Testicular Teratoma

Etiology

As previously described, according to WHO, one of the main changes is the division into postpubertal-type teratoma and prepubertal-type teratoma. Postpubertal type is considered as differentiation from other germ cell tumor types. Therefore, this specific type of teratoma can be associated with GCNIS and may develop metastases resembling the primary teratoma or other germ cell tumors.  

Germ cell tumors (GCT) originate from a primordial germ cell that can differentiate into ectoderm, mesoderm, and endoderm, thereby giving rise to a mixture of somatic cell tissues that characterize teratoma. Gains in chromosome 12p and expression of IMP3 are common in GCT.[2][3]

Prenatal Risk Factors

There are recognized risk factors in developing germ cell tumors, mainly intrauterine growth retardation (low birth weight and newborns small for gestational age), cryptorchidism, hypospadias, maternal bleeding, advanced maternal age, jaundice, and retained placenta. 

Cryptorchidism

Cryptorchidism is strongly associated with an increased risk of about 3-5 fold, and in a recent study, it is considered as high as 8 fold.[4] Subfertile and infertile men bear an increased risk of developing testicular cancer. In-utero exposure to exogenous and endogenous factors is still a matter of debate, and no international consensus has been met. Synthetic estrogen exposure (diethylstilboestrol) has been linked in some cases to cryptorchidism and, therefore, an increased risk of testicular cancer (about twofold).[5] Children whose mothers smoked during pregnancy had a 1.18 times higher risk of cryptorchidism as compared to controls.[6][7][8]

Past History

A personal history of GCT in the contralateral testis is the most important risk factor for developing a testicular tumor in the future.Also, pelvic irradiation is an important risk factor for the development of a testicular tumor.

Genetic Predisposition

A family history of testicular cancer increases the relative risk of developing a similar tumor, with a fourfold rise of the risk in brothers. Nevertheless, the US Preventive Services Task Force recommends against a screening, with a Grade D recommendation.[9][10]

Epidemiology

Testicular cancer is the most common solid tumor between the ages of 20 to 35 years. Testicular germ cell tumors (GCTs) are by far the most common malignant group of tumors arising in the testis (95%), mainly represented by seminoma. Non-seminomatous histotypes (embryonal carcinoma, choriocarcinoma, yolk sac tumor, teratoma) are less common, more aggressive in behavior, and can be pure or mixed.

Testicular teratoma can be found in children and young adults (20 to 35 is the most common age group, as stated previously). In children, it usually occurs in the first 2 years of life (mean age 20 months), representing the second most common GCT histotype after yolk sac tumor. It is rare in young adults as a pure form but is commonly encountered in a mixed form with other GCT histotypes.

Of all testicular cancer, nearly 90% present with locoregional disease. In general, testicular cancer is a highly curable disease with a 5-year survival rate of 95% (based on SEER 2010–2016), but data change when histotype-specific survival is taken into account. The presence of teratoma is associated with a higher cumulative incidence of disease-related death.[11] In the IGCCCG classification, seminoma and non-seminomatous histotypes are classified separately because of the different prognostic impact of histotype. Teratoma is associated with a higher metastatic rate and treatment resistance. However, Funt et al.[12][11] reported that 92% of deaths were associated with chemoresistant non-teratomatous GCT metastases.

Pathophysiology

The transcriptome analysis of germ cell tumors recognized a specific genetic range of alteration, with some differences between histotypes. Molecular studies [9] discovered a teratoma-specific gene signature.[13][14][15][16] There is a high frequency of mutations in the genes related to membrane-membrane interaction, matrix formation, and remodeling enzymes in testicular teratoma. RNA transcript analysis shows enhanced production of transmembrane proteins (CDH11, NCAM1, VCAM1, CLDN4, ITGA2, ITGB7, SDC1, SLC6A6), extracellular matrix-associated proteins (CYR61, COL1A1, COL3A1, COL6A3, THBS1, LGALS4, MFAP4, MGP, SPARC, SPON1), several enzymes and signaling mediators (MMP7, SERPINA1, SERPINA3, PLA2G2A, PLAT).[17] 

Two important genes are commonly up-regulated in teratomas (MMP7, EGR1). MMP7 is a metalloproteinase involved in tissue remodeling, mainly cleaving extracellular matrix components and nonmatrix proteins. EGR1 is an anti-apoptotic gene that promotes cell survival even after DNA damage. It is a possible molecular determinant of chemoresistance in teratomas.[18]

Teratoma with malignant transformation (MT) is an entity in which a component of teratoma undergoes malignant transformation (ex. adenocarcinoma, sarcoma, etc.) that is identical to a somatic malignancy.

Histopathology

Gross: Testicular teratoma is highly heterogeneous in appearance. The tumor is firm and usually well-circumscribed, occupying a portion or the entirety of the testis. The cut surface can appear solid or cystic, and different heterologous elements are a common finding, such as hairs, teeth, adipose tissue, cystic mass filled with keratin or mucinous material; solid areas formed by cartilage or bone may be recognizable. Those appearances correspond to different histologic differentiation that is typical of teratoma. 

Microscopy: Any epithelial, mesenchymal, or neural-derived tissue can be seen. Less common are tissues derived from the respiratory, gastrointestinal, or genitourinary tract. Skin-derived structures such as epithelial-derived (epidermoid cyst) or appendages is a quite common finding, especially in prepubertal-type teratomas, while postpubertal-type teratomas tend to appear as multiloculated cysts lined by other tissue types such as glandular epithelium and contain solid areas formed by parenchymal structure or mesenchymal tissues. A certain element of immature tissues can also be encountered, consisting of ectodermal, endodermal, or mesenchymal structures. Neuroectodermal tissue is the most common immature type and often has several differentiation stages of embryonic/fetal nervous system tissue. Historically teratoma has been differentiated into mature and immature, but this distinction is not recommended any more due to the lack of a prognostic significance. Teratoma can occur paired with other histotypes of germ cell neoplasia, such as yolk sac tumor or embryonal carcinoma. 

Teratomatous tissue can harbor various degrees of dysplasia ranging from mild cytological atypia to obvious malignancy. For instance, glandular tissue can hide areas of in situ or invasive carcinoma, and chondroid tissue can develop chondrosarcoma. Those cases are referred to as teratoma with somatic type malignancy and can behave accordingly, developing somatic-type metastases.

Careful microscopic examination is needed to define the grade of invasion of the surrounding tissues (para-testicular) and the invasion of vascular spaces. The adjacent testicular parenchyma is usually found to be atrophic with impaired spermatogenesis; finding of germ cell neoplasia in situ (GCNIS) is common. The fibrous stroma surrounding the teratomatous tissue was thought to be a physiological response to confine the tumor, but molecular analyses found the same genetic alterations of the teratoma. Therefore even the surrounding stroma is germ cell-derived and not reactive fibrosis. 

The metastatic spread of testicular cancer involves the para-aortic retroperitoneal lymph nodes in 95% of cases. Mesenteric lymphatics are not a well-described metastatic pathway, but sporadic cases have been reported.[19][20][21] Various mechanisms of spread to the mesentery have been proposed, including direct extension and hematogenous dissemination.

Immunohistochemistry: Teratomatous structures express the same antigens expected for the specific cell type. Glandular tissue is always positive for cytokeratin and epithelial membrane antigen; keratinocytes are positive for high molecular weight cytokeratins; mesenchymal tissue can express several antigens related to the mature tissue (S100 in neural-derived and adipous tissue, actin for muscular fibers, CD34 for fibroblastic cells, and so on). In mixed-type germ cell neoplasias, there might be the expression of other markers: human chorionic gonadotropin (from syncytiotrophoblastic cells), placental alkaline phosphatase, and LDH.

History and Physical

Patients presenting with a testicular mass or groin pain should be carefully evaluated. The younger age group is extremely susceptible to testicular cancer, and young men have obvious fertility concerns regarding therapy. A detailed history should be obtained, with information regarding undescended testis, previous testicular torsion, injury to the groin, the growth rate of the present lesion, and the presence of any associated symptoms. A history of surgery for undescended testis is also relevant since the testis that has been brought down into the scrotum still has a 10 fold higher risk for malignant change in comparison to the normal testis. Patients can be asymptomatic or complain of painless swelling of the testicle. In other cases, patients can present with painful testicular swelling, usually due to intratumoral hemorrhage and hematoma or testicular torsion.

A careful physical examination should be coupled with ultrasound examination and appropriate serologic studies. Bilateral tumors are uncommon; nevertheless, there should always be a comparison with the contralateral testis. An empty hemiscrotum with absent scrotal rugae would point towards undescended testis, and an associated groin swelling might indicate a malignant change in the undescended testis. Another caveat is that a fast-growing testicular cancer may feel soft due to secondary hydrocele. Still, on careful palpation, the solid mass can often be felt through the surrounding fluid. In later stages of progression, the growth incorporates the testis, and the cord structures are thickened. However, the scrotal skin is not involved until very late in the disease course. Enlarged para-aortic nodes may be palpable in a thin subject in the epigastric region. In advanced cases, the left supraclavicular lymph nodes may also be palpably enlarged (Virchow's node).

Evaluation

Laboratory and imaging evaluation to diagnose and stage the disease are serological tests, abdominal and retroperitoneal ultrasound, chest X-ray, CT-scan (abdominopelvic and thoracic), and in some cases MRI or PET.[22]

Serum tumor markers can help in the differential diagnosis of a germ cell tumor and can be used as a baseline for follow-up. In serum evaluation, hCG and AFP levels can be elevated. In those cases, the increased serum markers can be due to mixed histology of yolk sac tumor and hCG-secreting syncytiotrophoblast cells.

Ultrasound (US) is the preferred imaging study for evaluating testicular pathology. It is an easy and non-invasive procedure and is highly sensitive for identifying scrotal masses. The technique can differentiate between intratesticular and extra-testicular lesions with a sensitivity that reaches 99%. The affected testis can be compared with the contralateral one. A normal testis has a homogeneously granular texture and is located below the epididymis that appears iso/hyperechoic. A hydrocele would appear as extra testicular fluid in tunica vaginalis that can be easily differentiated from cystic testicular masses.

A solid intratesticular lesion should be considered malignant unless proved otherwise. The US appearance is closely related to the gross morphology of the lesion and therefore is extremely important to carefully evaluate and describe the US images. Testicular neoplasms are usually hypoechoic (compared to the normal parenchyma), and heterogeneity can appear if there are calcifications and cysts. Testicular teratoma can appear as an irregularly solid or predominately cystic mass. The presence of calcifications in the tumor is another helpful finding associated with teratomas. The vascularisation of the tumor can be evaluated with a Doppler scan, although this additional exam is not of particular use in the differential diagnosis. In contrast, epididymal masses are usually benign, but careful examination should exclude the involvement of the spermatic cord and intratesticular abnormalities. 

Magnetic resonance (MR) imaging is not widely used in clinical practice, and its role is mainly in difficult cases and for the characterization of extra-testicular neoplasms.

PET scan can rarely help in the differential diagnosis as teratoma lacks the usually increased glucose uptake of tumoral tissues, i.e., it is 2-deoxy-2-fluoro-D-glucose (FDG)-negative. PET scan is not useful for differentiating teratoma and necrosis.[23]

Treatment / Management

The International Germ Cell Consensus Classification studied more than 5000 cases of non-seminomatous GCTs with metastatic spread, treated with cisplatin chemotherapy and followed for 5 years. This provided important clinical data on metastatic cases, and in this consensus, a three-tier risk factor evaluation was created. Independent prognostic variables were identified: histotype, site of the primary tumor, tumor marker elevation (α-fetoprotein, human chorionic gonadotrophin, lactate dehydrogenase), and nonpulmonary visceral metastases. Based on this classification, the prognosis depends on the risk class of each patient, with a mortality risk of 10%, 20% to 30%, and 50% to 60% of good-, intermediate-, and poor-risk patients, respectively.[12](B2)

Radical orchiectomy is the gold standard for a patient presenting with a testicular mass with clinical features concerning malignancy. Placement of a testicular prosthesis is an aesthetic option that can be considered before surgery. Testis-sparing surgery is only applicable for lesions that do not infiltrate the testis and are not suspicious for germ cell origin. In those cases, in fact, germ cell neoplasia in situ is often present in the surrounding parenchyma suggesting a potential to develop invasive germ cell neoplasia if left untreated.[24] Subsequent therapy depends on serum markers, histotype, vascular invasion, lymph node involvement (if a regional lymphadenectomy is performed), and the result of a CT-scan for staging purposes. For teratoma, postoperative surveillance is recommended after orchiectomy.(B2)

Stage I tumors are treated depending on the lymphovascular invasion (LVI) of the spermatic cord, infiltration of the scrotum, and serum markers. Orchiectomy is the treatment of choice, and the patient is then sent to surveillance or retroperitoneal lymph node dissection (RPLND). The latter is the choice in cases with transformed teratoma and cases where radiology cannot exclude a lymph node involvement. Viable GCT may be found in as much as 20% of primary RPLND done for pure testicular teratoma and usually implies either a small volume NSGCT which was missed in the pathological report of the orchiectomy specimen) or regressed viable GCT elements in the testis. Patients who choose surveillance should adhere to a strict follow-up aimed to detect early metastases. In patients choosing preventive chemotherapy, accurate staging with a CT-scan and a single cycle of bleomycin, etoposide, and cisplatin (BEP) is recommended.

Stage I patients with positive nodes after RPLND are candidates for surveillance or adjuvant chemotherapy (suggested in pN2 cases, mandatory for pN3) with two cycles of etoposide+cisplatin (EP). Teratoma is not highly sensitive to chemotherapy, so it is not always recommended.

Patients in stage II present with regional lymphatic metastasis (retroperitoneum) without other metastasis (any T, N1–3, M0, SX). Stage IIA is a clinical or pathological stage N1, less than 2 cm; serum tumor markers are at normal levels or only slightly high (S1). In stage IIB, the largest lymph node mass is between 2 and 5 cm in size (N2), serum tumor markers are at normal levels or only slightly high (S1). In stage IIC, there is at least one lymph node metastasis larger than 5 cm (N3). Stage II disease should be treated with chemotherapy if serum markers are elevated [indicates mixed histology]or if lymph nodes are enlarged (>3 cm). 

Patients with incomplete resection (residual masses) should undergo RPLND in lesions containing mainly teratoma. In cases of infiltration of the inferior vena cava wall or thrombi, these should be completely resected. The resection needs to be as complete as possible because teratomas tend to have a local growth raising their risk of malignant transformation and relapse. Residual masses are usually chemoresistant, and they progress despite chemotherapy.

Differential Diagnosis

Testicular teratoma should be differentiated from:

• Other testicular germ cell tumors
• Epidermoid cyst
• Testicular metastases from other tumors
• Lymphoma
• Testicular torsion
• Inguinal hernia
• Testicular abscess

Radiation Oncology

Radiotherapy has practically no role in the management of testicular teratoma. It is primarily used as an adjuvant treatment if seminoma histology is present.

Treatment Planning

BEP (5-day schedule)

• Bleomycin 30 mg IV bolus day 1, 8, 15 or day 2, 9, 16
• Etoposide 100 mg/m2/day IV daily
• Cisplatin 20 mg/m2/day IV daily

EP (5-day schedule)

• Etoposide 100 mg/m2/day IV daily
• Cisplatin 20 mg/m2/day IV daily

Toxicity and Adverse Effect Management

Sperm banking should be discussed with patients of reproductive age. Therapies for testicular teratoma include surgery, radiation therapy, and chemotherapy, so fertility counseling should be initiated before treatment.

Medical Oncology

Teratoma, a histologic subtype of nonseminoma that represents terminally differentiated somatic tissue, is chemotherapy-resistant. When in the pure form, it is not associated with tumor marker production or FDG-avidity.However, about two-thirds of NSGCTs[including pure testicular teratomas]may present with advanced metastatic disease. This is generally due to the so-called "burnt out testicular NSGCT" and can present with elevated tumor markers and viable GCT (embryonal cell carcinoma or yolk sac tumor) in metastatic lesions. The patients would be managed initially with chemotherapy as per IGCCCG risk stratification followed by post-chemo RPLND. The final retroperitoneal specimen usually reveals fibrosis (44%) or teratoma (50%), or viable GCT (6%). The clinician might also encounter a poor response to induction chemotherapy in advanced NSGCT cases if teratomatous elements are present in the orchiectomy specimen.

Staging

To accurately stage the disease, it must be searched for metastatic or occult disease. Useful tools are serum tumor markers, CT scan, or MRI to screen for nodal pathway and visceral metastases. Metastases from mature and immature teratoma have been reported at initial presentation in 13% to 60% of cases.[25]

The AJCC's 8th edition of a TNM staging system is the international gold standard. It uses T (tumor primary), N (node involvement), M (metastases) for pathological and radiological staging, plus S (serum markers), which is a unique parameter of testicular cancer. 

Prognosis

The International Germ Cell Cancer Collaborative Group (IGCCCG) is the reference classification for assessing prognosis in patients with advanced non-seminomatous germ-cell tumors. Three risk classes are identified, as shown in the following table. 

Postpubertal-type teratomas have a less benign prognosis. Adults with pure mature teratoma have metastases in over 40%, but the overall survival is close to 100% after 5-year when the disease is localized.In metastatic somatic-type malignancies, patients do not respond well to conventional chemotherapy used for metastatic germ cell tumors, so that the overall survival drops.Teratoma, even the mature form, has an unpredictable behavior, being locally-invasive and bearing the possibility of malignant transformation into somatic tumors such as sarcoma (commonest type, especially rhabdomyosarcoma) or carcinoma.

The presence of teratoma is associated with a higher cumulative incidence of disease-related death.[11]

Complications

Orchiectomy procedure coupled with lymph node dissection has major morbidity of retrograde ejaculation, so a nerve-sparing resection is recommended whenever applicable (stage I disease with normal serum markers).