A 2009 revision of the traditional Chompret criteria for screening has been proposed:

A proband who has:

- tumor belonging to the LFS tumor spectrum - soft tissue sarcoma, osteosarcoma, pre-menopausal breast cancer, brain tumor, adrenocortical carcinoma, leukemia or lung bronchoalveolar cancer - before age 46 years;

and at least one of the following:

- at least one first or second degree relative with an LFS tumour (except breast cancer if the proband has breast cancer) before age 56 years or with multiple tumours

- a proband with multiple tumours (except multiple breast tumours), two of which belong to the LFS tumour spectrum and the first of which occurred before age 46 years

- a proband who is diagnosed with adrenocortical carcinoma or choroid plexus tumour, irrespective of family history

Genetic counseling and genetic testing are used to confirm that somebody has this gene mutation. Once such a person is identified, early and regular screenings for cancer are recommended for him or her as people with Li–Fraumeni are likely to develop another primary malignancy at a future time (57% within 30 years of diagnosis).

Following diagnosis and histopathological analysis, the patient will usually undergo magnetic resonance imaging (MRI), ultrasonography, and a bone scan in order to determine the extent of local invasion and metastasis. Further investigational techniques may be necessary depending on tumor sites. A parameningeal presentation of RMS will often require a lumbar puncture to rule out metastasis to the meninges. A paratesticular presentation will often require an abdominal CT to rule out local lymph node involvement, and so on. Patient outcomes are most strongly tied to the extent of the disease, so it is important to map its presence in the body as soon as possible in order to decide on a treatment plan.

The current staging system for rhabdomyosarcoma is unusual relative to most cancers. It utilizes a modified TNM (tumor-nodes-metastasis) system originally developed by the IRSG. This system accounts for tumor size (> or <5 cm), lymph node involvement, tumor site, and presence of metastasis. It grades on a scale of 1 to 4 based on these criteria. In addition, patients are sorted by clinical group (from the clinical groups from the IRSG studies) based on the success of their first surgical resection. The current Children's Oncology Group protocols for the treatment of RMS categorize patients into one of four risk categories based on tumor grade and clinical group, and these risk categories have been shown to be highly predictive of outcome.

GCNIS is not palpable, and not visible on macroscopic examination of testicular tissue. Microscopic examination of affected testicular tissue most commonly shows germ cells with enlarged hyperchromatic nuclei with prominent nucleoli and clear cytoplasm. These cells are typically arranged along the basement membrane of the tubule, and mitotic figures are frequently seen. The sertoli cells are pushed toward the lumen by the neoplastic germ cells, and spermatogenesis is almost always absent in the affected tubules. Pagetoid spread of GCNIS into the rete testis is common. Immunostaining with placental alkaline phosphatase (PLAP) highlights GCNIS cell membranes in 95 percent of cases. OCT3/4 is a sensitive and specific nuclear stain of GCNIS.

Rhabdomyosarcoma is often difficult to diagnose due to its similarities to other cancers and varying levels of differentiation. It is loosely classified as one of the “small, round, blue-cell cancer of childhood” due to its appearance on an H&E stain. Other cancers that share this classification include neuroblastoma, Ewing sarcoma, and lymphoma, and a diagnosis of RMS requires confident elimination of these morphologically similar diseases. The defining diagnostic trait for RMS is confirmation of malignant skeletal muscle differentiation with myogenesis (presenting as a plump, pink cytoplasm) under light microscopy. Cross striations may or may not be present. Accurate diagnosis is usually accomplished through immunohistochemical staining for muscle-specific proteins such as myogenin, muscle-specific actin, desmin, D-myosin, and myoD1. Myogenin, in particular, has been shown to be highly specific to RMS, although the diagnostic significance of each protein marker may vary depending on the type and location of the malignant cells. The alveolar type of RMS tends to have stronger muscle-specific protein staining. Electron microscopy may also aid in diagnosis, with the presence of actin and myosin or Z bands pointing to a positive diagnosis of RMS. Classification into types and subtypes is accomplished through further analysis of cellular morphology (alveolar spacings, presence of cambium layer, aneuploidy, etc.) as well as genetic sequencing of tumor cells. Some genetic markers, such as the "PAX3-FKHR" fusion gene expression in alveolar RMS, can aid in diagnosis. Open biopsy is usually required to obtain sufficient tissue for accurate diagnosis. All findings must be considered in context, as no one trait is a definitive indicator for RMS.

The diagnosis of renal medullary carcinoma is typically made after individuals with sickle cell trait present with the typical signs and symptoms outlined above, in combination with radiographic imaging (usually abdominal/pelvic CT scan) studies and ultimately surgical biopsy and pathological examination of the tumor. Findings on radiographic examination are non-specific and can reveal a mass deep within the kidney. Histopathology studies show a distinctive pattern that can be distinguished from other renal tumors.

Renal medullary carcinoma is extremely rare and it is not currently possible to predict those individuals with sickle cell trait who will eventually develop this cancer. It is hoped that early detection could result in better outcomes but screening is not feasible.

Spermatocytic seminomas are diagnosed based on tissue from orchiectomy (or partial orchiectomy), done for a lesion suspicious for cancer on medical imaging.

The macroscopic appearance of the tumour is of a mutinodular grey-white to tan coloured mass with gelatinous, haemorrhagic and necrotic areas. The tumour may extend beyond the testis.

Prognosis and treatment is the same as for the most common type of ovarian cancer, which is epithelial ovarian cancer.

The median survival of primary peritoneal carcinomas is usually shorter by 2–6 months time when compared with serous ovarian cancer. Studies show median survival varies between 11.3–17.8 months. One study reported 19-40 month median survival (95% CI) with a 5-year survival of 26.5%.

Elevated albumin levels have been associated with a more favorable prognosis.

The histology of EST is variable, but usually includes malignant endodermal cells. These cells secrete alpha-fetoprotein (AFP), which can be detected in tumor tissue, serum, cerebrospinal fluid, urine and, in the rare case of fetal EST, in amniotic fluid. When there is incongruence between biopsy and AFP test results for EST, the result indicating presence of EST dictates treatment. This is because EST often occurs as small "malignant foci" within a larger tumor, usually teratoma, and biopsy is a sampling method; biopsy of the tumor may reveal only teratoma, whereas elevated AFP reveals that EST is also present. GATA-4, a transcription factor, also may be useful in the diagnosis of EST.

Diagnosis of EST in pregnant women and in infants is complicated by the extremely high levels of AFP in those two groups. Tumor surveillance by monitoring AFP requires accurate correction for gestational age in pregnant women, and age in infants. In pregnant women, this can be achieved simply by testing maternal serum AFP rather than tumor marker AFP. In infants, the tumor marker test is used, but must be interpreted using a reference table or graph of normal AFP in infants.

The risk of renal cell carcinoma can be reduced by maintaining a normal body weight.

The presenting features may be a palpable testicular mass or asymmetric testicular enlargement in some cases. The tumour may present as signs and symptoms relating to the presence of widespread metastases, without any palpable lump in the testis. The clinical features associated with metastasising embryonal carcinoma may include low back pain, dyspnoea, cough, haemoptysis, haematemesis and neurologic abnormalities.

Males with embryonal carcinoma tend to have a normal range serum AFP. The finding of elevated AFP is more suggestive of a mixed germ cell tumour, with the AFP being released by a yolk sac tumour component.

Magnetic Resonance Imaging (MRI) scans provide an image of the soft tissues in the body using radio waves and strong magnets. MRI can be used instead of CT if the patient exhibits an allergy to the contrast media administered for the test. Sometimes prior to the MRI scan, an intravenous injection of a contrasting material called gadolinium is given to allow for a more detailed image. Patients on dialysis or those who have renal insufficiency should avoid this contrasting material as it may induce a rare, yet severe, side effect known as nephrogenic systemic fibrosis. A bone scan or brain imaging is not routinely performed unless signs or symptoms suggest potential metastatic involvement of these areas.

MRI scans should also be considered to evaluate tumour extension which has grown in major blood vessels, including the vena cava, in the abdomen. MRI can be used to observe the possible spread of cancer to the brain or spinal cord should the patient present symptoms that suggest this might be the case.

The 1997 International Germ Cell Consensus Classification is a tool for estimating the risk of relapse after treatment of malignant germ cell tumor.

A small study of ovarian tumors in girls reports a correlation between cystic and benign tumors and, conversely, solid and malignant tumors. Because the cystic extent of a tumor can be estimated by ultrasound, MRI, or CT scan before surgery, this permits selection of the most appropriate surgical plan to minimize risk of spillage of a malignant tumor.

Access to appropriate treatment has a large effect on outcome. A 1993 study of outcomes in Scotland found that for 454 men with non-seminomatous (non-germinomatous) germ cell tumors diagnosed between 1975 and 1989, 5-year survival increased over time and with earlier diagnosis. Adjusting for these and other factors, survival was 60% higher for men treated in a cancer unit that treated the majority of these men, even though the unit treated more men with the worst prognosis.

Choriocarcinoma of the testicles has the worst prognosis of all germ cell cancers

The prognosis for rhabdomyosarcoma has improved greatly in recent decades, with over 70% of patients surviving for five years after diagnosis.

GCNIS is generally treated by radiation therapy and/or orchiectomy. Chemotherapy used for metastatic germ cell tumours may also eradicate GCNIS.

Imaging studies such as Computerized Tomography (CT) and Magnetic Resonance Imaging (MRI) can aid diagnosis. Medulloepithelioma appears isodense or hypodense with variable heterogeneity and calcification on non-contrast CT scan, and enhances with contrast. This radiographical finding is consistent with a primitive neuroectodermal tumour, especially in children. Blood studies and imaging studies of the abdomen may be used to detect metastases.

Needle aspiration biopsy can be used to aid diagnosis. Definitive diagnosis requires histopathological examination of surgically excised tumour tissues.

Histologically, medulloepithelioma resemble a primitive neural tube and with neuronal, glial and mesenchymal elements. Flexner-Wintersteiner rosettes may also be observed.

Immunohistochemically, neural tube-like structures are vimentin positive in the majority of medulloepitheliomas. Poorly differentiated medulloepitheliomas are vimentin negative.

NMC when viewed microscopically, are poorly differentiated carcinomas which show abrupt transitions to islands of well-differentiated squamous epithelium. This tumor pattern is not specific or unique to NUT midline carcinoma, but this pattern is most suggestive of the diagnosis. The neoplastic cells will show a positive reaction with various cytokeratins, p63, CEA, and CD34 immunohistochemistry. However, the NUT antibody confirms the diagnosis (although only available in a limited number of laboratories).

The differential diagnosis is quite wide, but it is important to consider this tumor type when seeing a poorly differentiated tumor that shows abrupt areas of keratinization. Other tumors included in the differential diagnosis are sinonasal undifferentiated carcinomas, Ewing sarcoma/Primitive neuroectodermal tumor, leukemia, rhabdomyosarcoma, and melanoma. When NUT midline carcinoma is seen in the head and neck, the squamous lining of the cavities may be entrapped by the neoplastic cells, and so it is important to document the carcinoma cells in the rest of the tumor by a variety of stains (including cytokeratin or p63). One of the most helpful and characteristic findings is the focal abrupt squamous differentiation, where stratification and gradual differentiation are absent, resembling a Hassall corpuscle of the thymus.

The defining feature of NMCs is rearrangement of the "NUT" gene.

Most common is a translocation involving the BRD4 gene and NUT gene (t(15;19)(q13;p13.1)).

Women with benign germ cell tumors such as mature teratomas (dermoid cysts) are cured by ovarian cystectomy or oophorectomy. In general, all patients with malignant germ cell tumors will have the same staging surgery that is done for epithelial ovarian cancer. If the patient is in her reproductive years, an alternative is unilateral salpingoophorectomy, while the uterus, the ovary, and the fallopian tube on the opposite side can be left behind. This isn't an option when the cancer is in both ovaries. If the patient has finished having children, the surgery involves complete staging including salpingoophorectomy on both sides as well as hysterectomy.

Most patients with germ cell cancer will need to be treated with combination chemotherapy for at least 3 cycles. The chemotherapy regimen most commonly used in germ cell tumors is called PEB (or BEP), and consists of bleomycin, etoposide, a platinum-based antineoplastic (cisplatin).

Dysgerminomas, like other seminomatous germ cell tumors, are very sensitive to both chemotherapy and radiotherapy. For this reason, with treatment patients' chances of long-term survival, even cure, is excellent.

EST can have a multitude of morphologic patterns including: reticular, endodermal sinus-like, microcystic, papillary, solid, glandular, alveolar, polyvesicular vitelline, enteric and hepatoid.

Schiller-Duval bodies on histology are pathognomonic and seen in the context of the endodermal sinus-like pattern.

NUT midline carcinoma is very resistant to standard chemotherapy treatments. The tumor may initially respond to therapy, and then rapid recurrence is experienced, followed by death. A multimodality approach to treatment is advocated, especially since most patients present with advanced disease. Treatment must be tailored to the individual patient, with several promising new targeted molecular therapies in clinical trials. Specific molecular targeted therapies (BET inhibitors and histone deacetylase inhibitors (HDACi)) may help to yield growth arrest of the neoplastic cells. Overall, there is a mean survival of 6–9 months.

Unlike classical seminoma, spermatocytic seminomas rarely metastasise, so radical orchidectomy alone is sufficient treatment, and retroperitoneal lymph node dissection and adjuvant chemotherapy or radiotherapy are generally not required.

In the ovary, embryonal carcinoma is quite rare, amounting to approximately three percent of ovarian germ cell tumours. The median age at diagnosis is 15 years. Symptoms and signs are varied, and may include sexual precocity and abnormal (increased, reduced or absent) uterine bleeding.

There may be elevations in serum human chorionic gonadotropin (hCG) and alpha fetoprotein (AFP) levels but it would be in association with other tumors, (e.g. yolk sac tumor) because they themselves do not produce the serum markers. At surgery, there is extension of the tumour beyond the ovary in forty percent of cases. They are generally large, unilateral tumours, with a median diameter of 17 centimetres. Long-term survival has improved following the advent of chemotherapy. The gross and histologic features of this tumour are similar to that seen in the testis.

The symptoms of childhood rhabdomyosarcoma are visible and prominent and include swollen red lumps where the cancer starts developing. The lumps are hard and can grow in size unless treated. Other symptoms include poor bowel movements, blood in the urine, secretions from the genitals and nose, and headaches. Various tests can determine whether these related symptoms indicate childhood rhabdomyosarcoma. CT, X-ray, MRI, bone scans, and Ultrasounds may be performed to identify the location and size of the cancer. Biopsies of the lump can be taken along with bone marrow biopsies to detect whether the cancer has spread within the marrow, the bone, and the blood supply. Further determination of how aggressive and large the cancer is requires these scans.