Digging into uncertainty: a case report on Spitz lesions
Eva Klara Merzel Šabović1,2, Dragan Jejinić1, Andreja Pagon1, Nina Jugovar1, Violeta Hosta1 ✉
1Department of Dermatology, Ljubljana University Medical Center, Ljubljana, Slovenia. 2Faculty of Medicine, University of Ljubljana, Ljubljana, 
Slovenia.
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2024;33:49-52
doi: 10.15570/actaapa.2024.2
Introduction
Spitz lesions represent a spectrum of melanocytic proliferations, 
including benign Spitz nevi, atypical Spitz tumors with intermedi-
ate malignant potential, and malignant Spitz melanomas. Among 
the Spitz lesions, Spitz nevi are the most common and are mainly 
found in children and young adolescents. Atypical Spitz tumors are 
rarer than Spitz nevi, but they also appear in the same age group 
(1). They can be divided into two groups: low- and high-grade. This 
subtype can guide further management (2). However, the manage-
ment of atypical Spitz tumors is challenging and often requires a 
multidisciplinary approach because definite recommendations for 
management and treatment have not yet been established.
Case report
A 23-year-old female patient presented to the dermatology de-
partment with a long-standing pink papule on her right thigh 
(Fig. 1). The patient could not remember how long the lesion 
had been present. The clinical and dermatoscopic examinations 
were inconclusive; hence, she was referred for total excision and 
histopathological examination of the lesion. Low-magnification 
pathological examination revealed a small, symmetrical, and 
well-circumscribed compound melanocytic neoplasm (Fig. 2). 
Moreover, at high magnification, pathological examination re-
vealed melanocytes organized in large nests and short fascicles. 
The constituent melanocytes were plump and varied in shape, 
from epithelioid to spindle-like. Vertically oriented nests of mel-
anocytes were observed at the dermoepidermal junction. At the 
central part of the lesion, there were large melanocytes in a paget-
oid pattern at all levels of the epidermis, with a non-brisk lympho-
cytic infiltrate. Ulceration and mitotic activity were not observed 
(Fig. 3). Owing to the marked atypia of melanocytes, a significant 
diagnostic dilemma emerged in differentiating high-grade atypi-
cal Spitz tumor and melanoma. Immunohistochemical studies 
revealed negative BRAF V600E and n-RAS staining. Furthermore, 
a mosaic pattern of preserved p16, intradermally negative HMB45 
that was positive in the junctional component was observed. Mel-
anA/Ki67 showed no proliferation activity in intradermal melano-
cytes. ALK, ROS1, and pan-TRK staining was negative. Based on 
inconclusive immunohistochemical studies, mutational studies 
using RNA next-generation sequencing (NGS) have revealed an 
AGK-BRAF fusion. Taking all the data into account, the lesion was 
finally confirmed to be a high-grade atypical Spitz tumor. BRAF 
fusion has been proven to have a clear molecular genetic back-
ground without other genetic occurrences, such as mutations, de-
letions, and fusions. Owing to the final diagnosis of a high-grade 
atypical Spitz tumor, re-excision with 10 mm margins was recom-
mended. Further management of the patient included regular 
follow-up visits every 6 months for at least 5 years, in accordance 
with recent recommendations (2). Due to the AGK-BRAF fusion, 
she was also referred for locoregional lymph node sonography 
twice yearly for 5 years. During the follow-up of 2 years, we ob-
served no recurrence or metastasis, and locoregional lymph node 
sonography was negative each time. However, we will continue 
with patient follow-up.
Abstract
Spitz lesions represent a spectrum of melanocytic proliferations, and they include Spitz nevi, atypical Spitz tumors, and Spitz 
melanomas. Atypical Spitz tumors are intermediate melanocytic lesions with features between benign Spitz nevi and malignant 
Spitz melanomas. They often present a diagnostic challenge to pathologists and dermatologists alike because they can mimic 
melanoma, especially high-grade atypical Spitz tumors. Importantly, they present a relevant clinical management challenge be-
cause definite recommendations for their management and treatment have not yet been established. Here we present the case 
of a young patient with a high-grade atypical Spitz tumor along with the diagnostic procedure and further management. We also 
review potential pitfalls in the literature that should alert clinicians to the more aggressive potential of the lesion, such as some 
BRAF fusions.
Keywords: atypical Spitz tumor, intermediate melanocytic tumor, AGK-BRAF fusion
Acta Dermatovenerologica 
Alpina, Pannonica et Adriatica
Acta Dermatovenerol APA
Received: 2 February 2023 | Returned for modification: 8 May 2023 | Accepted: 16 October 2023
✉ Corresponding author: violeta.hosta@kclj.si
Figure 1 | Pink papule on the patient’s right thigh.
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Acta Dermatovenerol APA | 2024;33:49-52E. K. Merzel Šabović et al.
Discussion
Spitz nevi were initially termed juvenile melanomas because of 
their histological resemblance to melanomas. However, the young 
age of patients and their relatively good prognosis led to the as-
sumption that their nature is indolent, unlike that of melanomas 
(3). Spitz lesions present epithelioid and spindle cell melanocyte 
morphology. Spitz nevi are rare; of all excised melanocytic lesions 
in all age groups, only 1% to 2% were diagnosed as Spitz nevi (4). 
Its incidence varies between one and 10 cases per 100,000 indi-
viduals (4). Many Spitz nevi are difficult to distinguish from mela-
nomas (4). Therefore, the discovery of BRAF mutations in can-
cers, including melanoma, and the absence of BRAF mutations in 
Spitz nevi led to an easier distinction between the two. Moreover, 
kinase fusions and translocations, including ROS1, ALK, RET, 
BRAF, NTRK1, MET, NTRK3, and MAP3K8, which are commonly 
found in Spitz lesions, are of additional help (5, 6).
The clinical differential diagnosis includes melanoma and oth-
er melanocytic lesions, including congenital melanocytic nevus, 
blue nevus, atypical nevus, and Clark nevus. Due to the pink or 
red coloration of the lesions, vascular lesions are also included 
in the differential diagnosis; namely, hemangioma, pyogenic 
granuloma, and angiofibroma. Finally, other lesions, such as der-
matofibroma, seborrheic keratosis, or basal cell carcinoma, can 
resemble Spitz lesions (4). Nevertheless, the key question regard-
ing diagnosis is the differentiation between high-grade atypical 
Spitz tumors and (Spitz) melanomas.
Diagnostic dilemma
Atypical Spitz tumors pose a diagnostic challenge to both clini-
cians and pathologists because they clinically and histologically 
mimic melanoma. Therefore, a stepwise histopathological ap-
proach is useful for differentiating between melanoma, Spitz ne-
vus, or atypical Spitz tumors (2). In many cases, expert consulta-
tion is required to obtain the final diagnosis (2).
Clinical presentation
There are some clinical differences that can help differentiate 
Spitz lesions. Clinical characteristics such as patient age, lesion 
location, lesion appearance (color, shape, and size), and dermo-
scopic patterns are important (4).
Spitz lesions can present in all age groups. However, both Spitz 
nevi and atypical Spitz tumors are most frequent in people be-
tween 15 and 35 years old, with a mean age of 22 years, whereas 
Spitz melanomas present at a mean age of 55 years (7). The dis-
tribution of Spitz lesions appears to be equal in both sexes (7). 
All Spitz lesions most commonly appear in the lower extremities, 
followed by the trunk and upper extremities (4). Nevertheless, 
in studies exclusively observing pediatric cases, Spitz nevi and 
atypical Spitz tumors were more frequently located in the head 
and neck region (8).
Spitz lesions vary in color, ranging from pink to black. Spitz 
nevi are typically less than 6 mm in diameter and are dome-
shaped, flat, or polypoid. Atypical Spitz tumors range between 5 
and 10 mm in diameter and present as plaques or nodules. Spitz 
melanomas are typically nodular and larger than atypical Spitz 
tumors, with a mean diameter of 1 cm (4).
The most frequent dermatoscopic pattern found in Spitz nevi is 
a starburst pattern, followed by a dotted vessel pattern and globu-
lar pattern (9, 10). However, atypical Spitz tumors most commonly 
demonstrate a multicomponent and nonspecific pattern, followed 
by a pattern of dotted vessels and white lines (11, 12). The white 
line pattern is indistinguishable from melanoma, which shows 
significant clinical, dermatoscopic, and histological overlap with 
non-pigmented Spitz nevi (12). Nodular Spitz lesions and lesions 
with asymmetrically distributed spitzoid features should be ex-
cised regardless of patient age (9).
Histopathologic features
The hallmark of Spitz melanocytic proliferation upon histological 
examination is the presence of epithelioid and/or spindled mel-
anocytes with abundant eosinophilic cytoplasm and frequently 
associated hyperplasia of the epidermis (13). Atypical Spitz tu-
mors show histopathological characteristics of Spitz nevi and 
melanomas. They present with at least one of the following: asym-
metry, ulceration, poor lateral demarcation, lack of maturation in 
the dermis, absence of Kamino bodies, greater extension down-
ward, mitosis in the dermis (> 2–6 mitoses/mm²), and abundant 
isolated melanocytes in the superficial dermis (1). Histopathologi-
cal features that are correlated with a higher risk of metastasis are 
asymmetry, ulceration, a high degree of mitosis in the deep der-
mal part, and high-grade cytological atypia (14). However, there 
Figure 2 | Histological examination (low magnification): a small, symmetrical, 
and well-circumscribed compound melanocytic neoplasm identified as an atyp-
ical high-grade Spitz tumor.
Figure 3 | Histological examination (high magnification): high-grade atypical 
Spitz tumor. Melanocytes are organized in large nests and short fascicles. Con-
stituent melanocytes are plump and vary in shape from epithelioid to spindle-
like. Vertically oriented nests of melanocytes are seen at the dermoepidermal 
junction. At the central part of the lesion there are large melanocytes in a pa-
getoid pattern at all levels of the epidermis. There is a non-brisk lymphocytic 
infiltrate. There is no significant mitosis in the melanocytes.
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Acta Dermatovenerol APA | 2024;33:49-52 Spitz lesion dilemmas
is no single parameter that would place the lesion in the atypical 
Spitz tumor group.
Ancillary methods
Whenever histopathology is insufficient to make the final diagno-
sis, ancillary methods are utilized, such as immunohistochemical 
staining, fluorescence in situ hybridization (FISH), or molecular 
genetic analysis (1, 13).
Molecular genetic analysis reveals driver genetic aberrations 
required for melanocyte proliferation, whereas additional genetic 
events, such as biallelic inactivation of CDKN2A and TERT pro-
moter mutations, are required for the development of a malignant 
Spitz lesion in most cases, but not in all cases (13). Identification 
of a primary genetic alteration helps distinguish a Spitz lesion 
from other melanocytic tumors. However, it cannot distinguish 
between atypical Spitz tumors and Spitz melanomas (15). Some 
driver genetic aberrations are more commonly associated with the 
benign spectrum of Spitz lesions, namely 11p amplification/HRAS 
mutation and tyrosine kinase fusions, whereas others are more 
common in atypical or malignant Spitz lesions, such as serine/
threonine kinase fusions. The latter also has the potential for ag-
gressive biological behavior. However, none of the genetic aberra-
tions has been found to be specific to a particular Spitz lesion (13).
BRAF fusions in melanocytic Spitz lesions are rare, occurring 
in 5% to 6% (15). However, when present, they are more common 
in atypical or malignant Spitz lesions because they are more likely 
to develop chromosomal copy number imbalances and progress 
to Spitz melanoma (15, 16). Chromothripsis is another mechanism 
involved in melanoma development (17). There are numerous fu-
sion partners with the BRAF gene, with AGK-BRAF being the most 
common (13, 16). An AGK-BRAF fusion was also observed in our 
case report. BRAF fusions can only be reliably detected by NGS, 
in contrast to tyrosine kinase fusions (ALK, ROS, and NTRK) and 
MAP3K8 fusions, which can also be detected by immunohis-
tochemistry and FISH, respectively (13, 15). Molecular genetic 
analysis has two limitations: availability and cost. However, iden-
tification of the driver genetic change is particularly important in 
(Spitz) melanoma because of the availability of targeted therapies. 
Treatment with BRAF or MEK inhibitors appears to be effective for 
BRAF-fused melanomas (15).
Prognosis
Atypical Spitz tumors, especially high-grade tumors, have been 
reported to metastasize to sentinel lymph nodes in up to 30% of 
cases (18). However, the 5-year survival rate exceeds 99% (19). 
This is because the disease does not progress beyond the nodal 
basin (20, 21). This was also confirmed by a recent meta-analysis 
in which the outcome of patients with a positive sentinel lymph 
node biopsy did not differ from that of patients with a negative 
sentinel lymph node biopsy (19). Furthermore, complete lym-
phadenectomy and adjuvant therapy are no longer recommended 
for patients with positive sentinel lymph node biopsy (19, 20). 
According to the available data, sentinel lymphadenectomy in 
atypical Spitz tumors does not have significant diagnostic value. 
However, whether removal of metastatic lymph nodes is of thera-
peutic benefit remains unclear (20). Additional techniques, such 
as molecular genetic analysis of the primary tumor, might have a 
role in predicting which atypical Spitz tumor might have the po-
tential to progress beyond the sentinel lymph node. It has been 
shown that atypical Spitz tumors with chromosomal copy number 
aberrations, homozygous deletions of 9p21 (22), BRAF or MAP3K8 
fusions (2, 23), and TERT promoter mutations (2, 24) may correlate 
with tumor progression beyond the sentinel lymph node. There-
fore, additional techniques, such as molecular genetic analysis, 
are not only important for the correct histopathological diagnosis 
but also for further management and prognosis of the patient.
Management
Atypical Spitz tumors can be low- or high-grade. According to re-
cent recommendations by experts, their management differs (2). 
In low-grade atypical Spitz tumors, excision with a 2 mm margin 
is recommended. In cases of complete removal of the tumor, re-
excision is not mandatory but is recommended. In high-grade 
atypical Spitz tumors, excision with a 5 to 10 mm margin and fol-
low-up physical examination every 6 months for at least 5 years is 
recommended (2). Sentinel lymph node biopsy is not recommend-
ed; however, caution is recommended in cases in which BRAF or 
MAP3K8 fusions (2, 23), TERT promoter mutations (2, 24), or ho-
mozygous 9p21 deletions (22) are present because these cases may 
follow a more aggressive course. In such cases, 10 mm margins are 
recommended (2) and possibly locoregional lymph node sonog-
raphy every 6 months for at least 5 years. This recommendation 
was also followed in our patient because of the AGK-BRAF fusion.
Conclusions
Atypical Spitz tumors present not only a diagnostic challenge but 
also a management challenge. Because many questions regarding 
diagnosis, prognosis, and further management remain, a multi-
disciplinary approach is needed in challenging cases. Moreover, 
new studies are needed to clarify existing issues, such as the pre-
cise malignant potential of atypical Spitz tumors, screening for 
metastases, and predictors of metastatic disease.
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