Balloon Cell Melanoma: Presentation of Four Cases with a Comprehensive Review of the Literature

Background: balloon cell melanoma represents less than 1% of all histological forms of malignant melanoma and represents a diagnostic challenge for the dermatopathologist. Methods: in this paper we present our cases of BCM found in our daily practice from 1 January 2008 to 31 December 2021, and we conduct a review of the literature relating to this entity in the period from the first description, 1970, to early 2022. Results: four cases of melanoma balloon cell have been extrapolated from our electronic database, while in the review of the literature we have identified 115 cases of patients with primary and/or metastatic BCM. Conclusions: we believe that future studies with numerous case series are essential not only to increase the knowledge of the pathophysiology of this neoplasm but also to correctly evaluate the response of BCM patients to new oncological therapies.


Introduction
Malignant melanoma poses an ongoing challenge for health systems across the globe, and incidence and prevalence rates continue to rise, making prevention a crucial issue [1]. It is known that the histological diagnosis has a fundamental significance in the correct nosographic classification, which supports decision making and planning of the different therapies [2]. However, the diagnosis is not always easy, and every day the dermatopathologist has to deal with complex pictures that require integration with immunohistochemical and molecular data. Furthermore, this neoplasm can arise at the level of other parts of the body, such as mucous sites including the oral cavity [3], the vagina [4] or intestine [5]. In this context, balloon cell melanoma (BCM), is a fairly rare, bizarre entity that can sometimes manifest not only in a context of melanoma metastases but also as a primary lesion [6]. Over time, different explanations have been proposed to justify the morphological changes, but ultimately, the best accepted view (also thanks to electron microscopy studies and acquisitions) is that an overproduction of swollen and defective melanosomes is at the origin of this morphotype [7]. In this paper, we present four cases of balloon cell melanoma, discuss their main differential diagnoses and perform an extensive review of the current literature in order to trace the state of the art and future prospects.

Materials and Methods
To carry out this work, the historical archive of our laboratory was consulted from 1 January 2008 to 31 December 2021, applying the term "Balloon Cell" for the search, so that only cases of malignant melanoma were extrapolated. Sections staining with Hematoxylin/Eosin (EE) and blocks were retrieved and re-analyzed by two pathologists with expertise in skin pathology (G.C. and A.C.). In the event that there was no agreement, a third dermatopathologist (C.A.) was included in the discussion. Clinical information was retrieved from fellow dermatologists and plastic surgeons, and, when not available, the patient or family members were contacted directly. In addition, a systematic review was elaborated following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A databases search of PubMed, Web of Science (WoS) and Scopus was performed for the period 1970-2021 using the following terms: balloon cell melanoma and melanoma with balloon cell in combination with each of the following: dermatopathology, skin. Only articles in English were selected. The last search was run on 31 December 2021. Eligible articles were assessed according to the Oxford Centre for Evidence-Based Medicine 2011 guidelines [8]. Review articles, meta-analyses, observational studies, case reports, survey snapshot studies, letters to the editor and comments to the letters were all included. Other potentially relevant articles were identified by manually checking the references of the included literature. An independent extraction of articles was performed by two investigators according to the inclusion criteria. Disagreement was resolved by discussion between the two review authors.

Results
Four cases of melanoma balloon cell have been extrapolated from our electronic database, the clinical-pathological characteristics of which are reported in Table 1. Records of two male (50.0%) and two female patients (50.0%) were retrieved, with balloon cell melanoma localizations in four different body districts. In three of the four cases (75.0%) the clinical suspicion was malignant melanoma. Microscopically, all the lesions had the same characteristics, consisting of more than 50% of "balloon-shaped" melanocytes. (Figure 1A-C). These cells featured an abundant and finely vacuolized cytoplasm and hyperchromatic nuclei, generally located in the periphery of the cell, but not pycnotic ( Figure 1D). Very rare mitoses were observed, and melanin was quantitatively reduced within the cell, with a "disordered" dispersion within the lesion itself and in the numerous melanophages ( Figure 1D). Architecturally, in all four cases, the cells were organized in large pale masses that replaced the dermis and seemed to thin the epidermis ( Figure 1B). These large solid sheets of "ballooniform" melanocytes were divided into irregular aggregates by thin collagenous septa. There were no clear signs of activity at the dermo-epidermal junction and/or pagetoid spreading. In the second case ( Figure 1B), a component of "spindle cell" melanoma could be observed. organized in large pale masses that replaced the dermis and seemed to thin the epidermis ( Figure 1B). These large solid sheets of "ballooniform" melanocytes were divided into irregular aggregates by thin collagenous septa. There were no clear signs of activity at the dermo-epidermal junction and/or pagetoid spreading. In the second case ( Figure 1B), a component of "spindle cell" melanoma could be observed.
Immunohistochemically, all four cases expressed S-100 protein and Melan-A ( Figure  2A,B), as well as positivity for HMB-45 and SOX-10.  In the review of the literature, a total of 137 records was initially identified, of which 33 were duplicates. After screening for eligibility and inclusion criteria, 70 publications were ultimately included ( Figure 3). The authors and clinical/pathological characteristics are summarized in Table 2. Most of the publications were case reports (n = 51), followed by reviews (n = 10), case series (n = 6) and editorials (n = 3). All studies included were rated as evidence level 4 or 5 for clinical research, as detailed in the Oxford Centre for Evidence-Based Medicine 2011 guidelines [8]. In total, 115 patients with primitive or metastatic balloon cell melanoma were described.
Of these 115 patients, 36 (31.3%) had a primary lesion starting in the back (1 case starting in the left shoulder blade); 20 (17.4%) a lesion starting in the extremities (17 cases in the upper limbs and 3 cases in the lower limbs); 11 patients (9.6%) had a primary head/neck lesion; 9 patients (7.8%) had primary BCM of the choroid or ciliary body, while 2 patients (1.7%) had BCM originating in the conjunctiva. Metasases were present in 15 patients (13.0%) at the time of observation, while in 9 cases (7.8%), the site of the first melanoma was unknown. Finally, there were two cases (1.7%) of primary lesions originating in the orbit (one of which was a uveal melanoma), two cases (1.7%) originating in the chest and cases (6.9%) starting in the anal canal and another case in the urethra. The mean age was 54 years, and the dimensions ranged from 0.3 to 5 cm in maximum diameter. In almost 90% of the cases the immunohistochemistry described positivity for S-100 protein and HMB-45, with 7% of the cases positive for Neuron-Specific Enolase (NSE) and 23.5% of the lesions expressed the carcinoembryonic antigen.
In the vast majority of cases, the clinical suspicion was that of an atypical pigmented lesion, suggestive of malignant melanoma. In a small number of cases, amelanotic lesions were appreciated. In the review of the literature, a total of 137 records was initially identified, of which 33 were duplicates. After screening for eligibility and inclusion criteria, 70 publications were ultimately included ( Figure 3). The authors and clinical/pathological characteristics are summarized in Table 2. Most of the publications were case reports (n = 51), followed by reviews (n = 10), case series (n = 6) and editorials (n = 3). All studies included were rated as evidence level 4 or 5 for clinical research, as detailed in the Oxford Centre for Evidence-Based Medicine 2011 guidelines [8]. In total, 115 patients with primitive or metastatic balloon cell melanoma were described.
Of these 115 patients, 36 (31.3%) had a primary lesion starting in the back (1 case starting in the left shoulder blade); 20 (17.4%) a lesion starting in the extremities (17 cases in the upper limbs and 3 cases in the lower limbs); 11 patients (9.6%) had a primary head/neck lesion; 9 patients (7.8%) had primary BCM of the choroid or ciliary body, while 2 patients (1.7%) had BCM originating in the conjunctiva. Metasases were present in 15 patients (13.0%) at the time of observation, while in 9 cases (7.8%), the site of the first melanoma was unknown. Finally, there were two cases (1.7%) of primary lesions originating in the orbit (one of which was a uveal melanoma), two cases (1.7%) originating in the chest and cases (6.9%) starting in the anal canal and another case in the urethra. The mean age was 54 years, and the dimensions ranged from 0.3 to 5 cm in maximum diameter. In almost 90% of the cases the immunohistochemistry described positivity for S-100 protein and HMB-45, with 7% of the cases positive for Neuron-Specific Enolase (NSE) and 23.5% of the lesions expressed the carcinoembryonic antigen.
In the vast majority of cases, the clinical suspicion was that of an atypical pigmented lesion, suggestive of malignant melanoma. In a small number of cases, amelanotic lesions were appreciated.

Discussion
Malignant melanoma continues to represent a very frequent malignant neoplasm, rapidly increasing worldwide, and this increase is occurring at a faster rate than that of any other cancer except lung cancer in women [1,6]. Histopathological diagnosis is still the gold standard for programming subsequent steps in the therapeutic diagnostic path of the affected patient [6], and a correct morphological and immunohistochemical recognition is the basis for improving the outcome of patients (in fact, the five-year relative survival rate for patients with stage 0 melanoma is 97%, compared with about 10% for those with stage IV disease) [1][2][3][4][5]. Among the best known different histological patterns, there are unusual and bizarre forms of MM [6] whose knowledge is important to reduce and avoid the risk of wrong diagnoses. In this view, BCM represents a very rare variant (<1% of all histological forms of melanoma), defined by at least the presence of 50% of melanocytes with balloniform histological appearance [7]. Over the years, there have been different reports of BCM since Gardner's first report in 1970 [9], which reported a case of BCM developed at the level of the back of an older patient. Since then, descriptions of this entity have multiplied ; there are up to about 115 patients described in the literature, according to our review conducted and presented in this paper. From the analysis of the studies included, the most represented primitive localizations turned out to be the back, the lower and upper extremities, the choroid and the district head/neck, with also two rare cases to depart from the conjunctiva. This heterogeneity of distribution with predominance of the back has been found also in our new four described cases (two cases to the back, one left leg case and one right flank case). As described in the literature, even in our presented cases, there were no distinctive clinical characteristics, being generally present the suspicion of MM. In this regard, in recent years, some authors [57] have tried to look for suggestive and distinctive dermaoscopic criteria for the diagnosis of BCM. Resente F. et al., for example, have found that elements such as yellowish structureless areas, white lines, irregular hairpin-shaped and curved vessels can be suggestive of BCM. Regarding the prognosis, from the analyzed works it does not seem that there is a substantial difference compared to the conventional melanoma, always depending on the thickness of Breslow; therefore, the degree and depth of balloon cell changes do not affect the prognosis.
An aspect of great importance for the dermatopathologist is represented by the differential diagnostics with benign and/or malignant lesions to balloniform cells (such as the nevus, a balloon cell) or to other skin neoplasms to clear cells. The differential diagnosis between nevus and melanoma balloon cells can be very complex, as both of these entities may present very similarly [6,39,45]: in this regard, it may be necessary to dissect the sample extensively in search of areas of possible conventional malignant melanoma that may orient the diagnosis in the right direction. On the contrary, in the case of rather mild melanocytes, without cytological features being atypical, we can think of the diagnosis of nevus as balloon cells. Consideration should also be given to the possibility of being faced with a Spitz a balloon cell nevus [79][80][81] where the presence of certain histological details may help to orient oneself. In the case of large cells and epithelioids, with a ground glass cytoplasm and vesicular nucleus, in the absence of significant mitotic activity and with presence of epidermal hyperplasia, we can reasonably think of a Spitz balloon cell nevus, especially in the case of persons under 20 years of age [6,80]. BCM may also be confused with non-melanocytic entities, including a classic differential diagnosis of renal cell carcinoma, but also with lesions such as clear-cell sarcoma (malignant melanoma of soft parts), xanthoma, hibernoma and clear-cell carcinoma of the lung, ovary and endometrium. Regarding clear-cell melanoma, although some authors have proposed a distinction with BCM, we tend to avoid using this nosographic category, as it can be easily confused with clear-cell sarcoma [6]. We also remember entities such as clear-cell syringoma, granular cell tumor, malignant eccrine acrospiroma, sebaceous carcinoma, atypical fibroxanthoma and lepromatous leprosy. In all these cases, immunohistochemical investigations and essential integration with clinical-anamnestic information may help in the correct nosographic classification [41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60].
In recent years, some authors such as Chen Y. have described cases of BCM developing a mutation of BRAFV600E in the metastatic setting and, therefore, brought attention to how this entity, despite the peculiar morphological characteristics, is able to behave also from the molecular point of view as a conventional MM. This is already affecting the therapeutic side, as shown by recent papers [67].

Conclusions
In this work we have presented four new cases of BCM, and covering a rather long period of time, we ended up dwelling on the latest molecular acquisitions also in the context of such a rare variant of MM. We believe that future studies with numerous case series are essential not only to increase the knowledge of the pathophysiology of this neoplasm but also to correctly evaluate the response of BCM patients to new oncological therapies. Institutional Review Board Statement: Not applicable because this one is a retrospective study with cases diagnosed during routine pathological activity.