GCNIS stands for germ cell neoplasia in situ. These are precancerous germ cells that remain inside the sperm-producing tubules. They are not invasive cancer yet, but if untreated roughly half progress to invasive germ-cell cancer within five years.

GCNIS is found in the tissue next to an invasive post-pubertal germ-cell tumor in roughly 80-90% of cases, so most men whose testicle is removed for a germ-cell tumor have already had any GCNIS in that testicle removed at the same time.

GCNIS can also be found in the opposite testicle, but routine biopsy of the opposite testicle is uncommon in the United States and remains controversial internationally. Current European guidance recommends discussing contralateral biopsy mainly with higher-risk men, particularly those with a small testis and/or a history of undescended testis. If GCNIS is found in a remaining testis, options can include surveillance, local radiation, or orchiectomy depending on fertility, hormone function and the individual situation.

The T category describes how far the original tumor has extended in and immediately around the testicle. For most patients the definitive T category comes from examination of the orchiectomy specimen.

TX: The primary tumor cannot be assessed.

pT0: No evidence of a primary tumor. One example is a "burned-out" tumor where only a scar remains in the testicle.

pTis: Germ cell neoplasia in situ (GCNIS), without invasive cancer.

pT1: Tumor limited to the testis, including possible rete testis invasion, without lymphovascular invasion.

For pure seminoma only, AJCC divides pT1 into pT1a for a tumor smaller than 3 cm and pT1b for a tumor 3 cm or larger.

pT2: Tumor with lymphovascular invasion, or tumor invading hilar soft tissue or epididymis, or penetrating the visceral mesothelial layer covering the external surface of the tunica albuginea.

pT3: Tumor directly invades the soft tissue of the spermatic cord.

pT4: Tumor invades the scrotum.

The N category describes cancer in the regional retroperitoneal lymph nodes. cN is based mainly on imaging. pN is based on lymph nodes that were removed and examined, usually during an RPLND.

Clinical cN categories:
cNX: Regional lymph nodes cannot be assessed.
cN0: No regional lymph-node metastasis is identified.
cN1: A nodal mass is 2 cm or smaller, or there are multiple nodes with none larger than 2 cm.
cN2: A nodal mass is larger than 2 cm but no larger than 5 cm, or multiple nodes are present with at least one larger than 2 cm but none larger than 5 cm.
cN3: A nodal mass is larger than 5 cm.

Pathological pN categories:
pNX: Regional lymph nodes cannot be assessed pathologically. This is a formal code, but most patients who never have an RPLND simply have a clinical cN category and never need to think about pNX.
pN0: No regional lymph-node metastasis is found.
pN1: The nodal mass is 2 cm or smaller and 5 or fewer nodes are positive, with none larger than 2 cm.
pN2: The nodal mass is larger than 2 cm but no larger than 5 cm, or more than 5 nodes are positive with none larger than 5 cm, or tumor extends outside a lymph node (extranodal extension).
pN3: The nodal mass is larger than 5 cm.

The M category describes spread beyond the regional retroperitoneal lymph nodes. Distant metastases are usually identified clinically by imaging.

M0: No distant metastasis.
M1a: Cancer has spread to nonregional lymph nodes and/or the lungs.
M1b: Cancer has spread to another distant organ such as the liver, bone or brain.

Older records may use MX to mean distant metastasis could not be assessed. Current AJCC stage groupings do not use MX, but you may still encounter it in older records.

The S category combines AFP, beta-hCG and LDH. For the usual post-orchiectomy AJCC stage, these blood tests are obtained after orchiectomy and before additional treatment. The original pre-orchiectomy values are still important, but they are not automatically the values used for the final post-orchiectomy S category.

If the first postoperative values remain elevated, subsequent blood tests are reviewed. The lowest values reached by normalization or plateau before additional treatment, or before a marker starts rising again, are used.

SX: The post-orchiectomy marker studies are unavailable or cannot be fully assessed.

S0: AFP, beta-hCG and LDH are all within their laboratory normal ranges.

S1: At least one marker is above normal, but all three remain below the S2 thresholds: LDH less than 1.5 times the laboratory upper limit of normal, beta-hCG below 5,000 mIU/mL and AFP below 1,000 ng/mL.

S2: At least one marker reaches an S2 threshold: LDH 1.5 to 10 times the laboratory upper limit of normal, beta-hCG 5,000 to 50,000 mIU/mL, or AFP 1,000 to 10,000 ng/mL.

S3: At least one marker reaches an S3 threshold: LDH greater than 10 times the laboratory upper limit of normal, beta-hCG greater than 50,000 mIU/mL, or AFP greater than 10,000 ng/mL.

What is the upper limit of normal? This is the highest LDH value that the laboratory considers normal. LDH normal ranges vary from laboratory to laboratory. If your LDH is 500 and that laboratory says the upper limit of normal is 250, your LDH is 2.0 times the upper limit of normal.

Why does missing information matter? All three marker results are needed to distinguish S0 from S1. Only one sufficiently elevated result is needed to establish S2 or S3.

A note about LDH: LDH is the least specific of the three traditional tumor markers. Many illnesses and tissue injuries can raise it. It remains part of AJCC staging and IGCCCG prognosis, but by itself it is a weak test for deciding whether germ-cell cancer is present.

AJCC combines T, N, M and S to produce the overall stage.

The classic IGCCCG system is used when first-line systemic chemotherapy is being planned for metastatic or marker-positive germ-cell cancer. It is separate from AJCC stage.

The classic groups use histology, where the germ-cell tumor started, whether there are metastases to organs other than the lungs, and AFP, beta-hCG and LDH. The tumor-marker values should be measured immediately before starting first-line chemotherapy for metastatic disease, ideally the same day.

If cancer later relapses after prior cisplatin chemotherapy, doctors do not simply recalculate the original IGCCCG group. Salvage treatment has separate prognostic systems that also consider things such as the response to first-line therapy and the time until relapse.

Good prognosis requires all of the following: a testicular or retroperitoneal primary, no nonpulmonary visceral metastases, AFP below 1,000 ng/mL, beta-hCG below 5,000 IU/L and LDH below 1.5 times the upper limit of normal. Contemporary 5-year progression-free survival is about 90% and 5-year overall survival about 96%.

Intermediate prognosis requires a testicular or retroperitoneal primary and no nonpulmonary visceral metastases, with at least one marker in the intermediate range: AFP 1,000-10,000, beta-hCG 5,000-50,000, or LDH 1.5-10 times the upper limit of normal. Contemporary 5-year progression-free survival is about 78% and 5-year overall survival about 89%.

Poor prognosis applies if any one of the following is present: a mediastinal primary nonseminoma, a nonpulmonary visceral metastasis, AFP above 10,000, beta-hCG above 50,000, or LDH above 10 times the upper limit of normal. Contemporary 5-year progression-free survival is about 54% and 5-year overall survival about 67%.

The words good, intermediate and poor are the formal names of the groups. They do not mean that an individual patient has a 96%, 89% or 67% chance of cure.

Seminoma has only good and intermediate classic IGCCCG groups. There is no poor-prognosis group for seminoma.

Good prognosis requires a normal AFP and no nonpulmonary visceral metastases. The primary site can be anywhere, and beta-hCG and LDH can be at any level for the classic group. Contemporary 5-year progression-free survival is about 89% and 5-year overall survival about 95%.

Intermediate prognosis requires a normal AFP and the presence of a nonpulmonary visceral metastasis such as liver, bone or brain. Contemporary 5-year progression-free survival is about 79% and 5-year overall survival about 88%.

Modern data show that LDH can refine prognosis within the classic seminoma groups, but it does not create a separate standard IGCCCG treatment group.

The classic good/intermediate/poor groups are still used for treatment decisions. The newer IGCCCG Update model adds more detail for first-line metastatic nonseminoma. It uses age, primary site, lung metastases, nonpulmonary visceral metastases, AFP, beta-hCG and LDH to estimate an individual's 3-year progression-free survival (PFS).

In plain English, 3-year progression-free survival is the estimated chance that a patient will be alive without the cancer having progressed or returned three years after starting first-line chemotherapy. It is not the same thing as overall survival, and it should not be read as a literal chance of cure.

The IGCCCG/EORTC group maintains its own clinician-oriented web application for this model. TCRC does not try to reproduce it: Open the official IGCCCG Update calculator.

The official web application is for nonseminoma. The seminoma update refined prognosis but did not produce an equivalent individualized web calculator.