Atypical Spitz nevus versus Spitz melanoma: Is age a ... of...Another study [13] reported clinical...

Journal of Case Reports and Images in Pathology, Vol. 6, 2020.

J Case Rep Images Pathol 2020;6:100039Z11CJ2020. www.ijcripathology.com

Jian et al. 1

CASE REPORT PEER REVIEWED | OPEN ACCESS

Atypical Spitz nevus versus Spitz melanoma: Is age a deceiving factor?

Charles Jian, Samih Salama, Gabriela Gohla, Sarab Mohamed, Brian H Cameron, Barbara Heller, Salem Alowami

ABSTRACT

Introduction: Spitz melanoma is very rare in the young pediatric (0–10) population, with clinical behavior differing from adult melanoma. It may be challenging to distinguish diagnostically from an atypical Spitz nevus, and patients’ young age may cause hesitation despite histological support.

Case Report: We present a case report of pediatric-type Spitz melanoma in a 4-years-8-months-old girl which was reviewed by pathology groups from 1 tertiary and 2 quaternary centers. A diagnosis was made only after extensive genetic testing in conjunction with the supporting evidence from histology and immunohistochemistry. 19 previously published case reports of pediatric-type Spitz melanoma are also reviewed and summarized to give insight into its presentation and prognosis.

Conclusion: This case report and review of literature highlights that age can be a misleading factor in reporting atypical melanocytic lesions, and may deter pathologists from diagnosing a tumor as malignant. While clinical history is indispensable in pathology practice, the patient’s age should not distract us from the histology. It also demonstrates the usefulness of molecular pathology

Charles Jian1, Samih Salama1, Gabriela Gohla1, Sarab Mo-hamed1, Brian H Cameron2, Barbara Heller3, Salem Alowami1

Affiliations: 1Department of Pathology and Molecular Medi-cine, Hamilton Regional Lab Medicine Program, McMaster University, Hamilton, ON, Canada; 2Division of Pediatric Surgery, Department of Surgery, Hamilton Health Scienc-es, McMaster University, Hamilton, ON, Canada; 3Depart-ment of Surgical Oncology, Hamilton Health Sciences and Juravinski Hospital and Cancer Center, Hamilton, ON, Canada.Corresponding Author: Charles Jian, 1280 Main Street West, Hamilton, ON L8S 4L8, Canada; Email: [email protected]

Received: 27 July 2020Accepted: 26 August 2020Published: 30 September 2020

as a future adjunct in the practice of pathology. Entities that overlap morphologically or that present with conflicting histological features may be more easily categorized based on the presence of genetic variants or deletions. In our case, p16 deletion and anaplastic lymphoma kinase (ALK) translocation were supporting features that in conjunction with histology clinched the diagnosis of melanoma.

Keywords: Age, Atypical Spitz nevus, Molecular pa-thology, Pediatric, Spitz melanoma

How to cite this article

Jian C, Salama S, Gohla G, Mohamed S, Cameron BH, Heller B, Alowami S. Atypical Spitz nevus versus Spitz melanoma: Is age a deceiving factor? J Case Rep Images Pathol 2020;6:100039Z11CJ2020.

Article ID: 100039Z11CJ2020

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doi: 10.5348/100039Z11CJ2020CR

INTRODUCTION

Spitz melanoma is a very rare disease in the pediatric population, and differs from adult melanoma [1, 2], with variation even between infants (0–10 years of age) and adolescents (11–19 years of age) [3–5]. In the prepubescent population, the majority of melanomas are of the pediatric Spitz melanoma/atypical Spitz tumor type, as this patient was, with a second biologically separate category of melanomas arising in association with giant congenital nevi or de novo. Prognostically, the former tends to be more low-grade or borderline malignant in behavior, despite metastasis to lymph nodes [6, 7], while the latter is aggressive and invariably fatal. A note is made of recent changes in categorization by the WHO in 2018, which distinguishes spitzoid melanoma, a



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purely morphological diagnosis, from Spitz melanoma, a subset of spitzoid melanoma with both the morphological features and the specific genetic signatures of mitogen-activated protein kinase (MAPK) activating alterations, which is present in this case [8]. This case report highlights age as a misleading characteristic in the diagnosis of Spitz melanoma, and a literature review is performed to examine trends, presentation, and prognosis in previous diagnoses of pediatric Spitz melanoma.

CASE REPORT

A 4-years-8-months-old Caucasian girl presented with an 18-month history of a 2.5 × 2.0 cm polypoid lesion with a 5 mm base on the right lateral lower chest wall, which clinically resembled a pyogenic granuloma (Figure 1). It had been enlarging since it was first discovered, frequently bled and wept, and was painful to the touch. There were no abnormal nodes palpable in the groin, axilla, or neck. The patient had no known past medical history or relevant family history. Specifically, there was no family history of melanoma or other genetic syndromes that predisposed this patient to developing malignancies.

The lesion was removed by a pediatric surgeon (BHC) approximately three weeks later with 3 mm clinical margins. She had a postoperative cellulitis wound infection that resolved with antibiotics. The pathology was initially reported as an atypical Spitz nevus with positive deep margins with concerns for melanoma. However, there was hesitation to diagnose the lesion as melanoma due to the patient’s age. Interdepartmental dermatopathology review agreed with the diagnosis of atypical Spitz nevus, with concerns for melanoma.

An external dermatopathology review again diagnosed the lesion as an atypical Spitz tumor with high grade melanocytic atypia and features concerning for melanoma. A further quaternary care dermatopathology review made the diagnosis of a pediatric-type Spitz melanoma with ALK rearrangement.

Subsequently a local expert oncologic surgeon was consulted (BH), and there was discussion of management with other North American children’s hospitals. The patient also underwent further workup, including a complete staging with computed tomography (CT) of the chest, abdomen, and pelvis as well as a head magnetic resonance imaging (MRI) which showed no evidence of metastatic disease. A sentinel lymph node study showed focal activity in the right axilla in keeping with activity in sentinel nodes. This led to the decision to proceed with a scar re-excision with 2 cm clinical margins, flap reconstruction, and sentinel lymph node biopsy. Six nodes were excised from the right axilla, five of which were positive for metastatic melanoma.

The patient recovered well and has subsequently undergone close clinical follow-up with clinical exams and ultrasound imaging of the chest for recurrence. As of 16 months following the initial resection, the patient remains free of disease.

Investigations

Routine histology of the original lesionBasic histology revealed a 2.5 cm polypoid tumor

with neutrophilic crusts (see Figures 2 and 3). The dermal tumor contained both epithelioid and spindle cells arranged in solid nests and sheets with abundant eosinophilic cytoplasm with no maturation, and demonstrated significant cellular atypia throughout, with bizarre nuclei and prominent nucleoli, nuclear pseudoinclusions, and multi-nucleated giant cells (see Figures 4 and 5). Mitotic rate was brisk at 5/mm2. Tumor depth was at least 9.5 mm, with positive deep margins.

Figure 1: Clinical presentation preoperatively of patient’s polypoid lesion (2.5 × 2.0 cm) on the right lateral lower chest wall.

Figure 2: Excised primary lesion, 40× magnification, H&E stain. The lesion consists of an ulcerated hyperplastic epithelium with a neutrophilic crust. The dermal lesion consists of solid nests and sheets of both epithelioid and spindle cells. The box denotes the field of view in Figure 3.



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ImmunohistochemistryThe tumor cells were strongly positive for melan-A,

WT-1, S100, and CyclinD1. It was focally positive for HMB45 in the upper dermis, a feature found more commonly in benign nevi. It was also patchy positive for

p16 (CDKN2A), demonstrating partial loss of expression. This was later confirmed with fluorescence in situ hybridization (FISH) which showed homozygous deletion of this tumor suppressor gene. Anaplastic lymphoma kinase was diffusely positive in the tumor cells. Ki67 was diffusely positive, demonstrating a high proliferation index. Figures 6 and 7 show micrographs of selected stains.

The tumor cells were negative for AE1/AE3 (pankeratin), SMA, CD34, myogenin, and desmin.

Figure 3: Excised primary lesion, 100× magnification, H&E stain. Cells contained abundant eosinophilic cytoplasm, large nuclei, and prominent nucleoli, extending through the dermis. There was no pagetoid spread, and no Kamino bodies were identified.

Figure 4: Excised primary lesion, 400× magnification, H&E stain, dermis. The lesion did not mature and demonstrated a high degree of pleomorphism with prominent nucleoli, multinucleation (arrows) and nuclear pseudoinclusions (arrowheads).

Figure 5: Excised primary lesion, 400× magnification, H&E stain, dermis. There were an estimated 5 mitoses per mm2. Two prominent mitoses (arrowheads) are seen here surrounding the blood vessels.

Figure 6: Excised primary lesion with H&E (top left) at 40× and immunohistochemistry stains (same magnification). The tumor stained positive for Melan-A (top right), focally positive in the upper dermis with HMB45 (bottom left), and negative for AE1/AE3 (bottom right), which stained the non-lesional epidermis.

Figure 7: Excised primary lesion with H&E (top left) at 40× magnification and immunohistochemistry stains. The lesion stained focally positive for p16 (top right), and strongly and diffusely positive for S100 (bottom left). Ki67 (bottom right, 100× magnification) staining demonstrated a high index of proliferation in tumor cells.

Molecular pathologyFluorescence in situ hybridization testing using a

melanoma kit for RREB1, MYB, CEP6, and CyclinD1 (11q13) probes was positive. While this did not equate to a diagnosis of malignant melanoma, this kit was found to be positive in 80–90% of diagnosed melanomas, and



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negative in 95–100% of benign nevi. However, benign Spitz nevi do have a higher incidence of positivity (10–35%), possibly due to polyploidy [9, 10].

Fluorescence in situ hybridization demonstrated homozygous loss of p16 (CDKN2A) tumor suppressor gene in the tumor. Break-apart FISH showed an ALK rearrangement.

Next-generation sequencing was performed on the tumor which detected no clinically relevant variants (i.e., class 1–3A) [11] in BAP1, BRAF, CDK4, CDK6, CDKN2A, GNA11, GNAQ, KIT, NRAS, EIF1AX, SF3B1, or HRAS. Sanger sequencing did not reveal a telomerase reverse transcriptase (TERT) promoter mutation in this tumor, which was a favorable prognostic factor.

DISCUSSION

Diagnosis of melanoma in the pediatric population is challenging, as there are numerous benign histologic mimics, especially in the Spitz nevus/Spitz melanoma spectrum. Other possible differential diagnoses can include Reed nevi, cellular blue nevi, or pigmented epithelioid melanocytoma. An extensive literature search for cases of cutaneous pediatric melanoma (0–10 years of age) was performed and showed that since 1987, only 19 individual cases of cutaneous pediatric melanomas have been published, highlighting the rarity of the diagnosis in this age group. See Table 1 for details on these case

reports. Pediatric-type Spitz melanomas rarely develop distant metastases despite nodal metastases [6, 12]. This is supported by our review; a large proportion (11/19) of the published cases appear to be clinically well on follow-up at around 12 months, 6 of these 11 cases reported a Breslow depth greater than 4 mm and had positive sentinel lymph nodes.

Another study [13] reported clinical findings similar to our own case, in which the presented lesion appeared to mimic a pyogenic granuloma. The lesion evolved into a rubbery, erythematous papule over one month, and began to ulcerate and bleed, similar to our presented case. While a pyogenic granuloma would be overwhelmingly more likely than melanoma in a 10-month-old child, our case demonstrates that melanoma should be considered in the differential, and that changes in the lesion’s appearance should be closely monitored.

Management of Spitz melanoma and atypical Spitz lesions in the pediatric population generally derives from guidelines for adult melanoma [12]. A sentinel lymph node biopsy (SLNB) is often performed to assess for the need for a complete lymph node dissection and adjuvant therapy. In children, while this is prognostically significant, it does not improve melanoma-specific survival [14].

Histologically our patient’s lesion met criteria for a malignant lesion. However, given the history and the patient’s young age, three separate groups of pathologists from two quaternary academic centers were

Table 1: Summary of case reports of cutaneous pediatric melanomas since 1987, by chronological order

Case Age/Sex Presentation Primary tumor size

Diagnosis Treatment Follow-up

Yuen et al. (2019) [15]

5/M Brown papule, mid upper back found at 2 years old, no ulceration

0.6 × 0.6 cm Invasive melanoma 1.2 mm depth

Wide excision of primary

Disease free 20 months post-diagnosis

Yamaguchi et al. (2019) [16]

2/F Scalp, arising from congenital melanocytic nevus. Rapid growth at 29-mo with ulceration pre-excision

13 × 11 cm (nevus pre-transformation)

Invasive melanoma 8.5 mm depth; metastasis to cervical lymph nodes by PET

Wide excision of primary, completion wide re-excision. Nivolumab initiated post-metastasis

N/A

Kumar et al. (2018) [17]

5/F Right retroauricular swelling (metastatic nodule); pigmented nodule in right periorbital region (primary)

1.3 × 1.0 cm Invasive melanoma, 6 mm. Metastatic to intraparotid lymph node

Parotidectomy, neck dissection, wide excision of primary

N/A, ongoing

Weyand et al. (2018) [18]

0/F (congenital)

Dark raised scalp lesion at birth

N/A; tumor present in liver, lungs, left tibia

Pigment synthesizing melanoma, 7.3 mm depth; widely metastatic

Nivolumab every 2 weeks

Stable disease 70 weeks post-diagnosis

Albino et al. (2015) [19]

3/F Dark raised lesion, anterior right knee. No bleeding/ulceration

0.6 × 0.5 cm Invasive melanoma, 4.95 mm (pT4a). SLN positive

Wide excision of primary, SLNB, CLND, medical adjuvant Tx

N/A



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Batra (2015) [20]

6/F Extremity N/A Spitz melanoma of childhood (depth not available), SLN positive, regional LND negative

Partial excision of primary with wide local re-excision, SLNB, CLND

Alive on follow-up at 17 months

10/M Extremity N/A Spitz melanoma of childhood (depth not available), SLN positive, regional LND negative

Wide excision of primary, SLNB, CLND. Interferon × 1 year


2/F Head/Neck N/A Spitz melanoma of childhood (depth not available), SLN positive, regional LND negative

Partial excision of primary with wide local re-excision, SLNB, CLND


4/F Head/Neck N/A Spitz melanoma of childhood with Breslow depth >4 mm

Wide excision of primary


Kollipara et al. (2015) [21]

3/M, Li Fraumeni syndrome, congenital choroid plexus carcinoma

Pink nodule behind left ear

1.0 × 1.0 cm Spitzoid melanoma of childhood, 6.5 mm depth

Excision of primary with 2 re-excisions, SLNB

Developed and died of myelodysplasia 14 months post-diagnosis with no recurrence

Tashiro et al. (2014) [13]

11 mo/F Non-pigmented, rubbery erythematous papule, right face. Developed ulceration pre-excision

N/A Spitz type melanoma 7.6 mm depth, SLN positive

Excision of primary with wide re-excision, SLNB


Katibi et al. (2014) [22]

3/F 6-mo history of multiple nodules on congenital melanocytic nevus in right axilla, with swelling in the axilla for 4 weeks. Extensive hyperpigmented patches on trunks and limb at birth

Multifocal 2 cm cutaneous nodules, with 10 × 7 cm axillary mass

Metastatic nodular melanoma on background of giant congenital melanocytic nevus, Clark stage 4; SLN positive by fine needle aspiration

Complete course of cisplatin, dacarbazine, vinblastine, interferon α-2B, granulocyte colony stimulating factor with minimal response. (Interleukin 2 was not available)

Died 1 month post-chemotherapy (4 months post-presentation, 12 months post initial discovery of lesion)

Sestini et al. (2012) [23]

4/M Black nodule on scalp, with satellitosis; no ulceration

1.0 × 1.0 cm Animal-type melanoma, 4.1 mm depth. SLN positive

Wide excision of primary, SLNB, LND of neck


Miranda et al. (2011) [24]

4/F Red nodule, increased in sized over 3 months, bled easily. Anterior right shin

0.5 × 0.5 cm at biopsy

Spitzoid melanoma at least 3.0 mm depth

Wide excision of primary, SLNB, interferon α-2B 1 year


Table 1: (Continued)



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hesitant to label the tumor as malignant. Despite the use of immunohistochemistry, it was in fact only after exhaustive molecular analysis of the tumor at a third, subspecialized academic center in conjunction with the investigations performed prior that allowed the final diagnosis of pediatric-type Spitz melanoma to be made.

CONCLUSION

This case demonstrates two major lessons. The first is that age can be a misleading factor in reporting atypical melanocytic lesions, and may deter pathologists from diagnosing a tumor as malignant. While clinical history is indispensable in pathology practice, the patient’s age should not distract us from the histology. Children can get melanoma, although the clinical behavior generally

differs from melanoma in adults. The second lesson highlights the usefulness of molecular pathology as a future adjunct in the practice of pathology. Entities that overlap morphologically or that present with conflicting histological features may be more easily categorized based on the presence of genetic variants or deletions. In our case, p16 deletion and ALK translocation were supporting features that in conjunction with histology clinched the diagnosis of melanoma.

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Fox et al. (2011) [25]

8/M Fast-growing pink papule posterior right shoulder

N/A Invasive melanoma >4 mm depth. SLN positive

Completion wide re-excision, SLNB, CLND, Interferon α-2B for 7 months; stopped from elevated liver enzymes


Bernhardt et al. (2009) [26]

2/F (20 mo) Superficial nodule, arising in 14 × 8 cm melanocytic nevus across mid lower back

1.5 × 1.2 cm Invasive nodular melanoma, small cell type, 5 mm depth. SLN positive

Wide excision of primary with SLNB, CLND of bilateral axilla. Initially treated with interferon α-2B. Recurrent on therapy. Subsequently with high-dose IL-2, with recurrence

Died 90 days post-completion of high-dose IL-2

Stănescu et al. (2009) [27]

10/F Lesion arising in flat tan congenital lesion, cutaneous superior lip, 4 mm diameter

0.6 × 0.6 cm Invasive melanoma 1.5 mm depth

Wide completion re-excision


Adedoyin et al. (2004) [28]

2.5/F 5-mo history multiple swellings in upper back, left axilla, on background of congenital giant hairy nevus

Multifocal 3–10 cm lesions on back, 10 cm axillary mass

Malignant melanoma with axillary lymph node metastasis; depth not available

Initial two doses vincristine and cyclophosphamide

Lost to follow-up secondary to treatment costs

Prose et al. (1987) [29]

0/F (congenital)

Mid-gastric nodular skin lesion, 6 wk history of increasing in size vertically. Jet-black, irregular shiny surface with focal ulceration

2.5 × 2.0 cm Malignant melanoma 9 mm depth

Excision of primary


CLND: completion lymph node dissection; PET: positron emission tomography; SLNB: sentinel lymph node biopsy.

Table 1: (Continued)



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2. Han D, Zager JS, Han G, et al. The unique clinical characteristics of melanoma diagnosed in children. Ann Surg Oncol 2012;19(12):3888–95.

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8. Raghavan SS, Peternel S, Mully TW, et al. Spitz melanoma is a distinct subset of spitzoid melanoma. Mod Pathol 2020;33(6):1122–34.

9. Gerami P, Mafee M, Lurtsbarapa T, Guitart J, Haghighat Z, Newman M. Sensitivity of fluorescence in situ hybridization for melanoma diagnosis using RREB1, MYB, Cep6, and 11q13 probes in melanoma subtypes. Arch Dermatol 2010;146(3):273–8.

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19. Albino FP, Wood BC, Oh A, Rogers GF, Sauerhammer T. A case of pediatric melanoma: Treatment considerations in advanced disease. Plast Reconstr Surg Glob Open 2015;3(5):e402.

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21. Kollipara R, Cooley LD, Horii KA, et al. Spitzoid melanoma in a child with Li-Fraumeni syndrome. Pediatr Dev Pathol 2014;17(1):64–9.

22. Katibi OS, Ogunbiyi A, Brown BJ, Adeyemi OO. Giant melanocytic nevus with malignant melanoma: A rare disorder in a black African child. Int J Dermatol 2014;53(10):1241–3.

23. Sestini S, Gerlini G, Brandani P, et al. ‘Animal-type’ melanoma of the scalp with satellitosis and positive sentinel nodes in a 4-year-old child: Case report and review of the literature. J Plast Reconstr Aesthet Surg 2012;64(4):e90–4.

24. Miranda SG, Kashani-Sabet M, Zedek D, McCalmont TH, Leong SPL. Erratum: Cutaneous spitzoid melanoma in a very young girl of Asian descent. BMJ Case Rep 2011;2011:bcr0920103343corr1.

25. Fox M, Tahan S, Kim CC. Livedo reticularis: A side effect of interferon therapy in a pediatric patient with melanoma. Pediatr Dermatol 2012;29(3):333–5.

26. Bernhardt MB, Hicks MJ, Pappo AS. Administration of high-dose interleukin-2 in a 2-year-old with metastatic melanoma. Pediatr Blood Cancer 2009;53(7):1346–8.

27. Stănescu L, Popescu CF, Georgescu I, et al. Spitz nevus with an uncertain malignant potential. Rom J Morphol Embryol 2009;50(2):275–82.

28. Adedoyin OT, Johnson AWBR, Ojuawo AI, Afolayan EAO, Adeniji KA. Malignant melanoma in a black child: Predisposing precursors and management. J Natl Med Assoc 2004;96(10):1368–73.

29. Prose NS, Laude TA, Heilman ER, Coren C. Congenital malignant melanoma. Pediatrics 1987;79(6):967–70.

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Author ContributionsCharles Jian – Interpretation of data, Drafting the work, Revising the work critically for important intellectual content, Final approval of the version to be published, Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved

Samih Salama – Conception of the work, Analysis of data, Interpretation of data, Revising the work critically for important intellectual content, Final approval of the version to be published, Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved

Gabriela Gohla – Conception of the work, Analysis of data, Interpretation of data, Revising the work critically for important intellectual content, Final approval of the



Jian et al. 8

version to be published, Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved

Sarab Mohamed – Analysis of data, Interpretation of data, Revising the work critically for important intellectual content, Final approval of the version to be published, Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved

Brian H Cameron – Acquisition of data, Revising the work critically for important intellectual content, Final approval of the version to be published, Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved

Barbara Heller – Acquisition of data, Revising the work critically for important intellectual content, Final approval of the version to be published, Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved

Salem Alowami – Conception of the work, Design of the work, Analysis of data, Interpretation of data, Revising the work critically for important intellectual content, Final approval of the version to be published, Agree to be accountable for all aspects of the work in ensuring that

questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved

Guarantor of SubmissionThe corresponding author is the guarantor of submission.

Source of SupportNone.

Consent StatementWritten informed consent was obtained from the patient for publication of this article.

Conflict of InterestAuthors declare no conflict of interest.

Data AvailabilityAll relevant data are within the paper and its Supporting Information files.

Copyright© 2020 Charles Jian et al. This article is distributed under the terms of Creative Commons Attribution License which permits unrestricted use, distribution and reproduction in any medium provided the original author(s) and original publisher are properly credited. Please see the copyright policy on the journal website for more information.

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