ABSTRACT
Objective: To investigate the clinical and histopathological characteristics of testicular germ cell tumours in a sample at Jordanian population, and to compare it with worldwide findings.
Methods: The data of 75 patients who had undergone radical orchiectomy for the germ cell tumor at Prince Hussein Urological Center between 2010 and 2014 were collected. They were retrospectively analyzed according to clinical and histopathological parameters.
Results: 62% of the cases,(47 patients), were found to be seminomas, with the mean age being 36 years (22-80) with most of the cases were of classical seminoma. 38% of the cases (28 patients) had Non-Seminomatous Germ Cell Tumor (NSGCT). Although only 14% (4 patients) of the cases were of pure form, the rest were of mixed NSGCT. Yolksac and teratoma were found to be the most common histological types among Mixed NSGCT and the median age was 32 years (range 20-48). Overall, the average period that patients stayed before seeking medical attention was about 4 months, which ranged from 3 weeks to one year.
Conclusion: The age at presentation and the histopathological type of testicular germ cell among Jordanian patients are similar to those currently published in the world records. However, the diagnosis is delayed; this implies that the concerned stakeholders should emphasize the need of patient education and physician awareness.
Key words: Clinical characteristics, Histology, Germ cell tumor, Testicular.
JRMS March 2016; 23 (1): 22-27/ DOI: 10.12816/0023355
Introduction
Testicular Germ Cell Tumors
(TGCT) include a variety of types including seminoma, yolk sac tumor, teratoma,
choriocarcinoma and embryonic carcinoma or mixed variants made up of components
of the aforementioned types.(1) Although testicular tumors are rare tumors, representing about 1% of all
cancers, they are the most common types of tumors in males aged between 20 and
40.(2) Most studies have indicated
that delays in seeking diagnoses and accompanying treatments have been causing
negative impacts in their managements.(3,4) TGCT being
considered as a prototype of cancer of high cure and survival rate if properly
managed.(5) We think that it is important to study the trend of
this cancer in a given country (Jordan) to find out if there are specific
characteristics of it among its population. It is expected that the study will
be helpful in finding out certain risk factors so that outcomes can be
monitored. In this
retrospective study, we evaluated data
of a sample of 75 Jordanian patients who had undergone radical orchiectomy
at Prince Hussein Urology Centre/
Medical Service, a tertiary major referral
center that serves patients from all the provinces in Jordan, between from 2010 to September
2014 to configure histopathological patterns of this treatable and yet
potentially lethal cancer. In this regard, too, the study aimed at comparing
the findings with those in the worldwide studies.
Methods
After
the review and approval by the ethical committee, retrospectively, pathological
reports were reviewed between January 2010 and September 2014 in a bid to
obtain radical orchiectomy specimens that had germ cell testicular tumors for
analyses. In this regard, the specimens were analyzed in respect with variable
clinical and histopathological parameters.
All cases that had no germ cell tumors were excluded (two cases: one with lymphoma and
the other with sertoli cell tumor).
Moreover, all cases of pediatric GCT were excluded because of the
apparent differences in the behaviour and natural history between male adults
and male children. Finally, a total of 75 patients with germ cell tumors were
identified and their data taken for analyses with respects to type, stage, site
and presence of IGTN and age of patient and time of definite initial treatment.
Results
Seminoma
was the most common tumor sub-type of GCT that was identified among patients,
and was represented by about 62% (47 patients), with the average age being 36
years (22-80). However, the average maximum diameter of the tumor size was
about 5.07 cm (from all cases that ranged from 0.7 to 11cm). Whilst 28 cases of
the seminoma were at stage T1, 17 were at T2 (Table I). Cases that involved right
side were 63% and left side cases were 37%. Notably, however, no case had
bilateral involvement. Classical seminoma was the most dominant variant, at
95%. Two cases were varients form of seminoma : one case of seminona with syncytiotrophoblastic
elements, the other was spermatocytic
seminoma. Most common presentations were
painless masses at 91%. However, there
were also other less common presentations such as advance disease, pain and
hydrocele.
38% of the cases (28 patients)
had NSGCT, and the average age for this group was 32 years ranging (20-48) The
average size of the maximum diameter of the cancerous size was 5.7 cm (from
1.7-11cm). 53% of the NSGCT patients were at T1 stage, whilst the remaining
ones, (47%) were at stage T2.
Twelve (43%) of NSGCT involve the right side, and left side in 15 cases
(57%).
Importantly,
in this study, Intratubular Germ Cell Neoplasia (ITGCN) was present in 35% of
seminoma cases whilst 42% in the NSGCT cases, resulting to an overall
presentation of 37% of all people that had ITGCN. The study also revealed the
rate of testis invasion as 17% (from 8 cases) for cases of seminoma, and 10%
(from 3 cases) for cases that involved NSGCT.
Overall, painless masses were the most common presentation, at 91%. In addition, no bilateral cases were
identified.
Remarkable too, 85% of the
NSGCT cases were of mixed forms, with most common types being yolk sac tumor
and teratoma. The study also identified 4 cases of pure NSGCT: 2 cases of
embryonal carcinoma, one case of yolk sac tumor and the other choriocarcinoma.
Notably, the average time
for definitive treatment was 4 months
and 3 months for seminoma and NSGCT respectively, ranging from 3 weeks to 12
months.
Discussion
Germ Cell Tumors (GCT) are
classified by two systems: WHO histopathological system which divides the GCT
into pure or mixed form and the clinical based classification that broadly
classifies the GCT
into seminoma or non-seminoma types.(6) The clinical based
classification system has been so because the two subtypes, as seminoma GCT and
non-seminoma (NSGCT), have been showing very noticeable differences in their
natural history, prognosis and management guidelines.(7,8) TGCT being
considered as a prototype of cancer of high cure and survival rate if properly managed, up to 95% of cases excpected to be cured.(9-11)
Table I: Descriptive features
of Seminoma and NSGCT tumors.
|
Rete testis invasion
|
ITGCN*
|
Right VS left
|
T2 tumors
|
T1 tumors
|
Average size
(Cm)
|
Average Age
(Years)
|
Number of cases
|
Type
|
|
8cases
(17%)
|
16(34%)
|
Right 30 (63%)
Left 17 (37%)
|
18(39%)
|
29 (61%)
|
5.07
|
36
|
47(62%)
|
SEMINOMA
|
|
3cases
(10%)
|
12(42%)
|
Right 12 (43%)
Left15 (57%)
|
13(47%)
|
15(53%)
|
5.7
|
32
|
28(38%)
|
NSGCT *
|
*Non
Seminomatous Germ Cell Tumor..
Table II: T (Staging) Of Testicular Germ Cell Tumor
|
pT0
|
No
evidence of primary tumor
|
|
pTis
|
*CIS
|
|
pT1
|
Tumor
is limited to the testis and epididymis without vascular/lymphatic invasion;
tumor may invade into the tunica albuginea but not the tunica vaginalis.
|
|
pT2
|
Tumor
is limited to the testis and epididymis with vascular/lymphatic invasion, or
it is simply tumor extending through the tunica al buginea with involvement
of the tunica vaginalis
|
|
pT3
|
Tumor
invades the spermatic cord with or without vascular/lymphatic invasion
|
|
pT4
|
Tumor
invades the scrotum with or without vascular/lymphatic invasion
|
*Carcinoma In Situ: Intra Tubular Germ Cell
Neoplasm.
American Joint
Committee on Cancer. Cancer Staging Education 2014
Seminoma
is the most common germ cell tumor that occurs at an older age group that it is
the NSGCT.(12,13) Seminoma is further divided into sub-types:
classical seminoma,
syncytiotrophoblastic seminoma, spermatocytic
seminoma and seminoma with anaplastic features.(12) Non-seminomatous germ cell
tumors (NSGCT) include embryonal carcinoma, yolk tumor, teratoma and
choriocarcinoma.(14)
The NSGCT types can exist either alone in pure forms or as combinations
of mixed GCTs with or without subtypes of seminoma.(15) However, most NSGCTs occur as mixed tumors
composed of two or more GCT subtypes. In this study, the GCTs that contain both
seminoma and NSGCT subtypes are classified as NSGCTs.(16.8)
In this study, about 62% of cases were
seminoma; most cases of seminoma were classical seminoma; 2 of the seminoma
cases too, had variants with syncytiotrophblastic elements. Further, of the
seminoma cases, one case of spermatocytic seminoma was identified. The average
age of the seminoma patients was 36 years, and 25% of them had diffuse
involvement of the testis.
Of all the cases, 38% of the patients had
NSGCT, with most of them having mixed germ cell tumor.
Only 4 cases were established as
pure NSGCT; two cases were of embryonal carcinoma, with one yolk sac tumor
whilst the other as choriocarcinoma.
The most common type of the NSGCT, was teratoma. However, the most frequent types that were
present in the mixed tumor were yolk sac tumor and teratoma followed by
seminoma at 60%, 57% and 50%, respectively. As already mentioned, the average
age of patients with NSGCT was 32 years, which is lower than the mean age of
the seminoma patients.
Moreover, it seems that both right side and
left side involvement are almost equal (as right 54%, and left 46%). There is
no significant difference in prognoses between the two sites.(17)
However, right side and left side tumors require different surgical templates
if retroperitoneal lymph node dissection is needed due to the differences in
the primary lymphatic landing zones between left and right sided tumors.(18,19) The mean size of the tumor for seminoma was
5.07 cm, ranging from 0.7 to 11 cm. For NSGCT, it was 5.7 cm, ranging from 1.7
to 11cm. The Rete testis invasion was identified in 8 cases of seminoma (17%) and 3 case of
NSGCT (10% of cases). Overall, 15% of study population had Rete testis
invasion.
The most common presentation of the
Testicular Germ cell tumor has been painless mass.(4)
Similarly, most common presentaion in our patients was painless mass (91%).
Most invasive GCTs arise from a
precursor lesion called Intratubular Germ Cell Neoplasia (ITGCN).(20,21)
The ITGCN consists of undifferentiated germ cells located basally in the
seminiferous tubules.(21,22) Men with the ITGCN have had a
significant increase in risk of developing invasive GCT. Presence of ITGCN in
the orchiectomy specimen does not increase the risk of relapse in patients with
GCT.(21) In this study, ITGCN was present in 35% of cases of
seminoma. In NSGCT, it was found in 42% of all the cases; thus, in overall 37%
of the cases had ITGCN.
In 1997, the American Joint Committee on Cancer (AJCC) and the Union for International
Cancer Control (UICC) reached a consensus in developing the classification
criteria for the GCT that would recognize clinical stages of the disease based
on histopathological findings, pathologic stage of the primary tumor,
postorchiectomy serum tumor marker levels, and presence and extent of
metastatic diseases as determined by physical examination and staging imaging
studies.(23) (See
Table II)
In this study,
the extent of the primary tumor was included as the data were collected from
the pathological reports. Most cases identified (57%) were at T1 stage. Cases
at T2 were found to be 40%. However, incomplete data prevented researchers from
including lymph node and distant metastasis staging in the study. Impliedly,
early diagnoses were of paramount importance for the successful management of
the disease. Delays in diagnoses and hence associated management could lead to
adverse impacts, especially on prognosis.(24) The meantime
for one to receive definitive initial management, that is radical orchiectomy, from
the development of the symptoms was 4 months and 3 months for seminoma and
NSGCT respectively (ranging from 3 weeks up to 12 months).
It was clear that the patients manifested
significant delays before seeking diagnoses. In this regard, it was noted that
both patients and physicians did not play their roles significantly. Thus,
health authorities have to create awareness on physicians and education
programs on patients about the significance of early diagnoses. Studies have
regarded testicular cancer as a model of successful treatment of other cancers,
especially those that are solid. Even during advanced stage, high doses of
chemotherapies and rescue bone marrow transplantation can improve prognoses.(25,26)
In addition, techniques of radical retroperitoneal dissection have been found
to improve the effectiveness of GCT treatment, and reduce adverse complications.(27)
Indeed, more studies should be done on Jordanians so that outcomes of this type
of cancer can be realized, especially regarding delayed diagnoses. Fortunately,
here at Prince Hussein Urology and
Transplant Center, Jordan, data collection and management is now becoming
computerized, and it is expected that monitoring and evaluating trends of this
type of cancer will be easier. However, more prospective studies are needed for
follow-up of patients with germ cell tumor, and to evaluate the current
management of this curable cancer in our institution and in Jordan as
well. Although, the overall incidence of
the disease is increasing, innovations in chemotherapeutics and radiotherapy
and surgical therapies are marked to improve its management and patient
survival.
The
major limitation of this study is that, levels of tumor markers both
preoperative and post radical orchiectomy have not been included due to
incomplete data. Further, we
did not follow patients’ outcomes, and we did not also study the impacts of
delays of diagnoses and initiations of the management. It is hoped that future studies
will take these limitations as their concern to render more ameliorations on
this subject.
Conclusion
From this study it can be
elucidated that the histopathological type and the age of patients with testicular germ cell tumors are
comparable to those that are published in studies worldwide. Our patients manifested delays in diagnoses,
and are at the age risk (20-45), therefore, patients should be encouraged to do
testicular examination. Moreover, primary care physicians should be
educated about such types of tumors.
References
1.Mostofi F. K. Testicular tumors. Epidemiologic, etiologic,
and pathologic features.Article first published online: 28 JUN 2006
DOI: 10.1002/1097-0142(197311)32:5<1186::AID- CNCR2820320527>3.0.CO;2-8
2.Edble, et al. Pathology and Genetics of Tumours of the
Uninary System and Male Genital Organs. International Agency for
Research on Cancer 2006. Available at:
http://www.iarc.fr/en/publications/pdfs-online/pat-gen/bb7/BB7.pdf[Accessed
26th May 2015].
3. Fossa
SD, Oldenburg J, Dahl AA. Short-
and long-term morbidity after treatment for testicular cancer. BJU Int. 2009; 104:1418–1422.
4.Fossa
SD, Gilbert E, Dores GM, et al. Noncancerous causes of death in survivors of
testicular cancer. J Natl Cancer Inst
2007; 99:533–544.
5.Travis LB, Beard C, Allan
JM, et al.
Testicular Cancer Survivorship: Research Strategies and Recommendations. JNCI
Journal of the National Cancer Institute 2010;102(15):11141130.Doi:10.1093/jnci/djq216
6.George DW, Foster RS,
Hromas RA, et al. Update on late
relapse of germ cell tumor: a clinical and molecular analysis. J Clin Oncol 2003; 21:113–122.
7.Vergouwe Y, Steyerberg EW,
Eijkemans MJ, et al. Predictors of occult metastasis in clinical stage I nonseminoma: a
systematic review. J Clin Oncol 2003;
21:4092–4099.
8.Steyerberg EW, Keizer HJ,
Fossa SD, et al. Prediction of residual retroperitoneal mass histology after
chemotherapy for metastatic nonseminomatous germ cell tumor: multivariate
analysis of individual patient data from six study groups. J Clin Oncol. 1995; 13:1177–1187.
9.Ulbright, TM. Germ cell
tumors of the gonads: a selective review emphasizing problems in differential
diagnosis, newly appreciated, and controversial issues. Mod Pathol.2005; 2:61-79.
10.Stephenson AJ, Bosl GJ,
Motzer RJ, et al. Nonrandomized comparison of primary chemotherapy and retroperitoneal
lymph node dissection for clinical stage IIA and IIB nonseminomatous germ cell
testicular cancer. J Clin Oncol 2007;
25:5597–5602.
11.Stephenson AJ, Bosl GJ,
Motzer RJ, et al. Retroperitoneal lymph node dissection for nonseminomatous germ cell
testicular cancer: impact of patient selection factors on outcome. J Clin Oncol 2005;23: 2781–2788.
12.Chung P, Mayhew LA, Warde
P, et al.
Management of stage I seminomatous testicular cancer: a systematic review. Clin Oncol (R Coll Radiol). 2010;22:6–16.
13.Zuniga A, Kakiashvili D,
Jewett MA.
Surveillance in stage I nonseminomatous germ cell tumours of the testis. BJU Int 2009; 104(9 Pt. B):1351–1356.
14.Albers
P, Siener R, Krege S, et al. Randomized phase III trial comparing retroperitoneal
lymph node dissection with one course of bleomycin and etoposide plus cisplatin
chemotherapy in the adjuvant treatment of clinical stage I Nonseminomatous
testicular germ cell tumors: AUO trial AH 01/94 by the German Testicular Cancer
Study Group. J Clin Oncol. 2008;26:2966–2972.
15.Travis LB, Fossa SD,
Schonfeld SJ, et al. Testicular cancer patients:
focus on long-term survivors. J Natl
Cancer Inst 2005;97:1354–1365.
16.Wang, L et al. Choriocarcinoma
involving the pancreas as first manifestation of a metastaticregressing mixed
testicular germ cell tumor. Modern
Pathology 2004; 17:1573-1580.
17.Debono DJ, Heilman DK,
Einhorn LH, et al. Decision analysis for avoiding postchemotherapy surgery in patients
with disseminated nonseminomatous germ cell tumors. JClin Oncol 1997;15:1455–1464.
18.Feldman DR, Bosl GJ,
Sheinfeld J, et al. Medical treatment of advanced testicular cancer. JAMA. 2008; 299:672–684.
19. Einhorn LH. Treatment of testicular cancer: a new and
improved model. J Clin Oncol 1990;8:1777–1781.
20. Dieckmann KP, Skakkebaek
NE. Carcinoma in
situ of the testis: review of biological and clinical features. Int J Cancer 1999; 83:815–822.
21.Risk MC, Masterson TA. Intratubular germ cell neoplasms of the
testis and bilateral testicular tumors: Clinical significance and management
options. Indian Journal of Urology : IJU : Journal of the Urological Society
of India 2010;26(1):64.
22.Bazzi WM ,Raheem OA,Stroup
SP,Kane CJ,Derweesh IH, Downs TM. Partial orchiectomy and testis intratubular germ cell
neoplasia: World literature review. Urol Ann 2011 Sep-Dec; 3(3):
115–118.
23. American Joint Committee on Cancer. Cancer
Staging Education 2014. Available at:
https://cancerstaging.org/CSE/general/Pages/articles.aspx. [Accessed 26th May
2015].
24. De Santis M, Becherer A,
Bokemeyer C, et al. 2-18fluoro-deoxy-D-glucose positron emission tomography is a reliable
predictor for viable tumor in postchemotherapy seminoma: an update of the
prospective multicentric SEMPET trial. J
Clin Oncol 2004; 22:1034–1039.
25. Tinkle LL, Graham BS, Spillane TJ, et al. Testicular choriocarcinoma metastatic to
the skin: an additional case and literature review. Cutis 2001;67:117–120.
26. Oliver RT, Mason MD, Mead
GM, et al.
Radiotherapy versus single-dose carboplatin in adjuvant treatment of stage I
seminoma: a randomized trial. Lancet
2005;366:293–300.
27.Motzer RJ, Nichols CJ,
Margolin KA, et al. Phase III randomized trial of conventional-dose chemotherapy with or
without high-dose chemotherapy and autologous hematopoietic stem-cell rescue as
first-line treatment for patients with poor-prognosis metastatic germ cell
tumors. J Clin Oncol 2007;25:247–256.