—  SPECIALTY CONFERENCE  —

Dermatopathology

Case 5 - Skin, back: Malignant melanoma, nodular type, ulcerated, with epithelioid tumorigenic and mitogenic vertical growth phase, and Spitzoid features, extending to Clark's level IV at a greatest Breslow thickness of at least 1.1 mm, transected at the specimen base

David E. Elder, Hospital of The University of Pennsylvania, Philadelphia, PA





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Clinical History
  • A 9 year old child presented with a nodular lesion of the back.

  • The lesion had appeared suddenly and grown rapidly over several weeks, more recently developing a crust and occasionally bleeding.

  • A fragment of skin was received, with a central ulcerated nodule.


Case 5 - Figure 1
Low-power view of a shave biopsy of a nodular tumor.
Case 5 - Figure 2
The tumor abuts the adjacent epidermis without an associated junctional or in situ proliferation.
Case 5 - Figure 3
Higher power view of the adjacent epidermis and the tumor.
Case 5 - Figure 4
The tumor is ulcerated extensively across its surface.

Case 5 - Figure 5
Tumor cells are arranged in nests, rather loosely placed in a vascular fibrous stroma.
Case 5 - Figure 6
Frequent mitoses are present (e.g. in the green circle).
Case 5 - Figure 7
The tumor cells at the base resemble those near the surface (failure of maturation) - compare with figures 4 and 5. Mitotic activity is also present near the base.

Case 5 - Figure 8
The tumor is brightly and strongly positive with S100.
Case 5 - Figure 9
There is focal reactivity with Melan-A.
Case 5 - Figure 10
Low-power view of a bisected sentinel lymph node.

Case 5 - Figure 11
Small sub capsular deposits of atypical cells are present in the lymph node parenchyma. The cells resemble those in the primary tumor.
Case 5 - Figure 12
Melan-A stain of one of the deposits.
Case 5 - Figure 13
S100 stain.

Introduction:
This nine-year-old child presented with a lesion of the back that had appeared suddenly and grown rapidly, developing a crust which had recently bled, causing spotting of his sheets and clothing.

Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
Histological sections showed a moderately to highly cellular nodular tumor comprised of relatively large epithelioid cells which were melanocytic as judged by MelanA and S 100 reactivity. The cells were arranged mainly in nests, extending from near the surface which was extensively ulcerated, to the base of the biopsy specimen. There was no evidence of maturation from superficial to deep. There was no extensive in situ component of a melanoma and no characteristic junctional component of a nevus, although the lesional cells appeared to be in contact with the epidermis at the edges of the ulcer. Although the possibility of a benign Spitz nevus/tumor was considered, this lesion did not demonstrate the typical "large spindle and/or epithelioid" cell type of Spitz tumors, and nor did it have a characteristic junctional component. However, a single Kamino-like body was noted in a superficially located dermal nest. The presence of extensive consumption of the epidermis and of extensive ulceration was also against the diagnosis of a Spitz tumor. Finally, the dermal mitotic rate was very high at 11 per square millimeter. The ulcer was greater than 3 mm in diameter. Radial growth phase regression, microscopic satellites, and vascular, lymphatic or neural invasion could not be satisfactorily evaluated in this superficial biopsy. For these reasons, this lesion was interpreted as follows below. A subsequent reexcision procedure was negative for residual tumor. Multiple axillary sentinel nodes were biopsied, and one of these contained deposits of metastatic tumor, in the form of scattered small metastatic tumor deposits within the sinus and superficial parenchyma. Four additional sentinel nodes were negative for tumor. These findings were interpreted as follows below.

Differential Diagnoses:
Differential diagnoses include an ulcerated compound nevus, a Spitz nevus/tumor, an atypical Spitz nevus/tumor, a Spitzoid melanoma of childhood, or a malignant melanoma.

Final Diagnosis:
Skin, back: Malignant melanoma, nodular type, ulcerated, with epithelioid tumorigenic and mitogenic vertical growth phase, and Spitzoid features, extending to Clark's level IV at a greatest Breslow thickness of at least 1.1 mm, transected at the specimen base. Right Axillary Sentinel Node Number Three, Biopsy: Metastatic Melanoma involving one lymph node (1/1), without extracapsular extension. Skin and Subcutaneous Tissue, Right Lower Back, Wide Excision: Scar and healing surgical site changes, no residual melanoma identified.

Case Discussion:
This case exemplifies the difficulty in diagnosing Spitzoid tumors in patients of all ages. These lesions are most common in children. Metastasis to sentinel nodes is surprisingly common in these lesions, however the overall survival experience has been excellent in a number of reported series, albeit with somewhat limited follow-up intervals.

Review of the Literature/Treatment Options (if applicable):
The lesion described by Sophie Spitz has caused problems of interpretation ever since her seminal publication [1]. Initially, these were thought to be "juvenile melanomas", perhaps with a better prognosis than adult melanomas. However, one of the lesions described in her paper had resulted in the death of the child. Although most of these lesions are indeed benign, similar difficulties of prediction persist to this day in some atypical lesions which are rare in routine practice but common in consultation practices. It has therefore become the rule to refer to these lesions as "Spitz tumors" rather than "Spitz nevi" [2]. The term "melanocytoma" has also been used recently to convey a sense that the behavior of these lesions is somewhere between benign lesions (the usual situation), or lesions with various degrees of malignancy [2]. The single defining characteristic of a typical Spitz tumor is the presence of large spindle and/or epithelioid cells, a term attributable to Ackerman [3]. Characteristic Spitz tumors are small and symmetrical. The lesional cells are characteristically monotonously similar from side to side across the lesion at any given level, and show evidence of maturation to a smaller cell type toward the base. At the base, the cells disperse as single cells into the reticular dermis. The overlying epidermis is typically hyperplastic without evidence of "consumption of the epidermis" or ulceration. Curious globoid eosinophilic "Kamino bodies" are typically present near the interface. Typically there is little or no pagetoid scatter of lesional cells into the epidermis above the dermal component or adjacent to it. The mitotic rate is generally low, without abnormal mitoses and without mitoses in the lower third of the lesion [4]. Deviations from this ideal morphology may lead to characterization of the lesions as representing "atypical Spitz tumors", "Spitzoid melanocytomas of uncertain malignant potential", or "Spitzoid melanomas", depending on their severity [2]. Criteria for Spitz tumors as discussed above will usually permit a competent distinction of these lesions from invasive melanoma. However, some lesions demonstrate hybrid characteristics between classical Spitz tumors and vertical growth phase melanoma. These diagnostically challenging lesions have been termed "atypical Spitz tumors", as has been proposed by Barnhill and Spatz and colleagues [5, 6, 7]. For such lesions, it was proposed that points could be assigned if certain features were present (designated by asterisks in Table I). A patient age of > 10 years or a diameter > 10 mm are each assigned 1 point, the presence of fat involvement, of ulceration or a mitotic rate of 6-8 per square mm are each assigned 2 points, and a mitotic rate of > 8 is assigned 5 points. On this scale, 0-2 points indicates low risk, 3-4 indicates intermediate risk, and 5-11 indicates high risk. This system worked well in a series of 30 childhood Spitz tumor patients, eleven of whom had a history of metastasis and 19 of whom had long disease-free follow-up. However, validation in an external system is required, and therapeutic guidelines do not readily flow from this classification. Another study of 33 cases of Spitz tumor and 19 of malignant melanoma in patients aged 20 years or less identified prominent pagetoid spread, cellular pleomorphism, nuclear hyperchromasia and mitotic activity as the most striking differences between Spitz tumors and melanomas. These authors stressed the importance of cytological as well as architectural features in distinguishing between these two groups, and emphasized that there is overlap in the histologic features [8]. Although it is well known that mitoses may be seen in Spitz tumors, the mitotic rate is generally very low. Commonly there are no mitoses at all in a Spitz tumor. Failure to find mitoses after a careful search can be a very reassuring negative finding in a lesion that may have given rise to concern for some other reason, such as the presence of a few cells in the epidermis, or its size and depth. While mitoses may be seen in Spitz tumors, they are most common in the epidermis and in the upper third of the dermis; mitoses in the lower third of the lesion are uncommon except in young children [9]. Abnormal mitoses are quite rare in Spitz tumors [8], although it is said that they may occur [9]. Certainly, a clearly abnormal mitotic figure should prompt careful consideration of other aspects of the lesion before an unqualified benign diagnosis is issued. Few if any benign Spitz tumors exhibit a "high" mitotic rate (more than 6 mitoses per square mm). In the studies of Crotty et al, the presence of abnormal mitoses, a dermal mitotic rate of >2/mm2, and mitotic figures within 0.25 mm of the deep border of the lesion were features that favored melanoma [10]. In Spitz tumors, mitotic figures may be seen in hyperplastic keratinocytes, a finding rare in common nevi, but not unusual in melanomas. Spontaneous ulceration or necrosis is very uncommon in a benign Spitz tumor [8], as is the interesting phenomenon of "consumption of the epidermis" [11]. There are a few ulcerated Spitz tumors that presented with a history of trauma, especially in children who may pick at these occasionally itchy lesions. Spitz tumors that show several of the atypical features discussed above may be very difficult to distinguish from melanoma, and sometimes a descriptive diagnosis is all that can be rendered in a very difficult case. In a study in which nine cases selected for their diagnostic difficulty were circulated among "expert" pathologists, the reproducibility of the diagnosis of Spitz tumor was very poor [12]. In another study of diagnostic reproducibility for selected difficult and metastasizing lesions each of which exhibited some criteria for the Spitz tumor, evaluation of 17 Spitzoid lesions, some of which had metastasized, yielded no clear consensus as to diagnosis; in only one case did six or more pathologists agree on a single category, regardless of clinical outcome. Notably, some lesions that proved fatal were categorized by most observers as either Spitz nevi or atypical Spitz tumors [5]. Yet another study of diagnostic reproducibility found disagreement to be concentrated in the category of Spitz tumors" and "Spitzoid" melanomas, for which there was a 35-40% overall disagreement rate among 6 reference pathologists who reviewed a series of 72 cases chosen for their potential diagnostic difficulty; in contrast the agreement was very good for most other categories of lesions [13]. Metastasis of "Spitzoid" lesions, although uncommon, cannot be dismissed as a possibility in an atypical Spitzoid lesion. In a literature review, Urso found about 100 cases of "metastasizing Spitz tumors". Although histologic data were not uniformly recorded, this review indicated that any number of the following histologic features could be found in a metastasizing lesion [14]: 1. Nodular growth in the dermis and/or large confluent, solid, cellular sheets with no collagen fibers interposed between cells. 2. Extension of the neoplastic proliferation to the mid-deep dermis or to subcutaneous fat, especially if associated with absent or impaired maturation. 3. Dermal mitoses, especially in the deeper part of the tumor. 4. Marked nucleolar and/or nuclear pleomorphism. 5. Heavy melanization in the deeper part of the tumor. 6. Asymmetry. 7. Necrosis. 8. Epithelioid epidermal melanocytes below parakeratosis and/or epidermal ulceration. 9. Neoplastic cells in lymphatic vessels. Many of these tumors, in our opinion, are best regarded as "melanocytic tumors of uncertain malignant potential. Recently, a group of cases assembled by Lorenzo Cerroni, MD was studied by a group of experts and discussed at the annual meeting of the International Society of Dermatopathology in Graz, Austria [2]. These cases were selected as bulky tumors comprised of a uniform population of epithelioid or spindled cells. Not all were especially "Spitzoid"; some had features of deep penetrating nevi, pigmented epithelioid melanocytomas, or cellular blue nevi. Despite the size of the lesions, only a few small ulcers were observed and there was no in situ melanoma component. The lesional cells had abundant cytoplasm with large round or ovoid nuclei with regular nuclear membranes, pale chromatin and a single prominent nucleolus. Mitoses were absent in many lesions and if present the rate was low. About one third of these lesions had metastases, most often to regional nodes, and about 20% were fatal, often after a protracted at least initially indolent course. There were several instances of relatively long term survival after regional metastases, suggesting that some of these metastases, like the primary lesions, may be of uncertain malignant potential. It was considered that these lesions represented a form of relatively low grade malignancy compared to ordinary melanomas of similar depth, and use of the term melanocytoma was suggested as an expression of their intermediate characteristics between benign nevi and malignant melanomas. In addition to being noncommittal about prognosis, this term could encompass the range of morphologies observed in these lesions. Risk factors for aggressive behavior included the presence of mitoses, mitoses in the lower third of the lesion, and the presence of a lymphocytic infiltrate. Tentatively it has been proposed to classify these lesions into four risk groups: Minimal risk with none of these adverse factors, low risk with one of them, intermediate risk with two, and high risk with all three of the factors. Greater pigmentation and older age also correlated adversely with behavior to a lesser extent. Although as a gross generalization it may be true that "difficult" lesions are usually benign in terms of long-term follow-up [15], this is not invariably so. In our opinion, equivocal lesions exhibiting conflicting between those of benign and Spitz tumors and Spitzoid melanomas, if considered to fall short of an unequivocal diagnosis of melanoma, should be classified as "melanocytic tumors of uncertain potential (MELTUMP)" and the differential diagnosis of melanoma should be presented, with a discussion of staging attributes. More aggressive management of these atypical Spitz lesions may be warranted [16], and this in our opinion should be tailored to the individual case, including analysis of prognostic attributes that might apply if the lesion were interpreted as a melanoma. Management of problematical "Spitzoid" lesions should usually include a re-excision procedure, and follow-up of the patient. A sentinel lymph node sampling procedure may also be considered. In several reported studies the sentinel node has not uncommonly been positive [17, 18, 19, 20, 21, 22, 23, 24]. Interestingly, among these multiple reported cases of patients with atypical Spitzoid lesions and positive sentinel nodes, recurrences and especially deaths have been very rare. A recent study concluded that "pediatric patients have a higher incidence of SLN metastases than adults yet have a lower incidence of recurrence", and further "Sentinel lymph node status does not predict early recurrence in pediatric patients with melanoma or atypical Spitz nevi" [23]. Therefore, it seems likely that atypical Spitzoid lesions and even "Spitzoid melanomas" (at least those in children) may be associated with excellent survivals even after the finding of a positive sentinel node metastasis. For this reason, we will typically sign out these cases as "metastatic melanocytic tumor of uncertain malignant potential", recognizing that this is a descriptive and not a definitive diagnosis.

Conclusion(s):
In our present case, because of the very high mitotic rate, the ulceration, and lack of maturation of the dermal component, as well as other features, we regarded this young patient as having a malignant melanoma, with features consistent with a "Spitzoid melanoma of childhood". As discussed above, the prognosis is unpredictable, but better than one might expect for a usual form of melanoma with the same attributes. Currently, about 6 months after his sentinel node procedure, he remains free of disease.

References:
  1. Spitz S. Melanomas of childhood. Am J Pathol 1948;24:591-609.

  2. Cerroni L, Barnhill R, Elder D et al. Melanocytic tumors of uncertain malignant potential: results of a tutorial held at the XXIX Symposium of the International Society of Dermatopathology in Graz, October 2008. Am J Surg Pathol 2010 March;34(3):314-26.

  3. Paniago-Pereira C, Maize JC, Ackerman AB. Nevus of large spindle and/or epithelioid cells (Spitz's nevus). Arch Dermatol 1978 December;114(12):1811-23.

  4. Elder DE, Murphy GF. Melanocytic Tumors of the Skin. 2011.

  5. Barnhill RL, Argenyi ZB, From L et al. Atypical Spitz nevi/tumors: lack of consensus for diagnosis, discrimination from melanoma, and prediction of outcome. Hum Pathol 1999 May;30:513-20.

  6. Spatz A, Calonje E, Handfield-Jones S, Barnhill RL. Spitz tumors in children: a grading system for risk stratification. Arch Dermatol 1999 March;135(3):282-5.

  7. Barnhill RL, Flotte TJ, Fleischli M, Perez-Atayde A. Cutaneous melanoma and atypical spitz tumors in childhood. Cancer 1995;76:1833-45.

  8. Peters MS, Goellner JR. Spitz naevi and malignant melanomas of childhood and adolescence. Histopathology 1986;10:1289-302.

  9. Echevarria R, Ackerman LV. Spindle and epithelioid cell nevi in the adult. Clinicopathologic report of 26 cases. Cancer 1967;20:175-89.

  10. Crotty KA, Scolyer RA, Li L, Palmer AA, Wang L, McCarthy SW. Spitz naevus versus Spitzoid melanoma: when and how can they be distinguished? Pathology 2002 February;34(1):6-12.

  11. Hantschke M, Bastian BC, LeBoit PE. Consumption of the epidermis: a diagnostic criterion for the differential diagnosis of melanoma and Spitz nevus. Am J Surg Pathol 2004 December;28(12):1621-5.

  12. Schmoeckel C. How consistent are dermatopathologists in reading early malignant melanomas and lesions "precursor" to them? An international survey. Am J Dermatopathol 1984;6:13-24.

  13. Cerroni L, Kerl H. Tutorial on melanocytic lesions. Am J Dermatopathol 2001 June;23(3):237-41.

  14. Urso C. A new perspective for spitz tumors? Am J Dermatopathol 2005 August;27(4):364-6.

  15. McGovern VJ. Melanoma. Histologic diagnosis and prognosis. 1 ed. New York: Raven Press; 1983.

  16. Murphy ME, Boyer JD, Stashower ME, Zitelli JA. The surgical management of spitz nevi. Dermatol Surg 2002 November;28(11):1065-9.

  17. Urso C, Borgognoni L, Saieva C et al. Sentinel lymph node biopsy in patients with "atypical Spitz tumors." A report on 12 cases. Hum Pathol 2006 July;37 (7):816-23.

  18. Roaten JB, Partrick DA, Pearlman N, Gonzalez RJ, Gonzalez R, McCarter MD. Sentinel lymph node biopsy for melanoma and other melanocytic tumors in adolescents. J Pediatr Surg 2005 January;40(1):232-5.

  19. Su LD, Fullen DR, Sondak VK, Johnson TM, Lowe L. Sentinel lymph node biopsy for patients with problematic spitzoid melanocytic lesions: a report on 18 patients. Cancer 2003 January 15;97(2):499-507.

  20. Lohmann CM, Coit DG, Brady MS, Berwick M, Busam KJ. Sentinel lymph node biopsy in patients with diagnostically controversial spitzoid melanocytic tumors. Am J Surg Pathol 2002 January;26(1):47-55.

  21. Berk DR, Labuz E, Dadras SS, Johnson DL, Swetter SM. Melanoma and Melanocytic Tumors of Uncertain Malignant Potential in Children, Adolescents and Young Adults-The Stanford Experience 1995-2008. Pediatr Dermatol 2010 April 9.

  22. 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 January;15(1):302-9.

  23. Roaten JB, Partrick DA, Bensard D et al. Survival in sentinel lymph node-positive pediatric melanoma. J Pediatr Surg 2005 June;40(6):988-92.

  24. Ludgate MW, Fullen DR, Lee J et al. The atypical Spitz tumor of uncertain biologic potential: a series of 67 patients from a single institution. Cancer 2009 February 1;115(3):631-41.