522 may be worth considering megatherapy after conventional induction treatment. Either melphal an, busulphan, or TBI, or a combination, may be used as a conditioning regime. Prognosis The major prognostic factors are metastases at presentation and site and volume o f the tumor. For those with small tumors (<100 cc), usually in the long bones, over 80% can be cured. Pelvic tumors and those with lung metastases have a 30% chance of survival. With con- ventional therapy, the majority of those with bone metastases die. Ewing \200\231s tu mor may relapse up to 10 or more years after diagnosis. Late effects Cardiac and nephrotoxic late effects, as a result of chemotherapy, may occur, but these are not disease-speci \201c. Second primary tumors, most often osteosarcomas, ma y occur in the irradiation \201eld, and the late effects of major endoprosthetic surgery can be substantial. OHO-28(515-530) 11/18/02 8:43 AM Page 523 EWING \200\231S SARCOMA 523 OHO-28(515-530) 11/18/02 8:43 AM Page 524 BONE AND SOFT TISSUE MALIGNANCIES 524 Other primary bone tumors Primary malignant spindle cell sarcoma of bone Most often malignant \201brous histiocytom a, but other pathologies include: (cid:2) Liposarcoma (cid:2) Angiosarcoma (cid:2) Leiomyos arcoma (cid:2) Haemangiopericytoma All are rare; they comprise less than 1% of all bone tum ors. May arise in any bone (usually the metaphysis of a long bone) and tend to occur in mid dle age. Can occur after a previous insult to the bone, e.g. ioniz- ing radiation, bone inf arct, or \201brous dysplasia. The treatment is surgical removal of all disease but, as with osteo- sarcoma, limb-sparing surgery and insertion of a customized pro- sthesis may be feasible. The role of chemotherap y is still being explored and comparison with historical controls does suggest some bene \201t. Osteoclastoma Account for 5% of primary bone tumors and are usually benign. Occur in young adults, often in an epiphysis around the knee. Are treated by curettage and bone packing or bone resection and insertion of an endoprosthesis. Local recurrence occurs in 30 \200\2235 0%, but radio- therapy carries a de \201nite risk of malignant transformation and is only appropriate where the alternative local therapy is amputation. Rarely, these tumors can met astasize to the lung. Where possible, these should be dealed with surgically. Anecdotal res ponses to chemotherapy have been reported. Chondrosarcoma Slow-growing tumors of middle to late age and the second most common bone tu mor (approximately 20%). Occur around the pelvis and shoulders. Grade is a good guide to be havior, although about 10% of low-grade tumors transform to a higher grade. Treatment is su rgical resection with radiotherapy for incomplete resection or palliation of advanced disea se. Mesenchymal chondrosarcoma is a high-grade tumor of adoles- cence frequently involving the mandible, ribs, or spine. Combined treatment with surgery, chemotherapy, and radiotherapy p rovide a 50% cure rate. OHO-28(515-530) 11/18/02 8:43 AM Page 525 OTHER PRIMARY BONE tumors 525 Chordoma Slow-growing tumor that arises from notochord remnant cells in the sacrum/coccyx ( 50%), skull base/clivus (35%), or upper cervical vertebrae, in middle age. Presents with pe rsistent pain and often only discovered on CT or MRI after \200\230normal \200\231 plain X -rays of the bone. Metastases are rare (lung or bone) and survival is determined by the suc cess or failure of local control. Surgery is the treatment of choice but may not be feasible because of the tumor site. Radio therapy (55 \200\22360 Gy) is used after incomplete resection or as palliation. Particle th erapy with protons has shown some promise. 30 \200\22350% survive \201ve years but late r ecurrences are possible. Solitary plasmacytoma Isolated lytic lesion rich in plasma cells. The diagnosis depends on the exclusion of myeloma (no other skeletal lesions, no hypercalcaemia, no suppression of o ther immunoglobulins, and bone marrow con- tains <5% plasma cells). Paraproteinaemia is com mon. Treatment is either surgical excision of the lesion or, more common- ly, radiotherapy (45 \200\22350 Gy). Prognosis is good, with a median survival of over 5 years, but about a half will transform into myeloma. Primary bone lymphoma One of the differential diagnoses of malignant, small, round, dark ce ll tumors of bone (Ewing \200\231s neuroblastoma). Full staging with CT, bone scan, and bon e marrow examination is required to exclude systemic lymphoma. Localized high-grade NHL is treated with initial chemo- therapy (e.g. CHOP) followed by either radiotherapy or surgical exci- sion and endoprosthesis (latter is preferred for long, weight-bearing bones, where t here is otherwise a high risk of fracture). Multifocal disease is usually low-grade NHL. Tr eatment is with chlorambucil chemotherapy and radiotherapy. OHO-28(515-530) 11/18/02 8:43 AM Page 526 BONE AND SOFT TISSUE MALIGNANCIES 526 Soft tissue sarcomas Diagnosis and management of sarcomas (cid:2) Any enlarging mass, deep to deep fascia should be regarded as a potential sarcoma. (cid:2) Tissue for histology should be obtained by cutting needle (e.g. Trucut), not incisi onal biopsy. The biggest surgical problems are caused by injudicious incisions. Incision bi opsy should never be performed \200\224this disseminates the tumor and is never curative. S urgery should be preceded by appropriate CT or MRI. (cid:2) (cid:2) Multidisciplinary care of sarcomas is best carried out in centers with appropriate expertise \200\224including surgery, pathology, radio- therapy, and chemotherapy. Rhabdomyosarcoma (RMS) The commonest soft tissue tumor in childhood and adolescence. More t han half the cases occur in children under 10 years and is rare in adults over 40. Male to female ratio is approximately 1.3:1. Arises from primitive mesenchymal cells with the capac ity for rhabdomyoblastic development. Commonest sites of origin are: (cid:2) Head and neck (cid:2) Genitourinary tract (cid:2) Retroperitoneum (cid:2) Extremities Disease may spread locally (e.g. from the orbit to the meninges and central nervous system) and disseminates t o lymph nodes, lungs, bones, marrow, and brain. An aggressive disease requiring multi- moda lity treatment. Outlook depends on the disease site and histolog- ical subtype. Pleomorphic RMS is a rather rare adult soft tissue tumor, which behaves in a similar fashio n to other adult soft tissue tumors in that while it may be curable if localized it is not as chemosensitive as the childhood variety and carries a poor prognosis once metastatic. Diagnosis Presents with swelling or other local symptoms such as displacement of the eye, v aginal bleeding, dysuria, etc. In establishing a histological diagnosis it is currently adv isable to obtain fresh tissue for chromoso- mal studies. OHO-28(515-530) 11/18/02 8:43 AM Page 527 SOFT TISSUE SARCOMAS 527 Embryonal RMS Accounts for about 60% of cases. Occurs mainly in children under 15, most com monly affecting: (cid:2) Head and neck, including orbit (cid:2) Genitourinary tract (cid:2) Retroperitoneum \200\230Embryonal \200\231 refers to the spectrum of cell type, from prim itive round cells to rhabdomyoblasts, which may be thought to mimic the stages in muscle em bryogenesis. Botryoid RMS is a subtype characterized by polypoid growth, like a \200\230bu nch of grapes \200\231, and is usually found in hol- low organs such as the vagina, bladder , and nasopharyngeal sinuses. Alveolar RMS Characterized by poorly differentiated round or oval cells forming irregular s paces and separated by \201brous septae, giving the appear- ance of \200\230alveoli \200 \231. Sometimes this appearance is absent but the uniform appearance of the cells is distin ct from that of the embryonal variety. Multinucleate giant cells may be observed. Alveolar RMS has a signi \201cantly worse prognosis than embryonal. If fresh tissue is available, the diagnosis may be con \201rmed by the presence of a t(2;1 3) (q37;q14) or variant t(1;13) (p36;q14) chromo- somal translocation. The result is fusion of PAX3 or PAX7 genes respectively with the FKHR gene, producing a chimeric protein. Trans location may be identi \201ed by \202uorescence in situ hybridization (FISH) or reverse transcriptase polymerase chain reaction (RT-PCR) methods that require little tumor tissue. Translocation may be detected in about half of cases and, where present, reliably distin- g uishes alveolar from embryonal RMS. Staging Staging should include MRI or CT of the primary site, CT scan of the thorax, isotop e bone scan, and bone marrow aspirate and trephine. The stage is usually assigned using the SIOP-UICC TNM (tumor, nodes, metastases) staging system which is useful in determining app ropriate therapy. Prognostic factors The prognosis in RMS depends on site, size, extent of spread (i.e. stage , histology, sex, in that the outlook is somewhat worse in girls), and response to chemothe rapy. Treatment Treatment usually begins with combination chemotherapy, followed by local treatme nt i.e. complete surgical resection where possible plus radiotherapy if excision incomplete , or radiotherapy alone if resection OHO-28(515-530) 11/18/02 8:43 AM Page 528 BONE AND SOFT TISSUE MALIGNANCIES 528 Table 28.1 Prognostic factors in rhabdomyosarcoma Good Poor Orbit, paratesticular, vagina extremities Parameningeal, retroperitoneal, Localized to tissue of origin Contiguous spread, nodal or metastatic disease Unresectable Complete resection feasible Embryonal histology Infant or child Alveolar histology Adult Complete response to chemotherapy Poor response to chemotherapy is not feasible. Patients with embryonal histology may be treated with vincristine plus act inomycin D; treatment is intensi \201ed with the addi- tion of ifosfamide, doxorubicin, an d other drugs for worse staging his- tology. Additional drugs such as etoposide and carbopl atin and high-dose alkylating agent therapy, with peripheral blood progenitor cell rescue, may improve the outlook for some patients with metas- tatic disease, but the prognosis rema ins grave for alveolar RMS. RMS is highly sensitive to radiotherapy. In combination with chemotherapy, doses of 40 \200 \22350 Gy will usually ensure local disease control. However, there are serious long-term s equelae associated with the combined modality treatment in children. These include: (cid:2) Damage to sensitive organs, such as bladder, eye, brain, testis, ovary, and thyroid (cid:2) Risk of second malignancy Imbalanced bone growth, especially where epiphyses are included in the \201eld (cid:2) In infants and children with localized tumors and favorably histol- ogy, such as embryonal RMS of the orbit, it may be possible to omit radiotherapy. Extremity tumors, alveolar histo logy, and para- meningeal tumors require radiotherapy. Soft tissue Ewing \200\231s sarcoma and primitive neuroectodermal tumor (PNET) Ewing \200 \231s tumors are the second commonest bone malignancy in chil- dren. These are small round cell tumors of neuroectodermal origin and are characterized by chromosomal translocations i nvolving the EWS gene, located at chromosome 22q12, fused with FL11 [t(11;22) (q24;q12)] or , more rarely, ERG [t(21;22) (a22;q12)]. Genetic analysis with FISH or RT-PCR methods may a id diagnosis. Soft tissue Ewing \200\231s sarcoma or PNET most commonly involves the extrem ities, chest wall (Askin \200\231s tumor), or pelvis. OHO-28(515-530) 11/18/02 8:43 AM Page 529 SOFT TISSUE SARCOMAS 529 In terms of treatment, much of the management of RMS applies to the Ewing \200\231s family of tumors. Prognosis with surgery alone is dismal (<10% cure) because of the frequency of s ystemic spread. Pre- and post-operative combination chemotherapy (doxorubicin, actino- myci n D, ifosfamide, vincristine) is of crucial importance. Surgery is the preferred primary lo cal treatment but radiotherapy is required after incomplete resection or where surgery is n ot feasible. Tumor bulk and response to chemotherapy are the two most important prog- nosti c factors. The outlook is worse for those patients with tumors larger than 200 ml or with l ung metastases, worse still in the case of bone metastases at diagnosis. Site is also impor tant \200\224axial primaries fare worse through a combination of late presentation and prob lems achieving local control of disease. Five-year survival rates are about 60% overall \200\22480% for good-risk cases, falling to 20% in metastatic or larger tumors. Adult sarcomas Soft tissue sarcomas (STS) are rare tumors, accounting for 1% of adult malig nancies and 6% of those in childhood. There are about 1200 new cases in the UK annually. Ma ny histopathological varieties of STS are described, the most common being leiomyosarcoma, malignant \201brous histiocytoma, and liposarcoma. Classi \201cation of an individual tu mor is based on morphology and immunohisto- chemistry. Certain types of adult STS, such as clear cell, epithelioid, and syn- ovial, always behave in an aggressive fashion. For those tumors that are more variable in their behavior, such a s liposarcoma, grade is more important than subtype since grade, tumor size, and resecta- b ility are key prognostic factors. Low-grade, well-differentiated tumors may recur locally but rarely metastasize. Alveolar so ft part sarcoma may behave in an indolent fashion but nevertheless does metastasize, and th e prognosis is poor. Disease pattern and prognosis (cid:2) 50% have high-grade sarcomas (cid:2) 50% of high-grade sarcomas die from metastases (cid:2) Metastases \200\224rare with primary tumor <5 cms \200\224common with primary tumor >15 cms (cid:2) Super \201cial tumors have better prognosis (cid:2) Extremity tumors spread to lun g (cid:2) RMS, clear cell, epithelioid sarcomas spread to nodes (cid:2) Angiosarcomas, syno vial sarcomas spread to bone (cid:2) Retroperitoneal sarcomas spread to liver (cid:2) Gynec ological sarcomas \200\224diagnosed late, bad prognosis OHO-28(515-530) 11/18/02 8:43 AM Page 530 BONE AND SOFT TISSUE MALIGNANCIES 530 (cid:2) Older patients \200\224worse prognosis (cid:2) Liposarcoma \200\224better prognosis (cid:2) Synovial sarcoma is chemosensitive Treatment Radical surgery for the primary STS offers the only hope of cure. Complete compar tmental resection for extremity tumors is no longer advocated since it is known that sarcom as rarely cross fascial boundaries. If possible, some muscle in the compartment should be s pared. Sarcomas do, however, spread longitudinally. It is for this rea- son that careful pr e-operative planning is required using MRI or CT scan to delineate the tumor extent and rel ationship to major vessels or nerves that may indicate the need for reconstructive surgery. If required, in the case of diagnostic dif \201culty the surgeon performing the de \201n itive operation should carry out further biopsies. There needs to be close collaboration be tween surgeon and radiotherapist. Preservation of function should be a priority, and amputation is rarely necessary. For high -grade tumors and any locally recurrent tumor, adjuvant radiotherapy is advised. This may b e delivered pre- or post-operatively. Doses in the range of 55 \200\22365 Gy are recommende d. Retroperitoneal tumors are rarely radically resectable and recur- rence is common, espec ially for higher-grade tumors. While radio- therapy may reduce local recurrence, it is like ly to do little to in \202uence prognosis, and the dose which can be safely delivered to t he abdomen (40 \200\22350 Gy) will be insuf \201cient to control the majority of STS. Advanced disease Metastases may be surgically removed in the case of limited relapse in the lungs. Any bene \201t increases with the relapse-free interval and if metastases are few in number. Chemotherapy for resectable locally recurrent or metastatic disease is palliativ e. Ifosfamide and doxorubicin are the most active agents, but reported response rates are stil l disappointing (15 \200\22330%). There is clear evi- dence for a dose-response relationshi p with both drugs. Combination chemotherapy may produce higher response rates but is more t oxic. Synovial sarcoma is chemosensitive and complete responses are observed. Low-grade tum ors and especially gastrointestinal stromal tumors are generally unresponsive to convention al chemotherapy. The role of adjuvant chemotherapy remains unclear but a recent meta-analysis of primary dat a from all published randomized trials showed signi \201cantly improved progression-free s urvival and a small improvement in overall survival, amounting to 4% at 10 years, which fai led to reach statistical signi \201cance. There remains an urgent need for more effective systemic therapy in this group of diseases. OHO-29(531-542) 11/18/02 9:24 AM Page 531 Chapter 29 Cancer of unknown primary site Etiology/epidemiology/pathology 534 Clinical presentation 536 Investigation 538 Treatment 5 40 Further reading 542 OHO-29(531-542) 11/18/02 9:24 AM Page 532 CANCER OF UNKNOWN PRIMARY SITE 532 Such cancers are a common problem for oncologists, representing up to 15% of new referrals. Before accepting the diagnosis, it is important that the patient has: (cid:2) A thorough h istory (cid:2) Full clinical examination (including rectal, pelvic, and breast examination) (cid:2) Additional investigations OHO-29(531-542) 11/18/02 9:24 AM Page 533 CANCER OF UNKNOWN PRIMARY SITE 533 OHO-29(531-542) 11/18/02 9:24 AM Page 534 CANCER OF UNKNOWN PRIMARY SITE 534 Etiology/epidemiology/ pathology A mixed group of cancers with a high metastatic potential. The reason the primary site rema ins undetected may be due to spontaneous regression (well recognized in melanoma) or mucosa l sloughing, but in most cases is probably due to the unusual metastatic potential of the t umor. The pattern of metastatic disease is often very different from cases where the primar y site is known e.g. lung cancer causes bone metastases 10 times more often when the primar y site is known than when the lung cancer is occult. Rare under the age of 40 years, this is the third commonest cancer presentation in patients over 70 years of age. The mean age at diagno- sis is 60 years. It is a frequent cause of c ancer death with a median sur- vival of four months in most series. However, there are some patients with curable disease and some clinical scenarios are associated with a much longe r survival. In about 20% the primary site is detected ante- mortem, but in 25% it remains u ndetected even after post mortem. Four broad groups can be identi \201ed by light microscopy: (cid:2) Adenocarcinoma (60%) (cid:2) Poorly differentiated carcinoma (30%) (cid:2) Undiffer entiated malignancy (5%) (cid:2) Squamous carcinoma (5%) Appearances of adenocarcinoma and squamous carcinoma are similar irrespective of their site of origin and light microscopy ra rely provides further clues. The diagnosis of undifferentiated malignancy should be made wi th caution as a high proportion will turn out to be lym- phomas and further staining is ess ential. Poorly differentiated carci- noma may also be confused with seminoma, amelanotic me lanoma, and epidermal carcinoma. Immunohistochemical staining may be helpful, and is essential where lymphoma or germ cell t umor are possibilities. Unfortunately, few stains are speci \201c to a primary site e.g. n euro-endocrine markers and chorionic gonadotrophin may be found on many tumors other than s mall cell lung cancer and germ cell cancer respectively. Electron microscopy can con \201r m a diagnosis of lymphoma but rarely distin- guishes the primary site in other cancers. Identi \201cation of speci \201c genetic abnormalities is limited to a few tumors at pres ent (lymphoma, Ewing \200\231s sarcoma, rhabdomyosarcoma) but holds promise for the future. OHO-29(531-542) 11/18/02 9:24 AM Page 535 etiology/EPIDEMIOLOGY/PATHOLOGY 535 Table 29.1 Site-speci \201c immunohistochemical stains Stain Tumor Common leukocyte antigen (CLA) Lymphoma B & T cell gene rearrangement Non-Hodgkin \200\231s lymphoma Prostate speci \201c antigen (PSA) Prostate Thyroglobulin Thyroid OHO-29(531-542) 11/18/02 9:24 AM Page 536 CANCER OF UNKNOWN PRIMARY SITE 536 Clinical presentation Presentation with lymphadenopathy is commoner than visceral or bone metastases. A wide vari ety of presentations may occur but the following are of clinical importance. Axillary lymph nodes A woman with metastatic adenocarcinoma in the axillary lymph nodes may have an occult breast cancer. This group has a longer sur- vival than average. Negative ma mmography does not exclude the diagnosis. In the absence of distant metastatic disease, loc o-regional therapy with surgical excision and radiation, with or without chemotherapy, shou ld be given. Cervical lymph nodes Squamous or undifferentiated carcinoma in cervical lymph nodes must be referred for full ENT examination under anesthetic with biopsy of the naso-, oro-, and hyp o-pharynx. Radical loco-regional radiotherapy can result in median survival of several year s especially if the nodes are high in the neck. Thyroid cancer can be excluded by staining for thyroglobulin. Supraclavicular lymph node metastases are usually associated with widesp read malignancy and have a poorer prognosis. Inguinal lymph nodes A small anal cancer should be excluded by rectal examination and proct oscopy as this tumor may be curable with chemo-radiation. A thorough examination of the low er limbs may identify a primary skin cancer. Positive PSA staining Rectal examination may reveal an abnormality, but random transrectal biopsies may be indicated even with a normal prostate gland. Peritoneal carcinomatosis in women Ovarian cancer or a similarly behaving primary peritonea l carcinoma should be considered. Serum CA125, gynecological examination, and pelvic ultras ound may be useful but are not speci \201c. A mucin- secreting adenocarcinoma is more like ly to be of gastrointestinal ori- gin but can arise in the ovary. A trial of platinum-based chemotherapy may be pragmatic and good responses can be achieved. OHO-29(531-542) 11/18/02 9:24 AM Page 537 CLINICAL PRESENTATION 537 Retroperitoneal or mediastinal lymph nodes in men This pattern of disease in men \200\224th e extra-gonadal germ cell syn- drome \200\224is well recognized and associated with excelle nt responses to chemotherapy even in the absence of histological con \201rmation of germ c ell cancer or serum tumor markers. Chemotherapy with bleomycin, etoposide, and cisplatin sh ould be given. OHO-29(531-542) 11/18/02 9:24 AM Page 538 CANCER OF UNKNOWN PRIMARY SITE 538 Investigation There is a tendency to over-investigate these patients. Only tests that are likely to alter treatment should be performed. Tumors that respond well to therapy, even in the presence o f metastases, must be excluded (breast, prostate, thyroid, germ cell, lymphoma). Extensive investigation of the GI tract with barium and endoscopy is rarely useful. CT or MRI may ide ntify an incurable cancer and avoid inappropriate treatment. OHO-29(531-542) 11/18/02 9:24 AM Page 539 INVESTIGATION 539 OHO-29(531-542) 11/18/02 9:24 AM Page 540 CANCER OF UNKNOWN PRIMARY SITE 540 Treatment Diagnosis and investigations are directed at classifying the patient in one of the followin g groups: (cid:2) Potentially curable (cid:2) Effective palliation available (cid:2) No act ive treatment indicated The following cancers are potentially curable when presenting as cancers of unknown primary site: (cid:2) Germ cell tumors (cid:2) Lymphomas (cid:2) Thyroid cancer Effective palliation with chemotherapy is indicated if the patient is \201t and t he tumor is chemo-responsive. There is no convincing evidence Diagnosis of metastatic cancer Clinical evaluation and radiography Cancer of unknown primary site Primary identified Serum plus histological tumor markers Negative Positive Prostate Germ cell Hepatoma Ovary Other clinical presentation Lymph node presentation Bone Exclude breast and thyroid Exclude lymphoma Axillary node Exclude breast Thorax, CNS, and liver Low yield of treatable primaries Abdomen and pelvic Exclude ovary and prostate Cervical node Exclude head and neck Identi \201cation of treatable cancer of unknown primary site (reproduced with permission from the Oxford Textbook of Oncology, 1995). OHO-29(531-542) 11/18/02 9:24 AM Page 541 TREATMENT 541 that combinations are better than single agents but there have been very few randomized tri als. Hormone therapy is valuable in breast, prostate, endometrial cancer. Thyroidectomy and radioactive iodine therapy can provide long-term disease control in thyroid cancers. Radio therapy can provide useful palliation for painful bone metas- tases, brain metastases, and troublesome lymph node masses. Patients for whom no active treatment is indicated are often the most dif \201cult to mana ge. The situation should be discussed with the general practitioner and, if appropriate, re ferral should be made to community or hospice-based palliative care teams. OHO-29(531-542) 11/18/02 9:24 AM Page 542 CANCER OF UNKNOWN PRIMARY SITE 542 Further reading Hainsworth, J.D. and Greco, F.A. (1993) Treatment of patients with cancer of an unknown primary site. N Engl J Med 329, 257 \200\22363. Lindeman, G.J. and Tattershall, M. (1995) Tumors of unknown primary site. In Oxford Textboo k of Oncology (ed. Peckham, M., Pinedo, H., and Veronesi, U.), pp. 2155 \200\22365. Oxford University Press, Oxford. OHO-30(543-558) 11/18/02 9:25 AM Page 543 Chapter 30 Paraneoplastic syndromes Endocrine paraneoplastic syndromes 546 Neurological paraneoplastic syndromes 548 Hematologi cal paraneoplastic syndromes 550 Dermatological paraneoplastic syndromes 552 Other syndrome s 554 Constitutional symptoms 556 Further reading 557 OHO-30(543-558) 11/18/02 9:25 AM Page 544 PARANEOPLASTIC SYNDROMES 544 These pathological conditions are caused by a cancer but are not due to direct local in \201ltration or metastatic spread. Occurring in approxi- mately 10% of cancer patients over all, they are most commonly asso- ciated with certain cancer types. They are important to r ecognize because they may be the presenting feature of an undiagnosed cancer. Paraneoplasti c syndromes (PS) can also cause signi \201cant morbidity that may be treatable, and they m ay sometimes act as markers of disease activity. Cancers commonly associated with paraneoplastic syndromes (PS): (cid:2) Lung: small cell (SCLC) and non-small cell (NSCLC) (cid:2) Pancreatic (cid:2) Lymph oma: non-Hodgkin \200\231s (NHL) and Hodgkin \200\231s Disease (HD) (cid:2) Breast (cid:2) Prostate (cid:2) Ovary Although the mechanisms of PS are not fully understood, there appear to be two main causes: (cid:2) The inappropriate secretion of hormones and/or growth facto rs (cid:2) The production of anti-tumoural antibodies that cross-react with normal tissue antigens OHO-30(543-558) 11/18/02 9:25 AM Page 545 PARANEOPLASTIC SYNDROMES 545 OHO-30(543-558) 11/18/02 9:25 AM Page 546 PARANEOPLASTIC SYNDROMES 546 Endocrine paraneoplastic syndromes (PS) Syndrome of inappropriate ADH (SIADH) The most common endocrine PS is due to inappropriate secretion of anti-diuretic hormone (arginine-vasopressin). Cancer types SCLS (10% of patien ts), pancreatic, prostate, NHL, HD. Presentation Often asymptomatic. CNS effects \200\224fa tigue, headaches; progressing to altered mental state, confusion, and seizures. Diagnosis E xclude non-malignant causes e.g. CNS disease (infection, trauma, vascular), pulmonary disea se (infections, cystic lesions, asthma), drug-induced (thiazides, cytotoxics, narcotics); c linically euvolaemic; laboratory studies. Treatment Fluid restriction (0.5 \200\2231.0 L/da y); democlocycline (150 \200\223 300 mg 8 hourly). Laboratory criteria for diagnosis of SIADH (cid:2) Hyponatraemia Na+ <130 mmol/L (cid:2) Normal serum albumin and glucose (cid:2) Seru m hypo-osmolarity <275 mmol/Kg (cid:2) Urine osmolarity > serum osmolarity (cid:2) Urinary sodium >25 mmol/L (cid:2) Non-suppressed ADH Cushing \200\231s syndrome Inappropriate overproduction of adenocorticotrophic hormone (ACT H) precursors. Cancer types SCLC, NSCLC, pancreatic, thymic, and carcinoid tumors. Presenta tion Rapid onset, marked weakness secondary to proximal myopathy, hyper-pigmentation, metab olic disturbances (e.g. hyper- glycaemia, hypokalaemic alkalosis). Diagnosis Clinical featu res, especially hyper-pigmentation, myo- pathy; hypokalaemia and metabolic alkalosis; high 24-hr urinary cortisol, high plasma ACTH/precursors, no response to high-dose dexamethasone suppression or corticotropin-releasing hormone stimulation. Treatment Speci \201c anti-tu mor treatment. Decrease cortisol secretion either surgically (bilateral adrenalectomy) or m edically (metyrapone, octreotide, ketoconazole). OHO-30(543-558) 11/18/02 9:25 AM Page 547 ENDOCRINE PARANEOPLASTIC SYNDROMES 547 Hypercalcaemia A common problem that in many cases is due to bony metastases. True paraneop lastic hypercalcaemia is due to tumor production of parathyroid hormone-related protein. Th is syndrome is called Humoral Hypercalcaemia of Malignancy (HHM). Cancer types NSCLC, head and neck, renal, other squamous cancers. (Rare in breast cancer where hypercalcaemia is usu ally due to bone metastases.) Presentation Rapid onset of nausea, polyuria, polydipsia, deh ydra- tion, cardiac arrhythmias. Diagnosis Serum Ca2+ >2.7 mmol/l, serum chloride low, hype r- calcuria, high urinary phosphate, low/undetectable plasma para- thyroid hormone. Treatme nt Saline hydration, IV pamidronate (60 \200\223120 mg). Hypocalcaemia Associated with tumors with lytic bone metastases (breast, prostate, and lung ); can also occur with calcitonin-secreting medullary carci- nomas of the thyroid. Usually asymptomatic. Rarely develop tetany and neuromuscular irritability. Treatment with calcium infusions. Hypoglycaemia Rarely caused by non-islet cell pancreatic tumors; often associated with mese nchymal tumors of the mediastinum and retroperitoneum and with hepatic cancers. Most likely cause is tumor production of the precursor to insulin-like growth factor II. Treatment wit h glucose infusions, tumor debulking. OHO-30(543-558) 11/18/02 9:25 AM Page 548 PARANEOPLASTIC SYNDROMES 548 Neurological paraneoplastic syndromes Common, occurring in up to 7% of cancer patients. Most common syndromes are: (cid:2) periph eral neuropathy (cid:2) proximal myopathy Other major syndromes are relatively rare. Can af fect any part of the neurological system and most are thought to be secondary to autoim- mu ne mechanisms via production of anti-tumor antibodies that cross-react with nervous tissue e.g. anti-Hu, anti-Yo, anti-Ri. Treat- ment is based upon treatment of the cancer and decre asing antibody production by immune system suppression e.g. corticosteroids, IV immunoglobu lin, and plasma exchange. In contrast to endocrine syndromes, response to treatment is ofte n poor (except for Lambert- Eaton myasthenic syndrome (LEMS)). Peripheral neuropathy (PN) Asymptomatic PN is common; symptomatic PN less so. Usually occur s after diagnosis of cancer has been made and caused by axonal degeneration or demyelinatio n. Many types of PN e.g. motor, sensory, autonomic, sensorimotor. Cancer types SCLC, myelom a, HD, breast, GI cancers Presentation Depends upon type and site. Diagnosis Exclude non-pa raneoplastic causes; nerve conduction studies, nerve biopsy \200\224look for in \202ammato ry in \201ltrates; serum anti- Hu antibodies in some cases. Treatment Corticosteroids; tre at underlying cancer. Encephalomyelopathies Perivascular in \202ammation and selective neuronal degeneration at several levels of the nervous system. Can affect the limbic system, brainstem, and spinal c ord. Cancer types SCLC (75% of cases), breast, ovary, NHL. Presentation Slow, subacute onse t; progressive Diagnosis CSF \200\224raised protein/IgG level, pleocytosis; serum \200\224 anti-Hu antibody; MRI. Treatment Anti-tumor therapy. OHO-30(543-558) 11/18/02 9:25 AM Page 549 NEUROLOGICAL PARANEOPLASTIC SYNDROMES 549 Paraneoplastic cerebellar degeneration (PCD) Cancer types Breast, SCLC, ovary, Hodgkin \200 \231s disease (HD). Presentation Rapid onset and progression; usually prior to cancer diagn osis; bilateral cerebellar signs; late diplopia and dementia. Diagnosis CT \200\224cerebell ar atrophy (late); serum auto-antibodies \200\224 anti-Yo, -Tr, and -Hu. Treatment Response to anti-tumor treatment, steroids, plasma- pheresis. Cancer-associated retinopathy (CAR) Cancer types SCLC, breast, melanoma. Presentation Visua l defects i.e. blurred vision, episodic visual loss, impaired color vision; leads to progre ssive painless visual loss; usually precedes cancer diagnosis. Diagnosis Loss of acuity; sc otomata; abnormal electroretinogram; anti-retinal ab \200\231s. Treatment Corticosteroids. Lambert \200\223Eaton myasthenic syndrome (LEMS) Disorder of the neuro-muscular junction; r educed pre-synaptic calcium-dependent acetylcholine release. About 60% of patients with LEM S have underlying cancer. Cancer types SCLC (60 \200\22370%), breast, thymus, GIT cancers. Presentation Proximal muscle weakness. Diagnosis EMG \200\224normal conduction velocity wit h low-amplitude compound muscle action potential that enhance to near normal fol- lowing ex ercise. Treatment Cancer treatment, corticosteroids, plasma exchange (high response rate). Dermatomyositis/polymyositis In \202ammatory myopathies, often present prior to cancer dia gnosis. Cancer types NSCLC, SCLC, breast, ovary, GIT cancers Presentation Proximal myopathy , skin changes, other systemic fea- tures; cardiopulmonary conditions, arthralgias, retinop athy. Diagnosis Serum \200\224high CK, LDH, aldolase; muscle biopsy \200\224myo- sitis; EMG \200\223 \201brillation, insertion irritability, short polyphasic motor units. Treatment Search for and treat tumor; corticosteroids, azathioprine. OHO-30(543-558) 11/18/02 9:25 AM Page 550 PARANEOPLASTIC SYNDROMES 550 Hematological paraneoplastic syndromes Red cell disorders Erythrocytosis Common, often secondary to increased erythropoi- etin pro duction e.g. renal cell carcinoma, hepatoma. Treat with phleb- otomy if required. Haemolyti c anemia (cid:2) Autoimmune \200\224secondary to lymphoproliferative disorders (treat- ment \200\224corticosteroids). (cid:2) Micro-angiopathic \200\224secondary to vascular tumors, acute pro- myelocytic leuke mia, or widespread metastatic adenocarcinoma. Treat the tumor; replace coagulation factors; IV heparin. Red cell aplasia Seen in thymoma, CLL; rare in solid tumors. White cell disorders Autoimmune neutropenia (rare) (cid:2) Granulocytosis \200\224secondary to haemopoietic growth factor- secreting tumors (e.g. squamous cell cancers of lung, thyro id). (cid:2) Eosinophilia \200\224in patients with HD. Platelet disorders (cid:2) Thrombocytosis \200\224(>450 \227 109/L) is common and usually asymp- tomatic; in some cases may be secondary to IL-6 production. Idiopathic thrombocytopenia \200\224is associated with leukaemias and lymphomas. Coagulopathy (cid:2) Minor abnormaliti es of \201brin and \201brinogen degradation products (cid:2) are common. (cid:2) Overt disseminated intravascular coagulation is rare, associated with Acute Myelocytic Leukemia and adenocarcinomas. (cid:2) Diagnosed by triad of thrombocytopenia, abnormal prothrombin time, and hypo \201brinoginemia (cid:2) Treatment is controversial. OHO-30(543-558) 11/18/02 9:25 AM Page 551 hematological PARANEOPLASTIC SYNDROMES 551 OHO-30(543-558) 11/18/02 9:25 AM Page 552 PARANEOPLASTIC SYNDROMES 552 Dermatological paraneoplastic syndromes Pruritus Common; characteristic of HD, leukaemias, CNS tumors, NHL. Pigmentation Acanthosis nigricans Itchy brown hyperkeratotic plaques, mainly in \202exure s; may precede cancers by many years; associated with GIT tumors e.g. gastric adenocarcinom a. Vitiligo Patchy depigmentation, especially face, neck, and hands; associated with malign ant melanoma; possibility due to anti- melanoma immune response. Erythematous Necrolytic migratory erythema Exfoliative dermatitis \200\224cutaneous T-cell lymphoma. Islet cell tumor. Bullous Pemphigus Characteristic bullous lesions on skin and mucous membranes; associated w ith lymphoma, Kaposi \200\231s sarcoma, thymic tumors. Dermatitis herpetiformis Chronic, in tensely itchy vesicles over elbows, knees, and lower back; precede tumor by many years; ass ociated with lymphomas e.g. NHL of the small intestine. OHO-30(543-558) 11/18/02 9:25 AM Page 553 DERMATOLOGICAL PARANEOPLASTIC SYNDROMES 553 OHO-30(543-558) 11/18/02 9:25 AM Page 554 PARANEOPLASTIC SYNDROMES 554 Other syndromes Hypertrophic osteoarthropathy Characterized by \201nger clubbing, periosteal new bone for mation, and arthropathy. Cancer types Lung cancer, especially NSCLC. Presentation Painful, swollen joints. Diagnosis Clinical \200\224X-ray showing periosteal shadowing; bone scan \200\224increased uptake. Treatment Anti-tumor therapy, NSAIDS, corticosteroids, radiation. OHO-30(543-558) 11/18/02 9:25 AM Page 555 OTHER SYNDROMES 555 OHO-30(543-558) 11/18/02 9:25 AM Page 556 PARANEOPLASTIC SYNDROMES 556 Constitutional symptoms Fever Can be presenting feature of lymphomas, hepatomas, renal cell carcinoma; mediated by IL-1; treat with NSAIDS, corticosteroids; exclude other causes. Cachexia Very common, >10% loss of body weight is associated with poor prognosis; due to complex, multi-factorial meta bolic derange- ments; treat with enteral caloric supplements and appetite stimulants e.g. c orticosteroids, megesterol acetate. OHO-30(543-558) 11/18/02 9:25 AM Page 557 CONSTITUTIONAL SYMPTOMS 557 Further reading MacCaulay, V.M. and Smith, I.E. (1995) Paraneoplastic syndromes. Oxford Textbook of Oncology, p. 2228 \200\22353. Oxford University Press. John, W.J., Patchell, R.A., and Foon, K.A. (1994) Paraneoplastic syndromes. In Cancer \200\224Principles and Practice of Oncology (5th edn) (ed. V.T. DeVita et al) p. 239 7 \200\223422. Paraneoplastic syndromes (1997). Seminars in Oncology 24, 265 \200\223381. OHO-30(543-558) 11/18/02 9:25 AM Page 558 This page intentionally left blank OHO-31(559-570) 11/18/02 9:26 AM Page 559 Chapter 31 AIDS-related malignancies Kaposi \200\231s sarcoma 562 Non-Hodgkin \200\231s lymphoma 566 Primary CNS lymphoma 568 Ot her malignancies 570 OHO-31(559-570) 11/18/02 9:26 AM Page 560 AIDS-RELATED MALIGNANCIES 560 Patients with the acquired immune de \201ciency syndrome (AIDS) are at increased risk of d eveloping certain malignant tumors. At present four malignancies de \201ne the onset of AI DS. (cid:2) Kaposi \200\231s sarcoma (KS) (cid:2) Non-Hodgkin \200\231s lymphoma (NHL) (cid :2) Primary CNS lymphoma (cid:2) Cervical cancer Epidemiological research has identi \201e d other tumors, such as anal cancer and Hodgkin \200\231s disease, that also have an increa sed incidence in HIV-positive individuals. OHO-31(559-570) 11/18/02 9:26 AM Page 561 AIDS-RELATED MALIGNANCIES 561 OHO-31(559-570) 11/18/02 9:26 AM Page 562 AIDS-RELATED MALIGNANCIES 562 Kaposi \200\231s sarcoma (KS) Prior to the HIV epidemic, this tumor was seen in three clinical settings: (cid:2) The clas sical form affects predominantly the lower legs in men of East European or Jewish origin an d often follows an indolent course, rarely requiring any speci \201c treatment. (cid:2) An African variant, which has been endemic for many years. This can be indolent in nature or it may be more aggressive with wide- spread lymph node and visceral involvement.