Testicular Testicular microlithiasismicrolithiasis

By Dr. Wissam Kh. By Dr. Wissam Kh. KamalKamal

R2 Urology KAUHR2 Urology KAUH

??? Testicular ??? Testicular Microlithiasis ???Microlithiasis ???

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Introduction.Introduction.Incidence.Incidence.Etiology.Etiology.Diagnosis.Diagnosis.Clinical Clinical correlations.correlations.

Management.Management.Conclusion.Conclusion.

Testicular Microlithiasis or polytopic Testicular Microlithiasis or polytopic intralobular calcifications is intralobular calcifications is uncommon uncommon urologic entity of unclear etiology.urologic entity of unclear etiology.

It is usually an It is usually an incidental findingincidental finding during during investigation of unrelated testicular investigation of unrelated testicular symptoms by scrotal sonography.symptoms by scrotal sonography.

Prior to the clinical application of high Prior to the clinical application of high resolution U/S, TM was a histological resolution U/S, TM was a histological diagnosis established on autopsy or diagnosis established on autopsy or orchiectomy / testicular biopsy orchiectomy / testicular biopsy specimens.specimens.

The term “Testicular Microlithiasis” was The term “Testicular Microlithiasis” was used only when a significant number of used only when a significant number of seminiferous tubules contained seminiferous tubules contained microliths.microliths.

TM has been observed in patients TM has been observed in patients with:with:

Infertility.Infertility. Testicular atrophy.Testicular atrophy. Cryptorchidism or Cryptorchidism or

delayed testicular delayed testicular descent .descent .

Varicocele.Varicocele. Testicular torsion.Testicular torsion. Male Male

pseudohermaphroditpseudohermaphroditism.ism.

Pulmonary alveolar Pulmonary alveolar microlithiasis.microlithiasis.

Calcification of the Calcification of the sympathetic nervous sympathetic nervous system.system.

Down’s, Kleinfelter Down’s, Kleinfelter and Carney’s and Carney’s syndroms and cystic syndroms and cystic fibrosis.fibrosis.

It’s occurrence in It’s occurrence in otherwise normal otherwise normal testes has also been testes has also been reported.reported.

IncidenceIncidence The true incidence of TM is unknown due The true incidence of TM is unknown due

to a limited number of cases, significant to a limited number of cases, significant differences in studied populations, differences in studied populations, diagnostic methods and undefined diagnostic methods and undefined prevalence of TM in normal individuals.prevalence of TM in normal individuals.

Autopsy revealed TM in 0.04 to 11.8 % of Autopsy revealed TM in 0.04 to 11.8 % of prepubertal boys and 3% of adult males.prepubertal boys and 3% of adult males.

Nistal et al reported TM in 1 of 618(0.16%) Nistal et al reported TM in 1 of 618(0.16%) testicular biopsy specimens performed in testicular biopsy specimens performed in children.children.

In a retrospective analysis of 1710 In a retrospective analysis of 1710 testicular sonograms of adults, bilateral TM testicular sonograms of adults, bilateral TM was demonstrated in 11 cases (0.6).was demonstrated in 11 cases (0.6).

To answer the question of how To answer the question of how common testicular microlithiasis is in common testicular microlithiasis is in an an asymptomatic populationasymptomatic population a a prospective U/S screening studyprospective U/S screening study was made to establish the prevalence was made to establish the prevalence of the condition in a healthy of the condition in a healthy population of men undergoing annual population of men undergoing annual training for the U.S army.training for the U.S army.

A total of 1504 male participants A total of 1504 male participants were evaluated using were evaluated using physical physical examinationexamination and and testicular U/Stesticular U/S. .

TM was present in 84 (5.6%) and was TM was present in 84 (5.6%) and was bilateral in 66.7 % with the majority bilateral in 66.7 % with the majority having 5-25 microcalcification per having 5-25 microcalcification per testicle on U/S.testicle on U/S.

The frequency of detection of The frequency of detection of testicular microlithiasis in relationship testicular microlithiasis in relationship to the racial background of the study to the racial background of the study participants was participants was 4.2% White, 14.1% 4.2% White, 14.1% African-American, 8.5% Hispanic, African-American, 8.5% Hispanic, 5.6% Asian or Pacific Islander and 5.6% Asian or Pacific Islander and 5.2% who did not claim a race 5.2% who did not claim a race affiliationaffiliation..

EtiologyEtiology

The origin of these intrtubular The origin of these intrtubular calcification is unclear.calcification is unclear.

Numerous theories have been proposed Numerous theories have been proposed including liquefaction of protoplasmic including liquefaction of protoplasmic dendritus about a spermatocyte or dendritus about a spermatocyte or coalescence of colloid droplets, ectopic coalescence of colloid droplets, ectopic oocytes in dysgenetic testes, displaced oocytes in dysgenetic testes, displaced spermatogenia, undifferentiated, or spermatogenia, undifferentiated, or desquamated calcified cells, depostion desquamated calcified cells, depostion of glycoprotien about a nidus of cell of glycoprotien about a nidus of cell material sloughed into the tubular lumen material sloughed into the tubular lumen and abnormal Sertoli cells activity.and abnormal Sertoli cells activity.

After the application of electron microscopy; After the application of electron microscopy; vacoulized degenerating cells not vacoulized degenerating cells not phagocytized by Sertoli cells were phagocytized by Sertoli cells were suggested to form the nidus for microlith suggested to form the nidus for microlith with the tubular lumen. Further development with the tubular lumen. Further development of microliths may resemble the crystal-of microliths may resemble the crystal-matrix formation of urinary calculi.matrix formation of urinary calculi.

In two cases TM has been associated with In two cases TM has been associated with pulmonary microlithiasis and calcifications in pulmonary microlithiasis and calcifications in the sympathetic nervous system and brain. the sympathetic nervous system and brain.

This suggests the possibility of alteration in This suggests the possibility of alteration in the chemical composition of certain the chemical composition of certain mucosubstances which would enhance the mucosubstances which would enhance the deposition of Calcium in different organs. deposition of Calcium in different organs.

A systemic calcium metabolic disorder has A systemic calcium metabolic disorder has been hypothesized but never proven.been hypothesized but never proven.

Since TM was found in patients with Since TM was found in patients with Klinefelter’s, Down’s and Carney’s Klinefelter’s, Down’s and Carney’s syndroms and recently with cystic syndroms and recently with cystic fibrosis, genetic disorders were fibrosis, genetic disorders were thought to play a role in the thought to play a role in the development of TM and development of TM and chromosomal analysis was suggested chromosomal analysis was suggested for patient evaluation.for patient evaluation.

DiagnosisDiagnosis

HistologyHistology

On histologic examination microliths On histologic examination microliths (also called calcospherites) are (also called calcospherites) are eosinophylic, spherical, elongated or eosinophylic, spherical, elongated or ovoid in shape.ovoid in shape.

Under the light and electron Under the light and electron microscope the microliths are found microscope the microliths are found to consist of two zones: a central to consist of two zones: a central calcified zone and a multilayered calcified zone and a multilayered envelope of stratified collagen fibers.envelope of stratified collagen fibers.

The histological appearance of the The histological appearance of the remaining epithelium varies according remaining epithelium varies according to the patient’s age and associated to the patient’s age and associated conditions ( e.g. cryptorchidism, conditions ( e.g. cryptorchidism, infertility, CIS).infertility, CIS).

The uninvolved tubule segments were The uninvolved tubule segments were lined largely by undifferentiated cells lined largely by undifferentiated cells with increased cytoplasmic swelling.with increased cytoplasmic swelling.

Spermatogonia were clearly identified Spermatogonia were clearly identified within the tubules in normal numbers, within the tubules in normal numbers, but most tubules had a narrow or no but most tubules had a narrow or no lumen.lumen.

UltrasoundUltrasound The ultrasound appearance of TM The ultrasound appearance of TM

was first described by was first described by Doherty et alDoherty et al. . in 1987 as; innumerable tiny bright in 1987 as; innumerable tiny bright echoes diffusely and uniformly echoes diffusely and uniformly scattered throughout their substance.scattered throughout their substance.

This sonographic appearance was This sonographic appearance was further defined by further defined by Doherty and Doherty and JanzenJanzen as ` randomly distributed 1-2 as ` randomly distributed 1-2 mm diameter hyperechoic foci in one mm diameter hyperechoic foci in one or both testes.or both testes.

The classical description of TM is The classical description of TM is bilateral evenly distributed bright bilateral evenly distributed bright echoes.echoes.

TM has been divided into classic TM TM has been divided into classic TM (with five or more microliths on any (with five or more microliths on any single view) and limited TM (less than 5 single view) and limited TM (less than 5 microliths).microliths).

It has been graded as minimal/mild It has been graded as minimal/mild (grade1), moderate(grade2), and (grade1), moderate(grade2), and severe(grade3).severe(grade3).

This variable pattern was directly This variable pattern was directly correlated with the frequency of correlated with the frequency of occurrence of testicular malignancy.occurrence of testicular malignancy.

Large, less numerous, less well defined Large, less numerous, less well defined and commonly unilateral hyperechoic and commonly unilateral hyperechoic areas on testicular U/S were described areas on testicular U/S were described in patients with orchitis, sarccoidosis, in patients with orchitis, sarccoidosis, local infarction, calcified granulomas local infarction, calcified granulomas and focal scars, large-cell calcifying and focal scars, large-cell calcifying Sertoli cell tumors, tubular atrophy Sertoli cell tumors, tubular atrophy with fibrosis or calcifications in germ-with fibrosis or calcifications in germ-cell tumors and adrenal rests.cell tumors and adrenal rests.

The lack of uniformity and the liberal The lack of uniformity and the liberal definition of TM in the literature make definition of TM in the literature make it more difficult to correlate the it more difficult to correlate the spectrum of U/S findings with clinical spectrum of U/S findings with clinical diagnosis in different studies.diagnosis in different studies.

Clinical PictureClinical Picture

TM is usually asymptomatic but occasionally TM is usually asymptomatic but occasionally may be associated with orchialgia.may be associated with orchialgia.

DuchekDuchek et alet al presented one case of painful presented one case of painful testicular microlithiasis in an otherwise testicular microlithiasis in an otherwise healthy 22-year old patient.healthy 22-year old patient.

The mechanism of pain was suggested to be The mechanism of pain was suggested to be a distention of seminiferous tubules.a distention of seminiferous tubules.

MackinnonMackinnon reported five patients with reported five patients with orchialgia and infertility with TM diagnosed orchialgia and infertility with TM diagnosed in four of them.in four of them.

Clinical Clinical CorrelationCorrelation

InfertilityInfertility The relationship between TM and The relationship between TM and

fertility is not well understood.fertility is not well understood. In In Janzen’sJanzen’s series of 11 patients series of 11 patients

with TM, two(18 %) presented with with TM, two(18 %) presented with infertility.infertility.

Hobarth et alHobarth et al and and Mackinnon et alMackinnon et al reported oligo- or azospermia in 19 reported oligo- or azospermia in 19 and 80 % of their patients with TM and 80 % of their patients with TM respectively.respectively.

It was suggested that microliths and It was suggested that microliths and infertility may have a common infertility may have a common undefined etiologic factor.undefined etiologic factor.

Fertility potential may be decreased Fertility potential may be decreased by a mechanical obstruction of by a mechanical obstruction of seminiferous tubules with microliths, seminiferous tubules with microliths, atrophy of uninvolved tubules with atrophy of uninvolved tubules with spermatogenic arrest or a combination spermatogenic arrest or a combination of both.of both.

Limited cases of testicular biopsy in Limited cases of testicular biopsy in patients with infertility and TM patients with infertility and TM revealed microliths in 30 to 40% of the revealed microliths in 30 to 40% of the seminiferous tubules with obstruction.seminiferous tubules with obstruction.

Mackinnon et alMackinnon et al suggested testicular suggested testicular U/S in the work up of male infertility, U/S in the work up of male infertility, although it’s not usually recommended.although it’s not usually recommended.

The prognosis of fertility is not The prognosis of fertility is not necessarily affected by microlithiasis.necessarily affected by microlithiasis.

In a case of bilateral TM, bilateral In a case of bilateral TM, bilateral varicocele and normal varicocele and normal spermatogenesis, pregnancy was spermatogenesis, pregnancy was achieved after bilateral achieved after bilateral varicocelectomy.varicocelectomy.

Incidentally, discovered TM should not Incidentally, discovered TM should not change the treatment approach to change the treatment approach to infertile men.infertile men.

MalignancyMalignancy The evaluation of testicular biopsy or The evaluation of testicular biopsy or

orchiectomy specimens and total specimen orchiectomy specimens and total specimen radiography identified the coexistence of radiography identified the coexistence of intratesticular microcalcification and intratesticular microcalcification and malignancy.malignancy.

Wurster and MengesWurster and Menges retrospectively found retrospectively found microcalcifications in 46% of 127 germ cell microcalcifications in 46% of 127 germ cell tumors. tumors.

Only 8 of 49 (16%) specimens of benign Only 8 of 49 (16%) specimens of benign testicular disorders( cryptorchidism, testicular disorders( cryptorchidism, epididymitis, torsion) revealed epididymitis, torsion) revealed microcalcifications. microcalcifications.

TM is most commonly associated with TM is most commonly associated with non-seminoma germ cell tumor.non-seminoma germ cell tumor.

The association between TM and The association between TM and Testicular CIS has been well documented.Testicular CIS has been well documented.

In a retrospective study of testicular In a retrospective study of testicular specimens with CIS, but without testicular specimens with CIS, but without testicular tumor; tumor; Kang et al found TM in 14 of Kang et al found TM in 14 of 36(39%) specimen compared to 2.1% in 36(39%) specimen compared to 2.1% in controlled group.controlled group.

The limited results of prospective follow The limited results of prospective follow up studies of asymptomatic patients with up studies of asymptomatic patients with TM are controversial.TM are controversial.

JanzenJanzen found no interval malignancy found no interval malignancy in six patients with classical bilateral in six patients with classical bilateral TM within 14-49 months.TM within 14-49 months.

HobarthHobarth observed 16 patients with observed 16 patients with bilateral TM and unilateral testicular bilateral TM and unilateral testicular tumor. No contralateral tumors tumor. No contralateral tumors developed from 6-65 months.developed from 6-65 months.

WhitmanWhitman followed 21 patients with followed 21 patients with TM clinically and sonographically TM clinically and sonographically between one and nine years and no between one and nine years and no patients developed interval patients developed interval malignancy.malignancy.

Although most tumors were Although most tumors were detected simultaneously with TM detected simultaneously with TM recently cases in testicular recently cases in testicular malignancy developing after malignancy developing after diagnosis of testicular microlithiasis diagnosis of testicular microlithiasis have been reported.have been reported.

McEniff et alMcEniff et al presented a case of yolk presented a case of yolk sac tumor of the testis developing in a sac tumor of the testis developing in a 17 Y/O boy with TM 4 years after initial 17 Y/O boy with TM 4 years after initial evaluation of a unilaterally enlarged evaluation of a unilaterally enlarged testis.testis.

Winter et alWinter et al reported a case of unilateral reported a case of unilateral microlithiasis in a 21 Y/O man with microlithiasis in a 21 Y/O man with bilateral testicular pain and bilateral testicular pain and hematospermia. Three years later an U/S hematospermia. Three years later an U/S revealed a multifocal solid testicular revealed a multifocal solid testicular mass (embryonal cell carcinoma and mass (embryonal cell carcinoma and seminoma) in the involved testis.seminoma) in the involved testis.

Frush et alFrush et al described a patient with described a patient with unilateral microliths and subsequent (15 unilateral microliths and subsequent (15 month later) development of mixed germ month later) development of mixed germ cell tumor in the involved testis. cell tumor in the involved testis. Interestingly microliths were diagnosed Interestingly microliths were diagnosed also in the uninvolved testis.also in the uninvolved testis.

Kaveggia et alKaveggia et al presented a case of presented a case of unilateral testicular seminoma with unilateral testicular seminoma with contralateral TM. Three years later after contralateral TM. Three years later after radical orchiectomy and radiation radical orchiectomy and radiation treatment ( contralateral testis was not treatment ( contralateral testis was not shielded) the patient was diagnosed with shielded) the patient was diagnosed with CIS in the remaining testis and underwent CIS in the remaining testis and underwent orchiectomy.orchiectomy.

TM is often found in patients with TM is often found in patients with cryptorchidism, testicular atrophy cryptorchidism, testicular atrophy and infertility. These conditions and infertility. These conditions have been associated with an have been associated with an increased risk of developing CIS and increased risk of developing CIS and testicular tumor.testicular tumor.

It has been proposed that TM is a It has been proposed that TM is a manifestation of primary testicular manifestation of primary testicular dysfunction and this dysfunction is dysfunction and this dysfunction is associated with a higher prevalence associated with a higher prevalence of testicular malignancy.of testicular malignancy.

The development of Tumors in The development of Tumors in some testes with microliths were some testes with microliths were shown years after presentation, shown years after presentation, therefore TM is thought to be a therefore TM is thought to be a predisposing factor, a possible predisposing factor, a possible indirect indicator of premalignant indirect indicator of premalignant disease or a tumor marker.disease or a tumor marker.

ManagementManagement

There is a significant risk of testicular There is a significant risk of testicular neoplasms in patients with TM.neoplasms in patients with TM.

Since most patients with either TM or Since most patients with either TM or germ cell tumor are 20 to 50 years germ cell tumor are 20 to 50 years old, prompt evaluation of TM in this old, prompt evaluation of TM in this age group is indicated.age group is indicated.

Serial physical examination, serum Serial physical examination, serum tumor markers and high resolution tumor markers and high resolution testicular U/S are recommended to testicular U/S are recommended to rule out associated malignancy.rule out associated malignancy.

If no testicular malignancy is present, 6-If no testicular malignancy is present, 6-12 month intervals of clinical, U/S 12 month intervals of clinical, U/S surveillance and annual tumor markers surveillance and annual tumor markers are suggested.are suggested.

If future studies confirmed a strong If future studies confirmed a strong association between TM and CIS, TM association between TM and CIS, TM maybe viewed a specific marker of maybe viewed a specific marker of testicular malignancy and an indication testicular malignancy and an indication of testicular biopsy.of testicular biopsy.

Presently the results of limited studies Presently the results of limited studies and case reports and case reports do not justify routine do not justify routine testicular biopsytesticular biopsy in patients with typical in patients with typical U/S appearance of TM. U/S appearance of TM.

Indications for Testicular Indications for Testicular Biopsy:Biopsy:

Focal clumped and unilateral TM Focal clumped and unilateral TM without mass.without mass.

TM in infertile men, patients with TM in infertile men, patients with cryptorchidism and/ or atrophic cryptorchidism and/ or atrophic testes.testes.

Patients with ipsilateral testicular Patients with ipsilateral testicular tumor and TM in the contralateral tumor and TM in the contralateral testis.testis.

ConclusionConclusion

Although TM by itself is a benign disease Although TM by itself is a benign disease which does not require treatment, the which does not require treatment, the association of TM with testicular association of TM with testicular malignancy is clinically important.malignancy is clinically important.

Careful evaluation and follow up of Careful evaluation and follow up of asymptomatic patients with incidentally asymptomatic patients with incidentally diagnosed TM is recommended.diagnosed TM is recommended.

It is especially indicated for the patients It is especially indicated for the patients with cryptorchidism, infertility, testicular with cryptorchidism, infertility, testicular atrophy and contralateral testicular atrophy and contralateral testicular tumor who are at high risk for harboring tumor who are at high risk for harboring and developing malignancy.and developing malignancy.

The patient should be educated The patient should be educated about the known association about the known association between TM, testicular tumor and between TM, testicular tumor and CIS and instructed in testicular self CIS and instructed in testicular self examination as well as the need for examination as well as the need for semi-annual / annual testicular U/S, semi-annual / annual testicular U/S, physical exam and tumor marker.physical exam and tumor marker.

It is reasonable to consider biopsy It is reasonable to consider biopsy in high risk patients only if in high risk patients only if treatment of CIS is planned. treatment of CIS is planned.

ReferencesReferences

AUA series.AUA series.Current opinion in Urology Current opinion in Urology

2007.2007.Cambpel the 9Cambpel the 9thth edition. edition.

Dr. Wissam Kh. KamalDr. Wissam Kh. Kamal

R2 UrologyR2 Urology