2 | CASE REPORT
A 43-year-old Japanese woman with UCC was referred to the Department of
Radiation Oncology from the Department of Gynecology for definitive
radiotherapy. Histological analysis of the biopsy specimen showed the
presence of tumor cells with enlarged nuclei and pale-to-clear cytoplasm
exhibiting sheet-like growth and stromal infiltration (Figure
1 ). Immunohistochemical analysis of the biopsy specimen showed
positivity for p16, p53, and p63, leading to the diagnosis of squamous
cell carcinoma. In line with the pathological diagnosis, the patient
showed high levels of serum squamous carcinoma antigen (SCC, 19.0 ng/ml;
normal, <1.5 ng/ml). Genotyping of the biopsy specimen showed
positivity for human papillomavirus (HPV) type-31. Bimanual pelvic
examination revealed bilateral parametrium involvement not reaching the
pelvic sidewalls and the absence of vaginal involvement. Magnetic
resonance imaging detected a tumor (61 × 60 × 75 mm) located in the
uterine cervix with slightly increased intensity on T2-weighted images
extending to the bilateral parametria (Figure 2A, B ). Computed
tomography (CT) showed lymphadenopathy in the external iliac-, common
iliac-, and para-aortic-lymph node (PALN) regions (Figure
3A–C ). 2-deoxy-2-[18F]fluoro-D-glucose
(FDG)-positron emission tomography (PET) showed abnormal FDG uptake in
the primary tumor (Figure 2C ) and in the involved lymph nodes
(Figure 3D–F ). The CT and FDG-PET examinations showed no
evidence of metastasis to distant organ sites. The patient was diagnosed
as Stage IIB based on the 2008 definition by the International
Federation of Gynecology and Obstetrics.
The patient had a high-grade fever (39.1°C) with no symptoms of
infection. Blood tests showed a high white blood cell (WBC) count (28.3
× 103/mm3; normal, 3.0–9.0 ×
103/mm3) and high levels of serum
C-reactive protein (CRP, 6.21 mg/dl; normal, < 1.5 mg/dl).
Immature granulocytes suggestive of leukemia were not detected in the
peripheral blood. Serum G-CSF was abnormally high (323
pg/ml; normal, <39
pg/ml). Based on these data, the clinical diagnosis was G-CSF-producing
tumor.
The patient received concurrent chemoradiotherapy using cisplatin.
Radiotherapy consisted of external beam radiotherapy (EBRT) and
intracavitary brachytherapy (ICBT). EBRT was administered as follows:
(i ) whole pelvic irradiation with 50 Gy in 25 fractions (the last
20 Gy was delivered using a central shielding technique); (ii )
prophylactic irradiation targeting PALN regions at a dose of 40 Gy in 20
fractions; and (iii ) boost irradiation to the enlarged lymph
nodes (8 Gy in four fractions for pelvic lymph nodes and 16 Gy in eight
fractions for PALNs). ICBT was delivered at a dose of 24 Gy in four
fractions. Cisplatin (40 mg/m2) was administered
weekly for a total of three cycles starting on day 29 after improvement
of the fever and inflammatory response. The patient completed the
radiotherapy regimen as planned (Figure 4 ). The overall
treatment time was 49 days.
After completion of the treatment, the tumor achieved almost complete
response as assessed by the Response Evaluation Criteria in Solid Tumors
(version 1.1) (Figure 5 ). Serum G-CSF and SCC levels improved
to within normal limits (36.5 pg/ml and 0.8 ng/ml, respectively). The
patient experienced the following acute adverse effects as assessed by
the Common Terminology Criteria for Adverse Effects (version 4.0):
nausea (Grade 3), leukopenia (Grade 3), neutropenia (Grade 3), diarrhea
(Grade 2), anemia (Grade 2), and thrombocytopenia (Grade 1). These
adverse effects improved to Grade 0 within 2 months after completion of
the treatment.
The patient developed a fever (38.3°C) 2 months after completion of the
treatment. CT examination showed multiple metastases to a left
supraclavicular lymph node, the liver, and the lung (Figure 6 ).
The patient was considered ineligible for chemotherapy because of the
high inflammatory response (CRP, 18.30 mg/dl) and was provided with best
supportive care. CT performed 4 months after completion of the treatment
showed no evidence of in-field recurrence. Serum G-CSF was not assessed
after the metastases; however, a remarkably high WBC count (104.8 ×
103/mm3) suggested that the
G-CSF-producing property of the tumor was preserved at the metastatic
sites (Figure 7 ). The patient expired from disease progression
5 months after completion of the treatment. Permission for an autopsy
was not granted from the relatives at the time of mortality.
To better understand the biological basis of this aggressive tumor, we
analyzed mutation profiles. DNA was extracted from a pre-treatment
biopsy specimen in which the tumor cell content was higher than 50%.
The exons of 409 cancer-related genes (Supplementary Table 1 )
were sequenced using the Ion AmpliSeq Comprehensive Cancer Panel (Thermo
Fisher Scientific, Waltham, MA, USA). After quality filtering, the
number of sequencing reads per sample was 15.8 million, and the coverage
depth was 945 reads per base (Supplementary Table 2 ). Somatic
mutations were identified using the analytical pipeline described
previously14. Sixteen non-synonymous (Table
1 ) and four synonymous mutations were identified. The mutation spectrum
in a three-base context did not represent the APOBEC signature (i.e.,
enrichment of substitution of a C preceded by a T into either T, G, or
A) typical of HPV-associated cancers15 (Figure
8 ). Of the 16 non-synonymous mutations identified, PIK3C2B(T879N), KDR (V297I), and TET2 (P29R) were registered in
the Catalogue of Somatic Mutations in Cancer16 as
recurrent mutations.