General Info
Head and Neck


Metastases: Frequency and Sites, Oncology Syndromes, Path Clues to Tissue Origin, Pleural Effusions, Proto Oncogenes, Response Criteria, Tumor Marker Half Lives




Primary Brain Cancer, Carcinomatous Meningitis,




Colon: (Hereditary, Monitoring), Esophageal, Gastric, GISTs, Pancreatic: Prognosis, Rectal Ca: (Adjuvant Trials, Neoadjuvant Therapy, Prognosis with Surgery Alone)





Testicular: TNM Staging, TNM Risk Categories, Prognostic Markers, Risk of Sterility, Chemo Trials, RPLND

NSGCT: (NSGCT Adjuvant, Early NSGCT Options, High Risk Stage A, NSGCT Management, Indiana Risk)

Seminoma: Seminoma

NSGCT: Summary from MKSAP3





Adrenal Incidentalomas, Adrocortical ca, Carcinoid: (Symptomatic), Multiple Endocrine Neoplasia (MEN), Thyroid



Margins & LND, Adjuvant IFN Data,





Adrenocortical carcinoma is a rare tumor afflicting only one to two persons per million population. It usually occurs in adults and the median age at diagnosis is 44 years. Although potentially curable at early stages, only 30% of these malignancies are confined to the adrenal gland at the time of diagnosis.[1]. Approximately 60% of patients present with symptoms related to excessive hormone secretion, but hormone testing reveals that 60-80% of tumors are functioning.,3] Nonfunctioning carcinomas may be heralded by symptoms of local invasion by tumor or by metastases. The most common sites of metastasis are intra-abdominal, lung, liver, and bone. Initial evaluation should include, in addition to appropriate endocrine studies, computerized tomography and/or magnetic resonance imaging. Selective angiography and adrenal venography may be helpful for smaller lesions and for distinguishing tumors of the adrenal from tumors of the upper pole of the kidney. The detection of metastatic lesions may allow effective palliation of both functioning and nonfunctioning lesions.

Adrenal carcinoma may be curable if treated at an early stage. Radical surgical excision is the treatment of choice for localized malignancies and remains the only method by which long-term disease-free survival may be achieved. Overall five-year survival for tumors resected for cure is approximately 40%. Higher five-year survival rates may be obtained following surgery for tumors without invasion of local tissues or spread to lymph nodes.

Palliation of metastatic functioning tumors may be achieved by resection of both primary tumor and metastatic lesions. Unresectable or widely disseminated tumors may be palliated by antihormonal therapy with mitotane (o,p'-DDD), systemic chemotherapy, or (for localized lesions) radiation therapy. However, survival for patients with stage IV tumors is usually less than nine months unless a complete remission is achieved.[3-6] To date, there is no convincing evidence that systemic therapy will improve the survival of stage IV patients.


Differentiated (functioning tumors are usually differentiated)

Anaplastic (production of hormones by anaplastic tumors is rare)

Hormonal Classification: Approximately 60% of adrenocortical carcinomas

produce hormones. The associated clinical syndromes include the following: [1-3] hypercortisolism (Cushing's syndrome), adrenogenital syndrome, virilization, feminization, precocious puberty, hyperaldosteronism, primary hyperaldosteronism (Conn's syndrome).


The stage of adrenocortical carcinoma is determined by the size of the primary tumor, the degree of local invasion, and whether it has spread to regional lymph nodes or distant sites.[1-4] Proper staging should include computerized tomography (CT) of the abdomen. Magnetic resonance imaging is still considered investigational, but its use may add specificity to CT evaluation of an adrenal mass.[5] Vena caval contrast studies and angiography may provide additional staging information and allow for more complete preoperative assessment. Review of published data from 608 patients revealed the following stage distribution at diagnosis: 3% stage I, 29% stage II, 20% stage III, and 49% stage IV.

Stages are defined by TNM classification.[7]

-- TNM definitions --

Primary tumor (T)

            T1: Primary tumor no more than 5 cm in size; no local invasion

            T2: Primary tumor greater than 5 cm in size; no invasion

T3: Primary tumor of any size, locally invading to but not involving adjacent organs

            T4: Tumor any size, locally invading adjacent organs

Nodal involvement (N)

            N0: No regional positive nodes

            N1: Positive regional nodes

Distant metastasis (M)

MX: Minimum requirements to assess the presence of distant metastasiscannot be met

M0: No (known) distant metastasis M1: Distant metastasis present

-- Stage I --

Stage I adrenocortical carcinoma is defined by the following TNM grouping:

            T1, N0, M0

-- Stage II --

Stage II adrenocortical carcinoma is defined by the following TNM grouping:

            T2, N0, M0

-- Stage III --

Stage III adrenocortical carcinoma is defined by the following TNM groupings:

            T3, N0, M0

            T1 or T2, N1, M0

-- Stage IV --

Stage IV adrenocortical carcinoma is defined by the following TNM groupings:

            T3 or T4, N1, M0

            any T, any N, M1


The designations in PDQ that treatments are "standard" or "under clinical evaluation" are not to be used as a basis for reimbursement determinations.


Treatment options:


Complete surgical removal of the tumor is the treatment of choice for stage I adrenocortical carcinomas. The long-term survival with nonfunctioning tumors is comparable to that with functioning tumors. Removal of regional lymph nodes that are not clinically enlarged is not indicated. Under clinical evaluation:

Adjuvant radiation or chemotherapy with mitotane (o,p'-DDD) has not been proven to be of value in improving survival.


Treatment options:


Complete surgical removal of the tumor is the treatment of choice for stage II adrenocortical carcinomas. The long-term survival with nonfunctioning tumors is comparable to that with functioning tumors. Removal of regional lymph nodes that are not clinically enlarged is not indicated.[1-5]

Under clinical evaluation:

Adjuvant radiation or chemotherapy with mitotane (o,p'-DDD) has not been proven to be of value in improving survival.


Treatment options:


Complete surgical removal of the tumor, with or without regional lymph node dissection. The treatment for tumors with local invasion, but without clinically enlarged regional lymph nodes, is complete surgical removal as for stage I and stage II tumors. With enlarged regional lymph nodes, a lymph node dissection should be included in the procedure. These patients are at high risk for disease recurrence and should be considered for enrollment in a clinical trial.

Under clinical evaluation:

1. Clinical trials are appropriate for newly diagnosed patients when possible.

2. Radiation therapy: 4200-5000 rads given over 4 weeks to localized but unresectable tumors.[1]

3. Mitotane (o,p'-DDD) in doses up to 8.5 grams/day: This antitumor drug produces useful clinical responses which average 10 months in duration in about 30% of patients with measurable metastases. Responses in patients who achieve complete remission can be durable. Approximately 80% of treated patients with functioning tumors will show significant diminution in hormone production. The drug is not usually used unless either radiologically evaluable metastases are present or the residual tumor is producing measurable levels of hormone.


Temporary palliation of disseminated adrenocortical carcinomas can sometimes be achieved with the chemotherapeutic agent mitotane (o,p'-DDD). Although measurable partial remissions are unusual and are reported in only 19-34% of cases, excellent palliation of hormone symptoms is commonly observed.[1] Local recurrences and selected sites of metastatic disease can sometimes be palliated surgically.[2] Clinical trials are appropriate and should be considered whenever possible, especially phase I and II trials evaluating newer chemotherapeutic and biologic agents.[3-6]

Treatment options:


1. Chemotherapy with mitotane (o,p'-DDD).[1]

2. Radiation therapy to bone metastases.[7]

3. Surgical removal of localized metastases, particularly those that are functioning.[2]

Under clinical evaluation:

Cisplatin has been reported to produce beneficial effects in some selected patients with metastatic disease.[8-10]

Clinical trials of other chemotherapy regimens.[3-6] Refer to the PDQ Protocol File for a listing of active clinical trials.


The question and selection of further treatment for adrenocortical carcinoma depends on many factors including prior treatment and site of recurrence, as well as individual patient considerations. Local recurrence and selected sites of metastatic disease can sometimes be palliated by surgery. Although none of these patients can be considered curable, palliation of hormonal symptoms and occasional five-year survivals can be achieved.[1,2] Clinical trials are appropriate and should be considered whenever possible, especially phase I and II trials evaluating newer chemotherapeutic agents and biologicals.




I. General

A. Presentation

1. On initial presentation, 75% are superficial.

2. 75% recur, but < 25% invasion.

B. Focus

1. In superficial disease, 2 main considerations:

a. Prevention of recurrence

b. Prevention of progression

2. In muscle invasive disease, focus is on definitive treatment of primary and distant disease.

C. Risk Factors

1. Older white male (twice as common in whites than blacks)

2. Aniline dyes (aromatic amines)

3. Smoking (both transitional cell and squamous)

4. Schistosomiasis (bilharziasis)

5. Genetic - ? assoc with abnormalities of chromosomes 3, 9,17, especially 9.

6. RAS mutations found in about 10%.

7. Potential of superficial tumors to become invasive may be related to blood group secretor status. If a patient is a "secretor" and loses the ABH antigens from the tumor cells, more likely to develop invasive dz.

II. Pathology

A. Histology

1. Most transitional cell cell ca's are papillary.

                        Transitional 95%

                        Squamous 3

                        Adeno 2

2. Adenoca usually occurs on trigone.

3. 30% are multifocal at diagnosis.

4. WHO Grades: 1-3 correlate with natural history (1=best, 3=worst)

5. Confusion about "papilloma."

WHO grades it as 0, but many pathologists assign Grade 1. It really is benign, but represents unstable epithelium. Must follow carefully.

B. Preneoplastic Lesions – hyperplasia, atypical hyperplasia, dysplasia ca

C. CIS - high-grade lesion that has not yet invaded. Has aspectrum of biologic potential, but prior to advent of BCG, 54% progressed to muscle-invasive dz.

III. Clinical Presentation

A. Symptoms

1.Most common is painless hematuria (75%), urinary symptoms (30%)

2.Advanced disease often characterized by:

- pelvic pain

- flank pain ureteral obstruction

- leg edema lymphatic obstruction

B. Diagnosis

Cystoscopy & biopsy

Biopsies should include muscle wall so can assess invasion

C. Workup - CT, MRI

IV. Staging Systems

Marshall TNM

CIS TIS mucosa only

0 Ta lamina propria

A T1 stroma, but not muscle

B1 T2 invades muscle

B2 T3a thru muscle but not beyond bladder wall

C T3b thru wall

D1 T4 adjacent structures

D2 N+ regional lymph nodes | N1= single LN < 2cm

D3 juxtaregional LN's | N2= bilat LN's or single

D4 M+ distant mets | LN 2-5cm

| N3= any LN > 5cm

Best prognostic indicators are grade and stage, but clinical staging has limited usefulness because of the discrepancy between clinical and pathological findings.

V. Approach To Treatment

Overall risk of progression from superficial disease is low (10-20%), but still definite.

Despite aggressive surgical and radiation therapy for locally invasive disease, 5YS is still only 20-50%.

Most patients succumb to distant disease which was not apparent at time of surgery.

Thus need for adjuvant chemotherapy in invasive disease ...

Adjuvant therapy recommended for patients with:

1. diffuse CIS
2. persistently + cytology after TURB
3. tumors too large or too numerous to resect
4. tumors with submucosal invasion (T1)

VI. Treatment of Superficial Bladder Ca (Tis-T1)


1.Primary modality of treatment - can control >80%.
2.All tumors must be removed down to smooth muscle.
3.After TURB:

- recurrence rate up to 85%
- grade progression rate 30%
- stage progression rate 4-30%

4.Morbidity of repeated TURB is low.

B. Intravesical Therapy

1.Used to prevent recurrence in patients with unresectable lesions, persistent + cytology, or completely resected but minimally invasive disease.

2.Agents used:Thiotepa

Mitomycin C

3.These agents reduce recurrence rate, but they do not prevent stage/grade progression.

4.Effectiveness: BCG > MitoC = DOX > Thiotepa

BCG has overall RR 72%, but range is 40-100%. Recent SWOG study showed that CR rate can be increased from 73-->87% with just 3 additional BCG instillations given at 3 months. In complete responders, 3 wkly txs at 6 month intervals improves durability from 65-90%. (Onc 10/95)

5.BCG: MSKCC Study (Patients with Ta-T1 tumors txd & followed 10 yrs):

54% without evidence of disease
21 alive but required cystectomy for invasive disease
20 died with metastatic disease

6.Toxic effects:

bladder irritative symptoms (esp DOX and BCG)
allergic reactions

7.Maintenance with BCG most problems, but don't need maintenance therapy since it is no better than a 6 week course of therapy.

8.Therapy is usually adminstered by instilling drug in bladder for two hours once weekly for 6 weeks.


1.TURB (or fulgaration if you can get all the lesions)
2.If not sure or worried by irritative symptoms, give 6 wks of BCG

(BCG: 120 mg in sterile NS retained in bladder for 2 hrs.)

VII. Treatment of Invasive Disease


1. TURB - can work if relatively small amount of muscle invasion.

2. Partial cystectomy - consider in a patient with confined invasive disease and in whom you want to try to preserve bladder function. Only appropriate in 5-10% cases!

3. Radical Cystectomy

a.most common treatment
b.remove bladder, prostate, urethra (in women), uterus, ovaries, and anterior part of vaginal wall.
c.Most failures after radical cystectomy are due to distant disease.
d.Don't do if distant disease or bulky LN's apparent, but consider if N1 disease only.

4. Continent Urinary Diversion

_Ileal conduit used to be main urinary diversion in patients who had radical cystectomy, but nowadays continent reservoirs are more common.

_Continent reservoirs to the abdominal wall and urethra are developed with isolated bowel segments. (Ileal neobladder - form pouch with ileum. Patient can cath as needed.)

_Men are more frequently candidates than women for these procedures.

B.Radiation Therapy

1. XRT alone - some success, but not good studies (selection bias)

2. Preop XRT - controversial - indications unclear

3. XRT+Chemo - may work.

C. Adjuvant and Neoadjuvant Chemotherapy (for Locally Advanced Dz)


Was initially considered with view towards bladder preservation.

Response rates ~ 30-40%, but CR rate inversely related To depth of invasion. Thus not all that successful in T3 and T4 disease.

Has not yet been shown to improve survival

2. Adjuvant

Trend towards more complete endoscopic removal of even bulky tumors has increased need to consider adjuvant chemotherapy.

Patients who may be candidates include:

- pts with + LN's

- pts with vascular or lymphatic invasion

- pts with palpable masses on exam under anesthesia

Still, it is not clear that adjuvant therapy is of benefit, although many do it.

Difficult to asses response (no markers), so hard to know how long to continue therapy.

D. Bladder Preservation - not adequate surgery for most patients with invasive disease. Now that continent urinary diversions are available, there is less need to try to preserve the bladder.

VIII. Advanced Disease

Regimens used include MVAC, CMV (CDDP, MTX, VLB), and CISCA

(CDDP, CTX, Adria).

MVAC has been proven superior to CDDP alone, so single agent therapy not appropriate.

The only comparison between multi-drug regimens showed MVAC > CISCA.

Salvage: Dose-intense MVAC with G-CSF led to 32% RR.

However, this was phase II trial, and comparison needed to know whether any survival benefit to more intense therapy (JNCI 82:667, 1990).

Also have tried: 5FU + IFN (MDAnderson) (JNCI 83:285, 1991)




Prognosis of primary brain tumors is determined by histologic type, the grade of the tumor, postoperative size, and extent of tumor and by the patient's age, performance status, and duration of symptoms.[1,2] Some primary brain tumors are curable by surgery alone, some are curable by surgery and radiotherapy, and the remainder require surgery, radiotherapy, and chemotherapy. Tumors requiring all three modalities are infrequently curable.

Metastases to the brain from a primary outside the central nervous system (CNS) are more common than primary tumors of the brain. The most common primary tumors that metastasize to the brain are lung, breast, melanoma, and kidney. Metastases to the brain are usually multiple, but solitary metastases may also occur. Brain involvement may occur with cancers of the nasopharyngeal region by direct extension along the cranial nerves or through the foramina at the base of the skull. Metastatic meningeal involvement may also occur especially with leukemia, lymphoma, small cell lung cancer, breast cancer, and some primary CNS tumors such as medulloblastoma and ependymal gliomas. Treatment of cancers metastatic to the brain is discussed in the statement on metastatic cancer, and treatment of primary CNS lymphoma is discussed in the primary CNS lymphoma statement.

A lesion in the brain should not be assumed to be a metastasis just because a patient has had a previous cancer as this could result in overlooking appropriate treatment for a curable tumor. Primary brain tumors rarely spread to other areas of the body, but may spread to other parts of the brain and to the spinal axis.


Glial tumors: astrocytic tumors noninfiltrating juvenile pilocytic subependymal infiltrating well-differentiated mildly and moderately anaplastic astrocytoma anaplastic astrocytoma glioblastoma multiforme ependymal tumors myxopapillary and well-differentiated ependymoma anaplastic ependymoma ependymoblastoma oligodendroglial tumors well-differentiated oligodendroglioma anaplastic oligodendroglioma mixed tumors mixed astrocytoma-ependymoma mixed astrocytoma-oligodendroglioma mixed astrocytoma-ependymoma-oligodendroglioma medulloblastoma

Nonglial tumors: pineal parenchymal tumors pineocytoma pineoblastoma astrocytoma (see above) germ cell tumors germinoma embryonal carcinoma choriocarcinoma teratoma craniopharyngioma meningioma meningioma malignant meningiomas anaplastic meningioma hemangiopericytoma papillary meningioma choroid plexus tumors choroid plexus papilloma anaplastic choroid plexus papilloma


Brain tumors are classified on the basis of tumor cell type and histologic grade. For some tumors, location and metastatic spread within the CSF is also used in classification.

Cerebral Astrocytic Gliomas

Gliomas constitute the most common primary CNS tumors. Of the gliomas, astrocytomas of variable malignancy are the most prevalent. Cerebral astrocytomas are subdivided into categories (grades) based on the degree of tumor anaplasia and the presence or absence of necrosis.

-- Noninfiltrating astrocytomas -- These astrocytomas are relatively slow-growing tumors such as juvenile pilocytic and subependymal astrocytomas, which occur most frequently in childhood but can occur in adults.

-- Well-differentiated mildly and moderately anaplastic astrocytomas -- These are more infiltrative than the juvenile pilocytic and subependymal astrocytomas but are still relatively slow-growing tumors.

-- Anaplastic astrocytoma -- These tumors are highly anaplastic with obvious vascular abnormalities. This Grade III astrocytoma grows more rapidly than the more differentiated astrocytomas.

-- Glioblastoma multiforme -- This Grade IV astrocytoma is a poorly differentiated, rapidly growing tumor that occurs most often in adults.

Brainstem Gliomas

Brainstem gliomas are usually diagnosed on clinical grounds because biopsy may be hazardous. Tumors that diffusely enlarge the brainstem carry a worse prognosis than those that are more focal. Higher grades of malignancy (see above) carry poorer prognoses as well.

Cerebellar Astrocytoma

These tumors vary in grade of malignancy although the majority are of lower grade and frequently are curable. The higher grade lesions carry a worse prognosis, but prognosis is invariably better than for their cerebral counterparts.

Ependymal Tumors

Ependymal tumors are considered to arise from ependymal cells that line the ventricles and from ependymal rests. They vary in grade of malignancy.

-- Anaplastic ependymoma -- This tumor has more features of anaplasia and appears mitotically more active than the myxopapillary or well-differentiated ependymomas. Previously considered to do worse than the well-differentiated ependymoma, conflicting evidence suggests that patients treated with surgery and radiotherapy may do nearly as well.

-- Ependymoblastoma -- This is generally a tumor of childhood and is considered by some to be a primitive neuroectodermal tumor. It is rare.

Oligodendroglial Tumors

Oligodendroglial tumors are gliomas that arise from the oligodendroglia. They vary in grade of malignancy, and prognosis is related to grade.

-- Well-differentiated oligodendroglioma -- These tumors are usually slow-growing and well circumscribed.

-- Anaplastic oligodendroglioma -- These tumors are comparable to the highly anaplastic gliomas in prognosis.

Mixed Gliomas

Mixed gliomas can occur with combinations of generally two, but sometimes three, different cell types: astrocytoma, ependymoma, and/or oligodendroglioma. Survival statistics are inexact for this group since the cell types and grade of the most malignant appearing cell type influences prognosis. In general, these tumors carry a prognosis between the well-differentiated and anaplastic astrocytomas.


Medulloblastoma is a rapidly growing tumor arising in the posterior fossa and is found almost exclusively in children and young adults. It has the tendency to spread from the brain to the spinal axis. Prognosis is dependent on the staging following surgical resection.

Pineal Region Tumors

Pineal parenchymal tumors vary in histology and grade of malignancy relative to patient age at occurrence. They can vary from the slowly growing pineocytoma to the more malignant and faster growing pineoblastoma. Astrocytomas can also grow in this location (see above) as can a variety of primary germ cell tumors: germinoma, embryonal carcinoma, choriocarcinoma, and teratoma. These uncommon tumors vary in prognosis. The absence of biopsies in many series make prognosis for each tumor type difficult to evaluate.


Craniopharyngioma is a tumor that arises from the remains of a structure found in the developing embryo in the region of the pituitary. This tumor causes symptoms and signs by pressing on vital areas of the brain and the optic nerves and internal hydrocephalus by obstructing the foramen of Monro in children.


Meningiomas arise from the meninges surrounding the brain and spinal cord and are generally slow-growing. There are other variants that constitute a group called malignant meningioma and include malignant meningioma, hemangiopericytoma, papillary meningioma, and meningeal sarcoma. Malignant meningiomas are more likely than other meningiomas to metastasize within the craniospinal axis.

-- Meningioma -- Meningioma is usually curable with surgery if the initial resection is complete.

-- Malignant meningioma -- The prognosis for patients with malignant meningioma is worse than for the more well-differentiated meningiomas. Choroid Plexus Tumors

Choroid plexus tumors are rare tumors arising from choroid plexus epithelial cells. The more benign form is choroid plexus papilloma while the more malignant form is called anaplastic choroid plexus papilloma. These latter tumors are more likely to spread within the craniospinal axis.

Primary CNS lymphoma is discussed in the primary CNS lymphoma statement.


Surgical removal of brain tumors is recommended for most types and locations and should be as complete as possible within the constraints of preservation of neurologic function. An exception to this role for surgery is for deeply seated tumors, such as pontine gliomas, which are diagnosed on clinical grounds and are treated without initial surgery approximately 50% of the time. In the majority of cases, however, diagnosis by biopsy is preferred. Stereotaxic biopsy can be used for lesions that are difficult to reach and resect.

Radiotherapy plays a major role in the treatment of most tumor types and can increase the cure rate or prolong disease-free survival. Radiotherapy may also be useful in the treatment of recurrences in patients treated initially with surgery alone.

Chemotherapy may prolong survival in some tumor types and has been reported to increase the disease-free survival in patients with gliomas, medulloblastoma, and some germ cell tumors.

For brain tumors that are either infrequently curable or unresectable, patients should be considered candidates for clinical trials evaluating radiosensitizers, hyperthermia, or interstitial brachytherapy used in conjunction with external radiotherapy to improve local control of the tumor or for studies evaluating new drugs and biological response modifiers.

The designations in PDQ that treatments are "standard" or "under clinical evaluation" are not to be used as a basis for reimbursement determinations.


-- Juvenile pilocytic and subependymal astrocytomas --Noninfiltrating astrocytic tumors are often curable. Treatment options:


1. Surgery alone if totally resectable.

2. Surgery followed by radiotherapy to known or suspected residual tumor.

Under clinical evaluation: At recurrence following surgery, patients should be considered for reoperation and radiotherapy if not previously given. Patients who have received radiotherapy should be considered candidates for nitrosourea-based chemotherapies and clinical trials evaluating new drugs and biological response modifiers.


Well-differentiated mildly and moderately anaplastic astrocytomas are less often curable.

Treatment options:

Standard: Surgery plus radiotherapy, although some controversy exists and some physicians treat these patients with surgery alone if the patient is <35 years of age and the tumor does not contrast-enhance on CT scan.

Under clinical evaluation: Clinical trials in progress are evaluating the effect of adding drugs to local therapy, for example, radiotherapy with or without chemotherapy for incompletely resected well-differentiated mildly and moderately anaplastic astrocytomas. Other trials are evaluating the effect of deferring irradiation until the time of tumor progression and of high-dose versus low-dose irradiation.


For anaplastic astrocytomas of higher grade, the cure rate is low with standard local treatment.[1] These patients are appropriate candidates for clinical trials designed to improve local control by the addition of newer forms of treatment to standard treatment.

Treatment options:


1. Surgery plus radiotherapy.

2. Surgery plus radiotherapy and chemotherapy.[2-4]

Under clinical evaluation: Patients with brain tumors that are either infrequently curable or unresectable should be considered candidates for clinical trials evaluating hyperfractionated irradiation, accelerated fraction radiation, stereotactic radiosurgery, radiosensitizers, hyperthermia, interstitial brachytherapy, or intraoperative radiotherapy used in conjunction with external-beam radiotherapy to improve local control of the tumor, and/or studies evaluating new drugs and biological response modifiers following radiotherapy.[5-8] Cooperative group trials evaluating chemoradiotherapy, administered with either hyperfractionated irradiation or a combination of brachytherapy and external irradiation are now in progress.


For glioblastoma multiforme, the cure rate is very low with standard local treatment. These patients are appropriate candidates for clinical trials designed to improve local control by the addition of newer forms of treatment to standard treatment.

Treatment options:


1. Surgery plus radiotherapy and chemotherapy.[1,2]

2. Surgery plus radiotherapy.

Under clinical evaluation: Patients with brain tumors that are either infrequently curable or unresectable should be considered candidates for clinical trials evaluating hyperfractionated irradiation, accelerated fraction irradiation, stereotactic radiosurgery, radiosensitizers, hyperthermia, interstitial brachytherapy, or intraoperative radiotherapy used in conjunction with external-beam radiotherapy to improve local control of the tumor, and/or studies evaluating new drugs and biological response modifiers following radiotherapy.[3-6] Cooperative group studies evaluating hyperfractionated irradiation and interstitial brachytherapy are in progress.[7]


Brainstem gliomas have a relatively poor prognosis that is correlated with histology (when biopsied) and location and extent of tumor. The overall median survival in recent studies has been 44-74 weeks,[1-5] with the best results being attained with hyperfractionated radiotherapy.[5]

Treatment options:

Standard: Radiotherapy.[1-5]

Under clinical evaluation: At recurrence, patients should be considered for clinical trials evaluating new drugs and biological response modifiers.[6,7]


-- Myxopapillary ependymoma and well-differentiated ependymoma --

These ependymomas are often curable.

Treatment options:


1. Surgery alone if totally resectable.

2. Surgery followed by radiotherapy to known or suspected residual tumor.

Under clinical evaluation: At recurrence following surgery, patients should be considered for reoperation and radiotherapy if not previously used. Patients who have received radiotherapy should be considered candidates for nitrosourea-based chemotherapies and clinical trials evaluating new drugs and biological response modifiers.


-- Anaplastic ependymoma and ependymoblastoma --

Malignant ependymomas have a variable prognosis depending on location and extent of disease. Frequently, but not invariably, anaplastic ependymomas have a worse prognosis than well-differentiated ependymomas. The rare ependymoblastoma does much worse.

Treatment options:

Standard: Surgery plus radiotherapy.[1,2]

Under clinical evaluation: Adjuvant chemotherapy before, during, and after radiation are treatment options currently being evaluated. At recurrence, patients should be considered candidates for nitrosourea-based chemotherapies and clinical trials evaluating new drugs and biological response modifiers.


These tumors behave very similarly to the well-differentiated mildly and moderately anaplastic astrocytomas.

Treatment options:

Standard: Surgery plus radiotherapy, although some controversy exists. Some physicians treat these patients with surgery alone if the patient is < 45 years of age and the tumor is not contrast-enhanced on CT scan.[1]

Under clinical evaluation: Clinical trials in progress are evaluating the effect of adding drugs to local therapy, e.g., radiotherapy with or without chemotherapy for incompletely resected well-differentiated mildly or moderately anaplastic astrocytomas.


For anaplastic oligodendrogliomas of higher grade, the cure rate is low with standard local treatment.[1] Such patients are appropriate candidates for clinical trials designed to improve local control by the addition of newer forms of treatment.

Treatment options:


1. Surgery plus radiotherapy.[2-5]

2. Surgery plus radiotherapy plus chemotherapy.[6]

Under clinical evaluation: Patients with brain tumors that are either infrequently curable or unresectable should be considered candidates for clinical trials evaluating interstitial brachytherapy, radiosensitizers, hyperthermia, or intraoperative radiotherapy in conjunction with external beam radiotherapy to improve local control of the tumor, and/or studies evaluating new drugs and biological response modifiers following radiotherapy.


-- Mixed astrocytoma-ependymoma, mixed astrocytoma-oligodendroglioma, and mixed astrocytoma-ependymoma-oligodendroglioma --

These mixed glial tumors have a prognosis similar to that for anaplastic astrocytomas and can be treated as such.

Treatment options:[1]


1. Surgery plus radiotherapy.[2]

2. Surgery plus radiotherapy plus chemotherapy.

Under clinical evaluation: Patients with brain tumors that are either infrequently curable or unresectable should be considered candidates for clinical trials evaluating interstitial brachytherapy, radiosensitizers, hyperthermia, or intraoperative radiotherapy in conjunction with external-beam radiotherapy to improve local control of the tumor, and/or studies evaluating new drugs and biological response modifiers following radiotherapy.


Treatment options:

Standard: Surgery plus craniospinal irradiation for good-risk patients.[1]

Under clinical evaluation: For poor-risk patients, in addition to surgery plus craniospinal irradiation, various chemotherapy programs are being evaluated.[2] For further information on treatment of medulloblastoma, refer to the PDQ statement on childhood brain tumors.


-- Pineocytoma and pineoblastoma --

These diverse tumors require special consideration. Pineocytomas are slow growing and carry a variable prognosis for cure. Pineoblastomas are more rapidly growing and carry a worse prognosis.

-- Pineal astrocytoma --

Pineal astrocytomas vary in prognosis depending on the degree of anaplasia. Higher grades have a worse prognosis.

Treatment options:


1. Surgery plus radiotherapy for pineocytoma and lower grades of astrocytoma.

2. Surgery plus radiotherapy and chemotherapy for pineoblastoma and higher grades of astrocytoma.

Under clinical evaluation: Patients with brain tumors that are either infrequently curable or unresectable should be considered candidates for clinical trials evaluating radiosensitizers, hyperthermia, or intraoperative radiotherapy in conjunction with external-beam radiotherapy to improve local control of the tumor, and/or studies evaluating new drugs and biological response modifiers following radiotherapy.


-- Germinoma, embryonal carcinoma, choriocarcinoma, and

teratoma --

The prognosis and treatment of germ cell tumors depends on the histology, location, presence and amount of biological markers, and surgical resectability.[1,2]

** ADULT CRANIOPHARYNGIOMA ** Craniopharyngioma is often curable. Treatment options:


1. Surgery alone if totally resectable.[1]

2. Debulking surgery plus radiotherapy if unresectable.[2]


1. Baskin DS, Wilson CB: Surgical management of craniopharyngiomas: a review of 74 cases. Journal of Neurosurgery 65(1): 22-27, 1986.

2. Rajan B, Ashley S, Gorman C, et al.: Craniopharyngioma -long-term results following limited surgery and radiotherapy. Radiotherapy and Oncology 26(1): 1-10, 1993.


Meningioma is usually curable when resectable.

Treatment options:


1. Surgery.[1]

2. Surgery plus radiotherapy (in selected cases, such as for patients with known or suspected residual disease or with recurrence after previous surgery).[2-4]


-- Malignant meningioma, hemangiopericytoma, and papillary meningioma --

The prognosis for patients with malignant meningioma is worse

than for the more well-differentiated meningiomas since complete resections are less common and the proliferative capacity is greater.[1]

Treatment options:

Standard: Surgery plus radiotherapy.

Under clinical evaluation: Patients with brain tumors that are either infrequently curable or unresectable should be considered candidates for clinical trials evaluating interstitial brachytherapy, radiosensitizers, hyperthermia, or intraoperative radiotherapy in conjunction with external-beam radiotherapy to improve local control of the tumor, and/or studies evaluating new drugs and biological response modifiers following radiotherapy.


Treatment options:


1. Surgery alone or in conjunction with chemotherapy.[1-3]

2. Radiotherapy if not previously used, alone or with chemotherapy.

3. Interstitial irradiation.[4]

Under clinical evaluation: Numerous clinical trials (particularly phase II trials) are evaluating the use of newer drugs in the treatment of brain tumors.


(Man Onc)

Octreotide - inhibits release of tumoral neurotransmitters

100-600 mcg SQ qd in 2-4 divided doses


Most life-threatening complication, mediated by kinins, and can be precipitated by catecholamines. B-adrenergic drugs (dopamine, epi) must be strictly avoided since they may aggravate hypotension. Pure a-adrenergic (methoxamine, norepinephrine) and vasoconstrictive (angiotensin) agents are preferred for txing hypotension in carcinoid syndrome.

Methoxamine (Vasoxyl) 0.5 cc (10mg) IM or IV over 1-2min. Repeat as needed to maintain BP.

Angiotensin amide (Hypertensin) preferred by some.

Coticosteroids may prevent episodes of BP.


Mediated by kinins and histamine.
Prochlorperazine (Compazine) 10 mg po qid, or Phenoxybenzamine (Dibenzyline) 10-20 mg po bid, or Cyproheptadine (Periactin) 4-6mg po qid

Prednisone 20-40mg po qd for flushing due to bronchial carcinoids, and occ others

Combination of H1+H2 blockers helpful in some, esp with documented hypersecretion of histamine.

Methyldopa (Aldomet)

Monoamine oxidase inhibitors are contraindicated bec they block serotonin catabolism and can aggravate sxs.


Mediated by histamine. Managed by aminophylline. Adrenergic agents, (eg isoproterenol) do not worsen bronchospasm & may be used.


Mediated by serotonin, often hard to control.

Donnagel PG 15cc q3H prn. Take 15cc qid if >2-3 stools/day.


Periactin 4-6mg qid

Sansert 8-12 mg/day, Titrate to 20-22 mg/day if needed.

Prep for anesthesia

Pts at high risk for flushing and hypotension during surg. Must try to minimize or avoid adrenergic hormones and use of drugs that induce BP (mophine, succinycholine, curare).

Preop: Premed with Periactin 4-8mg po.

Methotrimeprazine 10mg IM 1hr preop (a phenothiazine with amnesic, analgesic, antihistaminic, & catechol-blocking properties: allows lower doses of anesthetics and use of MSO4).

Intraop: Aminophylline for bronchospasm

            Methotrimeprazine for flushing

            Methoxamine for hypotension





Cranial irradiation with intrathecal methotrexate 12 mg twice or three times weekly (or 10 mg/m2 but not > 15 mg) until negative cytology is achieved followed by

weekly MTX to a total of eight doses followed by

monthly MTX or MTX alternating with Ara-C for 1 year.

Thiotepa can be used in pts who are refractory to MTX and ARA-C.

Can add leucovorin to MTX at dose of 5 mg q 6 hrs for 4 doses after each it MTX injection.

Cytarabine (Ara-c) 50 mg tiw until csf cytology reveals no malignant cells on 2 occasions, then biw (separated by at least 3 days) for 2 consecutive weeks, then weekly for 4 consecutive weeks, then monthly for 6 months


CERVIX: Recommendations by Stage

CIN 1 - most do --> invasive ca, so can observe or ablative tx.

CIN 2-3, CIS - LEEP. If unable to do LEEP or if other reasons exist, do TAH.

Ia (microinvasive: <=3mm invasion and no lymph/blood invasion)- Conization

If dont want kids, do TAH

If 3-5mm invasion, also do bilat pelvic LN (5-10% risk)

Ib         15-25% risk LNs

Do radical TAH+LND

If not surgical candidate, XRT + implants


IIa treated like Ia

IIb and greater: cant get clear margins, so tx with max RT first

IV RT +/- chemotherapy




Due to mutations of p53 --> unusually high incidence of neoplasms that develop at young age, hard to treat, often lethal.

Auto D

Also see > incidence of: Breast, Sarcoma, Brain tumors, Leukemia, Osteosarcoma, Adrenal cortical ca


FAP (Familial Adenomatous Polyposis) = Gardner's Syndrome

Familial adenomatous polyposis gene (APC=adenomatous polyposis coli)

Dectectable by serum PCR assay                     


AutoD with incidence of 1/7000 (but <1% of all colon ca)

Can find the product of the APC mutation in >85% of classical FAP pts using PCR.

Can also find this in sporadic (ie, non-familial colon ca) 85% of time.

Not sure what APC gene does.

Multiple hits in development of colon ca:


HNPCC (Hereditary Nonpolyposis Coli) = Lynch Syndrome - increased risk for ovarian and endometrial cancers

Similar to FAP except pts do not have polyps to signal that they are at risk for colon ca. They do have genetic mutations that can be screened for, however.

In this syndrome, several mutations of 2p result in LOH (loss of heterozygosity) thereby allowing the rapid accumulation of the stepped defects illustrated above. There are 5 gene mismatches that can be detected. Look for these in pts < 35yo; the defects are only seen rarely in pts > 35yo.

Lynch I - colon ca only

Lynch II - colon ca plus others (ovary, endometrium, breast)


Turcot Syndrome - association of brain tumors (glioblastoma, medulloblastoma) with colon ca.



CEA monitoring NOT helpful for detecting resectable recurrent colon ca early. (Moertel, JAMA 270:943 8/93) CEA testing most sensitive for hepatic or retroperitoneal recurrence. Pts cured by salvage surgery <1%. (Moertel, JAMA 270: 943, 8/93)

Factors --> more likely recurrence: male, rectal site, Dukes C, high-grade, adhesion to adjacent structure, perforation, aneuploidy. Most likely to recur in: liver (33%), lung (22%), locoregional (21%), intraabdominal (18%) retroperitoneal (10%), peripheral LNs (4%). (Surg Gyn Obs 174:27, 1/92).




In upper & middle esoph, sq cell consititutes 98%. In lower esoph, most are adeno

Most cases occur in lower half

CT staging is 90% accurate for aorta, trachea, pericardium,

liver, & adrenals. 85% for abd nodes. 50% for paraesoph LNs

EUS (endo U/S) is > CT for depth & paraeoph LNs

Long range survival only in pts w tumors involving <5 cm of the esoph and neither obstruction nor extraesoph spread (T1N0M0) Pts rarely meet those criteria. Usu survival <10 mon 5YS < 10%

Neoadjuvant w 5FU/CDDP+ 3000cGy --> longer survival & higher response rates at expense of toxicity (MS=23 mon). Results have NOT been confirmed in randomized study. Survival rates same for CRs and PRs who got surgery, and 2YS was same for pts who got surgery after chemo and those who didn't. Therefore hard to recommend it presently.

ChemoRT wo surgery - 5FU/CDDP/5000cGy vs 6400cGy alone: Combo --> improved MS (12.5 vs 9 mon). Fewer local/distant recurs,

but more toxicity, some of which was life-threatening. Only 1/2 completed all cycles. Thus chemoRT only good in young.

RT is good for palliation.

Chemo is NOT useful for control or palliation. Single agents --> RRs 15-20% w 2-5 mon duration. Combi chemo --> higher RRs, but this does not translate into significant benefit, and outcome remains poor. Consider single agent if palliative chemo contmplated.






1.Until 1988 was the leading cause of cancer deaths worldwide.

2. Since 1935 the incidence has decreased from 9 to 3/100,000.

3.Highest incidence is in Japan (100/100,000). Number one cause of death nationally.


1.Poor prognosis: 5YS = 5-15%

2.Most cases advanced stage at diagnosis.

3.Even after "curative" surgery, recurrence rate is 80%.

4.In the past, the most common site was the body or antrum. During the last 10-15 yrs, the most common sites have been more proximal with poorer stage for stage prognosis than distal sites.

II. Etiology & Pathogenesis

A.Two Histologic Subtypes


a.Associated with epidemic cancer, suggesting environmental cause.

b.Arises from precancerous areas such as gastric atrophy or metaplasia.


a.Major type in endemic areas

b.More common in people with blood group type A, suggesting genetic predisposition.

B.Risk factors

1.Diet - low fat/low protein, salted meat or fish, gastric surgery, high nitrate consumption, low intake of vitamins A and C

2.Environmental - smoked foods, lack of refrigeration, poor drinking water, occupation (rubber, coal workers), smoking

3. Low social class

4. Medical - prior H. pylori infection, gastric atrophy & gastritis

III. Anatomical Considerations

Many organs close by quick involvement

Rich blood supply, including portan venous early liver mets

LN's: Virchow's node - L supraclavicular

Irish's node - L axilla

Sister Mary Joseph's nodes - periumbilical tumor deposits

IV. Pathology & Tumor Biology

A.Cell Types

1. Adenocarcinoma - 95%.

2. Lymphoma - most common site of lymphoma in GI tract

3. Squamous cell -

4. Adenocanthoma -

5. Carcinoid -

6. Leiomyosarcoma

B.Classification Schemes

1. Borrman - divides cancer into 5 types based upon macroscopic involvement

2. Ming - histomorphologic staging system

a. expansive - better prognosis

b. infiltrating - worse prognosis

3. Broder's - histologic classes 1-4

4. Bearzi & Ranaldi - based upon gross appearance on endoscopy

5. Lauren - most widely used

a. intestinal - better prognosis

b. difuse - worse

C.Tumor Biology

1. Stage for stage, Japanese seem to do better than Americans, perhaps due to different tumor biology. (No studies to verify this, however.)

2. Abnormal chromosome 11

3. Frequent ras oncogene mutations (Ki-RAS, HRAS, NRAS)

4. p53 important


6. EGF expression

D.Patterns of Spread

1. Tumor can spread through wall or along muscle layers into esophagus or duodenum

2. Lymphatic invasion occurs early.

a. 50% have +LN's at time of diagnosis

b. Site of spread depends upon part of stomach involved

3. The percentage of patients cured by surgery is low; local relapse rate is high.

4. Data suggest that gastric ca patients have disease recurrence because of inadequate surgical resection local failure and because of metastatic disease.

V.Clinical Presentation


1.Nonspecific - wt loss, fatigue, anorexia, pain

2.Symptoms caused by mets:

- large ovarian mass Krukenburg's tumor

- large peritoneal pelvic implant (Blumer's shelf) rectal obstruction

B.Evaluation - endoscopy, CT

C.Staging & Prognosis

1. 2 complicated staging systems - AJC and Japanese

2. For rough purposes:

0 - TIS

IA tumor invases lamina propria

IB into muscularis or perigastric LN's only

II thru muscle into adventitia or nodes > 3cm away from primary

IIIA thru wall with LN's or into other organs with LN's


IV thru wall with big LN's, mets.

VI. Treatment of Localized DISEASE


1.Disagreement about appropriate extent of resection because more radical surgery has not led to improved cure rates.

2.The issues are vs subtotal gastrectomy

b.extended lymphadenectomy?


B.Adjuvant Chemotherapy


a.Those at risk are those with T3-4, any N, M0 disease. Usually any adjuvant treatment is in addition to what is considered to be curative surgery. However, in one large study, and only 30-40% had a potentially curative resection. Thus, in situations where one hasn't or can't remove all tumor or in which you have positive margins, this isn't really adjuvant therapy.

b.In Japan they start chemo immediately. In US, wait 4-6 wks which risk of peritoneal spread. Thus timing of when to start is under study.

2.Adjuvant Protocols

- VA Study - thiotepa vs FUDR: neither any good

- 3 studies: 5FU +mCCNU: only modest results

- 1 study comparing chemo vs no treatment: survival in CT arm, but 2 other studies failed to confirm.

- DOX may be active

- Since some gastric tumors are ER+, tried TAM. Control group did better!

3.Neoadjuvant - attractive concept since gastric ca typically difficult or impossible to to resect and system spread common.

4.Intraperitoneal therapy - being tried in Japan.

5.Right now, the standard in the US is observation.

VII. Treatment of Advanced DISEASE

- Single agent therapy doesn't work, except perhaps 5FU.

- FAM (5FU, DOX, MITO) - introduced in 70's and used in 80's.

RR <30%.

Others have tried inc dose of Dox, but with no better results.

- There is evidence that etoposide + CDDP may be synergistic and that the combination may help overcome MDR.

- No combination has yet had decisively superior results to 5FU alone.

VIII. Conclusions

1. Decreased overall incidence in US, but in proximal poorly differentiated gastric cancers.

2. Most patients have advanced disease at diagnosis.

3. Gastric ca represents two types of ca with different epidemiology, pathogenesis, and prognosis.

4. Studies ongoing to address adjuvant/neoadjuvant therapy.

5. Role of radical surgery not defined.

6. May be a role for adjuvant XRT and/or intraperitoneal chemo.

7. FAMTX regimen (5FU, Adria, high dose MTX) about best. Modulated 5FU may be just as good.



Incidence & Location in Adults

Neurogenic                   21%     Posterior          (40% in kids)

Cyst                             20        All compartments (18 )

Thymoma                     19        Anterior            ( 0 )

Lymphoma                   13        Ant/middle        (18 )

Germ cell                      11        Ant                   (11 )

Mesenchymal               7         All                    ( 9 )

Endocrine                     6         Ant/middle        ( 0 )



Most common neoplasm in ant med. Myasthenia assoc w 15% of benign, and more if malignant. Usu thymomas cytologically benign w expression of malignancy by invasion of adjacent structures.

Benign neoplasms usu encapsulated and easily removed. True invasion signifies malignancy. Altho most freq in ant med, can occur in any portion of med. Histologic features include lymphocytic, epitheliod, spindle cell (fusiform), & mixed.

Stage I (5YS = 93%) Completely encapsulated microscopically.

Stage II (86%) Macroscopic invasion surrounding fatty tissue or pleura, or microscopic invasion into adjacent org.

Stage III (70) Macroscopic invasion --> adjacent organs

Stage IVA (50) Diffuse pleural/pericardial involvement

Stage IVB Lymphatic or hematogenous spread

Usu present in 5th-6th decade, & those w MG earlier. Most have stage I-II dz and no localizing sxs. Found on routine CXR.

MG, caused by Ab to acetylcholine receptor. Tensilon test may be diagnostic. Best test is SFEMG (single fiber EMG). Thymectomy is relatively safe procedure.

MG no longer influences outcome of surgical tx. Anueploidy is best predictor of worse peognosis and assoc w MG.


Stage I-II: Wide total excision

Stage III : Try to excise. Reconstruct major structures if able. Role of adj RT may depend upon degree of pleural involvement.

Role of adj chemo: not known. Is usu sens to both. Chemo includes CDDP, DOX, steroids. Can also use COPP, CVP, CHOP w RRs=60%, but CDDP-containing regimen seems to do better.

Neoadjuvant has been shown feasible in pilot studies.

Occasionally a small thymoma is discovered while doing a transcervical thymectomy for myasthenia. In such cases, the incision should be converted to a full sternotomy for wide excision.


Rare. <3% of all germ-cell tumors, and 10% of all mediastinal tumors. 3rd most frquent site of germ-cell ca behind testis and retroperitoneum. Despite common histologic and serologic features, is distinct from testicular ca.

Originally thought to be from occult testicular primary; now thoguht to arise from malignant transformation of germinal elements in med. (Testic cas rarely met to mediastinum)

Benign teratoma is most common one (60-70%)

Seminoma is most common malignant tumor (30% of malig)

Remaining 2/3 of malignant forms are non-seminomas.

Have been assoc w hematologic malignancies, usu occurring within 1 yr of treatment (therefore too early to be tx-related leukemia), & sometimes preceding diagnosis. Most common subtypes are M7, M6, and malignant histiocytosis.

Most common gene abnormality is isochrome 12p (i12p), which can be found both in the tumor & the marrow. Only found in pts w nonseminomatous med tumors and is assoc w very short survival.

Also assoc w thrompocytopenia, essential thrombocythemia, & hemophagocytic syndrome. Also Kleinfelter's (47,XXY).


Benign teratomas and dermoid tumors that may contain teeth often seen incidentally on CXR. In contrast, malignant germ-cell tumors often assoc w sxs due to local tumor growth, systemic sxs, or sxs due to mets.

>95% of pts w med tumors, abnormality in ant med. Only 3-8% in post med. Seminoma on CT-->large homogeneous mass without necrosis or calcification. Non-seminoma-->large heterogeous mass w areas of hemorrhage and necrosis.

Seminoma--> nl markers (occ incr bHCG). High AFP means non-seminomatous component. AFP up in 80% of non-seminomas; HCG high in only 30%. This differs from testicular in which HCG and AFP are elevated w = frequency.


Chest and abd CT. Careful exam of testicles. If significant RP adenopathy, do testic U/S. NO role for blind orchiectomy in pts w nl testic exam and U/S.


BENIGN TERATOMA: Resection-->near-universal cure. NO role for RT/chemo.

PURE SEMINOMA: Like testicular, very sens to RT which --> 60-80% long term survival. If small, may get by w surg alone, but adj RT usu recommended. Worse prognostic indicators: age >35, SVC syndrome. If bulky, may have to enlarge RT ports to include normal organs, increasing tox risk. 1/3 will fail distally.

At present, CDDP-based chemo is recommended as primary tx for pts w med seminoma. In a trial at MSKCC, 1/2 who were txd w RT alone relapsed, but only 10% of those txd w chemo did.

Concl: Pts w small tumors may have surg-->RT. All pts w distant mets need chemo. For pts w locally advanced dz, chemo is sometimes curative. Masses that remain after tx may need extirpation, both for removal and identification.

NONSEMINOMMATOUS GCT: Unlike mediastinal seminoma where options are controversial, preferred therapy is CDDP-based chemo. Surg and RT have no role.

Optimal regimen is BEPx4. If markers and CT normalize, but still have residual: resect then more chemo w salvage regimen such as VIP (VP16 or VBL, ifos, CDDP).

Although there has been improvement in prognosis, long-term survival only about 50%.

Role of Surgery

Usu txd w chemo/RT, but there is a specific role for surg. Since GCTs seldom involve the superior mediastinum, cervical mediastinosocy is seldom helpful.

Also needed when there is residual dz after chemo and markers are normal--need to determine if still any active dz. Should explore all areas of previous involvement, and all vestiges of dz completely removed. Surgeons will often do op even if markers still up. DONT do surgery if markers nl and no residual dz.



Med involved in: HD 60-90% NHL 18-45%. Primary med lymphoma is uncommon. If lymphoma in med, >90% chance ir is HD, diffuse lg cell, or lymphoblastic NHL.

-- HD: Altho HD is bimodal, primary med HD tends to occur in young age (15-30yo). Usu nod sclerosing histology.

-- Lymphoblastic: Usu teen male. Usu an immature T-cell, with early involvement of CNS and BM.

-- Diffuse Lg Cell: most common primary mediastinal NHL in adults. Usu B-cell.



Tumor most often --> curative surgical resection is thyroid.

Indications for radical lymphadenectomy of ant med: well-differentiated histology, superior mediastinal LNs. If not removed, will--> local compression problems in 60%. Other rare indications for surg: melanoma, unknown primary, pheo, pericardial mets.



Usu post mediastinum.

3 groups: (1) nerve sheath tumors (adults) - neurolemmoma, neurofibroma, Neurosarcoma (2) autonomic nerves (kids) - ganglioneuroma, ganglioneuroblastoma, neuroblastoma (3) paraganglionic system (rare) - chemodectoma, pheochromocytoma

In kids, usu malignant. Usu tx w surgery and chemo. In adults, usu benign. Operate only if > 5cm or fi impending sxs, or intraspinal extension.



Thyroid (ant med)




50% are malignant.

Liposarcoma -- most common. Usu ant med. Often confused w omental fat in Morgagni hernia and thymolipoma. Highly malignant

Endothelial tumors

Cystic hygroma (lymphangioma) -- most are cervical, only 10% extend into med

Hemangioma -- usu benign and asymptomatic, seldom recur after removal

Fibroma (benign fibrous mesothelioma), may be assoc w hypoglycemi, can transform into fibrosarcoma





in situ --> 0.5 cm
< 1mm --> 1 cm
1-4       --> 2 cm
> 4       --> 3 cm

LN Dissection:

< 1mm No: low risk for LN spread
1-4                   Yes: at risk
> 4                   No: nodes prob +



JCO 6/00 Intergroup Trial

Hi dose IFN vs Low dose IFN vs Observation.

5Y DFS: 44% v 40% v 35%

5Y OS : all about 50%

Pts in Obs arm were txd if they relapsed.

Conclusions: There is a dose dependent effect. Because there is no diff in OS, it may be reasonable to wait until relapse then treat.




Type I (Wermer's Syndrome)

-Pituitary (acromegaly, prolactinoma, ACTH-producing)
-Pancreatic islet cell (gastrinoma, VIPoma, glucagonoma, insulinoma)
-Parathyroid hyperplasia
-Pituitary adenomas usu functional.
-Prolactin most common hormone produced.
-Tx: Surgery
-Defect: 11q13 - 2 hits: genetics + environment

Type IIA (Sipple's Syndrome)

-Medullary thyroid ca is defining characteristic
-Parathyroid hyperplasia
-May be familial (AutoD) or sporadic
-Defect: ret gene on chrom 10
-Screen first degree family w pentagastrin stim test --> increased calcitonin

Type IIB (also called MEN-III)

-Med thyroid ca
-Multiple mucosal ganglioneuromas (lips, tongue, eyelids)
-Marfanoid features (High palate, pes cavus, sugar-loaf skull)






Signet ring cells = GI, Ovary, Lobular breast
Psammona bodies = Ovary, thyroid, breast
Papillary = Thyroid, ovary, mesothelioma
Nonacinar nests = Carcinoid, melanoma, paragangliom
Rossettes & areas of ganglion cell-like diff = Neuroblastoma
Very poorly diff = small cell     


Mucin (mucicarmine) = Adenoca (but not renal cell)
Glycogen = Renal cell, germ cell, some adrenal
Silver impregnation = Tumors of polypeptide-forming endocrine cells, enterochromaffin cells, melanoma


ER = Breast, endometrium, thyroid, meningioma
PR = Breast


Lamellar surfactant bodies = Alveolar lung ca
Intercellular bridges = Squamous cell
Premelasomes = Melanoma
Myofibrils,dilated rough endoplasmic reticulum = Sarcoma
Long surface microvilli = Mesothelioma (some)
Cytoplasmic secretory grans = Neuroendocrine tumors
Acinar spaces = Adenocarcinoma
Microvilli, glycocaliceal bodies = Adenoca colon
Intracellular neolumens = Adenoca breast
Staghorn microvilli = Adenoca ovary
Tubulofilamentous structure of cytoplasm = Adenoca kidney




BREAST CANCER SYNDROME – BRCA1 and BRCA2 mutations – These are tumor suppressor genes. In association with RAD51, they operate in a common pathway that repairs double-strand DNA damage. BRCA1 tumors are often higher grade and ER-. Often atypical or medullary histology. BRCA2 tumors do not tend to differ from sporadic cancers. Lifetime of risk with either mutation: breast = 50-87%  ovary = 15-65%. Women with these mutations also have a > 50% risk of developing a contralateral or second breast cancer. Also at risk for stomach, gall bladder, pancreas cancers.

COWDEN’S SYNDROME – PTEN mutation – account for <1% of hereditary breast cancers.

FAP - Familial Adenomatosis Polyposis - AutoD with 90% penetrance. Virtually all pts will develop colon ca without intervention. May have >1000 polyps by adolescence.

FAS - Flat Adenoma Syndrome - flat adenomas >5 mm appearing later in life with increased risk of colon and periampullary ca.

HNPCC (see Lynch I). When assoc with endometrial & others, called Lynch II.

GARDNER - familial polyposis (large and small bowel) + other mesenchymal Abnormalities (desmoid tumors of mesentery, lipomas, sebaceous cysts, osteomas, and fibromas)

LESER-TRELAT (Sign of) - sudden appearance or rapid increase in the number of seborrheic keratoses as a paraneoplastic harbinger of underlying occult malignancy

LI-FRAUMENI - loss of p53 gene resulting in: brain tumors, breast ca, adrenal ca, AML, sarcoma (Mnemonic: "BBAmlAS")

LYNCH I - familial colorectal cancer syndrome. - AutoD with 90% penetrance. Multiple colon cancers at an early age in several generations, often proximal. Also called HNPCC.

LYNCH II - hereditary adenocarcinomatosis syndrome. - families with colon AND extracolonic tumors (ovary, breast, biliary, urologic, endometrial, and gastric). In first degree relatives, 7x risk of colon ca.

MEN-I - pituitary /pancreas/parathyroid

MEN-IIA - med thyroid/pheo /parathyroid

MEN-IIB - same as IIA, but without parathyroid and w Marfanoid features + multiple mucosal ganglioneuromas (lips/tongue/eyelids)

OLDFIELD – familial adenocarcinoma colon + multiple sebaceous cysts

PEUTZ-JEGHERS – due to mutation of STK11 – AutoD – familial hamartomatous polyposis, usually clustered in the small bowel (duodenum); brown/black skin lesions near lip, mouth, face, fingers. Spots usually disappear between puberty & 20yo. Risk for colon ca lower than other syndromes. Can develop cancer of virtually any GI cancer plus thyroid, breast, lung, uterus.

SIPPLE'S S. - (MEN IIA) - medullary ca thyroid + bilateral pheochromocytoma + parathyroid hyperplasia

TROUSSEAU'S S. - see under Heme above.

TURCOT - assoc of colon ca with brain tumors glioblastoma, medulloblastoma)

VON HIPPEL-LANDAU - AutoD with variable penetrance. Angiomatous tumors in retinas, cerebellum, brain, spinal cord, adrenals, lung, & liver. Also see polycythemia, pheochromocytoma, pancreatic ca, and renal ca.


pituitary tumor (acromegaly, prolactinoma, ACTH)

pancreatic islet cell tumors (gastrinoma, VIPoma, glucagonoma, insulinoma)

parathyroid hyperplasia




Exudate if:

Pleural/serum Protein >0.5
Pleural/serum LDH >0.6
Pleural LDH > .66 the upper limit of normal serum LDH

Tests to order:

Protein, pH, glc, & cell count if suspect empyema
Gram stain and cultures (routine, AFB, fungus)
Amylase-if suspect pancreas-related cause

Cancer markers (like CEA) are not reliable or helpful


Not all effusions require treatment, especially if asymptomatic and not compromising pulmonary function. If responsive tumor, eg NHL, breast, SCLC, or GU -- can try treating underlying dz.

Malignant pleural effusion is grave prognostic sign. More than 50% will be dead within a few months.



Growth Factors: c-SIS, c-HST, c-INT-2

Tyrosine kinase receptors: c-ERB B-1, c-KIT, c-NEU, c-MET, c-FMS

Tyrosine kinase Nonreceptors: c-SRC, c-YES, c-ABL, c-FGR

Serine-threonine Kinases: c-MOS, c-RAF-MIL

G-proteins: c-Ha-Ras, c-Ki-Ras, c-N-RAS

Nuclear Proteins: c-ERB A, c-MYB,    c-JUN, c-MYC, c-FOS



Multiple randomized trials clearly indicate that chemoradiation produces better pelvic control than surgery alone, RT alone, or chemo alone. There is also evidence from the GITSG trial #7175 that combined treatment also produces better survival than chemo alone (which is better than radiation alone which is better than surgery alone).

Multiple trials have failed to show a survival benefit to adjuvant RT except for a single trial in which PREoperative RT improved survival.

Intergroup 0114, which included nearly 1700 patients. All pts received bolus 5FU with concurrent RT (given either pre- or post-op.) At 4 yrs there was NO benefit to adding LV, Levam or any combination of the two to bolus 5FU.

Questions that remain center on the sequencing of the individual components (chemo, RT, surgery), optimization of chemo and modulators, and the contribution of RT to survival.


(Sem Onc 18:571, 91)

After surgery alone (Low ant resect or APR)

Stage I:

T1 N0 Local failure 0-14% 5YS 80-100%
T2        Local failure 8-15% 5YS 61-100

Stage II:

T3 N0 Local failure 23-35% 5YS 43-71%
T4        Local failure 11-53% 5YS 29-67

Stage III:

T2 N1-3 Local failure 10-50% 5YS 33-90%
T3 N1-3 Local failure 24-63% 5YS 17-39
T4 N1-3 Local failure 22-67% 5YS 0-17



CR: Complete disappearance of all objective evidence of disease

Good PR: >= 50% dec in sum of products of diameters of measurable lesions

Minimal PR: 25-50% dec of sum of products

Stable: 0-25% dec of sum of products and no new lesions.

Worse: >= 25% increase in sum of lesions OR new lesions (Progression)



(JCO 13:2681) [See Testic Staging]

If fully resected --> BEP x 2

B1 --> 70% chance of remaining disease free w surgery alone, so close observation ok.

B2 --> immediate tx: BEP x 3 or EP x 4

Authors (from Indiana) argue that 2-drug regimen (EP) is NOT superior to the 3-drug regimen (BEP). They say that 8 wks of bleo (240u) is not all that toxic, so only real benefit of dropping it is cost savings, and not clear whether efficacy is sacrificed. May be that EP given q3 wks rather than q4 makes up for lack of bleo, but why mess with successful treatment?



VAB-6 (CTX, Bleo, Dactinomycin) vs EP: Equivalent efficacy. EP less toxic.

BEP v EP: Equivalent

EP v EC (VP16,CBDCA): EP superior

BEPx4 v BEPx3: Equivalent

BEPx3 v EPx3: Terminated: EPx3 not enough. Concluded BEPx3=EPx4




- Extends cure rate from 70-99%
- 10-25% chance of sterility due to retrograde ejaculation with nerve-sparing procedure. If classic bilateral LND done, risk is 50-90%.
- Small chance chemo might be needed anyway if N2 disease found.


- Extends cure from 70-99%
- 25% chance of sterility
- Small chance surgery may be needed later to remove occult teratoma that grows (and presumably would have been removed by RPLND)
- Risk of long-term complications such as leukemia, pulm tox, Raynauds probably < 5%


- Chance of cure remains at 70% (but can be extended to 95% by chemo in case of relapse
- Requires absence of "high risk" features
- Requires lab + CXR monthly x 1 yr, then bimonthly x 1 yr, and CT every 3 months for 2 yrs.
- Small risk of late relapse beyond 2 yr surveillance period.


TESTIC: High-Risk Stage A

Predictors of recurrence in Stage A Testic Ca:

Invasion of testicular veins
Invasion of lymphatics
Absence of yolk sac elements (normal AFP)
Presence of undifferentiated (embryonal) tumor

When all of these factors are present, there is 58% chance of relapse within 2 yrs.

Ref: Freedman, Lancet 8:2(8554):294-298, 8/87



Radical Orchiectomy -->

First decision: Is RPLND needed? Maybe not if truly CS A (BHCG and AFP return to normal, and normal CT chest/abd, and not "high-risk"). In this setting, can OBSERVE with 25-30% chance of relapse, usually in RP. But good salvage, so OS about as good as if had RPLND.

If RPLND IS DONE, then if:

A. CS I or IIA (LNs < 2cm on CT): --> RPLND -->

(1) PS I or IIA (1-5 positive LNs all < 2cm) --> Observe (Exception might be high-risk Stage I: If any invasion of testicular veins, invasion of lymphatics, absence of yolk sac elements (normal AFP), and presence of undifferentiated (embryonal) tumor -- if all present, then at 58% risk of relapse within 2 yrs, even if stage I -- so might consider adjuvant chemo.)

(2) PS IIB (> 5 LNs positive all < 5 cm, any LNs 2-5 cm, any extranodal extension) --> BEP x 2


B. CS IIB or III (RP LNs > 2cm on CT) : --> BEP x 3-4 -->

1. CR --> Observe

2. PR --> RPLND -->

(a) Cancer --> EP x 2 or
(b) Teratoma, Fibrosis --> Observe
(3) Progression --> salvage with VIP/ABMT

*Observation: monthly markers and CXR x 1yr, then bimonthly x 1yr. CT abd q 3 mon x 2yrs

If pt relapses after only 2 cycles of BEP, treat as disseminated disease: BEP x 3-4 followed by excision of any residual.


CLINICAL STAGE I (Confined to testis)

Inguinal orchiectomy: If any vascular invasion, involvement of tunica albuginea, or spermatic cord --> nerve-sparing RPLND (Can only consider nerve-sparing operation if true CS I)

If no invasion and markers returning to normal, observe. (25% chance of relapse, but 90+% salvagable)


RPLND --> Markers returning to normal, 5 or less LNs +, and no extranodal involvement --> Observe

Markers returning to normal, 5 or more LNs or extranodal extension --> BEP x 2

Markers remain elevated (implies not completely resected) --> BEP x 3-4 (can probably give 3 because 3 as good as 4)


BEP x 2


Good risk (70-80% pts): BEP x 3 OR EP x 4

Poor risk (Liver/bone/brain mets, RP LNs > 10cm, bulky lung): BEP x 4

Most investigators agree that all seminomas are good risk, and that all pts with primary extragonadal nonseminomatous tumors (pineal, mediastinal, RP, or sacral-coccygeal) are poor risk.

At Indiana, anyone with primary mediastinal tumor, a palpable abdominal mass and any disease above diaphragm is considered poor risk.


(JCO 15:594 2/97)


Good Prognosis -- 90% of seminomas. 5YS 86%

Any primary site AND
No non-pulmonary visceral mets AND
Normal AFP, any HCG, any LDH

Intermediate -- 10%; 5YS 72%

Any primary site AND
Non-pulm visceral mets AND
Normal AFP, any HCG, any LDH

Poor - No pts classified as poor prognosis


Good Prognosis -- 56%; 5YS 92%

Testis/RP primary AND
No non-pulm visc mets AND
Good markers: AFP < 1000 and HCG < 5000iu/L (1000ng/ml) and LDH < 1.5 x upper limit of normal

Intermediate -- 28%; 5YS 80%

Testis/RP primary AND
No non-pulm visc mets AND
Intermediate markers:   AFP 1000-10,000 OR HCG 5000-50,000 OR LDH 1.5-10 x N

Poor -- 16%; 5YS 48%

Mediastinal primary OR
Non-pulm visc mets OR
Poor markers: AFP > 10,000 OR HCG > 50,000 OR LDH > 10 x N



1. AFP or HCG after treatment
2. High LDH levels (correlate with tumor burden)
3. Bulky abdominal disease that cannot be removed with surgery or chemotherapy
4. Liver or brain mets

Pure choriocarcinoma in men is bad because usually advanced at dx.



Indiana Classification System of disseminated or incompletely resected disease:


- Elevated markers post RPLND
- Cervical lymph nodes
- Unresectable nonpalpable RP disease
- < 5 lung mets/lung and none > 2 cm


- Palpable abd mass or > 10cm on CT AND no dz above diaphragm
- 5-10 lung mets/lung (all < 3cm) OR single lung met any size > 2 cm OR mediastinal lymph nodes < 50% diameter


- Mediastinal primary OR mediastinal mets > 50% diameter OR > 10 mets/lung OR multiple lung mets with largest > 3 cm
- Palpable abd mass AND lung metastases
- Liver, bone, or CNS metastases

At Indiana, BEP x 3 is standard for minimal or moderate disease. For advanced disease, BEP is better than PVB, and BEP probably equal to VIP.



Who needs it?

CS IIA (RP LNs < 2 cm on CT) -- these do.
CS IIB (RP LNs > 2 cm) and up don't because they'll get chemo anyway.

Those without high-risk CS I may not because risk of relapse is only 25-30% but can easily be salvaged if they do. This means you have to have:

1. BHCG and AFP return to normal
2. Normal CT chest/abdomen
3. No embryonal component
4. No testic vein involvement
5. No lymphatic involvement
6. Some yolk sac present (with inc AFP intitally) – debatable
7. A highly motivated and compliant patient.


In experienced hands, the classic bilateral RPLND is assoc with minimal periop morbidity and virtually no mortality. Biggest problem is retrograde ejaculation --> infertility in over 90% of patients.

Nerve-sparing techniques help. If the LNs are grossly negative at the time of surgery, then one can do a unilateral dissection bec there is little chance there will be dz on the contralateral side. Particular attn is given to avoiding the region anterior to the aortic bifurcation. This preserves function in 75-90% of pts.

In early stage pts, especially stage A, RPLND can be performed with little risk of relapse.




70% present this stage

80% do not need adjuvant RT, but because can relapse as late as 8-10 yrs later, go ahead and give 2500 cGy to RP and ipsilat pelvic LNs.


2500 cGy to RP and ipsilat pelvic LNs with extra 500-1000 cGy boost to gross dz.

Do NOT radiate mediastinum: < 10% chance of relapse, and reduces chance of successful chemo if does


If bulk < 10cm, can try RT first, but usually need chemo anyway, so consider using it first. May not need RT then. If bulk > 10cm, treat with chemo.





General Principles, TNM Staging, Stage Classifications

General Principles

1.Seminomas can be staged clinically, but NSGCT must be staged pathologically.
2.Clinical staging results in understaging 25% of time.
3.Patients with PS I can be cured by surgery alone in 96% of cases.
4.If recur, still get 96% salvage rate.
5.Need careful follow-up for 2 yrs.

Most of the staging systems for seminomas define Stage I as disease limited to the testicle or scrotum. The discrepancies come in defining Stage II, with different weights being given to the perceived importance of multicentricity, tumor bulk, etc. Stage III typically means disease above the diaphragm, and Stage IV is distant mets.

TNM Staging

Primary - classified after radical orchiectomy

pTX - No radical orch has been done
pT0 - No tumor
pTis - Intratubular (in situ)
pT1 - Limited to testis and epididymus with no lymphovascular invasion. May invade tunica albuginea but not tunica vaginalis
pT2 - Beyond tunica albuginea into tunica vaginalis, into epididymus, or with lymphovascular invasion
pT3 - Into spermatic cord with or without lymphovascular invasion
pT4 - Into scrotum with or without lymphovascular invasion


N1 – One node or a node mass no greater than 2 cm
N2 – One node or a node mass no between 2-5 cm
N3 – Node mass > 5 cm


M1 – Nonregional nodal or pulmonary metastases
M2 – Nonpulmonary visceral metastases

Serum Tumor Markers (S)

S0 : Markers all normal
S1 : LDH < 1.5 x upper limit normal (ULN) and HCG < 5000 and AFP < 1000
S2 : LDH 1.5-10 x ULN or HCG 5000-50,000 or AFP 1000-10,000
S3 : LDH > 10 x ULN or HCG > 50,000 or AFP > 10,000


Stage 0 = pTis N0M0 = in situ

Stage I = T1-4 N0 M0 Sx = Limited to testis

Stage Ia = T1 N0 M0 S0
Stage Ib = T2-4 N0 M0 S0
Stage Is = AnyT N0 M0 S1-3 = Persistent marker elevation

Stage II = Any T Any N M0 = Node positive disease

Stage IIa = AnyT N1 M0 S0-1
Stage IIb = AnyT N2 M0 S0-1
Stage IIc = AnyT N3 M0 S0-1

Stage III = Any T Any N M1 = Distant mets

Stage IIIa = AnyT AnyN M1 S0-1
Stage IIIb = AnyT AnyN M0-1 S2
Stage IIIc = AnyT AnyN M0-1 and S3 or M2 and AnyS



Good Risk

NSGCT: Is (S1), IIA-C (S1), IIIA
Seminoma: IIC, IIIA-C

Intermediate Risk

NSGCT: Is (S2), IIC (S2), IIIB
Seminoma: IIIC by non-pulmonary visceral metastases

Poor Risk:

NSGCT: Mediastinal primary, non-pulmonary metastases (bone, liver, brain, etc.), Is (S3), IIC (S3), IIIC


Other Staging Systems for NSGCTs --

MKSCC -- Walter Reed -- Features -- (5YS)

A -- I -- Confined to testis. (95%) Treatment

B -- II -- Mets to retroperitoneal LN's (70)

- B1 IIa <=5 nodes w mass < 2.5cm Treatment
- B2 IIb >5 nodes or mass 2.5-10cm Treatment
- B3 IIc LN mass > 10cm

C -- III LN's above diaphragm or other organs (70) Treatment

*** Staging acc to MKSAP ***

Clinical Staging: Royal Marsden for Seminoma

I -- Confined to testis, epididymis, or cord

IIA -- RP LNs < 2cm
IIB       RP LNs 2-5cm
IIC       RP LNs > 5cm

III -- Disease above the diaphragm or visceral organs

Pathological Staging

II N1    Microscopic dz in 5 LNs or less
II N2a Macroscopic dz in 5 LNs or less, none > 2cm
II N2b Macroscopic dz in >5 LNs or any LN > 2cm
II N3    Dz into extranodal soft tissue
II N4    Unresectable dz




80% of pts oligospermic at diagnosis before treatment.
Risk with classic RPLND = 50-90%
Risk with nerve-sparing RPLND = 10-25%
Risk with chemo 25-50%



 Initial Work-up: AFP, HCG, LDH, CXR

Primary Treatment: Inguinal orchiectomy --> Seminoma (AFP negative. May have elevated HCG) or NSGCT


Post-diagnostic work-up: CT Chest/Abd/Pelvis, Repeat AFP and HCG, Brain MRI and/or Bone scan if clinically indicated, Discuss sperm banking

See NCCN guideline disc … to be finished later…



(Follicular and papillary often grouped together as "well-differentiated")


-Usu relatively benign course
-Metastasizes to cervical lymph nodes
-May be mixed with follicular, and presence of papillary components implies better prognosis than pure follicular
-Tx: thyroidectomy + lymph node dissection --> T4 suppression


-Similar to normal thyroid tissue
-Takes up iodine well
-More likely to --> morbidity/mortality than papillary
-Metastasizes to lung, bone
-Tx: thyroidectomy + lymph node dissection --> T4 suppression

-If pap/follic recurs in cervical LNs or lungs --> RAI


-Undifferentiated-may be difficult to categorize
-May be hard to tell from lymphoma
-Grows fast
-Surgery and RAI NOT good options
-Doesn't take up iodine well

-Tx: DOX (some add CDDP which --> >RR, but same survival)


-Derived from calcitonin-secreting cells
-Often multifocal within thyroid
-May be AutoD inheritance --> MEN
-Dx should prompt search for pheo
-Can occ produce other hormones (ACTH, serotonin)
-Dx rarely made pre-op without family history
-Test: pentagastrin --> abnormally high plasma calcitonin which is an indication of C-cell hyperplasia, appremalignant lesion, or early invasive lesion
-Familial form tends to occur in pts 20-40year old
-Sporadic form occurs 50-60year old
Tx: Total thyroidectomy -->XRT
-Doesn't concentrate iodine well
-Notoriously unresponsive to chemotx



THYROID: Well-Differentiated Ca

Papillary or papillary-follicular
Hurthle cell


-Age-may be most impt.
-low-risk-men < 40yrs and women <50,years
-high risk-all older patients
-Extension into adjacent neck structures
-Size- <3cm better than >3cm




                                    Metastatic Site (%)















The 5YS for even early stage disease is, at best, ~15%. For Stage IV disease, it is about 3%. Overall survival gets worse with the age of the patient, and is 5% or less in patients > 60 years old.

5YS is about 20% for those who have a resection, but unfortunately, < 20% have resectable disease. The operative mortality from resection is about 5%. Age should not be a risk factor if no comorbidities, but older patients have a lower median survival than younger patients having the same operation and stage.

5FU+RT improves survival from 11 to 20 months in patients who have good performance status and localized disease.

In unresectable cancer, gemcitabine improves performance status in 24% compared to 5% with 5FU alone. The average time to response was 7 weeks and lasted a mean of 18 weeks.

Most patients with gemcitabine had stable disease. Overall response rate is 5-10%. Median survival with gemcitabine was 5-6 months compared to 4 months with 5FU.



At autopsy, 32% have adrenal masses. Increased prevalence between 60-80 years old.

No evaluation needed if known polymetastatic disease. If suspect metastases or infection, get CT-guided FNA. Modify algorithm based on imaging phenotype, age, and clinical circumstance. With age the likelihood that it is benign increases, so tend to be less aggressive in evaluation.

Imaging: Most likely benign if: < 10 Hounsfield units, contrasts washes out at 5 and 15 minutes; increased signal on MRI (lipid and water in same phase – when they are out of phase it is more likely malignant with less lipid content); < 3 cm is most likely benign. If > 6 cm, probably malignant.

To determine whether functional: history, 24 hr urine for metanephrines, catecholamines; overnight 1 mg dex suppression test. If hypertensive, also check serum K (if > 3.9, it is not primary aldosteronism) and PAC/PRA.

If nonfunctioning adrenal mass and < 4 cm diameter, repeat imaging at 3 and 12 months. If > 1cm increase in diameter, surgically resect it. If remains unchanged and nonfunctional at 12 months, no further follow up.



AFP --- 5-7 days
HCG --- 1 day
CEA --- 1.5 days
CA 19.9 --- 0.5 d and 4.3 d (biphasic)
CA125 --- 5-10d
PSA --- 2-3d



GISTs  Diagnosis, Prognosis, Treatment

Gastrointestinal Stromal Tumor (GIST), a mesenchymal neoplasm derived from the cells of Cajal of the mesenteric plexus, has emerged as a prototypical neoplasm that responds to therapy directed against a single target molecule - the KIT receptor tyrosine kinase protein. The c-KIT proto-oncogene gets activated leading to increased production of the KIT cell-surface transmembrane receptor tyrosine kinase (CD 117). This, in turn, leads to the inhibition of apoptosis and uncontrolled cellular proliferation.

Gleevec (imatinib mesylate) inhibits the BCR-ABL in CML, but also inhibits the KIT kinase as well as that of platelet-derived growth factor (PDGF).

Advanced unresectable GIST responds poorly to chemotherapy and radiation therapy, and the median survival is about 20 months. Gleevec leads to a 54% PR rate and 27% stable disease. Median response duration was at least 6 months.

STI571 is one of the earliest examples of a "non-toxic" chemotherapeutic agent (an agent whose anti-cancer activity is NOT predicated on a cytotoxic mechanism). STI-571 had already demonstrated clinical value in BCR-ABL-positive leukemias. Early clinical results in GIST are so encouraging that oncologists may soon be wrestling with the opportunity of referring every patient with malignant GIST into clinical trials with STI-571. In order to ensure appropriate treatment, pathologists need to understand the biology and treatment of this tumor and to have standard methods and criteria for providing diagnosis (GIST or not GIST) and consistent prognostic classification (high risk of metastasis or low risk of metastasis).

The rationale for including GIST in clinical trials with a tyrosine kinase inhibitor resulted from a series of investigations demonstrating that gain-of-function KIT gene mutations are found in many GISTs and that these mutations result in constitutive activation of the KIT protein - a tyrosine kinase receptor - that stimulates proliferation of GIST tumor cells and may inhibit apoptotic cell death. STI-571 is highly effective in vitro in reducing KIT tyrosine kinase activity. GIST cells generally express the KIT protein (CD117); this enables the pathologist to utilize immunohistochemical reactivity for the KIT protein as a marker for discriminating GIST from other mesenchymal gastrointestinal neoplasms. Within the normal bowel wall, the interstitial cells of Cajal (which are of the same cell lineage that undergoes neoplastic transformation to give rise to GISTs) also express the KIT protein. KIT is thus a rare example of a proto-oncogene that serves as a relatively specific marker for histogenesis and serves as a substrate for targeted drug therapy; this is surely a model that will become more common in the future.

Diagnosis of GIST

GISTs occur predominantly in middle-aged or older persons. Most tumors (70%) occur in the stomach and about 20-30% occur in the small intestine. A small percentage of GISTs arise elsewhere in the GI tract, omentum, or retroperitoneum. GISTs tend to be primarily intramural tumors, usually involving submucosa and muscularis propria in continuity and often extending into the mesentery or subserosa. Pure submucosal GISTs have been reported. GISTs are often clinically silent until they reach a large size, bleed or rupture. Like other soft tissue sarcomas, they only rarely metastasize to lymph nodes, and thus surgical lymphadenectomy is seldom warranted.

There are differences in the frequency, typical morphology and biology of GISTs depending on their site of origin. GISTs can be single or multiple (as in Carney's triad or, rarely, neurofibromatosis), spindled or epithelioid, or mixed cell type. Tumors of the small intestine, including the duodenum, often contain extracellular collagen bundles, called skeinoid fibers. Most spindle cell lesions of esophagus are leiomyomas and stain negatively for CD117. GISTs rarely occur in the esophagus. In the experience of some workshop participants, large GISTs of stomach that are attached to the greater curvature usually demonstrate benign behavior, despite their size. Most duodenal GISTs occur in the second part of the duodenum where they push or infiltrate into the pancreas. These tumors and other small bowel GISTs have a high propensity for malignant behavior, compared to gastric GISTs, which are usually low-risk. Rectal tumors are usually deep intramural tumors with homogeneous morphology. Local recurrences, probably reflecting inadequate initial resections, are common in rectal GISTs.

Resected GIST tumors should undergo a gross examination similar to that of other GI tumors. The exact anatomic location of the tumor should be noted. The size of the tumor should be measured along its greatest axis, and the status of resection margins should be recorded. The general experience of the workshop participants was that true local recurrences (excluding mesenteric or peritoneal spread) occur only with unresectable tumors and with tumors in which the resection margins are grossly positive; recurrence follows rapidly (several months) in these cases. The main surgical objective is to achieve complete gross excision only. There is no known benefit in obtaining wide margins, and this empiric finding provides a rationale for routinely performing conservative wedge resections of gastric GISTs. Microscopic examination of resection specimen margins is recommended.

For the diagnosis of spindle cell tumors arising in the GI tract, the general consensus of the workshop pathologists was that CD117 immunostaining should be performed. A positive CD117 on a spindle cell lesion of GI tract confirms the diagnosis of GIST when morphologic and clinical features of the tumor are consistent with GIST. CD117 expression in GIST is generally seen in the majority of cells. Staining is typically cytoplasmic, strong and diffuse, but often shows dot-like accentuation. Focal positivity (in rare cells) or activity involving groups of cells comprising under 10% of the total number of tumor cells should be interpreted cautiously. Scattered single cells positive for CD117 are likely to be mast cells. Mast cells and insterstitial cells of Cajal are the only gut cells that are typically CD117 positive. It is helpful to perform CD117 staining on tumor sections that include mucosa, since gut mucosa will contain at least a few mast cells that can serve as a positive control.

Most pathologists present believed that diagnosis of GIST requires immunohistochemical confirmation by CD117. Two of the pathologists at the workshop did not believe that CD117 positivity is absolutely required in all cases of GIST, suggesting that an experienced pathologist may, on rare occasion, rely on clinical and morphologic features for GIST diagnosis, even when the CD117 immunostaining is deferred or the results of the staining are negative. Nevertheless, all present believed that those who do not have extensive experience with GIST should perform CD117 immunostaining before making this diagnosis. Pathologists who do not have access to CD117 immunostaining, or who do not perform the assay frequently enough to feel comfortable with the technical performance of the assay, should have the case examined by a pathologist experienced with GISTs. It should be noted that patients entered into current STI-571 trials for GIST must have tumors with CD117 positivity and must have central pathology review.

Gut spindle cell tumors that are negative for CD117 should generally be stained for desmin and S-100, which are helpful in supporting the diagnosis of smooth muscle and neural tumors, respectively. Both desmin and S-100 are generally negative in GISTs. Occasional desmin positive cells within GIST tumors usually are non-neoplastic smooth muscle cells infiltrated by GIST. Obviously-malignant atypical spindle cell tumors that demonstrate S-100 protein may sometimes be metastatic melanomas. Confirmation with additional melanoma immunostains and clinical correlation can be used to confirm this diagnosis. Among the lesions to be considered in the differential diagnosis when all these immunostains are negative are desmoid fibromatoses, solitary fibrous tumors, and inflammatory myofibroblastic tumors. As with other tumors, immunohistochemical staining itself is adjunctive to, not a replacement for, careful morphologic examination and clinical correlation.

Prognostic Factors

Our understanding of GIST prognostic/predictive markers is certain to change in the next few years. However, the group made a number of recommendations that can be used today by general surgical pathologists. Once a diagnosis of GIST is made in a tumor with no known metastases, the group recommended that in routine use two prognostic factors - tumor size and mitotic index - provide the most useful histologic indication of the future biologic behavior of the tumor. For this group of tumors, the mitotic index is measured by counting the number of mitotic figures in 50 high powered fields and expressing the result as the number of mitoses per 50 high power fields). Workshop participants did not recommend grading GISTs, but suggested that tumors be categorized by their relative risk of malignant behavior.

Although high cellularity is more prevalent in high-risk tumors and paucicellularity more common in low-risk tumors, the consensus was that cellularity was not a valuable independent prognostic indicator. Tumor necrosis, cystic change, nuclear atypia, infiltrative growth pattern, tumor vascularity and degree of intensity of CD117 positivity were not considered to be proven independent determinants of biologic behavior. Although an infiltrative growth pattern may be found in low-risk and high-risk GISTs, it was noted that a pattern of infiltration into the lamina propria, though rarely identified, was thought to be a useful criteria of malignancy. The criteria for malignancy based on tumor size and mitotic count vary depending on tumor location. For example, GIST arising in the small intestine demonstrate malignant behavior at lower levels of mitotic activity than do GISTS arising in the stomach.

As yet, the group has not come to agreement on specific cut-points to distinguish GIST tumors as low risk , intermediate risk (i.e. indeterminate) or high risk (i.e. malignant) based on size and mitotic count. There was serious concern by some of the pathologists that no GIST can be definitively labelled benign, particularly if it presents clinically as a mass. However, other pathologists felt comfortable equating "low-risk" and "benign" tumors. The argument was raised that small tumors (less than 2 cm) are occasionally found in stomachs and small intestine resected for reasons unrelated to the GIST tumor, and that experience would suggest that such patients never have GIST metastases (i.e. their GISTs are benign). Other pathologists were skeptical, suggesting that the risk of malignant behavior in GISTs has no zero-threshold, deprecating the term "benign", and favoring the term "low risk". There was group agreement for categorizing GIST tumors at the extremes of biologic behavior. Small tumors (less than 2 cm) with no mitotic figures are at very low risk for metastasis. Large tumors (> 5 cm) with a high mitotic count (> 50 mitotic figures per 50 high power fields) commonly metastasize. However, small tumors (i.e. tumors of any size) occurring in the intestine with >2 mitotic figures per 50 high power field were considered high risk (e.g. malignant) by some participating pathologists.

GIST Cytogenetics and Molecular Biology

The hallmark cytogenetic finding in both benign and malignant GISTs is monosomy of chromosome 14; loss of chromosome 22 is also frequent. Nevertheless, karyotyping is not a reliable method by which to establish the diagnosis of GIST. Not all GISTs can be successfully karyotyped, and a "GIST-like" cytogenetic profile is found occasionally in malignant peripheral nerve sheath tumors and in smooth muscle tumors. Various chromosomal deletions, including deletions of 1p and 9p, coincide with malignant progression in GISTs. Interestingly, chromosome 9p is the site of several tumor suppressor genes, including the cell cycle regulator CDKN2A (p16).

Using comparative genomic hybridization, DNA copy number changes can be observed in almost every GIST with benign GISTs having fewer changes than malignant GISTs. Losses of DNA copy numbers at 1p, 14q, and 22q are the most frequent changes seen in benign and malignant GISTs. These changes are rarely seen in other mesenchymal tumors, such as schwannoma, leiomyoma, and leiomyosarcoma. Gains and high-level amplifications at 5p, 8q, 17q, and 20q were significantly more frequent in malignant and metastatic GISTs than in benign GISTs. Losses in 9p were not seen in benign tumors, and they were more frequent in metastatic GISTs than in malignant primary GISTS.

The best-characterized gene alterations associated with GIST are found in the KIT gene. Most mutations consist of in-frame deletions and single nucleotide substitutions within exon 11, which codes for the juxtamembrane domain, but alterations have also been described in exons 9 and 13, which encode portions of the extracellular and kinase domains, respectively. Several studies suggest that tumors demonstrating exon 11 deletion behave more aggressively than those without. The clinical significance of the different types of mutation is not yet certain, however, as no investigation yet published has had sufficient statistical power to detect differences among mutation types. Studies at different centers show variation in both the frequency with which the KIT gene is mutated, and in the significance of these mutations. The differences in these studies may reflect differences in the types of tumors and patients which have been referred to these institutions, but technical factors cannot be excluded. The clinical role of KIT mutation analysis in characterization of GISTs thus remains incompletely defined.

It was suggested in the workshop that, in the future, GIST treatment decisions might require input from both surgical pathology and molecular pathology. It was noted that in vitro studies show a correlation between STI-571-responsiveness and the exon in which KIT mutation is found. Hence, GIST response to STI-571 likely depends on which KIT protein domain is altered by the underlying genomic mutation.

GIST Treatment and STI-571

Until recently, GIST treatment consisted of resection followed by surveillance for metastatic disease. Chemotherapy and radiation have been ineffective. GIST metastases are most often found in the liver or the peritoneum. Metastases can occur many years after initial resection, and metastases do occur in well over half of the patients diagnosed with malignant or high risk tumors at time of resection. Some patients have benefitted greatly from surgical resection of localized GIST metastases. Most importantly, development of metastatic GIST no longer carries the same implication of hopelessness as it did prior to the availability of STI-571.

Early clinical trial data with STI-571 are very encouraging, even for patients with metastatic disease. Enrollment in an ongoing STI-571 clinical trial should probably be considered for all GIST patients with metastases. Novartis has indicated that they have sufficient supply of STI-571 to include all GIST patients meeting this criterion into clinical trials.

The appropriate treatment for patients with the diagnosis of high risk (i.e. malignant) GIST but without metastases is currently undergoing debate in the oncology community. The American College of Surgeons Oncology Group (ACOSOG) has received approval from the NCI's Cancer Therapy Evaluation Program (CTEP) for a clinical trial testing the benefit of adjuvant STI-571 therapy in patients after complete resection of high risk (>10 cm or ruptured) primary GIST in the absence of metastases.

The side-effects of STI-571 treatment have been mostly mild dyspepsia and diarrhea, conditions that pale in comparison with those of tumor metastases. Oncologists presented with the availability of a "non-toxic" anti-GIST agent will surely be tempted to use the drug in patients with a high risk of metastasis who have not yet developed widespread disease. Since mechanisms by which GIST may escape responsiveness to STI-571 have yet to be completely elucidated, it is prudent to refer such patients for treatment in controlled clinical trials that can more clearly delineate the advantages and disadvantages of adjuvant treatment.

Long-term follow-up of STI-571-treated GIST patients does not yet exist, and no information regarding the likelihood of an initially responsive tumor later developing STI-571 resistance is available. The pharmacologic rationale for the use of STI-571 is clear since this compound potently inhibits KIT activity in vitro. However, KIT signaling pathways are known to regulate many aspects of cellular behavior, including proliferation, apoptosis, adhesion and differentiation. At present, it is uncertain which pathways determine clinical responses to STI-571. Nonetheless, STI-571 can reduce GIST tumor size, suggesting that the response of GIST to STI-571 is not merely cytostatic. Within 8 hours of STI-571 therapy, changes in tumors can be seen on PET scan, suggesting rapid metabolic changes in tumor cells. Histologic examination of STI-571-treated cases demonstrated that some of the tumors undergo myxomatous change, leaving small pyknotic nuclei in an eosinophilic myxoid background.

STI-571 will likely be approved by the FDA within the next few months for the treatment of chronic myelogenous leukemia. Early indicators of a role for STI-571 in the treatment of GIST may lead oncologists and patients to ask for CD117 immunostaining in other neoplasms. At this time, there are no data to support a role for STI-571 therapy in the treatment of non-GIST solid tumors expressing strong CD117 positivity (e.g. adenoid cystic carcinoma, seminoma, small cell lung carcinoma). Most participants emphasized that not all tumors that express KIT are likely to respond to STI-571. Tumor response to STI-571 will probably depend on the mechanism of KIT activation. It was noted that the detection of KIT expression (by immunohistochemical staining with the CD117) does not indicate KIT activation.

Concluding Remarks

Pathologists are called upon to provide oncologists with information that is critical to the correct treatment of GIST patients. Currently, that information is limited to an accurate diagnosis and some estimate of prognosis, based on clinical, anatomic and morphologic (size and mitotic activity) features. It would seem prudent for pathologists to freeze fresh samples of any GIST tumors they might accession. Uses for frozen GIST tissue may include ancillary research in support of Clinical Trial protocols.

In the next few years, we will know much more about which patients with GIST benefit from treatment and which patients do not. There will be methods to correlate molecular features with predictors of tumor response. GIST is a prototype for solid tumors treated with a "non-toxic" agent directed against a specific target molecule. Pathologists can expected a growing role in characterizing tumors, such as GIST, whose therapy is directed at specific molecular targets selected from tumor-classified molecular pathways.





Prognosis, Adjuvant Therapy (Stage I-II), Chemo, Duration


5 Year Survival (%) By Stage


IA                    61

IB                    38


IIA                   34

IIB                   24


IIIA                  13

IIIB                  5


IV                    1


In patients with metastatic disease and a performance status of 0-1, the response rate is 22%, median survival 7-8 months, and 1-Year survival 35%.


In meta-analyses comparing chemotherapy with best supportive care, the benefit of chemotherapy only extended to about 6 months in study, with no benefit shown over palliative care beyond 6 months. (My conclusion: chemotherapy only helps in the small number of patients who have responsive disease. Some have indolent disease in which case chemotherapy is not helpful – and probably also unnecessary.) In a second meta-analysis the survival benefit was 6 weeks. Finally, in a third meta-analysis, survival was improved from 6 to 8 months. (UpToDate)





Adjuvant chemo has some biological benefit in resectable NSCLC, but the results are not sufficient to consider adjuvant chemo to be the standard of care. Despite numerous adjuvant trials over the past several decades, no subset of patients with an undisputed benefit from adjuvant chemotherapy has been identified. Accordingly, adjuvant chemotherapy is not considered to be the standard of care for any subgroup of patients with resectable, early stage NSCLC at present.


However, the response rates with the currently active drugs exceed those seen in colon cancer and equal those in breast cancer, so there is a strong basis for optimism that trials will eventually show some benefit.


Radiation Therapy

Post-op RT does not improve survival in Stage II NSCLC, but it probably also does not have the adverse survival benefit as RT does when used as adjuvant therapy in Stage I disease.


Adjuvant RT in Stage II disease does change where the disease recurs, leading to a shift in distant recurrences.


One would think, then, that combined therapy would help. However, an ECOG trial did not show any benefit to adding 4 cycles of CDDP/Etoposide to RT alone in resected Stage II disease.


My Conclusion:


Stage I - no adjuvant therapy is beneficial and may be harmful.


Stage II - no proven benefit of adjuvant RT, chemo, or combined therapy. Still, might help, especially in higher risk situations such as adenocarcinoma or T3 disease.




Treatment Duration (JCO 20:1335  3/02)


Continuing Taxol/Carboplatin for advanced NSCLC beyond 3 months (4 cycles) adds only additional toxicity.


Over 200 patients were randomized to receive either 4 cycles of Taxol 200 + Carbo AUC=6 versus the same regimen continued until disease progression. Disease status was assessed every 6 weeks. Patients with disease progression were treated with low-dose weekly Taxol.


On the long arm, 40% received >4 cycles with 20% receiving >8 cycles. In the long arm, 30% stopped by choice (1/2 because of progression or death, and the remainder because of toxicity). The primary difference between groups was cumulative neurotoxicity – which occurred in 20% at 4 cycles, and 40% at 8 cycles. Quality of life over time was the same. Objective response rates were the same at 22%. Survival was the same with a MS of 8 months, and 1YS of 30%, 2YS of 13%.





RECOMMENDATIONS — Local excision and postoperative irradiation and chemotherapy appears to offer not only satisfactory local control and survival but, importantly, sphincter preservation for selected patients with distal rectal cancer. For patients with favorable histology T1 rectal cancer, local excision alone suffices. Postoperative irradiation and chemotherapy should follow local excision procedures for patients with unfavorable histology T1 and all T2 tumors. The data for T3 tumors with this approach are limited. However, results from single institution studies suggest unacceptably high local failure rates. As a result, radical resection is advised.

For patients with distal mobile rectal cancers that are not amenable to local excision, we recommend preoperative irradiation with concurrent chemotherapy prior to planned resection to permit sphincter-preserving LAR to be performed rather than APR. During the five and a half to six week course of irradiation, our patients receive continuous infusion 5-fluorouracil (225 mg/m2/24 hours) five days per week. Chemotherapy alternatives could include bolus 5-FU with leucovorin during the first and last weeks of irradiation.





Prognosis, Chemotherapy


Limited SCLC (40% of cases): (Chemotherapy)


  • No treatment --> MS 6-12 weeks.
  • With treatment --> 18-24 months, with 2YS 20-40% (see comment below).


Comment: 20% of all lung cancers are SCLC. Limited Stage is confined to the hemithorax. Cisplatin-etoposide is the treatment of choice. When combined with RT, 2 year survival is 40%. Best course is to give concurrent CDDP/Etoposide for 4-6 cycles. (Japanese study comparing sequential to concurrent RT in 231 patients showed a trend towards better survival with concurrent therapy. They only gave 4 cycles, but some question whether that is enough. JCO 20:3054 July 2002)


Extensive SCLC: (Chemotherapy)


  • MS 7-9 months with CDDP/etoposide.
  • With CDDP/irinotecan MS = 9-12 months. 2YS = 0.



Summary from MKSAP 3


T1:       limited to testis and tunica albuginea

T2:       invades lymph, vessels, or tunica vaginalis

T3:       invades spermatic cord

T4:       invades scrotum


Stage Groupings


I:          any T  LN-

II:         LN positive

            A         < 2 cm

            B          2-5 cm

            C         > 5 cm

III:        non-regional LN or distant metastases

            M1:      distant lymph nodes or lungs

            M2:      visceral metastases besides lungs


Adjuvant Guidelines


LN negative


            Negative scans

            Negative markers  ==> surveillance


LN positive

            No more than 5 LNs

            All < 2 cm                    ==> RPLND or surveillance


            > 5 LNs

            Any node > 2 cm

            Extra-nodal extension   ==> > 50% risk of occult disease --> BEP x 2


 Management by Risk Classification


Based upon probability of cure and transcend stage groupings


Good Risk

            Testicle or RP primary

            HCG < 500

            AFP < 1000

            No metastases outside lungs                  ==> EP x 4 or BEP x 3

            Also includes: seminoma with lung metastases


Intermediate Risk

            HCG 500-5000

            AFP 1000-10,000       ==> BEP x 4


Poor Risk

            HCG > 5000

            AFP > 10,000

            Non-lung metastases     ==> BEP x 4