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Testicular microlithiasis: A review and its association with testicular cancer
Urologic Oncology: Seminars and Original Investigations 22 (2004) 285–289
Review article
Testicular microlithiasis: a review and its association with testicular cancer Hani H. Rashid, M.D., Louis R. Cos, M.D., Eric Weinberg, M.D., Edward M. Messing, M.D.* Department of Urology, Strong Memorial Hospital, University of Rochester Medical Center, Rochester, NY 14652, USA Received 11 July 2003; received in revised form 30 September 2003; accepted 23 October 2003
Abstract Testicular microlithiasis (TM) is an entity of unknown etiology that results in the formation of intratubular calcifications. It is of concern to the urologist because of its possible association with intratubular germ cell neoplasia and testicular germ cell cancer. Although commonly present in patients with germ cell tumors, there appears to be no definitive association with TM and cancer. Therefore, follow-up at this time should be dictated based on risk factors for developing testis cancer more than on the presence of TM. © 2004 Elsevier Inc. All rights reserved. Keywords: Testicular microlithiasis; Testicular cancer; Intertubular germ cell neoplasia
1. Historical aspects and definition Testicular microlithiasis (TM) is a process that has become a concern for the practicing urologist because of its possible association with testicular cancer. Priebe and Garrett first reported the phenomenon in 1970, after seeing bilateral diffuse testicular calcifications on a pelvic X-ray of a 4-year-old boy being worked up for pharyngitis and right thigh tenderness [1]. Three years later, Weinberg et al. described bilateral TM in a child with one undescended testicle who had bilateral, large, calcified, intratubular concretions within otherwise normal testicular histology [2]. Over the last 20 years, TM has been seen in patients with cryptorchidism, varicoceles, infertility, testicular torsion, Klinefelter’s Syndrome, pulmonary alveolar microlithiasis, neurofibromatosis, AIDS, intratubular germ cell neoplasia, and most importantly, primary testicular neoplasms [3–11]. Ikinger and his colleagues, after reporting an association between TM and testicular tumor specimens, suggested that radiographic studies be incorporated into diagnosing TM because of the perceived risk for testicular cancer in testicles with microlithiasis [12]. Doherty et al. reported the first
* Corresponding author. Tel.: ⫹1-585-275-9273; fax: ⫹1-(585) 442-8350. E-mail address: [email protected] (E.M. Messing). 1078-1439/$ – see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1016/S1078-1439(03)00177-7
use of real time ultrasound to diagnose TM in a case report of a 23-year-old male with a history of cryptorchidism. This was the first case of TM in 670 scrotal ultrasounds at their institution [13]. Subsequently, Janzen and colleagues described findings in 11 cases they deemed to be TM, and along with Hobarth et al. helped formalize the sonographic definition of TM that is still used today (Fig. 1, Table 1) [4,14]. 2. Epidemiology The prevalence of TM was not determined until the widespread availability of real time scrotal ultrasound. TM prevalence has been reported to range from 0.6 to 9% depending on the population studied and the study design (Table 2) [11,14 –17]. Cast and associates used a computer search of keywords related to microlithiasis to breakdown the 4,892 patients who had scrotal ultrasounds performed at their institution and reported a prevalence of 0.68% [11]. Middleton et al. reviewed ultrasound data from 1,079 patients at their institution and found a prevalence of 3.7% [15]. Interestingly, another 14.4% had some microlithiasis but fewer than the documented 5 per image field needed to be called TM. Patients in these and most other studies had incidentally found TM during sonographic evaluations for reasons such as pain, palpable mass, scrotal enlargement, history of tumor, and infertility. To circumvent any possible
286
H.H. Rashid et al. / Urologic Oncology: Seminars and Original Investigations 22 (2004) 285–289
Fig. 1. Scrotal ultrasound showing a central hypoechogenic homogenous mass inside the right testicle with diffuse testicular microlithiasis throughout.
selection bias, Peterson and his colleagues at the Madigan Army Medical Center recently performed screening ultrasounds on 1,504 healthy nonsymptomatic reserve officers and reported the prevalence to be 5.6%. Ethnically, they noted the prevalence to be 4.0% in Whites, 14.4% in African Americans, 8.5% in Hispanics, and 5.6% in Asians [16]. Interestingly, the study shows that African-Americans have a higher incidence of TM than Whites even though studies have shown that African Americans have a lower incidence of testicular cancer. Also, it is unclear if the high prevalence rate in this report and other recent studies is a result of a true higher incidence, technical factors such as the development of high-frequency transducers resulting in enhanced spatial resolution and thus improved sensitivity, greater awareness of the entity by sonographers and radiologists, or a combination of the above. 3. Etiology The etiology of TM is also not certain. Previous theories have included the persistence of bisexual gonadal elements as well as the accumulation of tubular secretions surrounding a mechanical nucleus [18,19]. The current popular theory, first postulated by Vegni-Talluri et al. claims the calcifications result from degenerating cells within the seminiferous tubules [20,21]. Secondary calcification of glycoproteins secreted in the tubules may play an additional role [18]. 4. Association of TM and intratubular germ cell neoplasia Regardless of etiology, the correlation with primary testicular cancer and even Intratubular Germ Cell Neoplasia
(IGN) has raised concern on the parts of urologists and radiologists when TM is diagnosed. There is a known association between IGN and testicular cancer with as many as 50% of patients with IGN developing testicular tumors within 5 years [22,23]. However, review of the literature fails to reveal any prospective studies conclusively following patients with TM testes and known IGN pathology or even evaluating treatment in these patients. In fact, most of the associations between IGN and TM (or TM and ipsilateral germ cell cancer for that matter) are case reports in patients with previous histories of contralateral testicular tumors. Parra et al. published a case report of a 31-year-old with an ultrasound revealing a left testicular mass and TM on the right side. The patient had a left radical orchiectomy and a right testicular biopsy. Pathology showed mixed germ cell tumor on the left and IGN on the right [10]. Kaveggia et al. reported the case of a man with a left testicular mass who had a left radical orchiectomy that revealed seminoma. An ultrasound done 3 years later revealed an atrophic right testicle with TM (the patient had received scrotal radiation). Biopsy showed IGN and subsequent radical orchiectomy confirmed IGN with microfoci of seminoma [24]. In both of these instances, because approximately 2 to 3% of testicular tumors are bilateral, occurring either simultaneously or successively, TM’s role in this process is difficult to evaluate [25]. Larger studies with longer follow-up are needed to see if there truly is an association between TM and testis cancer, or IGN.
5. Association of TM and testicular germ cell cancer The correlation between TM and testicular tumors has also been documented extensively in the literature (Table 2) [12,14,17,26,27]. Ikinger et al. reported that 74% of testes with tumors had associated ipsilateral TM on radiological inspection, whereas only 8% of testicular specimens with benign conditions had microcalcifications [12]. Renshaw found laminated calcifications in 4% of normal testicles upon histologic evaluation compared with 50% of cryptorchid testicles and 40% of testicles with germ cell tumors [26]. Backus et al. in a cross sectional retrospective study, reviewed 42 cases of TM and their association with identified intratesticular abnormalities. They noted 40% of patients with TM on ultrasound had associated tumors. However, they also showed that the extent, location, and Table 1 Ultrasound diagnosis of TM Greater than 5 calcifications per image field Calcifications less than 2 mm in diameter Diffuse in nature No acoustic shadowing No loss of testicular shape or volume
H.H. Rashid et al. / Urologic Oncology: Seminars and Original Investigations 22 (2004) 285–289
287
Table 2 Association between TM and testis cancer Studies
TM prevalence
Number of pts with TM
Percentage of TM pts with cancer
Number of testis cancer pts
Percentage of testis cancer pts with TM
Comments
Bach [17] Middleton [15] Derogee [37] Cast [11] Peterson [16] Ganem [9] Ikinger [12] Bennett [33] Backus [27]
9% 3.70% 4.60% 0.68% 5.60% 2% — — —
48 40 63 33 84 22 32 39 42
27% 8% 46% 21% 4% 36% 80% 18% 40%
43 15 60 54 — — 43 — —
12% 20% 48% 12.50% — — 74% — —
8% without TM had tumors 2.9% with tumor history 0.02% without TM had tumor Used computerized word search Asymptomatic Population 23% of patients were infertile 28% of TM were solitary No tumors on follow up (mean 45 months) 14% with history of tumor
laterality of TM did not correlate with the presence or absence of tumor [27]. Recently, Bach and colleagues from Memorial Sloan Kettering Cancer Center reviewed scrotal ultrasounds of 528 patients and found a prevalence of 9% with TM (48 patients). Of these 48 patients, 13 (27%) had testicular cancer compared with only 8% having cancer of the 480 men without TM [17]. They did not follow these patients long term to determine if additional patients with TM eventually develop testicular cancer. In fact, there have been only 5 reported cases of patients with known TM on ultrasound exam without a prior or concomitant testis tumor, who eventually developed a primary testicular cancer (Table 3) [5, 22–31]. Salisz and Goldman reported on a 32-year-old man with a history of a left orchidopexy who underwent a scrotal ultrasound as part of an infertility evaluation, which showed right TM. One year later, the patient developed right testicular tenderness and an ultrasound revealed a mass that was histologically confirmed to be an embryonal cell carcinoma [5]. McNiff et al. reported a yolk sac tumor developing in a 17-year boy being followed for bilateral TM that was originally detected because of an initial sonographic evaluation of unequal sized testes [28]. Frush et al. described the case of a 25 year old who presented with a metastatic mixed germ cell cancer of the left testicle 16 months after TM was diagnosed on a work-up for left testicular enlargement [29]. Winter et al. reported the case of a man with TM seen on sonographic studies done for bilateral testicular pain who presented with a metastatic germ cell tumor of the left testicle 3 years later [30]. Finally, Golash and colleagues reported the case of a 47-year-old man with an atrophic right testicle with TM on
ultrasound, who developed a seminoma 6 months later in that testicle [31]. It is interesting to note that in 2 of these 5 cases, prior abnormalities that are known to be risk factors for testicular cancer existed (cryptorchidism, atrophic testicle). If the prevalence of TM in men in the United States is truly between 2 to 6%, and there are only 3 documented cases of patients with TM without evident testicular abnormalities that are known to predispose for testicular cancer who eventually developed an ipsilateral testicular cancer, it would seem likely that TM does not lead to testicular tumors. It would thus follow that patients with TM need not be monitored for subsequently developing a testis cancer unless they have other findings that would put them at an increased risk for developing testicular cancer (e.g., cryptorchidism, testicular atrophy, contralateral testis tumor). The Madigan Army Center prospective study clearly assessed this risk by showing that, in an asymptomatic young population of over 1,500 men with a 5.6% prevalence of TM, only 3 had testis cancer [16]. Peterson et al. asserted that if an association between TM and cancer really existed, there would be a higher number of testicular tumors occurring in men with TM without other testicular cancer risk factors [16]. This has not been seen. Additionally, as mentioned earlier, the racial prevalence of TM does not correlate with that of germ cell cancer, which would again seriously question a causative relationship between TM and testis cancer. In fact, other studies have followed patients with known TM for moderate durations (currently up to 4 years) with no tumors noted [9,32–34]. Ganem et al. had ultrasound follow-up in 9 of 22 patients with TM for a mean of 32 months,
Table 3 Development of ipsilateral testicular cancer with TM history Case report
Year
Age
Duration of known TM
Testis cancer type
Tumor risk factors
Salisz et al. [5] McNiff et al. [28] Winter et al. [30] Frush et al. [29] Golash et al. [31]
1990 1995 1996 1996 2000
32 17 21 25 47
Right TM for 14 months Bilateral TM for 6 years Left TM for 3 years Left TM for 16 months Bilateral TM for 6 months
Embryonal cell carcinoma Left yolk sac tumor Metastatic left mixed GCT Metastatic left mixed GCT Right seminoma/CIS
Cryptoorchidism None None None Left atropic testicle
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H.H. Rashid et al. / Urologic Oncology: Seminars and Original Investigations 22 (2004) 285–289
without any newly developing tumors diagnosed [9]. Additionally, Skyrme et al. followed 5 patients with TM for a mean of 29 months, Bennett et al. followed 7 patients with TM for a mean of 45 months, and Furness et al. followed 26 patients with TM for a mean of 27.6 months without any developing testis tumors [32–34]. Larger studies are needed to determine if TM frequently coexists with neoplasia at the time of cancer diagnosis, and longer follow up is needed to determine if TM is a precursor for cancer. If the latter is true, then close followup of TM is needed. However, currently, this seems unlikely as the association is mostly seen in those men with coexistent or pre-existent testis tumors who, of course, are at a much higher risk to develop a contralateral germ cell cancer [5,28 –31]. Thus, even under standard care, they would already be followed closely.
Table 5 Suggested follow-up for patients with TM A. No Risk Factor(s) for Testicular Cancer 1. Self Testicular Exam 2. Annual Physical Exam by PCP 3. Follow-up as needed with Urologist (per symptoms, PE and reason for initial ultrasound) B. Risk Factor(s) for Testicular Cancer 1. Self Testicular Exam 2. Annual Physical Exam by Urologist/PCP 3. Annual Ultrasound
follow-up of patients with TM, its true likelihood of leading to cancer will be elucidated, and more evidence-based guidelines can be established. References
6. Conclusion and recommendations In summary, TM is a finding that appears to be quite prevalent in young men, as it is reported to occur in 2 to 6% of tested populations [15–17]. It is widely associated with other pathologies; the most important being primary testicular malignancies. There is evidence showing TM to be seen more frequently in patients with testicular tumor histories than in those without such histories. Current studies are less convincing for a role for TM in subsequent cancer occurrence, despite the association between the two [12,14,27]. Management for newly found TM remains controversial, ranging from no follow-up to performing complete chest, abdominal and pelvic computed tomography scans, to biopsying the involved testicle [16,29,35–36]. Monitoring of serum tumor markers in the absence of other indications is not appropriate as most studies have not found elevated tumor markers in those with incidental TM [16]. At this time, based upon the data described above, we believe in performing monthly testicular self exams, annual physical exams by a urologist and ultrasound follow-up of TM in patients with risk factors for developing testicular cancer (Table 4), while relying on testicular self exams and annual physical exams by a primary care provider in those patients with incidental TM (Table 5). Further work-up can be done when signs and symptoms dictate. With longer
Table 4 Risk factors for testicular tumors Cryptorchidism Atrophy Infertility Intratubular germ cell neoplasia (IGN) Gonadal dysgenesis Contralateral testicular tumor Exogenous estrogen administration
[1] Priebe C, Garret R. Testicular calcification in a 4-year-old boy. Pediatrics 1970;46:785– 8. [2] Weinberg AG, Currarino G, Stone IC Jr. Testicular microlithiasis. Arch Path 1973;95:312– 4. [3] Nistal M, Paniagua R, Diez-Pardo JA. Testicular microlithiasis in 2 children with bilateral cryptorchidism. J Urol 1979;121:535–7. [4] Janzen DL, Mathieson JR, Marsh et al. Testicular microlithiasis: sonographic and clinical features. AJR 1992;158:1057– 60. [5] Salisz JA, Goldman KA. Testicular calcifications and neoplasia in patient treated for subfertility. Urology 1990;36:557– 60. [6] Aizenstein RI, DiDomenico D, Wilbur AC, et al. Testicular microlithiasis: association with male infertility. J Clin Ultrasound 1998;26: 195– 8. [7] Jaramillo D, Perez-Atayde A, Teele RL. Sonography of testicular microlithiasis. Urol Radiol 1989;11:55–7. [8] Aizenstein RI, Hibbeln JF, Sagireddy B, et al. Klinefelter’s syndrome associated with testicular microlithiasis and mediastinal germ cell tumor. J Clin Ultrasound 1997;25:655– 6. [9] Ganem JP, Workman KR, Shaban SF. Testicular microlithiasis is associated with testicular pathology. Urology 1999;53:209 –13. [10] Parra BL, Venable DD, Gonzalez E, Eastham JA. Testicular microlithiasis as a predictor of intratubular germ cell neoplasia. Urology 1996;48:797–9. [11] Cast JE, Nelson WM, Early AS, et al. Testicular microlithiasis: prevalence and tumor risk in a population referred for scrotal sonography. AJR 2000;175:1703– 6. [12] Ikinger U, Wurster K, Terwey B. Microcalcifications in testicular malignancy. Urology 1982;19:525– 8. [13] Doherty FJ, Mullins TL, Sant GR, et al. Testicular microlithiasis: a unique sonographic appearance. J Ultrasound Med 1987;6:389 –92. [14] Hobarth K, Susani M, Szabo N, et al. Incidence of testicular microlithiasis. Urology 1992;40:464 –7. [15] Middleton WD, Teefey SA, Santillan CS. Testicular microlithiasis: prospective analysis of prevalence and associated tumor. Radiology 2002;224:425– 8. [16] Peterson AC, Bauman JM, Light DE, et al. The prevalence of testicular microlithiasis in an asymptomatic population of men 18 to 35 years old. J Urol 2001;166:2061– 4. [17] Bach AM, Hann LE, Hadar O, et al. Testicular microlithiasis: what is its association with testicular cancer? Radiology 2001;220:70 –5. [18] Bieger RC, Passarge E, McAdams AJ. Testicular intratubular bodies. J Clin Endocrinol 1965;25:1340 – 6. [19] Bunge RC, Bradbury JJ. Intratubular bodies of the human testis. J Urol 1961;85:306 –10.
H.H. Rashid et al. / Urologic Oncology: Seminars and Original Investigations 22 (2004) 285–289 [20] Miller FN, Sidhu PS. Does testicular microlithiasis matter? A review. Clin Radiol 2002;57:883–90. [21] Vegni-Talluri M, Bigliardi E, Vanni MG, Tota G. Testicular microliths: their origin and structure. J Urol 1980;124:105–7. [22] Von der Maase H, Rorth M, Walbom-Jorgensen S, et al. Carcinoma in situ of contralateral testis in patients with testicular germ cell tumors: study of 27 cases in 500 patients. Br Med J 1986;293:1398 – 1401. [23] Giwercman A, Skakkebaek NE. Carcinoma in situ of the testis: biology, screening, and management. Eur Urol 1993;23:19 –21. [24] Kaveggia FF, Strassman MJ, Apfelbach GL, et al. Diffuse testicular microlithiasis associated with intratubular germ cell neoplasia and seminoma. Urology 1996;48:794 – 6. [25] Sokal M, Peckham MJ, Hendry WF. Bilateral germ cell tumours of the testis. Br J Urol 1980;5:158 – 62. [26] Renshaw AA. Testicular calcifications. J Urol 1998;160:1625– 8. [27] Backus ML, Mack LA, Middleton WD, et al. Testicular microlithiasis: imaging appearances and pathologic correlation. Radiology 1994; 192:781–5. [28] Mcniff N, Doherty F, Katz J, et al. Yolk sac tumor of the testis discovered on a routine annual sonogram in a boy with testicular microlithiasis. AJR 1995;164:971–2. [29] Frush DP, Kliewer MA, Madden JF. Testicular microlithiasis and subsequent development of metastatic germ cell tumor. AJR 1996; 167:889 –90.
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[30] Winter TC III, Zunkel DE, Mack LA. Testicular carcinoma in a patient with previously demonstrated testicular microlithiasis. J Urol 1996;155:648. [31] Golash A, Parker J, Ennis O, Jenkins BJ. The interval of development of testicular carcinoma in a patient with previously demonstrated testicular microlithiasis. J Urol 2000;163:239. [32] Skyrme RJ, Fenn NJ, Jones AR, Bowsher WG. Testicular microlithiasis in a UK population: its incidence, associations, and follow-up. BJU Int 2000;86:482–5. [33] Bennett HF, Middleton WD, Bullock AD, Teefey SA. Testicular microlithiasis: US follow-up. Radiology 2001;218:359 – 63. [34] Furness PD III, Husmann DA, Brock JW III, et al. Multi-institutional study of testicular microlithiasis in childhood: a benign or premalignant condition? J Urol 1998;160:1151– 4. [35] Wittenberg KH, Hattery RR, Gorman B, Charboneau JW. Testicular microlithiasis and testicular tumours: association or pre-malignant condition. Radiology 2000;217:S366. [36] Wegner HE, Hamm B, Loy V, Dieckmann KP. Testicular microlithiasis: case report and discussion of management under special consideration of germ cell tumours. Int Urol Nephrol 1996;28: 533–7. [37] Derogee M, Bevers RFM, Prins HJ, et al. Testicular microlithiasis, a premalignant condition: prevalence, histopathologic findings and relation to testicular tumor. Urology 2001;1133–7.
Review article
Testicular microlithiasis: a review and its association with testicular cancer Hani H. Rashid, M.D., Louis R. Cos, M.D., Eric Weinberg, M.D., Edward M. Messing, M.D.* Department of Urology, Strong Memorial Hospital, University of Rochester Medical Center, Rochester, NY 14652, USA Received 11 July 2003; received in revised form 30 September 2003; accepted 23 October 2003
Abstract Testicular microlithiasis (TM) is an entity of unknown etiology that results in the formation of intratubular calcifications. It is of concern to the urologist because of its possible association with intratubular germ cell neoplasia and testicular germ cell cancer. Although commonly present in patients with germ cell tumors, there appears to be no definitive association with TM and cancer. Therefore, follow-up at this time should be dictated based on risk factors for developing testis cancer more than on the presence of TM. © 2004 Elsevier Inc. All rights reserved. Keywords: Testicular microlithiasis; Testicular cancer; Intertubular germ cell neoplasia
1. Historical aspects and definition Testicular microlithiasis (TM) is a process that has become a concern for the practicing urologist because of its possible association with testicular cancer. Priebe and Garrett first reported the phenomenon in 1970, after seeing bilateral diffuse testicular calcifications on a pelvic X-ray of a 4-year-old boy being worked up for pharyngitis and right thigh tenderness [1]. Three years later, Weinberg et al. described bilateral TM in a child with one undescended testicle who had bilateral, large, calcified, intratubular concretions within otherwise normal testicular histology [2]. Over the last 20 years, TM has been seen in patients with cryptorchidism, varicoceles, infertility, testicular torsion, Klinefelter’s Syndrome, pulmonary alveolar microlithiasis, neurofibromatosis, AIDS, intratubular germ cell neoplasia, and most importantly, primary testicular neoplasms [3–11]. Ikinger and his colleagues, after reporting an association between TM and testicular tumor specimens, suggested that radiographic studies be incorporated into diagnosing TM because of the perceived risk for testicular cancer in testicles with microlithiasis [12]. Doherty et al. reported the first
* Corresponding author. Tel.: ⫹1-585-275-9273; fax: ⫹1-(585) 442-8350. E-mail address: [email protected] (E.M. Messing). 1078-1439/$ – see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1016/S1078-1439(03)00177-7
use of real time ultrasound to diagnose TM in a case report of a 23-year-old male with a history of cryptorchidism. This was the first case of TM in 670 scrotal ultrasounds at their institution [13]. Subsequently, Janzen and colleagues described findings in 11 cases they deemed to be TM, and along with Hobarth et al. helped formalize the sonographic definition of TM that is still used today (Fig. 1, Table 1) [4,14]. 2. Epidemiology The prevalence of TM was not determined until the widespread availability of real time scrotal ultrasound. TM prevalence has been reported to range from 0.6 to 9% depending on the population studied and the study design (Table 2) [11,14 –17]. Cast and associates used a computer search of keywords related to microlithiasis to breakdown the 4,892 patients who had scrotal ultrasounds performed at their institution and reported a prevalence of 0.68% [11]. Middleton et al. reviewed ultrasound data from 1,079 patients at their institution and found a prevalence of 3.7% [15]. Interestingly, another 14.4% had some microlithiasis but fewer than the documented 5 per image field needed to be called TM. Patients in these and most other studies had incidentally found TM during sonographic evaluations for reasons such as pain, palpable mass, scrotal enlargement, history of tumor, and infertility. To circumvent any possible
286
H.H. Rashid et al. / Urologic Oncology: Seminars and Original Investigations 22 (2004) 285–289
Fig. 1. Scrotal ultrasound showing a central hypoechogenic homogenous mass inside the right testicle with diffuse testicular microlithiasis throughout.
selection bias, Peterson and his colleagues at the Madigan Army Medical Center recently performed screening ultrasounds on 1,504 healthy nonsymptomatic reserve officers and reported the prevalence to be 5.6%. Ethnically, they noted the prevalence to be 4.0% in Whites, 14.4% in African Americans, 8.5% in Hispanics, and 5.6% in Asians [16]. Interestingly, the study shows that African-Americans have a higher incidence of TM than Whites even though studies have shown that African Americans have a lower incidence of testicular cancer. Also, it is unclear if the high prevalence rate in this report and other recent studies is a result of a true higher incidence, technical factors such as the development of high-frequency transducers resulting in enhanced spatial resolution and thus improved sensitivity, greater awareness of the entity by sonographers and radiologists, or a combination of the above. 3. Etiology The etiology of TM is also not certain. Previous theories have included the persistence of bisexual gonadal elements as well as the accumulation of tubular secretions surrounding a mechanical nucleus [18,19]. The current popular theory, first postulated by Vegni-Talluri et al. claims the calcifications result from degenerating cells within the seminiferous tubules [20,21]. Secondary calcification of glycoproteins secreted in the tubules may play an additional role [18]. 4. Association of TM and intratubular germ cell neoplasia Regardless of etiology, the correlation with primary testicular cancer and even Intratubular Germ Cell Neoplasia
(IGN) has raised concern on the parts of urologists and radiologists when TM is diagnosed. There is a known association between IGN and testicular cancer with as many as 50% of patients with IGN developing testicular tumors within 5 years [22,23]. However, review of the literature fails to reveal any prospective studies conclusively following patients with TM testes and known IGN pathology or even evaluating treatment in these patients. In fact, most of the associations between IGN and TM (or TM and ipsilateral germ cell cancer for that matter) are case reports in patients with previous histories of contralateral testicular tumors. Parra et al. published a case report of a 31-year-old with an ultrasound revealing a left testicular mass and TM on the right side. The patient had a left radical orchiectomy and a right testicular biopsy. Pathology showed mixed germ cell tumor on the left and IGN on the right [10]. Kaveggia et al. reported the case of a man with a left testicular mass who had a left radical orchiectomy that revealed seminoma. An ultrasound done 3 years later revealed an atrophic right testicle with TM (the patient had received scrotal radiation). Biopsy showed IGN and subsequent radical orchiectomy confirmed IGN with microfoci of seminoma [24]. In both of these instances, because approximately 2 to 3% of testicular tumors are bilateral, occurring either simultaneously or successively, TM’s role in this process is difficult to evaluate [25]. Larger studies with longer follow-up are needed to see if there truly is an association between TM and testis cancer, or IGN.
5. Association of TM and testicular germ cell cancer The correlation between TM and testicular tumors has also been documented extensively in the literature (Table 2) [12,14,17,26,27]. Ikinger et al. reported that 74% of testes with tumors had associated ipsilateral TM on radiological inspection, whereas only 8% of testicular specimens with benign conditions had microcalcifications [12]. Renshaw found laminated calcifications in 4% of normal testicles upon histologic evaluation compared with 50% of cryptorchid testicles and 40% of testicles with germ cell tumors [26]. Backus et al. in a cross sectional retrospective study, reviewed 42 cases of TM and their association with identified intratesticular abnormalities. They noted 40% of patients with TM on ultrasound had associated tumors. However, they also showed that the extent, location, and Table 1 Ultrasound diagnosis of TM Greater than 5 calcifications per image field Calcifications less than 2 mm in diameter Diffuse in nature No acoustic shadowing No loss of testicular shape or volume
H.H. Rashid et al. / Urologic Oncology: Seminars and Original Investigations 22 (2004) 285–289
287
Table 2 Association between TM and testis cancer Studies
TM prevalence
Number of pts with TM
Percentage of TM pts with cancer
Number of testis cancer pts
Percentage of testis cancer pts with TM
Comments
Bach [17] Middleton [15] Derogee [37] Cast [11] Peterson [16] Ganem [9] Ikinger [12] Bennett [33] Backus [27]
9% 3.70% 4.60% 0.68% 5.60% 2% — — —
48 40 63 33 84 22 32 39 42
27% 8% 46% 21% 4% 36% 80% 18% 40%
43 15 60 54 — — 43 — —
12% 20% 48% 12.50% — — 74% — —
8% without TM had tumors 2.9% with tumor history 0.02% without TM had tumor Used computerized word search Asymptomatic Population 23% of patients were infertile 28% of TM were solitary No tumors on follow up (mean 45 months) 14% with history of tumor
laterality of TM did not correlate with the presence or absence of tumor [27]. Recently, Bach and colleagues from Memorial Sloan Kettering Cancer Center reviewed scrotal ultrasounds of 528 patients and found a prevalence of 9% with TM (48 patients). Of these 48 patients, 13 (27%) had testicular cancer compared with only 8% having cancer of the 480 men without TM [17]. They did not follow these patients long term to determine if additional patients with TM eventually develop testicular cancer. In fact, there have been only 5 reported cases of patients with known TM on ultrasound exam without a prior or concomitant testis tumor, who eventually developed a primary testicular cancer (Table 3) [5, 22–31]. Salisz and Goldman reported on a 32-year-old man with a history of a left orchidopexy who underwent a scrotal ultrasound as part of an infertility evaluation, which showed right TM. One year later, the patient developed right testicular tenderness and an ultrasound revealed a mass that was histologically confirmed to be an embryonal cell carcinoma [5]. McNiff et al. reported a yolk sac tumor developing in a 17-year boy being followed for bilateral TM that was originally detected because of an initial sonographic evaluation of unequal sized testes [28]. Frush et al. described the case of a 25 year old who presented with a metastatic mixed germ cell cancer of the left testicle 16 months after TM was diagnosed on a work-up for left testicular enlargement [29]. Winter et al. reported the case of a man with TM seen on sonographic studies done for bilateral testicular pain who presented with a metastatic germ cell tumor of the left testicle 3 years later [30]. Finally, Golash and colleagues reported the case of a 47-year-old man with an atrophic right testicle with TM on
ultrasound, who developed a seminoma 6 months later in that testicle [31]. It is interesting to note that in 2 of these 5 cases, prior abnormalities that are known to be risk factors for testicular cancer existed (cryptorchidism, atrophic testicle). If the prevalence of TM in men in the United States is truly between 2 to 6%, and there are only 3 documented cases of patients with TM without evident testicular abnormalities that are known to predispose for testicular cancer who eventually developed an ipsilateral testicular cancer, it would seem likely that TM does not lead to testicular tumors. It would thus follow that patients with TM need not be monitored for subsequently developing a testis cancer unless they have other findings that would put them at an increased risk for developing testicular cancer (e.g., cryptorchidism, testicular atrophy, contralateral testis tumor). The Madigan Army Center prospective study clearly assessed this risk by showing that, in an asymptomatic young population of over 1,500 men with a 5.6% prevalence of TM, only 3 had testis cancer [16]. Peterson et al. asserted that if an association between TM and cancer really existed, there would be a higher number of testicular tumors occurring in men with TM without other testicular cancer risk factors [16]. This has not been seen. Additionally, as mentioned earlier, the racial prevalence of TM does not correlate with that of germ cell cancer, which would again seriously question a causative relationship between TM and testis cancer. In fact, other studies have followed patients with known TM for moderate durations (currently up to 4 years) with no tumors noted [9,32–34]. Ganem et al. had ultrasound follow-up in 9 of 22 patients with TM for a mean of 32 months,
Table 3 Development of ipsilateral testicular cancer with TM history Case report
Year
Age
Duration of known TM
Testis cancer type
Tumor risk factors
Salisz et al. [5] McNiff et al. [28] Winter et al. [30] Frush et al. [29] Golash et al. [31]
1990 1995 1996 1996 2000
32 17 21 25 47
Right TM for 14 months Bilateral TM for 6 years Left TM for 3 years Left TM for 16 months Bilateral TM for 6 months
Embryonal cell carcinoma Left yolk sac tumor Metastatic left mixed GCT Metastatic left mixed GCT Right seminoma/CIS
Cryptoorchidism None None None Left atropic testicle
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without any newly developing tumors diagnosed [9]. Additionally, Skyrme et al. followed 5 patients with TM for a mean of 29 months, Bennett et al. followed 7 patients with TM for a mean of 45 months, and Furness et al. followed 26 patients with TM for a mean of 27.6 months without any developing testis tumors [32–34]. Larger studies are needed to determine if TM frequently coexists with neoplasia at the time of cancer diagnosis, and longer follow up is needed to determine if TM is a precursor for cancer. If the latter is true, then close followup of TM is needed. However, currently, this seems unlikely as the association is mostly seen in those men with coexistent or pre-existent testis tumors who, of course, are at a much higher risk to develop a contralateral germ cell cancer [5,28 –31]. Thus, even under standard care, they would already be followed closely.
Table 5 Suggested follow-up for patients with TM A. No Risk Factor(s) for Testicular Cancer 1. Self Testicular Exam 2. Annual Physical Exam by PCP 3. Follow-up as needed with Urologist (per symptoms, PE and reason for initial ultrasound) B. Risk Factor(s) for Testicular Cancer 1. Self Testicular Exam 2. Annual Physical Exam by Urologist/PCP 3. Annual Ultrasound
follow-up of patients with TM, its true likelihood of leading to cancer will be elucidated, and more evidence-based guidelines can be established. References
6. Conclusion and recommendations In summary, TM is a finding that appears to be quite prevalent in young men, as it is reported to occur in 2 to 6% of tested populations [15–17]. It is widely associated with other pathologies; the most important being primary testicular malignancies. There is evidence showing TM to be seen more frequently in patients with testicular tumor histories than in those without such histories. Current studies are less convincing for a role for TM in subsequent cancer occurrence, despite the association between the two [12,14,27]. Management for newly found TM remains controversial, ranging from no follow-up to performing complete chest, abdominal and pelvic computed tomography scans, to biopsying the involved testicle [16,29,35–36]. Monitoring of serum tumor markers in the absence of other indications is not appropriate as most studies have not found elevated tumor markers in those with incidental TM [16]. At this time, based upon the data described above, we believe in performing monthly testicular self exams, annual physical exams by a urologist and ultrasound follow-up of TM in patients with risk factors for developing testicular cancer (Table 4), while relying on testicular self exams and annual physical exams by a primary care provider in those patients with incidental TM (Table 5). Further work-up can be done when signs and symptoms dictate. With longer
Table 4 Risk factors for testicular tumors Cryptorchidism Atrophy Infertility Intratubular germ cell neoplasia (IGN) Gonadal dysgenesis Contralateral testicular tumor Exogenous estrogen administration
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