Browse Month: April 2008

Nonseminomatous Germ Cell Tumors


Nonseminomatous histology comprises about 50% of all GCTs, and most frequently presents in the third decade of life. Most tumors are mixed, consisting of two or more cell types. Seminoma may be a component, but the definition of a pure seminoma excludes the presence of any nonseminomatous cell type. The presence of any nonseminomatous cell type (other than syncytiotrophoblasts) imparts the prognosis and management principles of a nonseminomatous tumor.

Embryonal Carcinoma
Embryonal carcinoma is the most undifferentiated somatic cell type. Individual cells are epithelioid in appearance and may be arranged in glandular or tubular nests and cords or as solid sheets of cells. Tumor necrosis and hemorrhage are frequently observed.


By definition, choriocarcinoma consists of both cytotrophoblasts and syncytiotrophoblasts. If cytotrophoblasts are not present, then the diagnosis of choriocarcinoma cannot be made. Pure choriocarcinoma is an extremely rare presentation usually associated with widespread hematogenous metastases and high levels of hCG. Hemorrhage into the primary tumor is frequent and is an occasional severe complication when it spontaneously occurs at a metastatic site. Elements of choriocarcinoma are frequently found in mixed tumors but appear to have no prognostic importance. Syncytiotrophoblastic giant cells can be seen as a component of any GCT (including pure seminoma). They impart no prognostic value by themselves.

Yolk Sac Tumor

Yolk sac tumor (endodermal sinus tumor) is often confused with a glandular form of embryonal carcinoma. This tumor mimics the yolk sac of the embryo and produces alpha-fetoprotein (AFP). The cells may have a papillary, glandular, microcystic, or solid appearance; and may be associated with Schiller-Duval bodies, which are perivascular arrangements of epithelial cells with an intervening extracellular space. Rarely, embryoid bodies resembling the early embryo can be seen. Yolk sac histology is rarely present as the only histologic subtype except in the mediastinum where pure yolk sac tumors account for a substantial minority of primary tumors. Pure yolk sac histology is the most common histology found in childhood GCT.

A teratoma is composed of somatic cell types derived from two or more germ layers (ectoderm, mesoderm, or endoderm). Mature teratoma consists of adult-type differentiated elements such as cartilage, glandular epithelium, nerve tissue, or other differentiated cell types. Immature teratoma generally refers to a tumor with partial somatic differentiation, similar to that seen in a fetus. Teratoma with malignant transformation refers to a form of teratoma in which one of its components, either immature or mature, develops aggressive growth and histologically resembles another malignancy. These usually take the form of sarcomas (most frequently embryonal rhabdomyosarcoma); and, less frequently, carcinomas (e.g., enteric-type adenocarcinoma), neuroectodermal tumors, or combinations of these. Acute nonlymphocytic leukemias have arisen in the context of mediastinal GCT, but not from other primary sites. Acute lymphocytic leukemia has been described. Although a mature teratoma may be histologically benign, it is derived from a totipotential, malignant precursor cell (embryonal carcinoma or yolk sac tumor). Therefore, a primary testicular tumor in a postpubertal male that displays only teratoma must be considered to be a fully malignant GCT, and management should proceed as if malignant components are present.



Carcinoma in situ (CIS) (intratubular germ cell neoplasia) precedes invasive testicular GCT in virtually all cases of typical and anaplastic seminoma and all nonseminomatous histologies in the adult. CIS is frequently present in retroperitoneal presentations and is rarely, if ever, present in mediastinal presentations. It has not been described in spermatocytic seminoma and rarely in tumors arising in prepubertal patients. Cytologically, CIS preceding seminoma and nonseminoma is identical. The median time for progression of CIS to invasive disease is 5 years. In the general population, the incidence of CIS is very low, while in men with impaired fertility, the incidence is about 0.5%. The incidence of CIS is 2% to 5% in both cryptorchid testes and the contralateral testis in patients with a documented prior testicular GCT.

Seminoma accounts for approximately 50% of all GCT and most frequently appears in the fourth decade of life. The typical or classic form consists of sheets of large cells with abundant cytoplasm and round, hyperchromatic nuclei with prominent nucleoli. A lymphocytic infiltrate or granulomatous reaction with giant cells, or both, is frequently present. Trophoblastic giant cells capable of producing human chorionic gonadotropin (hCG) are present in 15% to 20% of tumors. The presence of syncytiotrophoblastic giant cells in an otherwise pure seminoma does not influence prognosis or treatment. Anaplastic seminoma is an older term used when three or more mitotic figures are seen per high-powered field, and it has no clinical or prognostic importance. Stage for stage, anaplastic seminoma is similar in response and prognosis to classic seminoma.

An atypical form of seminoma has been described with unusual immunohistochemical features. While the cells cytologically resemble classic seminoma, lymphocytic infiltrate and granulomatous reaction are absent, necrosis is more common, and the nuclear: cytoplasmic ratio is higher. These tumors must be distinguished morphologically from solid variants of embryonal carcinoma and yolk sac tumor. Atypical seminoma frequently shows cytoplasmic expression of low-molecular-weight keratin or the type 1 precursor to the blood group antigens, while typical seminoma stains negative. Electron microscopic studies have shown that the individual tumor cells acquire cytoplasmic cytokeratin intermediate filaments, suggesting epithelial differentiation. There has been no specific association of atypical seminoma with an adverse prognosis, and its management is currently the same as any other seminoma.

Spermatocytic seminoma is a rare histologic variant seen almost exclusively in men above the age of 45. The relationship of spermatocytic seminoma to other GCTs is not clear, because it is not associated with CIS or bilaterally, does not express placental alkaline phosphatase (PLAP) (see later), and has not been shown to have the same genetic abnormalities as other GCTs. Metastatic potential is minimal.

Initial presentation and management


The pathognomonic presentation of a primary testicular tumor is a painless testicular mass that may range in size from a few millimeters to several centimeters. However, the painless testicular mass occurs in only a minority of patients. The majority present with more diffuse testicular pain, swelling, hardness, or some combination of these findings. Because infectious epididymitis or orchitis, or a combination of the two, is more common, a trial of antibiotic therapy is often reported in questionable cases. Acute testicular pain, simulating testicular torsion, occurs less frequently and may represent intratumoral hemorrhage. If the testicular discomfort does not abate or findings do not revert to normal within 2 to 4 weeks, a testicular ultrasound is indicated. On ultrasound, the typical testicular tumor is intratesticular, and may produce one or more discrete hypoechoic masses or diffuse abnormalities with microcalcifications. The latter is more frequently found in seminoma. Delay in diagnosis, caused by either patient- or physician-related factors, or both, generally results in higher stage at presentation and presumably lower survival. These data on delay in diagnosis require that this highly curable neoplasm be properly managed at all stages.


A radical inguinal orchiectomy, using an inguinal incision with early high ligation of the spermatic cord at the deep inguinal ring, minimizes local tumor recurrence and aberrant lymphatic spread and is the only acceptable therapeutic and diagnostic procedure. The vasal and vascular components are doubly clamped and divided separately; their respective stumps are pushed into the retroperitoneal space to facilitate future removal of the gonadal vessels at the time of retroperitoneal lymph node dissection (RPLND). The testicle and spermatic cord are removed en bloc, avoiding any spillage, and meticulous hemostasis is achieved. The testis embryologically originates in the genital ridge, and descends during fetal life through the abdomen and inguinal canal into the scrotum. Therefore, the primary lymphatic and vascular drainage of the testis is to the retroperitoneal lymph nodes and the renal or great vessels, respectively. A transscrotal orchiectomy is contraindicated, because it permits the development of alternate lymphatic drainage pathways to the inguinal and pelvic lymph nodes, and leaves intact the spermatic cord from the external to the internal ring. In the rare situation when the diagnosis of a testicular tumor is in question, then an inguinal incision is required for an open biopsy. The testis can then be examined in situ in a sterile field and an appropriate biopsy taken with minimal risk of scrotal or inguinal contamination. Regardless of the preoperative diagnosis, all potential, primary testicular malignancies should be managed through an inguinal approach.

Extragonadal GCTs comprise fewer than 10% of all GCT presentations. The mediastinum and retroperitoneum are the most common primary sites. Pineal tumors, occurring most frequently in children, are usually GCT. Because of their unique access to the meninges, the metastatic pattern of pineal germ GCT includes intradural sites along the neuraxis and is infrequently systemic. The management of pineal GCT is discussed elsewhere in this text. In extremely rare circumstances, primary GCTs have been found in unusual sites such as the sacrum, thyroid, paranasal sinuses, and soft tissues of the head and neck. In patients with extragonadal presentations of GCT, a testicular ultrasound is required. The management of extragonadal and testicular GCT is the same, and primary site is an independent factor in current staging and risk classifications.

Testicular Cancer

Testicular cancer is the most common solid tumor in men between the ages of 20 and 35 years. There are three modal peaks: infancy, ages 25 to 40, and about age 60.

A solid testicular mass in a man aged 50 or greater is usually a lymphoma. An estimated 6000 new cases and 350 deaths due to testicle cancer occured in the United States in 1995. The lifetime probability of developing a GCT is approximately 0.2% for an American Caucasian male. The incidence of testis cancer varies significantly according to geographic area. The reported incidence is highest in Scandinavia, Switzerland, Germany, and New Zealand; intermediate in the United States and Great Britain; and lowest in Africa and Asia. The worldwide incidence of testis GCT has more than doubled in the past 40 years.


GCTs are seen principally in young Caucasians, rarely in African-Americans. The published ratio between Caucasian and African-American patients is approximately 4 to 5:1, although it was closer to 40:1 ratio in the US Military. In African-Americans, GCT behaves similarly to that of the general population, and the incidence of GCT in African-Americans has not increased over the past 40 years. Familial clustering has been observed, particularly among siblings.
The cause of GCT is unknown. Hypotheses implicating an endocrine-driven, pituitary stimulation of damaged germinal epithelium have not been proved. Instead, random genetic events occurring during the early stages of meiosis seem to be responsible for the malignant transformation of germ cells (see section on biology). A few congenital developmental defects predispose to the disease.


The risk of GCT occurring in the cryptorchid testis is several times the risk in normally descended testes. Between 5% and 20% of patients with a history of cryptorchidism develop a tumor in the normally descended testis.An abdominal cryptorchid testis is more likely to develop GCT than an inguinal cryptorchid testis. The protective effect of orchiopexy is difficult to quantify, but most data suggest a reduced likelihood of GCT if orchiopexy is performed prior to puberty. If the testis is inguinal, hormonally functioning, and easily examined, surveillance is recommended. If the testis is not amenable to orchiopexy or cannot be adequately examined, orchiectomy is recommended.

Fusion defects. Endometrial Polyps

Fusion defects include unicornuate uterus (AFS class II), uterus didelphys (AFS class III), bicornuate uterus (AFS class IV), and septate uterus (class V).

A unicornuate uterus has a single hemi-uterus that is attached to its fallopian tube. It may also be associated with a rudimentary cavity from the contralateral side. A didelphys uterus has two uterine cavities, and each has a separate cervix. The fundus of the uterus also has a deep cleft between the cavities. A bicornuate uterus has a single cervix, a heart-shaped fundus, and two uterine cavities separated by myometrium. Conversely, a septate uterus has a single cervix, a flat fundus, and two uterine cavities separated by relatively avascular scar tissue.

Two clinically relevant points for fusion defects are:
In a woman with a unicornuate uterus, a rudimentary horn can result in pain because of obstruction orretrograde flow, either of which may cause endometriosis or be a site of infection.
Fusion defects may be associated with reproductive problems, from recurrent miscarriage to premature labor. The incidence of these problems is uncertain, however, because in women who have had only uncomplicated pregnancies, anomalies may never have been noted.
Among patients with AFS class I to IV uterine anomalies, there is an increased incidence of renal anomalies, usually renal agenesis ipsilateral to the associated hypoplastic mullerian defect. Therefore, a search for uterine anomalies should be conducted in patients with renal agenesis, and pelvic pain, or reproductive dysfunction.

Advances in the Treatment of Endometrial Polyps

Endometrial polyps are benign tumors consisting of surface endometrium, fibrous stroma, and thick-walled, centrally positioned blood vessels. A clonal rearrangement of chromosome 6p21 is common in the mesenchymal (stroma) cells in the polyp. The endometrial cells do not have the chromosome 6 rearrangement. One possible explanation of these findings is that an endometrial polyp begins when a stromal cell undergoes a rearrangement in chromosome 6p21 resulting in an abnormal signal to grow. The stromal elements proliferate and bring the endometrial glands along as “innocent bystanders.”

Most endometrial polyps are solitary. In approximately 20% of cases multiple polyps are present. Polyps peak between ages 40 and 50 years, but many cases occur in menopausal women. In fewer than 1% of cases, polyps are associated with cancer. The usual presenting symptom is intermenstrual bleeding or menometrorrhagia.

Polyps are typically diagnosed by sonography (especially sensitive in the follicular phase), saline infusion hysterosonography, hysterosalpingography, hysteroscopy, or curettage. Curettage often fails to remove endometrial polyps because of the mobility of their body and tip. In menopausal women taking hormone replacement therapy who have abnormal uterine bleeding, polyps are commonly found by hysteroscopy. Multiple case reports indicate that tamoxifen treatment may stimulate the development and growth of endometrial polyps.

Other Benign Uterine Disorders

Adenofibromas are benign tumors of epithelium and stroma that contain fewer that 4 mitoses per 10 high-power fields. Women with adenofibromas usually are elderly. Abnormal vaginal bleeding is the most frequent presentation.

Uterine Conservation at the Time of Adnexal Removal

In women who desire future childbearing, every effort should be made to preserve ovarian tissue unless a cancer diagnosis necessitates the removal of both ovaries. Occasionally, the clinician is confronted with a large benign ovarian cyst and must decide whether to remove the entire ovary or perform a cystectomy. If the woman has a desire for more children, an effort should be made to perform a cystectomy and to leave as much ovarian tissue as possible.

For some conditions, both ovaries require surgical removal. The clinician then is confronted with the issue of uterine conservation. If the woman has clearly and consistently communicated that she has no interest in further pregnancies and does not desire to retain her uterus, the uterus can be removed. If the woman has clearly expressed an interest in future childbearing, the uterus may be left in place so she may be able to become pregnant through oocyte or embryo donation.

Congenital Anomalies. Endometrial Polyps

The uterus is formed from the paired mullerian ducts during embryogenesis. Uterine anomalies result from their defective migration, fusion, or absorption during embryonic life. The incidence of anomalies is difficult to estimate because many congenital anomalies do not result in clinical manifestations (Rock and Jones, 1977). Patients with symptomatic mullerian anomalies usually have signs of menstrual outflow obstruction or reproductive dysfunction. Diagnostic methods for determining the exact nature of a mullerian anomaly have evolved from bimanual examination, postpartum manual exploration, and D & C, to the more sophisticated techniques of hysterography, laparoscopy, hysteroscopy, ultrasonography, and MRI. Increased capacity of the latter techniques to yield complete information will undoubtedly be reflected in a higher reported incidence of the more subtle anomalies.

Retrospective studies reveal that approximately 25% of women with congenital uterine anomalies encounter re- productive difficulties, although conception rates are not different than they are among women in control groups (Abramovici et al, 1983; Harger, 1983). Spontaneous abortions, premature births, and fetal malpresentations are common in women with congenital uterine anomalies.

Anomalies can be classified as problems with hypoplasia or agenesis (American Fertility Society [AFS] class I) or as fusion defects (AFS classes II-V). Class I anomalies, also referred to as mullerian anomalies, usually are diagnosed in women who seek treatment for primary amenorrhea or for an inability to have vaginal intercourse. These defects are thought to occur developmentally when the mullerian structures fail to join with the structures arising from the vaginal bulb. There is a wide spectrum of defects ranging from isolated vaginal agenesis to hypoplasia of the vagina, cervix, ileus, and tubes.

Clinically important points of these anomalies include:

  1. In patients with complete mullerian agenesis, the possibility of complete androgen insensitivity (testicular feminization syndrome) should be considered because these women have Y chromosomes and must have their gonads removed because there is a high risk for neoplasia.
  2. The patient with an absent vagina can have one that is adequate for intercourse created through the use of progressive dilators or surgery.

Endometrial Polyps

Endometrial polyps are hyperplastic overgrowths of glands and stroma that are localized and that form a projection above the surface. Such polyps may be sessile or pedunculated and rarely include foci of neoplastic growth.

The prevalence of polyps has been estimated at 10% to 24% among women undergoing endometrial biopsy or hysterectomy. Endometrial polyps are rare among women younger than 20 years of age. The incidence of these polyps rises steadily with increasing age, peaks in the fifth decade of life, and gradually declines after menopause.

The most common symptom in women with endometrial polyps is metrorrhagia, or irregular bleeding; it is reported in 50% of symptomatic patients. Postmenstrual spotting is also common. Less common symptoms include menorrhagia, postmenopausal bleeding, and breakthrough bleeding during hormonal therapy. Overall, endometrial polyps account for 25% of abnormal bleeding in premenopausal and postmenopausal women (Van Bogaert, 1988).

Endometrial polyps can sometimes be seen prolapsing through the cervix. Often they are diagnosed by microscopic examination of a specimen obtained after dilatation and curettage (D & C) or after endometrial biopsy. As is the case with submucous fibroids, polyps can escape detection if the uterus is not distended. Increasingly these lesions are diagnosed by modalities such as ultrasonography and hysteroscopy.

Endometrial polyps usually are cured by thorough curettage. However, polyps or other structural abnormalities may be missed by blind curettage, and hysteroscopic-guided curettage is often useful.

Uterine anomalies may be congenital or they may be acquired after infection or mechanical trauma, and they may lead to reproductive or menstrual dysfunction.