Keywords:
Adenocarcinoma - Clear Cell - Urethral Neoplasms - Male Urogenital Diseases - Systemic
Management.
Descritores:
Adenocarcinoma de células claras - Neoplasias uretrais - Doenças urogenitais masculinas
- Manejo sistêmico.
INTRODUCTION
Primary urethral tumors are uncommon, especially clear cell adenocarcinoma (CCA),
which is most commonly described in females,[1]
[2] with only nine cases reported in men since 1981 ([Table 1]). CCA presents clinically as other urethral carcinomas, with obstructive symptoms,
hematuria, and urinary tract infections.[3] The origin and risk factors for this malignancy are unknown. So far, it is known
that is an aggressive disease, that in most cases the diagnosis is with the localized
disease and, in this condition, local surgical treatment would be the most appropriate
approach.[1]
Table 1
Summary of Cases of Clear Cell Adenocarcinoma of the Male Urethra
|
Reference
|
Year
|
Age
|
Stage
|
Inicial therapy
|
Recurrence
|
Survival
|
|
Cantrell et al[2]
|
1981
|
68
|
Locally advanced
|
Radiotherapy
|
20 months
|
29 months
|
|
Oliva et al[7]
|
1996
|
46
|
Unknown
|
Unknown
|
Unknown
|
Unknown
|
|
Seseke et al[14]
|
2001
|
57
|
Localized
|
Surgery
|
10 months
|
30 months
|
|
Gogus et al[13]
|
2003
|
44
|
Locally advanced
|
Surgery
|
5 months
|
10 months
|
|
Varachhia et al[11]
|
2009
|
68
|
Unknown
|
No treatment
|
-
|
2 months
|
|
Liu et al[6]
|
2012
|
37
|
Metastatic
|
Chemotherapy
|
-
|
29 months
|
|
Gandhi et al[9]
|
2012
|
55
|
Localized
|
Surgery
|
Unknown
|
Unknown
|
|
Lewis et al[12]
|
2015
|
36
|
Localized
|
Brachytherapy
|
Unknown
|
Unknown
|
|
Sugimura et al[15]
|
2018
|
56
|
Localized
|
Surgery
|
Unknown
|
Unknown
|
|
Santos et ala
|
2020
|
36
|
Localized
|
Surgery
|
30 months
|
NR
|
NR: Not reached; a: Present report
We report a clinical case of primary clear cell adenocarcinoma of the urethra (CCAU)
in male. This is the tenth patient with this malignancy found in the literature and
the one with the longest disease-free survival after local primary tumor surgery.
This is also the first case with complete radiological response after platinum-based
systemic chemotherapy.
CASE REPORT
This is a 36-year-old white man previously healthy, social drinker, non-smoker, with
no comorbidities or previous surgery, and also no family history of cancer. He presented
an amorphous material during urination and the urine analysis ruled out malignancy.
An urethrocystoscopy was performed showing that the urethral segment had nodular lesions
protruding into the urethral lumen, hindering the progression of the device during
the exam. These lesions were partially resected and the analysis showed epithelial
proliferation with cellular atypia, areas of necrosis and Ki-67 30%. A18 F- fluorodeoxyglucose positron emission tomography (18 F-FDG PET/CT) showed narrowing area with hypermetabolism and enhancement in the membranous
urethra of about 10.0mm (SUV: 9.7). No other loco-regional or distant lesions were
demonstrated on18 F-FDG PET/CT.
The patient underwent transurethral resection (TUR) and the lesion was totally resected.
The pathological analysis of the lesion was compatible with primary clear cell adenocarcinoma
of the urethra without invasion of the muscle layer ([Figures 1A], [1B] and [1C]). The immunohistochemistry (IHC) demonstrated a Ki67 60% and positivity for cytokeratin,
PAX-8, HNF1B, and focal GATA-3 ([Figure 1D]).
Figure 1 The analysis of the lesion from transurethral resection shows:
A. Polymorphic epithelial proliferation with papillary, tubulocystic and solid pattern,
the stroma is hyalinized (hematoxylin-eosin stain, 40x);
B. Papillary pattern showing hobnail cells and hyalinized stroma (hematoxylin-eosin
stain, 400x);
C. Solid pattern consisting of atypical epithelial cells with clear cytoplasm and high
number of mitotic figures and apoptotic bodies (hematoxylin-eosin stain, 400x);
D. PAX-8 immunohistochemistry with diffuse strong nuclear positivity.
A partial urethrectomy was performed with proximal segment ureterostomy due to the
difficulty of performing end-to-end anastomosis. After the surgery, the patient presented
with weak urinary stream and serial urethra dilations were needed. Despite this, he
maintained renal function preserved with serum creatinine values ranging from 0,76mg/dl
to 0,91mg/dl. The patient also maintained a good urinary continence and sexual activity.
He was followed every three months with computed tomography (CT) of the chest, magnetic
resonance imaging (MRI) of abdomen and pelvis, and cytopathological analysis of urine.
After 2.5 years of follow-up, the patient presented with severe right pelvic pain.
A pelvis CT showed an irregular lytic bone lesion in right ischium. A18 F-FDG PET/CT was performed in 03/15/2019 and showed a hypermetabolic lesion (SUV:
11.1) on the surgical bed of the urethra and another hypermetabolic lytic lesion (SUV:
15.5) with soft tissue component measuring 31mm between the pubis and right ischium
compatible with neoplastic involvement ([Figures 2A] and [3A]). A bone lesion biopsy was performed, and the pathological analysis demonstrated
poorly differentiated metastatic carcinoma and IHC showed PAX-8, napsin A and CA-125
coexpression suggesting metastatic CCA of urogenital tract origin.
Figure 2 18F-FDG PET/CT* examination evaluation:
A. Baseline 18F-FDG PET/CT (March 15, 2019): abnormal FDG uptake in the membranous urethra
(SUV: 11.1) and between the pubis and right ischium (SUV: 15.5);
B. 18F-FDG PET/CT after six cycles of chemotherapy (October 22, 2019): complete metabolic
response of bone and urethra lesions;
C. 18F-FDG PET/CT (February 7, 2020): absence of hypermetabolic lesions suspected of
malignancy;
D. 18F-FDG PET/CT (June 2, 2020): no evidence of disease, similar to the previous study.
*18F-FDG PET/CT = 18Ffluorodeoxyglucose positron emission tomography.
Figure 3 Axial18F-FDG PET/CT* fusion of the pelvis evaluation:
A. Baseline 18F-FDG PET/CT (March 15, 2019): hypermetabolic lesion in the urethra and
hypermetabolic lytic lesion between the pubis and right ischium;
B. 18FFDG PET/CT after six cycles of chemotherapy (October 22, 2019);
C. 18F-FDG PET/CT (February 7, 2020) shows absence of hypermetabolic lesions suspected
of malignancy; and
D. 18F FDG PET/CT ten months after last dose of chemotherapy (June 02, 2020). *18F-FDG
PET/CT = 18Ffluorodeoxyglucose positron emission tomography.
Considering the clinical condition of the patient as well as the results of the exams,
he underwent systemic chemotherapy with cisplatin 35mg/m2 plus gemcitabine 1000mg/m2 both in day 1 and 8 every 3 weeks for a total of 6 cycles. After the first cycle,
he evolved with complete bone pain improvement. The patient had an excellent tolerance
of entire treatment and had no other complications. After six cycles of systemic chemotherapy,
a new18 F-FDG PET/CT from 10/22/2019 showed complete metabolic response of bone and urethra
lesions ([Figures 2B] and [3B]). A new18 F-FDG PET/CT was performed in 02/07/2020 and showed absence of hypermetabolic lesions
suspected of malignancy ([Figures 2C] and [3C]) and at the moment, after ten months of the last chemotherapy, a18 F-FDG PET/CT from 06/02/2020 remains with no evidence of disease, similar to the
previous study ([Figures 2D] and [3D]). So far, the patient is asymptomatic and without radiological evidence of disease.
DISCUSSION
Primary urethral cancer is uncommon, being the incidence three times higher in males.
Typically the urothelial carcinoma is the most common histological type, followed
by squamous cell carcinoma and adenocarcinoma.[4]
[5] The CCAU is even more rare and, in contrast to other histological types, the most
common clinical presentation is in the female genitourinary tract, often associated
with the development of urethral diverticulum.[1] Several hypotheses about the origin of the CCAU have already been raised: mullerian
origin, glandular differentiation of the urothelium, and clonal evolution of nephrogenic
metaplasia are the most considered, but this origin remains uncertain.[3]
[6]
The pathological characteristics of the CCAU may be tubulocystic, papillary or diffuse
pattern, with polygonal cells with large or clear eosinophilic cytoplasm and hobnail
cells.[3]
[7]
[8] In IHC, the CCAU may exhibit positivity for PAX-2, PAX-8, CK-7, p16, p53, CA-125,
CAM.2, and AE1/AE3,[1] in our case, PAX-8 and CA-125 were positive.
Most described clinical manifestations of this malignant neoplasia include hematuria,
obstructive symptoms, urinary retention, and recurrent urinary tract infections.[9]
[10] However, in two clinical cases reports the clinical presentation was periurethral
abscess and fistula,[11] and chronic symptoms related to urethral trauma from a vehicle accident.[9] In the case described above, the patient remained oligosymptomatic until diagnosis
and subsequent surgery.
The surgical resection of the primary tumor is defined as the most appropriate treatment
option and has been adopted in most cases of localized disease. Despite this, considering
the rarity of disease, there is no standard recommendation about the extension of
the surgery. There is data suggesting that the partial penectomy could be a reasonable
treatment approach for a primary localized urethral cancer as well as the urethrectomy
with or without cystoprostatectomy for locally advanced disease.[10] Regarding the treatment with radiation therapy, its applicability and benefit are
uncertain. Thus, there are only some clinical cases reports of patients who were treated
with radiation therapy for localized disease.[2]
In previous clinical case reports, the time from the primary tumor treatment and the
disease recurrence ranged from 5 to 20 months with the most frequent sites of metastasis
being lymph nodes, bones, and lungs.[6] In this case report, the time for recurrence was 30 months with bone and urethra
being the site of disease recurrence. Regarding the systemic therapy, platinum-based
chemotherapy is the most commonly used for primary urethral cancer with uncertain
response rate and no data of survival benefit.[10] In this context, one case report described absence of response rate with MVEC (mitoxantrone,
vinblastine, epirubicin, and cisplatin) after relapse and the patient died 10 months
after surgery.[13] On the other hand, another case report of a patient with metastatic disease at diagnosis
demonstrated a disease stability and clinical benefit with cisplatin plus gemcitabine
after 6 cycles, but radiological exams showed disease progression three months later.
This patient was treated again with cisplatin and gemcitabine, followed by gemcitabine
alone and after new disease progression he received nabpaclitaxel, with 29 months
of overall survival.[6]
Therefore, this report describes a male patient with primary clear cell adenocarcinoma
of the urethra with the longest disease-free survival after surgery reported so far
and the first clinical case with complete radiological response after platinumbased
chemotherapy.
CONCLUSION
Male urethral clear cell adenocarcinoma is a rare neoplasia, with only 10 clinical
cases described in the medical literature. This tumor has an aggressive behavior,
even in the localized disease scenario, and consequently a poor 5-year survival. Due
to its rarity, data about the best approach to the disease are scarce and divergent.
Surgery is the most appropriate treatment for localized disease and platinum-based
chemotherapy seems to be a good option for systemic treatment, but optimal treatment
is not yet wellestablished and further data and studies are needed.
Bibliographical Record
Juliana Sinezio Santos, Gabriella Oliveira Mendes, Fernando Sabino Marques Monteiro.
Clear cell adenocarcinoma of the male urethra: clinical case report. Brazilian Journal
of Oncology 2021; 17: e-20210007.
DOI: 10.5935/2526-8732.20210007
