Clinical Image
Focal Fibrocartilaginous Dysplasia (FFCD)
Zied Jlalia* and Mahmoud Smida
Department of pediatric orthopedics, Kassab institute, Kasar Said 2010 La Manouba, Faculty of Medicine, Tunis El
Manar University, Tunis, Tunisia
*Corresponding author: Hilary Somerset, Department of Pathology, University of Colorado SOM 12605 East 16th Avenue, Mail Stop F768, Aurora, CO 80045, Colorado
Published: 24 Oct, 2016
Cite this article as: Somerset H. Hyalinizing Clear
Cell Carcinoma as a Secondary
Malignancy in a Childhood Survivor of
Rhabdomyosarcoma. Ann Clin Case
Rep. 2016; 1: 1166.
Abstract
Secondary malignancies are an infrequent but well-known phenomenon whereby radiation treatment may predispose a patient to a subsequent malignant neoplasm years after his or her initial diagnosis. The head and neck is a common site for post radiation carcinomas including salivary gland tumors such as mucoepidermoid carcinoma (MEC), acinic cell carcinoma, and even (more recently described) mammary analogue secretory carcinoma (MASC). Hyalinizing clear cell carcinoma (HCCC) is a rare, low-grade carcinoma of the minor salivary glands with characteristic histologic and molecular findings. We report a case of HCCC of the lower lip arising as a secondary malignancy in a 40-year-old woman with a history of childhood rhabdomyosarcoma for which she received radiation therapy. To our knowledge, this report represents the first instance of HCCC being presented as a secondary head and neck malignancy. This case contributes to the spectrum of post radiation carcinomas and highlights the persistent risk of subsequent malignancies in childhood cancer survivors.
Keywords: Hyalinizing clear cell carcinoma; Rhabdomyosarcoma; Secondary malignancy; Radiation therapy
Introduction
Hyalinizing clear cell carcinoma is a rare minor salivary gland tumor characterized by a consistent
EWSR1-ATF1 fusion and distinct histology including some component of clear cells within a
hyalinized stroma [1]. HCCC was first described by Milchgrub et al. [1] in 1994, although it was
initially regarded as a diagnosis of exclusion in the absence of characteristic features of other clearcell
salivary gland tumors (e.g. mucoepidermoid carcinoma, epithelial-myoepithelial carcinoma,
myoepithelial carcinoma, etc.). HCCCs are now recognized as a distinct pathologic entity with a
EWSR1-ATF1 fusion oncogene due to a t (12;22) [2]. Although this translocation is also described
in other tumor types including some clear cell sarcomas and angiomatoid fibrous histiocytomas, the
exact breakpoints of EWSR1 and ATF1 are considered a unique and defining feature of HCCC [2].
HCCCs occur most commonly in the minor salivary glands of the oral cavity--especially
the palate and tongue base--with perhaps a slight female predilection [3]. As the name implies,
histologically HCCCs demonstrate nests and cords of clear cells within a hyalinized stroma with
infiltrative borders and frequent perineural invasion [1,3]. Despite these latter features, HCCCs
are typically low-grade carcinomas and tend to pursue an indolent clinical course with only rare
reported metastases and/or aggressive features [1,4-5].
Thus far, HCCC has only been reported as a primary malignancy. Herein we report a case of
HCCC arising in the post-radiation setting of a childhood survivor of rhabdomyosarcoma.
Case Presentation
A 40-year-old woman with a history of rhabdomyosarcoma of the left cheek / nose area (diagnosed at age 1 with a recurrence at age 8) presented to the ENT clinic with a one year history of a left lower lip mass. The patient reported that the mass may have slightly increased in size during her recent pregnancy, but was otherwise stable. MR Imaging of the face was non-diagnostic due to the patient's dental implants which obscured any interpretable views of the lips. On exam, the patient was found to have a firm, non-mobile lower lip mass measuring approximately 0.5 cm. The mass was excised and the postoperative course was unremarkable. Per the electronic medical records, the patient's childhood rhabdomyosarcoma was managed with wide local excision and adjuvant therapy including chemotherapy and radiation therapy.
Results
Pathological evaluation
Sections show a highly infiltrative tumor located adjacent to
minor salivary glands with extension into underlying skeletal muscle
(Figure 1A). The overlying squamous epithelium is uninvolved. The
tumor is characterized by nests and cords of monomorphic polygonal
cells with clear (to pale eosinophilic) cytoplasm in a densely hyalinized
stroma (Figure 1B and C). Mitoses are inconspicuous. Perineural
invasion is present, but there is no lymph-vascular invasion (Figure
1D). No high-grade features such as necrosis, anaplasia or increased
mitotic activity were seen. Attempts to retrieve the slides from the
original rhabdomyosarcoma were unsuccessful, as materials were no
longer available.
Molecular evaluation
Fluorescence in situ hybridization (FISH) for EWSR1 was
performed on the lip mass with a EWSR1 dual-color break-apart
22q12 probe (Abbott Molecular, Des Plaines, IL) where the 5' EWSR1
signal was labeled with orange and the 3' EWSR1 signal was labeled
with green. One hundred tumor nuclei were evaluated and split
signals defined as 5' and 3' signals observed at a distance greater than
one-time signal width. Fused (i.e. yellow) signals in uninvolved cells
served as an internal control and the FISH was considered positive if
greater than 20% of nuclei demonstrated a split or isolated 5' signal.
The FISH was positive for a EWSR1 rearrangement (Figure 2).
Discussion
Despite ongoing advances in cancer therapeutics, the unfortunate
paradox of cancer treatment persists: that is, it can be both curative and
oncogenic. Specifically, secondary malignancies are an uncommon
but important complication of radiation therapy. Meadows et al.
[6] recently reported the thirty-year cumulative incidence of second
malignant neoplasms in childhood survivors of cancer as 9.3%,
a figure that remained elevated even when age-matched controls
independently reached ages associated with an increased likelihood of cancer [6].
This enduring risk underscores the importance of judicious use
of radiation therapy especially in children as well as the need for
ongoing surveillance and follow-up of this unique patient population
(i.e. childhood cancer survivors) even well into adulthood.
In our case the patient was diagnosed with a childhood
rhabdomyosarcoma for which she received radiation therapy. She
then presented over thirty years later with a second malignancy. This
experience is congruent with the findings from the Childhood Cancer
Survivor Study Cohort, as the cohort demonstrated: 1) a greater
risk for female versus male survivors, 2) a four-fold higher risk of
carcinoma than expected comparted to the general population, and
3) head and neck carcinomas (especially the parotid gland) as among
the most common sites for carcinomas [6].
Among head and neck tumors, several salivary gland tumors have
been previously documented as secondary malignancies including
mucoepidermoid carcinoma, acinic cell carcinoma, and more
recently mammary analogue secretory carcinoma [7-10]. To our
knowledge, however, heretofore hyalinizing clear cell carcinoma has not been implicated as a secondary malignancy.
The purported mechanism of carcinogenesis for secondary
malignancies involves chromosomal rearrangements between
nearby locations and break-points induced by ionizing radiation,
a phenomenon that has been previously described in head and
neck tumors including papillary thyroid carcinoma (PTC) and
mucoepidermoid carcinoma [11]. It is not surprising then, that many
of the second malignancies (e.g. PTC, MEC, MASC) tend to harbor a
defining translocation, as was seen in our case. Although we cannot
firmly prove that this HCCC is radiation-induced, it does meet Cahan
criteria in that it: 1) arose within the radiation field, 2) occurred
greater than five years following the original receipt of radiation,
and 3) exhibited different histology that the original diagnosis [12].
Also, the patient did not have any known cancer predisposition
syndromes. Finally, while we acknowledge that we can't fully exclude
a coincidental occurrence of sarcoma and carcinoma in our patient,
we feel that the rarity of each diagnosis, the novel molecular changes,
and the history of radiation therapy make a causal relationship much
more plausible.
In summary, we expand the breadth of secondary head and
neck malignancies by describing for the first time the occurrence
of HCCC, a rare salivary gland tumor, in a childhood survivor
of rhabdomyosarcoma. This case emphasizes how novel fusion
transcripts (i.e. EWSR1-ATF1) may result after treatment of the
primary cancer, and reminds us that the risk of secondary malignancy
remains relevant even decades after the initial diagnosis. Although
certain types of head and neck tumors are well recognized to occur
after receipt of radiation therapy to the region, there is always a level
of uncertainty when new tumor types appear to be radiation-induced.
We document this current case of HCCC to make other investigators
aware of the possibility that HCCC may also radiation-induced and
to provide the precedent case.
Figure 1
Figure 1
(a) HCCC adjacent to minor salivary glands with uninvolved squamous epithelium (hematoxylin and eosin x20). (b,c) Characteristic histology for HCCC
with clear cells arranged in nests and cords within a hyalinized stroma (hematoxylin and eosin, x200, x400). (d) HCCCs are highly infiltrative tumors with frequent
perineural invasion (hematoxylin and eosin x200).
Figure 2
Figure 2
A FISH dual-color break-apart probe confirmed the present of
EWSR1 (22q12) gene rearrangement. The split orange and green signals
(arrows) indicate a positive break-apart pattern. Images courtesy of Dr. Raja
Seethala at UPMC.
Acknowledgement
Special thanks to Dr. Raja Seethala at the University of Pittsburgh for his expert consultation including FISH studies and images.
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