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CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL
Case 30-2010 — A 15-Year-Old Boy with a Recurrent Skin Lesion
Richard C. Cabot, Nancy Lee Harris, M.D., Jo-Anne O. Shepard, M.D., Eric S. Rosenberg, M.D., Alice M. Cort, M.D., Sally H. Ebeling, Christine C. Peters
Hensin Tsao, M.D., Ph.D., Kenneth K. Tanabe, M.D., Donald P. Lawrence, M.D., Adriano Piris, M.D.
N Engl J Med 363:1352-1360 | September 30, 2010
Presentation of Case
Dr. Adam D. Lipworth (Dermatology): A 15-year-old boy presented at the outpatient cancer center at this hospital with a recurrent skin lesion.
Approximately 18 months earlier, the patient noted a small, white lump on the posterior upper portion of the right arm that initially resembled a wart; it later became reddish, and a surface scab developed. Sixteen months before this evaluation, he went to see his pediatrician and a surgeon at another hospital. On examination, the lesion measured 0.75 cm by 0.5 cm and was thought to be consistent with a basal-cell carcinoma; an excisional biopsy specimen was obtained. Pathological examination of the tissue revealed an ulcerated lesion (0.8 cm by 0.5 cm). A diagnosis of a compound type, traumatized Spitz nevus was made. The lesion extended to the lateral border of the specimen.
Approximately 2 to 3 months after the excision, the patient's mother noted small, raised red lesions in a starburst pattern near the scar; the complex of lesions slowly grew to approximately 2.5 cm in diameter during the ensuing year. One month before this evaluation, the abnormal area was excised at the other hospital. Pathological examination of the specimen led to a diagnosis of severely atypical, recurrent, multifocal, epithelioid-cell melanocytic proliferation, with features consistent with melanoma. Three weeks later, the patient was seen in the cancer center at this hospital.
The patient did not have weight loss, night sweats, fatigue, cough, other skin lesions, bleeding, gastrointestinal symptoms, or headaches. He had received a diagnosis of attention deficit disorder, for which he took a combination of amphetamine and dextroamphetamine. He had no known allergies. He lived with his parents and a sibling and was a student. He did not smoke or drink alcohol. There was no family history of melanoma or other cancers; his parents and sibling were well.
On examination, the vital signs were normal; the height was 175.3 cm, and the weight 63.5 kg. There was a healing incision, 5 cm in length, on the posterior right upper arm, without residual pigmentation. The remainder of the examination was normal.
A diagnostic procedure was performed, and management decisions were made.
Dr. Hensin Tsao: This 15-year-old boy had a melanocytic tumor that recurred within a year after excision. I am aware of the diagnosis. This case raises several important questions. First, is the lesion a melanoma, a Spitz nevus, or a borderline lesion? Second, if it is melanoma, is melanoma in the pediatric population a different disease from melanoma in the adult population? Finally, what should be the treatment for the recurrent lesion? I would like Dr. Piris to review the first biopsy specimen for us.
Dr. Adriano Piris: The original biopsy specimen was reviewed at this hospital after the recurrence. The lesion was pigmented and had two distinct patterns. The first pattern had several features of a Spitz nevus (first described in 1948 by Sophie Spitz1), and the second pattern was that of a markedly atypical melanocytic proliferation. Spitz nevi once had the misnomer of juvenile melanoma. Today we know that the classic Spitz nevus is a benign lesion, common in children and young adults. In this case, as in the typical Spitz nevus, we saw a predominantly dermal proliferation of nested epithelioid cells with ample eosinophilic cytoplasm and prominent nuclei, with a homogeneous chromatin pattern and conspicuous eosinophilic nucleoli. The lesion had the typical inverted-cone architecture of a nevus (Figure 1A), with the base applied against the epidermal surface and the apex pointing toward the deeper layers of the skin. These areas showed the typical pattern of maturation of a Spitz nevus, with single, smaller cells toward the base (Figure 1B). There was prominent epidermal hyperplasia, a feature commonly seen in Spitz nevi. Amorphous eosinophilic aggregates known as Kamino bodies, often seen in Spitz nevi, were not present. There was extensive ulceration with overlying scale crust.
Skin-Biopsy Specimen of the Original Lesion (Hematoxylin and Eosin).
In their typical presentation, Spitz nevi are easily recognized. Some, however, present with various degrees of architectural and cytologic atypia. The main atypical architectural feature is the loss of maturation deep in the lesion, manifested by continuous expansile nests. Atypical cytologic features include pleomorphic nuclei, prominent dark nucleoli, and mitotic activity.2 Other atypical features of the lesion include a diameter measuring more than 6 mm, asymmetry, minimal epidermal reaction, marked pagetoid spread, prominent radial growth phase, and irregular pigmentation.
In this case, in some areas of the lesion, the typical architecture of the Spitz nevus was lost and there was no evidence of maturation (Figure 1C); instead, deep expansile nests proliferated on one side of the lesion, representing the growing edge of the tumor and resulting in loss of the typical triangular shape. Moderately to severely atypical cytologic features in these areas (Figure 1D) included pleomorphic nuclei with an irregular chromatin pattern and prominent basophilic nucleoli. There were also numerous mitotic figures toward the base of the lesion (marginal mitoses). Also atypical was the size, with a diameter of more than 6 mm. The depth of the lesion was 3.8 mm.
Atypical lesions that have features of Spitz nevi can be very difficult to interpret. The difficulty in evaluating the morphologic features of these lesions is mirrored by the difficulty in predicting their behavior.3,4 Some lesions can be cured by complete excision, and others metastasize. Therefore, such lesions have been designated variously as atypical Spitz tumors, melanocytic tumors of uncertain malignant potential,2 severely atypical spitzoid melanocytic proliferations, or even spitzoid melanoma. Molecular genetic studies have attempted to categorize these lesions on the basis of their genetic alterations,4,5 but the data are not conclusive. A small number of pigmented lesions with overt malignant features occur in children and are similar to adult melanomas. If the cytologic features and architecture qualify the lesion as malignant, the term malignant melanoma should be used, even in children. Some studies have shown no difference in outcome between children and adults with melanoma.6,7
Considering the young age of this patient, the typical and atypical architectural and cytologic features of a classic Spitz nevus, and the deep dermal mitoses, we made a diagnosis of a severely atypical spitzoid melanocytic proliferation — a borderline lesion between an atypical Spitz nevus and melanoma. The margins of the biopsy specimen were involved by the lesion.
Dr. Tsao: These borderline lesions present three important questions for the patient and the clinician. What is it? Should it be reexcised, and if so, with what margins? And should one perform a sentinel-lymph-node biopsy?
The features of atypical Spitz tumors that are predictive of metastatic potential have been codified (Table 1).8 If our patient's lesion is an atypical Spitz tumor, it confers a high risk in view of his age and the presence of ulceration and mitoses. What if it is a melanoma? The incidence of melanoma in children is increasing, as it is in adults; however, the 10-year survival rate for metastatic melanoma in the pediatric population approaches 60% for stage III disease and 50% for stage IV disease.9 These rates are strikingly different from those among patients with common adult-type melanomas; in this patient population, the 10-year survival rate is less than 10% for stage IV melanoma.10 On clinical grounds, pediatric melanoma thus appears to be a slightly different disease from adult melanoma, although canonical adult-type melanoma, with all its attendant prognostic features, can develop in children.
Grading System for Atypical Spitz Tumors.
On a genetic level, melanocytic tumors appear to be driven by distinct oncogenic triggers (Figure 2). Unlike other melanocytic nevi, up to 30% of Spitz tumors have amplifications and point mutations of the HRAS gene,11 whereas BRAF12 and NRAS13 mutations occur more frequently in acquired and congenital nevi, respectively, and in the more common types of cutaneous melanoma.14 Since approximately 80% of superficial spreading and nodular melanomas harbor mutations at either NRAS or BRAF,15 we performed an assessment for mutations at these loci in the original specimen and found none of the recurrent changes (exons 11 and 15 in BRAF, and exons 2 and 3 in NRAS) reported in the common melanomas; no mutations were detected in HRAS. The absence of any changes at NRAS or BRAF argues against but certainly does not rule out a more common variant of melanoma.
The RAS Pathway and Melanocytic Tumors.
In summary, this boy had a pigmented lesion that was incompletely excised and then recurred shortly after partial removal; these events are compatible with a recurrent nevus. The tumor does not have the genetic signatures associated with more common types of melanoma.
Dr. Hensin Tsao's Diagnosis
Recurrent atypical (borderline) spitzoid tumor.
Dr. Piris: The recurrent lesion was characterized by a dermal scar flanked by several nodules of epithelioid cells with varying degrees of inflammation (Figure 3A). These nodules were connected through neurovascular bundles and adnexal structures and thus do not represent microsatellites (defined as tumor nodules ?0.05 mm in diameter, separated from the main lesion by ?0.3 mm of normal dermis).10 Close examination of the predominant nodule (Figure 3B) revealed marked cellular pleomorphism and malignant nuclei with marked irregularity of the chromatin pattern and prominent dark nucleoli. Furthermore, there were several mitotic figures, some of which were markedly atypical. In this recurrent lesion, no areas resembled a Spitz nevus. The overall changes were frankly malignant, and the diagnosis of malignant melanoma was rendered. In view of this diagnosis, we concluded that in retrospect, the original lesion had been a malignant melanoma with spitzoid features, although this diagnosis could not have been made with confidence at the time.
Biopsy Specimen of the Recurrent Skin Lesion.
The depth of the malignant nodules in the specimen of the recurrent lesion was approximately 5 mm. A reexcision with appropriate negative margins and a sentinel-lymph-node biopsy were recommended.
Discussion of Management
Dr. Kenneth K. Tanabe: The patient was referred for consideration of additional surgical management of his skin lesion, including reexcision and sentinel-lymph-node mapping.
Appropriate surgical management of melanomas includes wide excision of the primary tumor, with the use of lateral margins that minimize the risk of local recurrence. Several prospective, randomized trials that compared narrower surgical margins with wider surgical margins in patients who were randomly assigned to one or the other approach have led to the recommendation that 1-cm surgical margins be used for melanomas that are less than or equal to 1 mm in thickness, and 2-cm surgical margins for melanomas that are more than 1 mm in thickness.16–20 However, these trials involved adults who had invasive cutaneous melanomas, and they did not involve either patients under 18 years of age or those with atypical Spitz tumors. In this 15-year-old patient with a lesion that was 5 mm thick, we recommended 1-cm surgical margins.
Strategies for the management of regional nodes are elective lymph-node dissection; clinical observation of the nodes, with therapeutic lymphadenectomy reserved for patients in whom palpably enlarged nodes with metastatic melanoma develop; or selective lymphadenectomy for patients in whom lymphatic mapping and sentinel-node biopsy indicate the presence of positive nodes. The technique of lymphatic mapping and sentinel-node biopsy is well standardized, with rates of successful sentinel-node identification exceeding 95%.21,22 The status of the sentinel nodes carries far more prognostic significance than factors associated with the primary tumor.23
The goals of surgical staging of regional nodes are to minimize morbidity and improve staging accuracy, regional disease control, and survival rates. Lymphatic mapping and sentinel-node biopsy, with complete lymphadenectomy for patients with positive sentinel nodes, has been shown in a large randomized trial (Multicenter Selective Lymphadenectomy Trial [MSLT] I) to provide superior disease control in regional lymph-node basins and improved survival rates among patients with positive nodes, as compared with observation and subsequent therapeutic lymphadenectomy performed on detection of recurrence.24 The potential benefit of complete lymphadenectomy is the removal of additional nodes containing melanoma cells before they give rise to distant metastases or create problems with regional control. However, since complete lymphadenectomy reveals additional positive nodes in only 15 to 20% of cases, it is conceivable that this procedure is not beneficial for patients. This question is the subject of an ongoing study (MSLT II), in which patients with positive sentinel nodes are randomly assigned to either complete lymphadenectomy or close clinical observation of the nodal basin with ultrasonography. At present, the standard of care is complete lymphadenectomy in patients with positive sentinel nodes.
This 15-year-old patient appeared to have an atypical Spitz tumor that recurred after incomplete excision. The prognostic significance of positive sentinel nodes in patients with atypical Spitz tumors is not the same as that of positive sentinel nodes in adults with melanoma, and the practice of performing sentinel-node biopsy in patients with atypical Spitz tumors is falling out of favor. However, a case has been reported in which a Spitz tumor that had not been completely excised recurred locally and metastasized, and the patient died.3 Because of that report, and because malignant melanoma rather than an atypical Spitz tumor was diagnosed after histologic examination of the recurrent lesion in this patient, strong consideration was given to lymphatic mapping and sentinel-node biopsy. After discussion with the patient and his family, a decision was reached to perform lymphatic mapping and obtain a sentinel-node–biopsy specimen at the time of wide excision.
One-centimeter margins were used; the excision was carried out down to the muscular fascia, and the resulting defect was closed. Three axillary sentinel lymph nodes were identified.
Dr. Piris: There was no evidence of residual melanoma in the reexcision specimen. Two of three sentinel lymph nodes were positive for metastatic disease (Figure 3C and 3D). A complete lymphadenectomy was later performed, and there was no evidence of metastatic melanoma in 37 lymph nodes.
Dr. Tsao: The presence of nodal metastases does not necessarily mean that this lesion is an adult-type melanoma. In one report, specimens from sentinel-lymph-node biopsies showed nodal deposits in 5 of 10 atypical Spitz tumors, although all patients were alive at a mean follow-up of 35 months.25 In a more recent study involving 67 patients with atypical Spitz tumors, 27 of 57 patients who underwent sentinel-lymph-node biopsy (47%) had tumors with nodal involvement; after 3 years, 1 patient who did not undergo sentinel-lymph-node biopsy died.26 This death serves as a reminder that even atypical Spitz tumors can be lethal. However, among adults, about half of all patients with microscopic nodal metastasis eventually die of the disease. The presence of tumor cells on examination of a specimen from a sentinel-lymph-node biopsy in this case is a concern but is nonetheless consistent with the documented behavior of atypical Spitz tumors.
Dr. Donald P. Lawrence: After undergoing wide local excision and lymph-node dissection, the patient was referred for consideration of systemic adjuvant therapy for melanoma with lymph-node metastases. Computed tomographic scans of the chest, abdomen, and pelvis and magnetic resonance imaging of the brain revealed no evidence of distant metastatic disease. In view of the morphologic features of the recurrent lesion, the original lesion was also considered to be melanoma. The original lesion is best characterized as an incompletely excised, ulcerated melanoma. The maximum thickness of the primary tumor on reexcision was 5 mm. Microscopic foci of melanoma were present in 2 of 3 right axillary sentinel lymph nodes and 0 of 37 nodes from the complete lymph-node dissection. Therefore, the lesion would be categorized as T4bN2aM0 according to the American Joint Committee on Cancer (AJCC) tumor–node–metastasis (TNM) staging system and would meet the criteria for AJCC stage IIIB melanoma.10 The recurrent lesion contained multiple tumor nodules. However, these did not meet criteria for satellite lesions (which would have resulted in classification as Stage IIIC), since they were all connected microscopically.10 Stage IIIB melanoma in adults is associated with a 5-year survival rate of 59%.
Conventional prognostic features applicable to melanoma, including thickness and regional nodal spread, are of uncertain clinical significance in cases of atypical Spitz tumors, which usually follow a benign course even in the presence of nodal involvement. The age of this patient and the spitzoid features of the original lesion are suggestive of a low metastatic potential. However, the aggressive local recurrence would be unusual for an atypical Spitz tumor. Furthermore, the histologic features of the recurrence were convincingly malignant and indistinguishable from adult-type melanoma. On the basis of these considerations, there is uncertainty about the prognosis, but we were concerned that it was probably more similar to the prognosis associated with a true melanoma than to that associated with an atypical Spitz tumor.
Clinical trials have shown an association between the use of interferon alfa-2b and an improvement in relapse-free survival among patients with high-risk melanoma. In a meta-analysis of 12 trials, the hazard ratio for recurrence among patients who received interferon therapy as compared with control patients was 0.83 (95% confidence interval, 0.77 to 0.90). However, the effect of interferon on overall survival was not statistically significant.27 Interferon is associated with substantial but typically manageable toxic effects, including influenza-like symptoms, fatigue, depression, myelosuppression, and reversible hepatotoxicity. Adjuvant trials of interferon for melanoma have been restricted to adults; therefore, its efficacy in the pediatric population is not well established.
After discussion of the uncertainties regarding the prognosis and the risks and benefits of interferon, the patient and his parents elected to pursue this treatment. He had side effects, including fatigue, nausea, and occasional headaches, which caused him to miss some school, as well as elevated liver-enzyme levels that necessitated a 1-week hiatus in the treatment. His symptoms improved after a 33% decrease in the dosage. Fifteen months after the diagnosis of recurrent melanoma, he is nearing completion of his treatment and has no evidence of recurrent or metastatic disease.
Dr. Steven R. Tahan (Pathology, Beth Israel Deaconess Medical Center): Dr. Piris, why did you classify this as melanoma, since it recurred adjacent to the scar, probably from residual tumor cells left behind after the first excision. Why isn't this a recurrent atypical Spitz nevus?
Dr. Piris: All we can rely on when dealing with such a lesion is morphologic criteria. When the recurrence is next to the scar, we usually err on the side of calling it a recurrent nevus or a recurrent atypical melanocytic proliferation, rather than malignant melanoma. However, in this recurrence, the cytologic features were obviously malignant and different from an atypical borderline lesion; there were no features of a Spitz nevus. This case was reviewed in our consensus conference by Drs. Lyn Duncan, Mai Hoang, and Martin Mihm. It was also reviewed by Dr. George Murphy at Brigham and Women's Hospital. We all agreed that it had to be called melanoma.
A Physician: Is this a recurrence of melanoma or a transformation of a Spitz nevus to melanoma?
Dr. Piris: We believe it is a recurrence of melanoma, because it was associated with the scar and because the original lesion had cytologically atypical features that we thought were borderline between an atypical Spitz nevus and melanoma. The recurrence met the diagnostic criteria for melanoma; this led us to think that the original lesion was also melanoma. The pathologist involved with the first biopsy recommended reexcision of the original lesion, which could have prevented the recurrence.
Malignant melanoma with features resembling a Spitz nevus.
Dr. Tsao reports receiving consulting fees from SciBase, Quest Diagnostics, and Genentech; Dr. Tanabe, consulting fees from Best Doctors, Morningside Technology Advisory, LEK Consulting, Medical Mutual Insurance Company of Maine, Norcal Mutual Insurance Company, and ProMutual Group; and Dr. Lawrence, consulting fees from Schering-Plough and Novaratis.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
No other potential conflict of interest relevant to this article was reported.
This case was presented at the postgraduate course, Dermatopathology Update, September 25, 2009 (course directors: Drs. Lyn M. Duncan, Mai Hoang, Martin C. Mihm, Jr., George F. Murphy, and Steven R. Tahan), sponsored by the Harvard Medical School Office of Continuing Education.
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