OHO-24(443-468) 11/18/02 8:35 AM Page 460 HEAD AND NECK CANCER 460 visual \201xation, or by a white re \202ex that is indicative of a large intra- ocular t umor. Treatment (cid:2) Small tumors not adjacent to the macula or optic disc \200\224photo- coagulation (cid:2) Small/moderate tumors \200\224radioactive plaques (iodine, ruthenium plaques \200\22340 Gy) (cid:2) Large or multiple tumors \200\224external radiotherapy (cid:2) May need to radiate whole eye (40 Gy, 20 fractions over 4 weeks), try to maintain vision (cid:2) Occasionally enucleation is required (cid:2) Tumor is also chemosensitive \200\224p latinum \200\224etoposide \200\224vincristine \200\224doxorubicin \200\224cyclophospham ide (cid:2) Chemotherapy is useful if tumor has a bad prognosis or in neo- adjuvant setting (cid:2) Prognosis \200\22490% survival; 80% of patients can have eye preserved Optic nerve tumors Optic nerve tumors are rare and usually their treatment is surgery. When excision is not possible high-dose radiotherapy can be given, usually using paired wedge \201elds and giving doses of the order of 55 Gy conventionally fractionated. Rhabdomyosarcoma This is a rare tumor but its most frequent location is the orbit. Metastatic disease Metastatic disease involving the eye is usually associated with choroida l metastases. The commonest tumors implicated are lung and breast. Presentation is usually with visual loss and sometimes pain. This is an oncological emergency. Treatment with radio therapy should usually be with a lateral \201eld to the orbit giving 20 Gy in \201ve fr actions over a week. The \201eld may be angled \201ve degrees posteriorly to avoid the contralateral lens. However, the prognosis is usually poor and cataract is not an issue. Widespread bone metastases may affect the eye. This can lead to ocular pain, diplopia, and exophthalmos. When this occurs it is usually due to a breast primary, but does also occur w ith lung and prostate cancers. Systemic treatment is often appropriate, although local radi otherapy may be helpful. OHO-24(443-468) 11/18/02 8:35 AM Page 461 EYE AND ORBIT 461 OHO-24(443-468) 11/18/02 8:35 AM Page 462 HEAD AND NECK CANCER 462 Salivary gland tumors Salivary gland tumors present initially as a painless lump within the substance of a saliva ry gland, as opposed to an enlargement of the whole gland. This is usually obvious with par otid gland tumors, but the outline of the submandibular salivary gland is more dif \201cul t to de \201ne and the differentiation between an enlarged gland and a lump in the gland i s often impossible. Pleomorphic adenoma (mixed parotid tumor) This benign epithelial tumor is the most common t umor of the parotid gland. It may present at any age, normally as a painless, slowly growin g, \201rm lump with a smooth surface with no deep tissue \201xation. Rarely, the tumor may be soft and feel cystic. Distant metas- tases are very rare but local recurrence follow ing enucleation is com- mon. This is because the slowly expanding tumor compresses surround ing salivary tissue, forming a pseudo-capsule through which the tumor may penetrate. Occasi onally this benign tumor can undergo malignant transformation. Other benign tumors Much less common benign tumors arising in the salivary gland include: ( cid:2) Monomorphic adenoma (cid:2) Adenolymphoma (cid:2) Sebaceous lymphadenoma (cid:2) Onc ocytoma (cid:2) Myoepithelioma (cid:2) Vascular tumors The majority are clinical indistingu ishable from pleomorphic adeno- ma, and their true nature is revealed only after pathologic al examina- tion of a removed tumor. Acinic cell and mucoepidermoid tumors Whereas most of these tumors are microscopically low- grade, some are high-grade and more aggressive with local invasion and a tendency to metast asize to lymph nodes and through the bloodstream. Most present as a painless mass and a pot entially malignant tumor is revealed only on microscopic examination after surgical removal . With wide removal, as recommended for the pleomorphic adenoma, the majority of well-diffe rentiated tumors of this type will be cured. OHO-24(443-468) 11/18/02 8:35 AM Page 463 SALIVARY GLAND tumors 463 Carcinomas These may be immediately apparent clinically because of their more aggressive be havior. Adenoid cystic carcinoma sometimes presents as a very slowly growing, painless mass of many years \200\231 duration. Epidermoid carcinoma occurs usually in adults but in the rare case in children the disease can be highly malignant. Adenocarcinoma and undifferentiated carcinoma are usually aggressive. There is a particular tendency for salivary gland carcino- mas, especially of the mucoepidermoid type, to in \201ltrate and spread along the perineural spaces. Eventually, all the characteristics of m alig- nancy, including adherence to and in \201ltration of surrounding struc- tures such a s skin, muscle, and bone, develop. With parotid gland cancer, facial nerve malfunction is c ommon. Submandibular gland cancers are more dif \201cult to recognize pre-operatively. Lymphoid tissue occurs within the parotid and submandibular glands where it may be involved with secondary carcinomatous spread, for example from the lung and breast. This also expla ins the occurrence of lymphoma, apparently within the salivary glands. Most commonly, howev er, there are other adjacent lymph nodes involved and biopsy con \201rms the diagnosis. Management of clinically benign lumps At least 50% of submandibular lumps prove to be malig nant and the only logical treatment is therefore submandibular excision if suspi- cious. In the parotid, about 50% prove to be benign pleomorphic ade- nomas, but potentially malignan t tumors may present with identical clinical features. Investigations must provide reliable information on the relationship of a lump to the facia l nerve and its branches, and of the histological diag- nosis. Sialography is often perform ed but provides no such useful infor- mation. Ultrasound examination of salivary lumps is a lso misleading because both benign adenomas and carcinomas may have cystic areas. CT, in co mbination with tissue-density assessment studies, may be infor- mative, but cannot provide an accurate diagnosis. However, CT or MRI scanning do help determine the extent of deep inv asion. Pre-operative histological diagnosis could re \201ne management, but biopsy by incision or with a Tru-cut needle carries risks of tumor seeding. Fine-needle aspiration (FNA) cytolog y is probably risk-free but is not always helpful. Some 90% of FNA specimens are adequate a nd of these, the precise histological nature of a tumor cannot be determined in 10%. Thus F NA will provide a reliable diagnosis in about 80% of cases. Parotidectomy The aim of this operation is to remove the parotid lump with as wide a margin of normal tissue as possible while preserving the facial nerve. OHO-24(443-468) 11/18/02 8:35 AM Page 464 HEAD AND NECK CANCER 464 Because tumor in \201ltration of the facial nerve may require a total parotidectomy, with sacri \201ce of the facial nerve trunk, patients must be warned of this possible outcome b eforehand. When a clinically unremarkable lump is removed by formal parotidectomy with a wide margin o f normal tissue and is shown to be malignant, no further treatment is necessary with muco- epidermoid or acinic cell tumors. If histology reveals adenoid cystic or carcinoma, or if t he margin of normal tissue is inadequate, then post-operative radiotherapy is advisable bec ause of the known risks of perineural invasion and spread. Management of clinically malignant lumps The characteristic features of \201xation to adj acent structures, facial nerve malfunction, and enlarged lymph glands are usually indicatio ns of malignancy. In this situation the diagnosis may be safely established by incisional b iopsy. If malignancy is con \201rmed, the subsequent wide surgery will remove the biopsy w ound and there will be no risk of tumor seeding. Following microscopic con \201rmation, a CT or MRI scan will help to determine the local e xtent of the tumor. Treatment must be planned in conjunction with radiotherapy, faciomaxill ary, and plastic surgery colleagues. Adjuvant radiotherapy is most commonly delivered post- operatively, but also as a split course, giving two-thirds of the treat- ment before and o ne-third after the operation. Pre-operative radiotherapy has two advantages: a large tumor mass may shrink considerably, simplifying removal; and sometime an in- operable tumor will be rendered operable. However, surgery after radiotherapy is technically demanding. Radiotherapy Pleomorphic adenomas are essentially benign tumors. However, the rate of local recurrence after local enucleation has led to the use of post-operative radiotherapy by so me; there is no proof that this is bene \201cial. A lapse of 10 years or more is seen in a bout half of all those patients who relapse. Better treatment is the removal of the lump wi th an adequate wide margin of normal tissue. When a mucoepidermoid or acinic cell tumor is removed, there is no place for radiotherapy u nless there is concern about the margin of normal tissue. In malignant salivary gland tumors, post-operative radiotherapy reduces the incidence of lo cal recurrence. With clinically malignant tumors arising in the parotid gland, post-operati ve radiotherapy is indicated when: (cid:2) The tumor is high-grade (cid:2) The surgical mar gins are close (cid:2) Resection has been performed for recurrent disease OHO-24(443-468) 11/18/02 8:35 AM Page 465 SALIVARY GLAND tumors 465 (cid:2) There is invasion of extra-parotid tissue (cid:2) There is regional node involvemen t (cid:2) There is gross residual post-operative disease Orthodox radiotherapy techniques u se 6 \200\22310 MV photons, often with a wedged pair of \201elds, to give a dose of 55 \200\22365 Gy over 6 \200\2237 weeks. The tumor volume will include the courses of adjacent cranial nerves up to the skull base, to control any perineural spread (which is parti- cul arly common with adenoid cystic carcinoma). Dryness of the mouth is usual but recovers if t he opposite salivary glands are avoided. Trismus is common following treatment. Pre-operative radiotherapy may be advantageous in the manage- ment of large tumors, particu larly those considered to be inoperable. The situation should be reviewed after 45 \200\223 50 Gy, when tumor shrinkage may have already made surgery possible. Split-course post- oper ative radiotherapy is given as soon as possible after healing \200\224a further 20 \200\223 25 Gy in 2 \200\2233 weeks. Electron therapy has potential advantages in the treatment of parotid tumors. More recently other forms of particulate irradiation have been used, in particular neutrons. In a multi- center randomized study of patients with locally advanced parotid gland cancer, with neutro ns a local control rate of 67% was obtained, whereas the rate for photons was 17%. Chemotherapy Chemotherapy has no part in the management of low-grade salivary tumors. More aggressive tumors including mucoepidermoid, adenoid cystic, and undifferentiated carcinomas appear initially to respond well but these responses are short-lived. The most commonly us ed drugs are: (cid:2) Cisplatin (cid:2) 5- \202uorouracil Table 24.4 Results of treatment of salivary gland tumors Histology 5-yr survival (%) Acinic cell 92 Mucoepidermoid (low-grade) 76 Adenocarcinoma 66 Adenoid cystic 50 Squamous cell 50 Mucoepidermoid (high-grade) 46 Undifferentiated 33 OHO-24(443-468) 11/18/02 8:35 AM Page 466 HEAD AND NECK CANCER 466 (cid:2) Doxorubicin (cid:2) Cyclophosphamide Adjuvant or neo-adjuvant therapy has not been fully evaluated. OHO-24(443-468) 11/18/02 8:35 AM Page 467 SALIVARY GLAND tumors 467 Further reading Ho, J.H. (1978) An epidemiologic and clinical study of nasopharynx carcinoma. Int J Radiat Oncol Biol Phys 4, 182 \200\22398. International Nasopharynx Cancer Study Group. (1996) Preliminary results of a randomized tr ial comparing neoadjuvant chemotherapy (cisplatin, epirubicin and bleomycin) plus radiother apy vs. radiotherapy alone in Stage IV (> or = N2, M0) undifferentiated nasopharynx carcino ma. A posi- tive effect on progression-free survival. Int J Radiat Oncol Biol Phys 35, 463 \200\2239. Teo, P., Tsao, S.Y., Shiu, W., et al. (1989) A clinical study of 407 cases of nasopharyngeal carcinoma in Hong Kong. Int J Radiat Oncol Biol Phys 17, 515 \200\22330. OHO-24(443-468) 11/18/02 8:35 AM Page 468 This page intentionally left blank OHO-25(469-480) 11/18/02 8:36 AM Page 469 Chapter 25 Tumors of the central nervous system Primary brain tumors 470 Brain metastases 476 Further reading 480 OHO-25(469-480) 11/18/02 8:36 AM Page 470 tumors OF THE CENTRAL NERVOUS SYSTEM 470 Primary brain tumors Etiology The majority of primary brain tumors are sporadic. Gliomas and meningiomas may be induced by radiation, and there is an association between primary CNS lymphoma and immunosu ppression, includ- ing AIDS. There are other candidate aetiological agents, but none has be en proven and all remain controversial: Industrial and agricultural chemicals (cid:2) (cid:2) Electro-magnetic \201elds (cid:2) Viruses (cid:2) Trauma Epidemiology The incidence worldwide is very uniform with a few exceptions such as a higher incidence of pineal tumors in Japan and CNS lymphoma in the AIDS population of the West co ast of the US. Recent reports suggest the incidence of glioma and (non-AIDS) lymphoma is in creasing in developed countries. Primary brain tumors occur at any age but display two peak s. One occurs in children, where they are the most common solid tumor, and the other in (la te) middle age. Pathology Primary brain tumor pathology is extremely varied re \202ecting diverse histogen esis. The most widely used classi \201cation system is the WHO 1993 scheme. Gliomas are th e most common tumors. Their behav- iour and prognosis are strongly linked to histological s ubtype. Benign tumors (e.g. meningiomas) are not uncommon and some malignant non-glial tumo rs carry a good prognosis (medulloblastoma, pineal Table 25.1 Syndromes associated with primary brain tumors Predisposing syndrome Tumor Neuro \201bromatosis type 1 Glioma Neuro \201bromatosis type 2 Glioma, meningioma, Schwannoma Li \200\223Fraumeni syndrome Glioma von Hippel \200\223Lindau syndrome Cerebellar haemangioblastoma Gardener \200\231s syndrome Glioma Familial glioma Glioma Tuberose sclerosis Subependymal giant cell astrocytoma OHO-25(469-480) 11/18/02 8:36 AM Page 471 PRIMARY BRAIN tumors 471 germinoma). Precise histological identi \201cation is therefore essential to appropriate m anagement. Primary brain tumors rarely metastasize outside the CNS but are highly in \201ltrative, wi th a tendency to spread along white matter tracts to more distant regions of the brain, a f eature which contributes to their resistance to treatment. Spread through cerebrospinal \202uid (CSF) to remote areas of the neuraxis is a feature of germ cell tumors, medulloblas toma, and other primitive neuroectodermal tumors. This has important implications for their treatment. The dominant prognostic features for the majority of brain tumors are usually a combination of histological type and clinical features such as age and performance status. Therefore, staging sys- tems that are commonly used for other tumor types are rarely used for brain tu mors. Molecular changes associated with glioblastoma are: (cid:2) Type 1 \200\224loss of tumor suppression (p53 mutation in 65%) \200\224oncogene upregulation \200\224chromosome changes \200\224younger patients \200 \224may arise in pre-existing low-grade tumor \200\224better prognosis (cid:2) Type 2 \200\224mainly chromosome changes \200\224oncogene overexpression \200\224older patients \200\224poor prognosis Presentation Brain tumors present either with neurological dysfunction or with signs of rai sed intracranial pressure. Presentation with epilepsy or with slow onset of symptoms carrie s a relatively favorable prognosis. Table 25.2 Abbreviated WHO (1993) classi \201cation of intracranial gliomas Subgroup Grade or type Prognosis Astrocytoma Pilocytic Low-grade Excellent Good Anaplastic Poor Glioblastoma Very poor Oligodendroglioma Low-grade Anaplastic Good Poor Ependymoma Low-grade Good Anaplastic Poor OHO-25(469-480) 11/18/02 8:36 AM Page 472 tumors OF THE CENTRAL NERVOUS SYSTEM 472 Table 25.3 Presenting symptom in patients with intracranial glioma Symptom Frequency as principle presenting symptom (%) presentation (%) Overall frequency at Epilepsy 30 53 Headache 25 71 Cognitive distance 12 52 Motor disturbance 8 43 Speech disturbance 5 27 Clouding of consciousness 4 25 Visual disturbance 4 25 Sensory change 2 14 Miscellaneous 10 Investigation is dominated by brain imaging. Maximal tumor reso- lution in structural imagi ng involves full-sequence magnetic reso- nance scanning with gadolinium enhancement. Contra st-enhanced CT is more readily available and frequently adequate. Functional imaging with S PEC, PET, and MR are gaining importance both in diagnosis and assessment of response to tre atment. The imaging agents 201thallium and 123I-tyrosine in SPECT scanning and 18FDG glucos e in PET give important insights into the functional activity of the tumor and can frequent ly aid differentiation between high- or low-grade neoplasms and treatment-induced necrosis. Tumors that spread via CSF pathways require whole neuraxis MRI. Treatment options Surgery alone is the treatment of choice for most benign lesions though a dditional radiotherapy is appropriate after incomplete resection in some (e.g. pituitary ad enoma or meningioma). Low- grade astrocytomas presenting with epilepsy alone and without ma ss effect on scan can often be managed medically; the development of other neurological sym ptoms or imaging evidence of growth or trans- formation are indications for surgery. The ro le of radiotherapy for these tumors remains controversial though treatment is frequently gi ven following partial resection. Suspected high-grade gliomas require surgery for histological con \201rmation. This may be with stereotactic biopsy or, where possible, by craniotomy and debulking of tumor. Whilst resection is often valuable for relief of pressure symptoms its value in tumor control is m ore contentious. \200\230Blind \200\231 burr-hole biopsy carries a high risk of mor- bidit y. Without further treatment the median survival for patients with anaplastic astrocytoma o r glioblastoma is approximately one year and three months respectively. Radiotherapy improv es median OHO-25(469-480) 11/18/02 8:36 AM Page 473 PRIMARY BRAIN tumors 473 survival to three years for anaplastic tumors and one year for glioblastoma. Post-operative radiotherapy is normally given, except in elderly patients or those with low performance status when the prognosis is too poor irrespective of treatment. The area irra diated is usually limited to tumor-bearing brain and doses of 30 \200\22360 Gy are given ov er 2 \200\2236 weeks depending on prognostic factors. Chemotherapy adds little, if any, advantage in the adjuvant setting and is usually reserved for relapse. The nitrosoureas (BCNU, CCNU) are the most common agents used. Procarbazine a nd the platinum compounds and Temozolomide may also have some value. Medulloblastoma is managed by resection followed by cranio-spinal radiotherapy; the role of chemotherapy is currently being explored. Overall, 50% of patients are disease-free at \201ve years. Similar approaches are required for ependymomas and supratentorial primi- tiv e neuro-ectodermal tumors. Patients with brain tumors suffer a wide variety of related physical, cognitive, and emotional problems. Prominent are: (cid:2) Movement disorders (cid:2) Tumor- associated epilepsy (cid:2) Pain (headache) (cid:2) Speech disorders Intellectual decline (cid:2) These are best managed jointly by the GP and a specialized unit with access to a dedicated tumor surgeon, a neuro-oncologist, a neurolo- gist, a nurse specialist, and rehabilitation team, whose intentions are to maximize the quality of life as well as delivering optimal th erapy to improve survival. Early involvement of the palliative care team can be valuable. Recent advances and future treatments Surgery and radiotherapy remain the mainstays of trea tment for these tumors and most advances involve applying these modalities more effectively to more precisely delineated tumors. Prominent in surgery is the use of neuro-navigation, where recently acquired images of the patient \200\231s brain and tumor are projected intra -operatively onto the operating \201eld. Laser or ultrasound resection allows the identi \201ed tumor to be completely resected. The use of intra-operative, photo- activated, cyto toxic compounds to improve the tumor clearance fur- ther is being investigated. Following s urgical clearance the application into the resection cavity of sustained-release chemothera py (BCNU- Gliadel) has shown some survival bene \201t. The availability of stereotactic localization and beam conformation allow an identi \201ed intracranial target to be more accurately delineated and irradiated with consequent sparin g of normal brain tissue. This OHO-25(469-480) 11/18/02 8:36 AM Page 474 tumors OF THE CENTRAL NERVOUS SYSTEM 474 sparing in turn allows for an escalation of dose to the tumor with the possibility of great er tumor control. These techniques are currently being evaluated. Third generation radiatio n sensitizers such as the hypoxic cell cytotoxin, tirapazamine, have shown some early promi se in glioblastoma. The rationale for using angiogenesis inhibitors in the brain is strong. The drug thalidomide has shown early activity and new generation drugs are in development. Conventional chemotherapy has been disappointing in brain tumors. However, modi \201cation of the local environment with O-6- alkylguanine DNA alkyltransferase inhibitors or blood \200\223brain barrier modi \201ers may improve the poor results seen with the nitrosoureas or platinum compounds. Some new compounds (e.g. temozolomide) have shown activity. The brain has been an intensive research target in the use of gene therapy, much of it invo lving the HSVtk/Acyclovir suicide gene sys- tem. Many other therapeutic strategies are poss ible but the lack of effective vectors currently limits the applicability of this approach. The prospect of using adenovirus or herpes simplex virus might over- come the limitations inherent in the current retroviral approaches and represents the greatest hope currently fo r an improvement in the management of malignant gliomas. OHO-25(469-480) 11/18/02 8:36 AM Page 475 PRIMARY BRAIN tumors 475 OHO-25(469-480) 11/18/02 8:36 AM Page 476 tumors OF THE CENTRAL NERVOUS SYSTEM 476 Brain metastases Incidence Metastasis to the brain from an extracranial primary is common. Symptomatic metas tases have an incidence of around 6 per 100 000, but autopsy studies have revealed an overa ll incidence in 24% of patients with known cancer. There is a slight male preponderance and the incidence increases with age. Whilst brain metastases may arise from any primary site, the most common are from the respi ratory tract (50%), breast (15%), and melanoma (10%). In (at least) 10% the primary site is unknown. Some cancers which commonly metastasize to other organs rarely involve the brain e.g. prostate, bladder, cervix, and ovary. The reason for this is not known. Rare tumors th at have a predilection for the brain include choriocarcinoma and clear cell renal cancer. C arcino- matous meningitis is less common but may occur in: (cid:2) Leukemia (cid:2) Lymphom a (cid:2) Cancers of the lung and breast Pathology (cid:2) Site \200\22480% in cerebral hemispheres \200\22415% in cerebellum \200\2245% in other sites e.g. basal ganglia (cid:2) Macroscopically \200\224discrete \200\224circumscribed \200\224areas of bleeding, necrosis, cystic \200\22450% are multip le (cid:2) Histology \200\224similar to primary \200\224vascular proliferation, tumor necrosis common \200\224usually well demarcated fro m adjacent tissue Presentation The presentation of brain metastases is similar to that of primary brain tumor s with the additional complication that the patient may be unwell with systemic disease. Th e most sensitive investigation is high-resolution contrast-enhanced MR scan. Metastases most frequently appear as multiple, discrete, well- demarcated lesions that are hypo-intense on T1 and hyper-intense on T2 and with marked gadolinium enhancement. There is often copious surrounding vasogenic oedema. Up to 20% of lesions revealed in this OHO-25(469-480) 11/18/02 8:36 AM Page 477 BRAIN METASTASES 477 way are not seen on CT scan where visible lesions again appear as discrete, enhancing masse s. Various reports have suggested that brain metastases are solitary in 20 \200\22350% of cases. Management Initial management requires control of the presenting symptoms, with anti-convul sants, analgesics, and other medication as appro- priate. Dexamethasone is indicated in the majority of patients and frequently produces a reversal of symptoms. A starting dose of 8 \200\22316 mg daily is common and improvement can often be maintained with doses of 2 \200 \2234 mg. The failure of a response to dexamethasone may be an argument against more aggres sive therapy. Since the outcome for patients with multiple adverse prognostic fac- tors is so poor, irres pective of treatment, it is reasonable to manage those individuals with symptomatic therapy alone. For patients whose condition is improved following dexamethasone, treatment with ra diotherapy can be offered. This approach may produce temporary tumor control, improve survi val, and allow a reduction in the steroid dose. Typically, the whole brain is irradiated. A dose of 20 Gy in \201ve fractions has been shown to be as effective as any of the more p ro- tracted fractionation schemes. Solitary metastases should be considered differently in an otherwise \201t patient, espec ially if originating from a primary with \200\230good progno- sis \200\231 histology. Here , tumor resection, where possible, is the treatment of choice. The growth pattern of brain metastases often allows complete macroscopic removal to be achieved. Post-operatively, whol e- brain radiotherapy is given (20 Gy in 5 fractions or 30 Gy in 10 frac- tions) with or wi thout a local boost. An alternative approach is to offer stereotactic radiosurgery (20 Gy i n a single fraction), again with whole- brain radiotherapy to follow. Although it is conven tionally given, the value of additional whole-brain treatment is not determined. Chemotherapy can be useful in patients with brain metastases from chemo-sensitive primaries . It should be used as \201rst-line therapy (or following resection) in germ cell tumors or as an alternative to radi- ation in small cell lung cancer and lymphoma. It can also be used as second-line treatment in less chemo-sensitive tumors such as breast cancer. The dis ruption of the blood \200\223brain barrier by the tumor means that agents normally used to treat systemic metastases in these diseases may be tried, with response in about 30%. Outcome Overall, the prognosis is poor for patients with brain metastases from the common c ancers. For patients with poor prognostic features, the median survival may be only 6 \200 \2238 weeks, irrespective of treatment. At the opposite end, patients with \200\230good pr ognosis \200\231, solitary metastases OHO-25(469-480) 11/18/02 8:36 AM Page 478 tumors OF THE CENTRAL NERVOUS SYSTEM 478 Table 25.4 Prognostic factors for patients with brain metastases Factor Description In \202uence Age Increasing age (>50) Adverse Performance status Poor general condition Adverse Fixed neurological de \201cit Adverse Histology Adenocarcinoma Favorable Squamous (esp. lung) Adverse Germ cell Very favorable Number Solitary Favorable Multiple Adverse Size Small Favorable Large Unfavorable Operability Resectable Favorable that are adequately treated with surgery and radiotherapy enjoy a much better outlook, with many surviving two years or more. OHO-25(469-480) 11/18/02 8:36 AM Page 479 BRAIN METASTASES 479 Further reading Davies, E. and Hopkins, A. (ed.) (1997) Royal College of Physicians, Improving care for patients with malignant glioma London. Kleihues, P. and Cavenee, W.K. (ed.) (1997) Pathology and genetics: tumors of the nervous s ystem. International Agency for Research on Cancer, Lyon. OHO-25(469-480) 11/18/02 8:36 AM Page 480 This page intentionally left blank OHO-26(481-488) 11/18/02 8:37 AM Page 481 Chapter 26 Skin cancer Primary cutaneous malignant melanoma 482 Non-melanoma skin cancers 486 Further reading 488 OHO-26(481-488) 11/18/02 8:37 AM Page 482 SKIN CANCER 482 Primary cutaneous malignant melanoma De \201nition Primary cutaneous malignant melanoma arises from the melanocytes found in th e basal layer of skin. These cells produce melanin pigment and are responsible for producin g the tanning response after exposure to ultraviolet radiation. Etiology (cid:2) Excess exposure to UV radiation (cid:2) Genetic susceptibility \200\224CDKN2A found on chromosome 9 (tumor suppressor gene) (cid:2) 33% of patients with familial melanoma have mutations of CDKN2A Incidence The incidence of melanoma in the UK is around 10 new cases per 100 000 per year \200\224approximately 6000 patients annually. Clinical presentation Primary melanoma of the skin presents as a growing, irregular brown o r black lesion on the skin. Important features to alert clinical suspi- cion include an irr egular outline to the lesion; irregular pigmentation containing shades of brown, black, and red; and, occasionally, oozing or crusting. Most melanomas are around 5 mm in diameter whe n \201rst recognized but a small number are identi \201ed at an earlier stage. They may arise on previously normal skin or on a previously apparently benign melanocytic naevus. Pathology Pathological examination shows neoplastic melanocytic cells invading beneath the basement membrane into the underlying dermis. The depth to which these cells have invaded c an be measured accurately from the granular layer of the epidermis to the deepest invading cell. This is referred to as the tumor thickness or Breslow thickness and is the most impor tant prognostic feature. For patients with tumors thinner than 1.5 mm, the \201ve-year di sease-free survival rate is over 90%, but those with tumors thicker than 3.5 mm have less t han 50% chance of survival even after appropriate and adequate surgery. OHO-26(481-488) 11/18/02 8:37 AM Page 483 PRIMARY CUTANEOUS MALIGNANT MELANOMA 483 Staging The current UICC staging of melanoma divides the tumor into four stages. (cid:2) St age 1: tumors less than 1.5 mm thick (cid:2) Stage 2: primary tumor thicker than 1.5 mm (ci d:2) Stage 3: tumor spread to the local draining lymph nodes (cid:2) Stage 4: distant disea se Prognosis for patients with Stage 3 and 4 disease is poor, with only 25% disease-free tw o-year survival for Stage 3 and around 6% two- year survival for Stage 4. Differential diagnosis Growing pigmented lesions on the skin can be divided into benign and malignant. Benign lesions are more common, including benign melanocytic naevi in young adu lts and seborrhoeic keratoses in older adults. A small excision biopsy is frequently necess ary to differentiate between these benign lesions and malignant melanoma. Treatment The treatment for primary malignant melanoma is complete excision of the lesion. There is still controversy and ongoing trials to establish the exact margin of excision of normal skin necessary around the lesion. This is generally tailored to the tumor thickness with tumors thinner than 1 mm requiring only 1 cm of normal skin; tumors between 1 \200\223 2 mm thick are often excised with a margin of 2 cm of nor- mal skin; and the largest margin recommended, even for very thick tumors, is 3 cm of normal skin. It is important that exci sion is ade- quate in depth as well as at the lateral margins. Most patients with primary melanoma currently have the defect resulting from excision of th e lesion closed directly, but a small num- ber may require either a \202ap or a graft to achieve closure. Patients with Stage 3 disease should have dissection of the regional lymph nodes. At presen t there is one study suggesting that adjuvant alpha interferon, given subcutaneously for on e year after lymph node dissection, statistically improves survival for this group of patie nts. Con \201rmatory trials are in progress. For patients with Stage 4 disease there is no current accepted proven chemotherapy or immun otherapy. All patients should be accurately staged with CT or MRI as appropriate. Limited a dditional surgical procedures to debulk the tumor will often improve the patient \200\231s quality of life. Chemotherapy regimes include DTIC and/or vindesine and produce around 30% response rate, but responses are short-lived and do not sign \201ciantly increase survival time. A recent study suggest- ing that the addition of tamoxifen to combination chemothera py for OHO-26(481-488) 11/18/02 8:37 AM Page 484 SKIN CANCER 484 melanoma improved response rates has not been con \201rmed. Trials are concentrating on th e use of biotherapy that includes the use of inter- leukin 2, often combined with melanoma- directed vaccines. Melanoma is in general not responsive to radiotherapy, but good palliation can be achieved in the case of pain from skeletal metastases. Cerebral metastases are relatively common in long-term survivors from melanoma. If these are asymptomatic there is controversy as to whe ther or not they should be treated. In some centers neurosurgery to one or two isolated met astases is practiced. If cerebral metastases are symptomatic, systemic corticosteroid thera py, with or without additional radiotherapy, may bring symptomatic relief. Experimental surgical approaches (cid:2) Adjuvant limb perfusion \200\224melphalan alone \200\224melphalan + tumor necrosis factor \200\224good palliation for recurrent melanoma \200\224no survival advantage for primary melanoma (cid:2) Sentinel node biopsy \200\224radio-labeled colloid \200\224methylene Blue \200\224if this node is clear then block dissection is not required OHO-26(481-488) 11/18/02 8:37 AM Page 485 PRIMARY CUTANEOUS MALIGNANT MELANOMA 485 OHO-26(481-488) 11/18/02 8:37 AM Page 486 SKIN CANCER 486 Non-melanoma skin cancers Epidemiology These cancers are the commonest malignancies in Western popula- tions, occurri ng particularly in fair-skinned Caucasians exposed to ultraviolet radiation (e.g. farmers, \201shermen). The causes are: (cid:2) Ultraviolet radiation Ionizing radiation (cid:2) Ch ronic in \202ammation (cid:2) Human papillomavirus Immunosuppression (cid:2) (cid:2) (cid:2) Hereditary conditions (Xeroderma pigmentosum, basal cell naevus syndrome) As well as these primary lesions, metastases to skin are fairly common from carcinomas of t he breast, lung, and GI tract. Pathology Basal cell carcinomas (75% of non-melanoma skin cancers) are lesions which arise on sun-exposed areas \200\224face, neck, ears, scalp, and arms. They are normally con \201 ned to hair-bearing skin. They present as a slow- growing, pink papule with telangiectasia. Variant lesions include: (cid:2) Nodular (cid:2) Ulcerative (cid:2) Pigmented (cid:2) Supe r \201cial (cid:2) Cystic (cid:2) Morphoeic (cid:2) Multicentric Metastases are rare and t hey are usually curable by either surgical exci- sion or radiotherapy. The latter is prefer red around the eyelids, nose, lips, and ears. Other treatment strategies are cryosurgery an d topical 5- \202uorouracil. Squamous cell carcinoma (20%): this malignant lesion also ari ses on sun-exposed sites, but appears as a faster-growing, red papule which may erupt on a background of actinic keratosis. Ulceration, bleeding, and metastases to regional nodes may occur. Treatment is either surgery or radiotherapy; chemotherapy has been used for dissemi nat- ed disease (cisplatin, methotrexate, 5- \202uorouracil, bleomycin are active agents). OHO-26(481-488) 11/18/02 8:37 AM Page 487 NON-MELANOMA SKIN CANCERS 487 Merkel cell carcinoma is a rare but highly malignant neuroendocrine tumor of the skin. It p resents as a dermal nodule on the head or neck of an elderly patient, rarely ulcerates, but commonly spreads to adja- cent skin and regional nodes. Treatment is surgical but palliati ve radiotherapy is useful in controlling metastatic disease. Less than 50% survive three ye ars. Apocrine and eccrine gland cancers: a variety of these are described but all are rare and most are only locally invasive. Other uncommon malignancies are: (cid:2) Cutaneous angiosarcoma (cid:2) Kaposi \200\231s sarcoma (HIV-associated or endemic) (cid:2) Other soft tissue malignancies OHO-26(481-488) 11/18/02 8:37 AM Page 488 SKIN CANCER 488 Further reading Kirkwood, J.M., et al. (1996) Interferon alfa-2b adjuvant therapy of high risk resected cut aneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin. Oncol. 14, 7 \200\22317. OHO-27(489-514) 11/18/02 8:38 AM Page 489 Chapter 27 Hematological malignancies Acute leukemia 490 Chronic lymphoid leukaemias 494 Hodgkin \200\231s disease 498 Non-Hodgki n \200\231s lymphomas 502 Myeloma 508 Further reading 513 OHO-27(489-514) 11/18/02 8:38 AM Page 490 hematological MALIGNANCIES 490 Acute leukemia Epidemiology The incidence of acute leukemia is 4 \200\2237 cases per 100 000. The peak inc idence of acute lymphoblastic leukemia (ALL) is 3 \200\2234 years and of acute myeloid leuk emia (AML) is over 60 years. Etiology The cause of most cases is unknown. Some inherited diseases carry an increased ris k: (cid:2) Fanconi \200\231s anemia (cid:2) Bloom \200\231s syndrome (cid:2) Klinefelter \200\231s syndrome (cid:2) Ataxia telangiectasia There is a 3 \200\2235 times increased ris k in identical twins. Environmental factors such as ionizing radiation, chemical carcino- gens, or chemotherapeut ic drugs, and infectious agents (e.g. T-cell leukemia virus 1 in the Caribbean or Japan) or more subtle mecha- nisms such as exposure in the very young of naive immune systems to inf ections, have all been implicated as rare causes. Diagnosis and classi \201cation Peripheral blood pancytopenia is the commonest \201nding , but a minority have an elevated white blood cell count (WBC) which may be a clinical mani festation of anemia, bleeding, or infection. There may be associated adenopathy or hepatosp lenomegaly, which is more likely in lymphoid disease. A marrow examination using morphology, immunophenotyping, and cytogenetics will allow class i \201cation into myeloid or lymphoid leukemia, with morphological subtypes related to cel l maturity (desig- nated FAB 0 \200\2237 for myeloid and L1 \200\2233 for lymphoid disease) . CNS in \201ltration can be a feature of ALL and requires a diagnostic lumbar puncture. Acute lymphoblastic leukemia (ALL) ALL is the commonest cancer in children but is responsiv e to effective treatment, with a 70% cure rate. Adult disease responds less well, with only 30% long-term survivors. Chemotherapy Induction of remission is routinely achieved by combining vincri- stine, predn isolone, and L-asparaginase. Additional anthracycline is OHO-27(489-514) 11/18/02 8:38 AM Page 491 ACUTE leukemia 491