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An atypical chondroid syringoma with malignant degeneration: An atypical chondroid syringoma with malignant degeneration:

Utility of comparative genomic hybridization in confirming the Utility of comparative genomic hybridization in confirming the

diagnosis diagnosis

Shereen Zia

Brandon Shaw

Stephanie Chapman

Ben J. Friedman

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C A S E R E P O R T

An atypical chondroid syringoma with malignant degeneration:Utility of comparative genomic hybridization in confirming thediagnosis

Shereen Zia MD1 | Brandon Shaw PhD1 | Stephanie Chapman MD, MS2 |

Ben J. Friedman MD1,2

1Department of Pathology and Laboratory

Medicine, Henry Ford Hospital, Detroit,

Michigan

2Department of Dermatology, Henry Ford

Hospital, Detroit, Michigan

Correspondence

Ben J. Friedman, MD, Department of

Dermatology, Henry Ford Hospital, 3031 West

Grand Boulevard, Detroit, MI 48202.

Email: bfriedm1@hfhs.org

Abstract

Chondroid syringoma (CS) represents the cutaneous counterpart of mixed tumor

(pleomorphic adenoma) of salivary glands. Definitive diagnosis is made on histopa-

thology and is based on the presence of characteristic epithelial and stromal compo-

nents. We report a case of an atypical CS arising on the extremity of an elderly male

patient. Histomorphologic features of necrosis and cellular atypia raised suspicion for

malignant degeneration, an exceptionally rare circumstance in this context. To further

support the diagnosis of malignancy, array comparative genomic hybridization was

performed from both low and higher grade areas of the tumor. Both regions demon-

strated multiple copy number gains and losses, with additional loss of q7p (TP53), loss

of 19p, and loss of heterozygosity on16q demonstrated in the more atypical foci. To

our knowledge, this is the first case description of malignant degeneration of a CS

with correlative microarray analysis. The findings in this case may prove useful in

confirming the diagnosis in future ambiguous cases.

K E YWORD S

chondroid syringoma, comparative genomic hybridization, mixed tumor

1 | INTRODUCTION

Chondroid syringoma (CS; also known as cutaneous mixed tumor) is a

benign cutaneous neoplasm of sweat gland origin consisting of both

epithelial and mesenchymal components.1 It bears morphologic and

genetic resemblance to pleomorphic adenoma, the most common

tumor of the salivary glands.2 Features that contribute to a diagnosis

of CS include monomorphous epithelial cells arranged in cords and

tubules with a peripheral myoepithelial layer, and occurring within a

myxoid or chondroid stroma.3 Other variably present features include

foci of squamous differentiation and keratocyst formation, fat meta-

plasia, and bone formation. Recently it was discovered that some CSs

may harbor fusions in PLAG1, similar to those seen in pleomorphic

adenoma.2,4 Atypical and malignant forms of CS have been described,

though due to the uncommon nature of these tumors, reliable diag-

nostic criteria on histomorphology are a matter of debate.5,6

Moreover, the molecular events leading to malignant CS are largely

unknown. Interestingly, there have been cases of CS with a decep-

tively bland cytological appearance (analogous to so-called benign

metastasizing pleomorphic adenoma) that have later proven to behave

in a malignant fashion.7,8 In this report, we describe a case of malig-

nant CS arising within an atypical CS in which array comparative

genomic hybridization (aCGH) was found to be especially useful in

supporting a diagnosis of malignancy. To our knowledge, this is the

first report describing cytogenetic alterations in atypical and

malignant CS.

2 | CASE REPORT

An 84-year-old Caucasian male with the past medical history of diabe-

tes and hypertension presented with a slow-growing mass on his right

Received: 12 November 2020 Revised: 11 January 2021 Accepted: 12 January 2021

DOI: 10.1111/cup.13965

J Cutan Pathol. 2021;1–6. wileyonlinelibrary.com/journal/cup © 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. 1

upper extremity near the axilla that had been present for seven years.

On physical examination, a 9 × 7 cm subcutaneous nodule was seen

at the anteromedial aspect of the right arm. Excision of the mass was

recommended given its large size, though the clinical impression was

initially that of a lipoma.

Gross examination revealed a 7.5 × 7 × 4 cm multilobulated

mass with a thin pseudocapsule. The cut surfaces ranged from pink-

tan and indurated to red, soft, and hemorrhagic (Figure 1). Micro-

scopically, sections revealed a bulky proliferation of epithelial cells

arranged in large clusters and solid cords, embedded in a myxoid

and fibrous stroma (Figures 2 and 3). A surrounding rim of fibrosis

was observed, with the tumor cells seen expanding the dermis and

bulging into the subcutis. A large proportion of the epithelial cells

had associated cytoplasmic vacuolation and clear-cell morphology

(Figure 4). Focal gland formation and areas of chondroid matrix

were appreciated.

In the more central and deeper portions of the tumor, areas of

cystic degeneration and necrosis, irregular gland formation, cellular

atypia, and mitotic activity were identified (Figure 5). An extended

panel of immunohistochemical stains was performed. The cells of

interest were positive for Sox10, CK7, INI-1, S100, AE1/3 and GATA

(patchy), and were negative for hepatocyte antigen, PAX8, CK20,

CD31, HMB45, Melan A and CD34. Taken together, these findings

were consistent with a CS with atypical features worrisome for

F IGURE 1 Gross findings: Pseudoencapsulated multilobulated subcutaneous nodule with considerable hemorrhagic necrosis

F IGURE 2 Variably sized bluenodules are seen expanding thedermis and are enveloped infibrosis (H&E, ×15)

2 ZIA ET AL.

malignant degeneration. As the lesion was dissected out from sur-

rounding normal tissue, margin status could not be determined

microscopically.

A diagnosis of malignancy was favored based on

histomorphological features alone; namely, the large size, degree of

necrosis, presence of areas with increased mitotic activity, cellular

F IGURE 3 The tumor is seenbulging through the subcutis andcontains numerous cystic focialong with considerable necrosis(H&E, ×15)

F IGURE 4 Numerousinterlacing cords/whorls ofbasophilic cuboidal-polygonalcells are seen embedded in amyxoid and hyaline stroma (top

panel, H&E, ×100). On higherpower, mucinous foci (bottom leftpanel, H&E, ×400) along withclear-cell cytomorphology isevident (bottom right panel,H&E, ×400)

ZIA ET AL. 3

F IGURE 5 Areas of tumordemonstrating cysticdegeneration and necrosis (toppanel, H&E, ×100). On higherpower, mitotically activebasophilic-pale cuboidal cells areseen forming irregular glandularstructures and linear cords.Increased nuclear

hyperchromasia, pleomorphism,and apoptotic forms are alsoevident (lower panel, H&E, ×400)

F IGURE 6 Microarray plot. Top panel represents lower grade areas of the tumor corresponding to the photomicrographs in Figure 4. Lowerpanel represents the more atypical areas of the tumor corresponding to the photomicrographs in Figure 5. Lower panel with additional copynumber changes indicated by the red bar

4 ZIA ET AL.

atypia, and the identification of highly irregular glandular structures.

However, a small degree of doubt was raised based on the lack of dis-

cernable host tissue invasion and the possibility that the necrosis was

procedure-induced/trauma-related. Therefore, aCGH was performed

from two separate regions within the tumor: (a) more conventional-

appearing low grade area (top plot, Figure 6) more atypical-appearing

higher grade area (lower plot, Figure 6). Multiple copy number gains

and deletions were identified in both sampled areas, consistent with

atypical/unstable tumor clones. Specifically gains were seen in

1p22.2p21.3, 1p21.3p21.1, 1p21.1p13.2, 1q21.1q23.3, 4p16.3q35.2,

16p13.3q22.1, 16q22.1q24.3, 22q11.1q13.33, with losses seen in

1q32.2q44, 6p25.3q27, 8q12.1q12.2, 12p13.33, 12q12q14.2, and

Xq28 (homozygous loss). The deletions seen at 8q12 and 12q12

regions further supported the diagnosis of a myoepithelial neoplasm.9

Additionally, the more atypical portion of the tumor demonstrated

evidence of clonal evolution with additional loss of 17p13.3p11.2

(TP53), loss of 19p13.3p13.11, and loss of heterozygosity (LOH) on

16q11.2q24.3. Based on this additional information, a low-grade

malignant CS was the favored diagnosis. Correlation with

intraoperative findings was recommended to ensure that the tumor

was adequately excised. A positron emission tomography-computed

tomography scan failed to reveal any evidence of metastatic disease.

After discussion of the potential risks/benefits with the patient, the

decision was made to forgo a wider excision and to proceed with

close clinical surveillance alone. The patient has remained free of

detectable recurrence for seven months.

3 | DISCUSSION

CS is considered a rare tumor of sweat glands, first described by

Hirsch and Helwig in 1961.3 The reported incidence of CS is 0.01% to

0.098%.10,11Although there is no distinct clinical feature to aid in defi-

nite diagnosis, it usually presents as a firm, asymptomatic, skin col-

ored, slow-growing, solitary dermal, or subcutaneous nodule. The

typical size ranges from 0.5 to 3 cm.11-13 The most common site of

involvement is the head and neck, and it predominantly affects

middle-aged men.10

Histopathologically, the lesion is characterized by an admixture of

epithelial and mesenchymal elements; hence the term “mixed tumor.”The proposed histopathologic criteria by Hirsch and Helwig included five

features: (a) nests of cuboidal or polygonal cells; (b) intercommunicating

tubuloalveolar structures lined with two or more rows of cuboidal cells;

(c) ductal structures composed of one or two rows of cuboidal cells;

(d) occasional keratinous cysts; and (e) a matrix of varying composition.

The stroma exhibits varying density and can be chondroid, myxoid,

fibrous, hyaline, or osseous. The ductal and tubuloalveolar structures

consist of two types of cells: the darker, cuboidal to polyhedral cells lin-

ing the inner layer of these structures exhibit epithelial lineage, whereas

the light, low-cuboidal cells forming the outer layer of these tubular and

ductal structures manifest myoepithelial differentiation. Varela-Duran

et al proposed the pluripotentiality of the myoepithelial cells, citing their

role in the production of the chondroid areas of the tumor.14 Later on,

Mills determined that CSs are clonal neoplasms consisting of replicating

cells with the potential to differentiate toward epithelium or mesen-

chyme, which explains the tremendous diversity in histopathologic

appearance.15

The malignant variant of CS is extremely infrequent and may arise

from malignant transformation of an otherwise ordinary CS.16 Fea-

tures previously attributed to malignant CS include a greater propen-

sity to occur on the extremities, larger size, the presence of cellular

atypia and increased cellularity, increased mitotic rate, invasion of sur-

rounding tissue, and tumoral necrosis.5,6 Metastasis to regional lymph

nodes, as well as to distant sites such as bone and visceral organs, has

also been described.5,17 The term “cutaneous mixed tumor with

atypical features” was previously proposed for tumors with architec-

tural features of malignancy, though without evidence of metasta-

sis.5 Wide excision of the primary tumor is generally regarded as the

preferred treatment for the primary tumor, with radiation therapy

and chemotherapy potentially having a role in the setting of metasta-

sis (though the optimal efficacious systemic therapy is unknown

given the rarity of the tumor overall and lack of randomized con-

trolled trials).18

Progressive accumulation of genomic changes is a crucial step in

the alteration of normal biological mechanisms and eventual devel-

opment of malignancy within a tumor. aCGH is a molecular cytoge-

netic technique used in detecting chromosomal abnormalities and

locating regions of genomic imbalances. Results from our aCGH

assay further confirmed the lineage of the tumor by identifying early

known genetic events. In the context of myoepithelial neoplasms,

such as CS and pleomorphic adenoma, deletions of the 8q21 region

and the 12q12q14.2 regions are commonly reported findings.9 The

8q21 loss results in the loss of the first exon of the PLAG1 gene and

is most consistent with a PLAG1 gene (nuclear oncoprotein)

rearrangement with an unknown partner gene resulting in PLAG1

overexpression.2,4,19 The loss of 12q12q14.2 results in dysregulation

of the HMGA2 gene, which encodes for a transcriptional gene

regulator.20,21

Furthermore, our results show that aCGH may have a role in the

clinical setting when faced with a CS with atypical features to help

support or refute a diagnosis of malignant degeneration. This may be

particularly useful when only some, but not all the morphologic fea-

tures of malignant CS are identified on prepared sections or when

there is considerable atypia confined focally within the lesion. In this

case, the presence of considerable copy number changes (n = 14)

combined with the morphologic atypia observed and demonstrable

clonal evolution with loss of 17p (TP53) and LOH on 16q (likely

reflecting loss of another tumor suppressor gene) support a diagnosis

of malignant transformation. In particular, loss of TP53 is known to be

associated with disease progression and an adverse prognostic impact

in multiple settings including other cutaneous adnexal neoplasms.22,23

Additional larger studies examining the cytogenetic changes in benign

CS, atypical CS, and bona fide malignant CS are needed before firm

conclusions can be drawn regarding the exact number/threshold or

consistent genetic events that are associated with aggressive behavior

in this context.

ZIA ET AL. 5

4 | MATERIALS AND METHODS

4.1 | Summary of cytogenetic analysis

Following review by a pathologist, 10 slides were cut at 10 μm thickness

from a representative formalin-fixed and paraffin-embedded (FFPE) tissue

block and tumor was macrodissected using a H&E-stained slide as a guide.

DNA was extracted and purified according to the manufacturer's protocols

(Qiagen QIAmp DNA Mini Kit). Extracted DNA was quantified following

the manufacturer's instructions and diluted to a final concentration of

12 ng/μL with a total of 80 ng utilized. Chromosomal microarray analysis

of tumor samples was performed using the OncoScan FFPE Assay, which

utilizes Molecular Inversion Probe (MIP) technology to obtain accurate

genome-wide copy number and LOH profiles. The assay contains 22 000

probes across the genome and targeted cancer regions, allowing for detec-

tion of copy number abnormalities at 50 to 100 kb resolution in�900 can-

cer genes and at 300 kb resolution in other chromosomal regions. Patient

hybridization results are compared to data derived from over 300 FFPE

samples from unaffected tissues. All data were analyzed and reported using

the February 2019 Genome Reference Consortium Human Build 38 patch

release 13 (GRCh38.p13).

4.2 | Reportable range

Deletions larger than 1 megabase, duplications larger than 2 mega-

bases, and copy neutral LOH larger than 5 megabases are generally

reported; however, complex genomic alterations may be reported in

aggregate, and well-documented pathogenic constitutional and/or

acquired abnormalities of any size may also be reported. The genome

coordinates described are best estimates and may not represent pre-

cise breakpoints, especially for abnormalities detected in a low per-

centage of cells. The detection threshold for mosaicism is variable,

depending on the size of the segment. Common population number

variants cited in the Database of Genomic Variants are not reported.

CONFLICT OF INTEREST

The authors declare no potential conflict of interest.

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the

corresponding author upon reasonable request.

ORCID

Ben J. Friedman https://orcid.org/0000-0002-2266-8197

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How to cite this article: Zia S, Shaw B, Chapman S,

Friedman BJ. An atypical chondroid syringoma with malignant

degeneration: Utility of comparative genomic hybridization in

confirming the diagnosis. J Cutan Pathol. 2021;1–6. https://

doi.org/10.1111/cup.13965

6 ZIA ET AL.