melanocytes in the epidermis and a dermal proliferation that mimics some features of a compound or intradermal nevus. Due to the lack of prominent intraepidermal component some of these lesions are diagnosed as nevi. The main histological features to look for in these lesions include: dermal mitotic figures, sheet-like growth pattern, nuclear pleomorphism and lack of conventional maturation (monomorphous appearance of the melanocytes throughout the lesion. Although the diagnosis of melanoma continues to rest on microscopic morphologic features, immunohistochemistry may be helpful in a number of cases, especially in like spitzoid or nevoid melanoma. HMB-45 usually shows a stratified pattern with diminished expression toward the base of the lesion (maturation) in most nevi, including Spitz nevi, in contrast with the patchy pattern of expression throughout melanomas. Blue nevi, deep penetrating nevi, plexiform nevi, and a minority of Spitz nevi show diffuse labeling with HMB45. Spitz nevi also have low proliferation rates (1-2%) when assessed with Ki-67, compared with much higher rates in melanomas (15-30%). Moreover, melanoma has labelling throughout the lesion while nevi have more staining at the top of the lesion than at the bottom (maturation). S100 protein and MART-1 (melanoma antigen recognized by T cells-1) show diffuse expression throughout both Spitz nevus and melanoma; however, desmoplastic melanomas may lose MART1 expression while preserving S100; this finding may be diagnostically helpful. Any spindle cell melanocytic lesion that shows either patchy or negative expression of MART1 should be carefully evaluated to rule out melanoma. 3

6 Other markers have been studied in spitzoid and other childhood melanocytic lesions. p16 and its related protein CDK4 show a mostly inverse pattern of expression; many Spitz nevi express p16 but not CDK4 and the opposite is true for melanoma. However, more recent studies question the usefulness of immunohistochemical analysis of p16 to distinguish Spitz nevus from spitzoid melanoma. Expression of CD133, a stem-cell marker, has been reported to be associated with aggressive behavior (lymph node and visceral metastasis) in childhood melanoma. During the period , there were 643 deaths attributed to melanoma among children aged 0-19 years in US (2.25/year/million at-risk individuals). We have shown that presence of metastases at the time of diagnosis is one of the two main factors that influence overall survival in children with melanoma. Along these lines, it has been reported that pediatric patients have a survival at 10 years of with 94.5% in stage I-II and 60.1% in stage III. Regarding sentinel lymph node (SLN), recent studies indicate that this procedure has a less significant predictive value in childhood melanomas than in adult lesions. While approximately 20% of melanomas in adults are associated with positive SLN, pediatric lesions show values between 25 and 60. This seems to indicate that even with positive SLN, those children appear to have a better prognosis than adults. Although it is unclear why, it have been suggested possible differences in lymphatic flow density and immune system, which would be able to clear micrometastases in children. Another possibility is that some of these positive SLN actually contain benign melanocytes (nodal nevi). These nodal nevi are usually small clusters of benign-appearing melanocytes within the capsule (and rarely in the parenchyma) of lymph nodes, in contrast with the common subcapsular location of metastatic melanoma. Overall, up to 20% of lymphadenectomies from the axilla or groin contain such benign collections of melanocytes. These benign nodal melanocytes usually lack gp100 expression (with HMB45), and show very low Ki67 expression, thus consistent with benign melanocytes. In order to facilitate the identification of proliferating melanocytes, it is possible to use a cocktail that includes anti-mart1 and MIB1 (against Ki67). Since these two markers are expressed in different cellular components (Ki67 in the nucleus and MART1 in the cytoplasm) it is relatively easy to determine how many of the melanocytes (i.e., cells expressing MART1) are proliferating (i.e., expressing Ki67). In view of the apparent differences between prognostic information derived from SLN examination in children and adults, only long-term follow-up studies will be able to determine the actual value of SLN in melanocytic lesions from children. In conclusion, careful analysis of histological features as well as the additional immunohistochemistry should allow establishing the right diagnosis in most cases of childhood melanoma. Although it seems that pediatric melanoma patients still a number of children will develop metastasis and die of their disease, particularly when melanoma is diagnosed after puberty. References: Al Dhaybi R, Sartelet H, Powell J, Kokta V. Expression of CD133+ cancer stem cells in childhood malignant melanoma and its correlation with metastasis. Mod Pathol. Mar 2010;23(3): Aldrink JH, Selim MA, Diesen DL, et al. Pediatric melanoma: a single-institution experience of 150 patients. J Pediatr Surg. Aug 2009;44(8): Conti EM, Cercato MC, Gatta G, Ramazzotti V, Roscioni S; EUROCARE Working Group. Childhood melanoma in Europe since 1978: a population-based survival study. Eur J Cancer 2001;37(6):

7 de Vries E, Steliarova-Foucher E, Spatz A, et al. Skin cancer incidence and survival in European children and adolescents ( ): report from the Automated Childhood Cancer Information System project. Eur J Cancer. 2006; 42: Ducharme EE, Silverberg NB. Pediatric malignant melanoma: an update on epidemiology, detection, and prevention. Cutis. Oct 2009;84(4): Ellis ZM, Jassim AD, Wick MR. Anorectal melanoma in childhood and adolescence. Ann Diagn Pathol. Apr 2010;14(2): Hilliard NJ, Krahl D, Sellheyer K. p16 expression differentiates between desmoplastic Spitz nevus and desmoplastic melanoma. J Cutan Pathol. Jul 2009;36(7): Howman-Giles R, Shaw HM, Scolyer RA, et al. Sentinel lymph node biopsy in pediatric and adolescent cutaneous melanoma patients. Ann Surg Oncol. Jan 2010;17(1): Jen M, Murphy M, Grant-Kels JM. Childhood melanoma. Clin Dermatol. Nov-Dec 2009;27(6): Juhl AL, Byers TE, Robinson WA, Morelli JG, Crane LA. The anatomic distribution of melanoma and relationships with childhood nevus distribution in Colorado. Melanoma Res. Aug 2009;19(4): Kirkwood JM, Jukic DM, Averbook BJ, Sender LS. Melanoma in pediatric, adolescent, and young adult patients. Semin Oncol. Oct 2009;36(5): Mason A, Wititsuwannakul J, Klump VR, Lott J, Lazova R. Expression of p16 alone does not differentiate between Spitz nevi and Spitzoid melanoma. J Cutan Pathol. Dec 2012;39(12): McNutt NS, Urmacher C, Hakimian J, Hoss DM, Lugo J. Nevoid malignant melanoma: morphologic patterns and immunohistochemical reactivity. J Cutan Pathol. 1995;22(6): Mills O, Messina JL. Pediatric melanoma: a review. Cancer Control. Jul 2009;16(3): Moore-Olufemi S, Herzog C, Warneke C, et al. Outcomes in pediatric melanoma: comparing prepubertal to adolescent pediatric patients. Ann Surg. Jun 2011;253(6): Murali R, Sharma RN, Thompson JF, et al. Sentinel lymph node biopsy in histologically ambiguous melanocytic tumors with spitzoid features (so-called atypical spitzoid tumors). Ann Surg Oncol. 2008; 15: Pappo AS. Melanoma in children and adolescents. Eur J Cancer 2003;39(18): Paradela S, Fonseca E, Pita S, Kantrow SM, Goncharuk VN, Diwan H, Prieto VG. Spitzoid melanoma in children: clinicopathological study and application of immunohistochemistry as an adjunct diagnostic tool. J Cutan Pathol 2009; 36: Paradela S, Fonseca E, Pita-Fernández S, Kantrow SM, Diwan AH, Herzog C, Prieto VG. Prognostic factors for melanoma in children and adolescents: a clinicopathologic, single-center study of 137 Patients. Cancer 2010; 116: Paradela S, Fonseca E, Prieto VG. Melanoma in children. Arch Pathol Lab Med 2011; 135: Paradela S, Fonseca E, Pita-Fernández S, Prieto VG. Spitzoid and non-spitzoid melanoma in children. A prognostic comparative study. J Eur Acad Dermatol Venereol. e-pub 8/2012 Prieto VG, Shea CR. Immunohistochemistry of melanocytic proliferations. Arch Pathol Lab Med 2011; 135: Somers GR, Chilton-MacNeill S, Zheng K, et al. Increased detection of metastatic melanoma in pediatric sentinel lymph node biopsies using RT-PCR on paraffin-embedded tissue. Appl Immunohistochem Mol Morphol. Jul 2010;18(4): Strouse JJ, Fears TR, Tucker MA, Wayne AS. Pediatric melanoma: risk factor and survival analysis of the surveillance, epidemiology and end results database. J Clin Oncol ;23(21): Tcheung WJ, Marcello JE, Puri PK, Abernethy AP, Nelson KC. Evaluation of 39 cases of pediatric cutaneous head and neck melanoma. J Am Acad Dermatol. Aug 2011;65(2):e Toro J, Ranieri JM, Havlik RJ, et al. Sentinel lymph node biopsy in children and adolescents with malignant melanoma. J Pediatr Surg. 2003; 38: Wang YL, Uhara H, Yamazaki Y, Nikaido T, Saida T. Immunohistochemical detection of CDK4 and p16ink4 proteins in cutaneous malignant melanoma. Br J Dermatol. Feb 1996;134(2):