PARANEOPLASTIC SYNDROMES & ONCOLOGIC EMERGENCIES

INTERNAL MEDICINE − MEDICAL ONCOLOGY

ANN MEREDITH U. GARCIA, MD, FPCP, DPSMO, MCMMO

PARANEOPLASTIC SYNDROMES & ONCOLOGIC EMERGENCIES

ç

PARANEOPLASTIC SYNDROMES

CANCER CELL

NEUROLOGIC

HORMONAL HEMATOLOGIC

DERMATOLOGIC

§  Disorders that accompany benign or malignant tumors but are not directly related to mass effects or invasion

§  Almost every type of tumor has the potential

to produce hormones or to induce cytokine and immunologic responses. o Neuroendocrine tumors (small cell lung

carcinoma, carcinoids) – common causes

§  Atypical clinical manifestations in a patient with cancer should prompt consideration of a paraneoplastic syndrome.

PARANEOPLASTIC SYNDROMES

§  Hormones can be produced from eutopic or ectopic sources. o  Eutopic – normal tissue of origin o  Ectopic – atypical tissue source

§  Ectopic expression o High levels of hormones o Abnormal regulation of hormone production –

defective feedback control o Abnormal peptide processing – large,

unprocessed precursors

ENDOCRINE SYNDROMES

§  Cellular dedifferentiation – probably underlies most cases of ectopic hormone production

§  Excessive and unregulated production of hormones can lead to substantial morbidity and complicate the cancer treatment plan. o May be a presenting clinical feature of

underlying malignancy and prompt the search for an unrecognized tumor

ENDOCRINE SYNDROMES

HUMORAL HYPERCALCEMIA

ECTOPICHORMONE TYPICALTUMORTYPES

REMARKS

Parathyroidhormone-relatedprotein(PTHrP)(mostcommon)

–Squamouscell(head&neck,lung,skin)–Breast–Genitourinary–Gastrointes<nal–Bonemetastases–Mul<plemyeloma

–BindstothePTHreceptor–Playsakeyroleinskeletaldevelopment&regulatescellularprolifera<on&differen<a<oninother<ssues–Causeslocalosteolysis–Affectstheini<a<on&progressionoftumorsbyac<ngthroughpro-survival&chemokinepathways

1,25-dihydroxyvitaminD

–Lymphomas –Produc<onofanenzymethatconverts25-hydroxyvitaminDtothemoreac<ve1,25-dihydroxyvitaminD–Enhancedgastrointes<nalcalciumabsorp<on

Rare:Parathyroidhormone(PTH),prostaglandinE2(PGE2)


§  Patient with a known malignancy who is found to be hypercalcemic on routine laboratory tests o  Typical presentation o May present with fatigue, mental status changes,

dehydration, or symptoms of nephrolithiasis when calcium levels are markedly increased (>3.5 mmol/L or >14 mg/dL)

o Accompanied by hypercalciuria, hypophosphatemia, and metabolic alkalosis


§  Features that favor HHM vs. primary hyperparathyroidism: o  Known malignancy o  Recent onset of hypercalcemia o Very high serum calcium levels o  Suppressed PTH

§  Elevated PTHrP (or 1,25-dihydroxyvitamin D)

– confirms the diagnosis


MANAGEMENT REMARKS

Removalofexcesscalcium Inthediet,medica<ons,orIVsolu<ons

SalinerehydraNon Todiluteserumcalcium&promotecalciuresis

Forceddiuresis(furosemideorotherloopdiureNcs)

Canenhancecalciumexcre<onbutprovidesrela<velyliVlevalueexceptinlife-threateninghypercalcemia;shouldbeadministeredonlyaXercompleterehydra<on

Oralphosphorus Administerun<lserumphosphorusis>1mmol/L(>3mg/dL)

Bisphosphonates(pamidronate,zoledronate)

Canreduceserumcalciumwithin1–2days&suppresscalciumreleaseforseveralweeks

Dialysis Considerinseverehypercalcemiawhensalinehydra<on&bisphosphonatetreatmentsarenotpossibleoraretooslow

Calcitonin Considerforrapidcorrec<onofseverehypercalcemia

GlucocorNcoidtreatment(prednisone)

Considerinhypercalcemiaassociatedwithlymphomas,mul<plemyeloma,orleukemia

SIADH


REMARKS

Vasopressin/anNdiureNchormone(ADH)

–Mostcommon:Lung(smallcell),carcinoids–Lung(squamous)–CNS–Head&neck–Gastrointes<nal–Genitourinary–Ovary

–Hyponatremia&reducedserumosmolalityinthese^ngofaninappropriatelynormalorincreasedurineosmolality–Normalorincreasedurinesodiumexcre<onunlessvolumedeple<onispresent

SIADH

§  Most patients are asymptomatic and are identified because of the presence of hyponatremia on routine chemistry testing.

§  Symptoms may include weakness, lethargy, nausea, confusion, depressed mental status, and seizures. o  The severity of symptoms reflects the rapidity of onset as well

as the severity of hyponatremia. o  Hyponatremia usually develops slowly.

§  Vasopressin measurements – not usually necessary to make the diagnosis

SIADH

§  The rate of sodium correction should be slow (0.5–1 meq/L per hour) unless mental status is altered or there is risk of seizures. o  To prevent rapid fluid shifts and the possible

development of central pontine myelinolysis (osmotic demyelination syndrome)

§  Treatment of the underlying malignancy may reduce ectopic vasopressin production, but this response is slow if it occurs at all.

SIADH

MANAGEMENT REMARKS

FluidrestricNontolessthanurineoutput,plusinsensiblelosses

OXensufficienttocorrecthyponatremiapar<ally

Demeclocycline Inhibitsvasopressinac<onontherenaldistaltubule,butitsonsetofac<onisrela<velyslow

V2receptorantagonists(conivaptan,tolvaptan)

Par<cularlyeffec<vewhenusedincombina<onwithfluidrestric<onineuvolemichyponatremia

Hypertonic(3%)ornormalsalineinfusiontogetherwithfurosemide

Forseverehyponatremia(Na<115meq/L)ormentalstatuschanges

Salttablets NOThelpfulunlessvolumedeple<onisalsopresent

CUSHING’S SYNDROME


REMARKS

AdrenocorNcotropichormone(ACTH)(mostcommon)

–Mostcommon:Lung(smallcell)–Carcinoids–Pancrea<cisletcell–Pheochromocytomas–Medullarythyroid

–Increasedexpressionoftheproopiomelanocor<n(POMC)gene

Rare:Cor<cotropin-releasinghormone(CRH),gastricinhibitorypep<de(GIP),luteinizinghormone(LH)/humanchorionicgonadotropin(hCG),otherGprotein-coupledreceptors


§  The clinical features of hypercortisolemia are detected in only a small fraction of patients. o  Less marked weight gain and centripetal fat redistribution o  Dominated by fluid retention and hypertension, hypokalemia,

metabolic alkalosis, glucose intolerance, and occasionally steroid psychosis

o  Marked skin fragility and easy bruising

§  The very high ACTH levels often cause increased pigmentation, and melanotrope-stimulating hormone (MSH) activity derived from the POMC precursor peptide is also increased.

§  Opportunistic infections – usual cause of death in patients with ectopic ACTH production


§  Urine free cortisol levels fluctuate but are typically greater than 2-4 times normal, and the plasma ACTH level is usually elevated to >22 pmol/L (>100 pg/mL). o  A suppressed ACTH level excludes this diagnosis and

indicates an ACTH-independent cause of Cushing’s syndrome (e.g., adrenal or exogenous glucocorticoid).

§  In contrast to pituitary sources of ACTH, most ectopic sources of ACTH do not respond to glucocorticoid suppression.


MANAGEMENT REMARKS

Treatmentoftheunderlyingmalignancy

MayreduceACTHlevelsbutisrarelysufficienttoreducecor<sollevelstonormal

Adrenalectomy Notprac<calformostpa<entsbutshouldbeconsideredduringsurgeryforthemalignancyoriftheunderlyingtumorisunresectable&theprognosisisotherwisefavorable(e.g.,carcinoid)

Medicaltherapy(ketoconazole,metyrapone,mitotane,orotheragentsthatblocksteroidsynthesisoracNon)

OXenthemostprac<calstrategy,butmanypa<entseventuallyprogress

LESS COMMON ENDOCRINOPATHIES

CHAPTER 121Paraneoplastic Syndromes: Endocrinologic/Hematologic

609 TABLE 121-1 PARANEOPLASTIC SYNDROMES CAUSED BY ECTOPIC HORMONE PRODUCTIONParaneoplastic Syndrome Ectopic Hormone Typical Tumor Typesa

CommonHypercalcemia of malignancy

Parathyroid hormone–related protein (PTHrP) Squamous cell (head and neck, lung, skin), breast, genitourinary, gastrointestinal

1,25-dihydroxyvitamin D Lymphomas

Parathyroid hormone (PTH) (rare) Lung, ovary

Prostaglandin E2 (PGE2) (rare) Renal, lung

Syndrome of inappropriate antidiuretic hormone secretion (SIADH)

Vasopressin Lung (squamous, small cell), gastrointestinal, genitourinary, ovary

Cushing’s syndrome Adrenocorticotropic hormone (ACTH) Lung (small cell, bronchial carcinoid, adenocarcinoma, squamous), thymus, pancreatic islet, medullary thyroid carcinoma

Corticotropin-releasing hormone (CRH) (rare) Pancreatic islet, carcinoid, lung, prostate

Ectopic expression of gastric inhibitory peptide (GIP), luteinizing hormone (LH)/human chorionic gonadotropin (hCG), other G protein–coupled receptors (rare)

Macronodular adrenal hyperplasia

Less CommonNon–islet cell hypoglycemia Insulin-like growth factor type II (IGF-II) Mesenchymal tumors, sarcomas, adrenal, hepatic, gastrointestinal,

kidney, prostate

Insulin (rare) Cervix (small-cell carcinoma)

Male feminization hCGb Testis (embryonal, seminomas), germinomas, choriocarcinoma, lung, hepatic, pancreatic islet

Diarrhea or intestinal hypermotility

Calcitoninc Lung, colon, breast, medullary thyroid carcinoma

Vasoactive intestinal peptide (VIP) Pancreas, pheochromocytoma, esophagus

RareOncogenic osteomalacia Phosphatonin (fibroblast growth factor 23 [FGF23]) Hemangiopericytomas, osteoblastomas, fibromas, sarcomas, giant

cell tumors, prostate, lung

Acromegaly Growth hormone–releasing hormone (GHRH) Pancreatic islet, bronchial, and other carcinoids

Growth hormone (GH) Lung, pancreatic islet

Hyperthyroidism Thyroid-stimulating hormone (TSH) Hydatidiform mole, embryonal tumors, struma ovarii

Hypertension Renin Juxtaglomerular tumors, kidney, lung, pancreas, ovaryaOnly the most common tumor types are listed. For most ectopic hormone syndromes, an extensive list of tumors has been reported to produce one or more hormones. bhCG is pro-duced eutopically by trophoblastic tumors. Certain tumors produce disproportionate amounts of the hCG α or hCG β subunit. High levels of hCG rarely cause hyperthyroidism because of weak binding to the TSH receptor. cCalcitonin is produced eutopically by medullary thyroid carcinoma and is used as a tumor marker.

levels in SCLC associated with ectopic ACTH. The activity of hASH-1 is inhibited by hairy enhancer of split 1 (HES-1) and by Notch pro-teins, which also are capable of inducing growth arrest. Thus, abnor-mal expression of these developmental transcription factors appears to provide a link between cell proliferation and differentiation.

Ectopic hormone production would be merely an epiphenomenon associated with cancer if it did not result in clinical manifestations. Excessive and unregulated production of hormones such as ACTH, PTHrP, and vasopressin can lead to substantial morbidity and com-plicate the cancer treatment plan. Moreover, the paraneoplastic endocrinopathies may be a presenting clinical feature of underlying malignancy and prompt the search for an unrecognized tumor.

A large number of paraneoplastic endocrine syndromes have been described, linking overproduction of particular hormones with specific types of tumors. However, certain recurring syndromes emerge from this group (Table 121-1). The most common paraneoplastic endocrine syndromes include hypercalcemia from overproduction of PTHrP and other factors, hyponatremia from excess vasopressin, and Cushing’s syndrome from ectopic ACTH.

HYPERCALCEMIA CAUSED BY ECTOPIC PRODUCTION OF PTHRP(See also Chap. 424)

Etiology Humoral hypercalcemia of malignancy (HHM) occurs in up to 20% of patients with cancer. HHM is most common in cancers of the lung, head and neck, skin, esophagus, breast, and genitourinary tract and in multiple myeloma and lymphomas. There are several distinct humoral causes of HHM, but it is caused most commonly by overproduction of PTHrP. In addition to acting as a circulating

humoral factor, bone metastases (e.g., breast, multiple myeloma) may produce PTHrP, leading to local osteolysis and hypercalcemia. PTHrP may also affect the initiation and progression of tumors by acting through pro-survival and chemokine pathways.

PTHrP is structurally related to PTH and binds to the PTH recep-tor, explaining the similar biochemical features of HHM and hyper-parathyroidism. PTHrP plays a key role in skeletal development and regulates cellular proliferation and differentiation in other tissues, including skin, bone marrow, breast, and hair follicles. The mechanism of PTHrP induction in malignancy is incompletely understood; how-ever, tumor-bearing tissues commonly associated with HHM normally produce PTHrP during development or cell renewal. PTHrP expres-sion is stimulated by hedgehog pathways and Gli transcription factors that are active in many malignancies. Transforming growth factor β (TGF-β), which is produced by many tumors, also stimulates PTHrP, in part by activating the Gli pathway. Mutations in certain oncogenes, such as Ras, also can activate PTHrP expression. In adult T cell lym-phoma, the transactivating Tax protein produced by human T cell lymphotropic virus 1 (HTLV-1) stimulates PTHrP promoter activity. Metastatic lesions to bone are more likely to produce PTHrP than are metastases in other tissues, suggesting that bone produces factors (e.g., TGF-β) that enhance PTHrP production or that PTHrP-producing metastases have a selective growth advantage in bone. PTHrP activates the pro-survival AKT pathway and the chemokine receptor CXCR4. Thus, PTHrP production can be stimulated by mutations in onco-genes, altered expression of viral or cellular transcription factors, and local growth factors. In addition to its role in HHM, the PTHrP path-way may also provide a potential target for therapeutic intervention to impede cancer growth.

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HEMATOLOGIC SYNDROMES

PART 7Oncology and Hematology

612 TABLE 121-2 PARANEOPLASTIC HEMATOLOGIC SYNDROMES

Syndrome ProteinsCancers Typically Associated with Syndrome

Erythrocytosis Erythropoietin Renal cancers, hepatocarci-noma, cerebellar hemangio-blastomas

Granulocytosis G-CSF, GM-CSF, IL-6 Lung cancer, gastrointesti-nal cancer, ovarian cancer, genitourinary cancer, Hodgkin’s disease

Thrombocytosis IL-6 Lung cancer, gastrointestinal cancer, breast cancer, ovarian cancer, lymphoma

Eosinophilia IL-5 Lymphoma, leukemia, lung cancer

Thrombophlebitis Unknown Lung cancer, pancreatic cancer, gastrointestinal cancer, breast cancer, genitourinary cancer, ovarian cancer, prostate cancer, lymphoma

Abbreviations: G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macro-phage colony-stimulating factor; IL, interleukin.

necessary to prevent hypoglycemia. Glucagon and glucocorticoids have also been used to enhance glucose production.

HUMAN CHORIONIC GONADOTROPINhCG is composed of α and β subunits and can be produced as intact hormone, which is biologically active, or as uncombined biologically inert subunits. Ectopic production of intact hCG occurs most often in association with testicular embryonal tumors, germ cell tumors, extragonadal germinomas, lung cancer, hepatoma, and pancreatic islet tumors. Eutopic production of hCG occurs with trophoblastic malignancies. hCG α subunit production is particularly common in lung cancer and pancreatic islet cancer. In men, high hCG levels stimulate steroidogenesis and aromatase activity in testicular Leydig cells, resulting in increased estrogen production and the development of gynecomastia. Precocious puberty in boys or gynecomastia in men should prompt measurement of hCG and consideration of a testicular tumor or another source of ectopic hCG production. Most women are asymptomatic. hCG is easily measured. Treatment should be directed at the underlying malignancy.

ONCOGENIC OSTEOMALACIAHypophosphatemic oncogenic osteomalacia, also called tumor-induced osteomalacia (TIO), is characterized by markedly reduced serum phosphorus and renal phosphate wasting, leading to muscle weakness, bone pain, and osteomalacia. Serum calcium and PTH levels are normal, and 1,25-dihydroxyvitamin D is low. Oncogenic osteoma-lacia is usually caused by benign mesenchymal tumors, such as heman-giopericytomas, fibromas, and giant cell tumors, often of the skeletal extremities or head. It has also been described in sarcomas and in patients with prostate and lung cancer. Resection of the tumor reverses the disorder, confirming its humoral basis. The circulating phospha-turic factor is called phosphatonin—a factor that inhibits renal tubular reabsorption of phosphate and renal conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D. Phosphatonin has been identified as fibroblast growth factor 23 (FGF23). FGF23 levels are increased in some, but not all, patients with osteogenic osteomalacia. FGF23 forms a ternary complex with the klotho protein and renal FGF receptors to reduce renal phosphate reabsorption. Treatment involves removal of the tumor, if possible, and supplementation with phosphate and vitamin D. Octreotide treatment reduces phosphate wasting in some patients with tumors that express somatostatin receptor subtype 2. Octreotide scans may also be useful in detecting these tumors.

HEMATOLOGIC SYNDROMESThe elevation of granulocyte, platelet, and eosinophil counts in most patients with myeloproliferative disorders is caused by the proliferation of the myeloid elements due to the underlying disease rather than to a paraneoplastic syndrome. The paraneoplastic hematologic syndromes in patients with solid tumors are less well characterized than are the endocrine syndromes because the ectopic hormone(s) or cytokines responsible have not been identified in most of these tumors (Table 121-2). The extent of the paraneoplastic syndromes parallels the course of the cancer.

ERYTHROCYTOSISEctopic production of erythropoietin by cancer cells causes most paraneoplastic erythrocytosis. The ectopically produced erythropoi-etin stimulates the production of red blood cells (RBCs) in the bone marrow and raises the hematocrit. Other lymphokines and hormones produced by cancer cells may stimulate erythropoietin release but have not been proved to cause erythrocytosis.

Most patients with erythrocytosis have an elevated hematocrit (>52% in men, >48% in women) that is detected on a routine blood count. Approximately 3% of patients with renal cell cancer, 10% of patients with hepatoma, and 15% of patients with cerebellar heman-gioblastomas have erythrocytosis. In most cases, the erythrocytosis is asymptomatic.

Patients with erythrocytosis due to a renal cell cancer, hepatoma, or CNS cancer should have measurement of red cell mass. If the red cell

mass is elevated, the serum erythropoietin level should be measured. Patients with an appropriate cancer, elevated erythropoietin levels, and no other explanation for erythrocytosis (e.g., hemoglobinopathy that causes increased O2 affinity; Chap. 77) have the paraneoplastic syndrome.

TREATMENT ERYTHROCYTOSISSuccessful resection of the cancer usually resolves the erythrocy-tosis. If the tumor cannot be resected or treated effectively with radiation therapy or chemotherapy, phlebotomy may control any symptoms related to erythrocytosis.

GRANULOCYTOSISApproximately 30% of patients with solid tumors have granulocy-tosis (granulocyte count >8000/μL). In about half of patients with granulocytosis and cancer, the granulocytosis has an identifiable nonparaneoplastic etiology (infection, tumor necrosis, glucocorticoid administration, etc.). The other patients have proteins in urine and serum that stimulate the growth of bone marrow cells. Tumors and tumor cell lines from patients with lung, ovarian, and bladder cancers have been documented to produce granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and/or interleukin 6 (IL-6). However, the etiology of granulocytosis has not been characterized in most patients.

Patients with granulocytosis are nearly all asymptomatic, and the differential white blood cell count does not have a shift to immature forms of neutrophils. Granulocytosis occurs in 40% of patients with lung and gastrointestinal cancers, 20% of patients with breast cancer, 30% of patients with brain tumors and ovarian cancers, 20% of patients with Hodgkin’s disease, and 10% of patients with renal cell carcinoma. Patients with advanced-stage disease are more likely to have granulo-cytosis than are those with early-stage disease.

Paraneoplastic granulocytosis does not require treatment. The granulocytosis resolves when the underlying cancer is treated.

THROMBOCYTOSISSome 35% of patients with thrombocytosis (platelet count >400,000/μL) have an underlying diagnosis of cancer. IL-6, a candidate molecule for the etiology of paraneoplastic thrombocytosis, stimulates the produc-tion of platelets in vitro and in vivo. Some patients with cancer and thrombocytosis have elevated levels of IL-6 in plasma. Another can-didate molecule is thrombopoietin, a peptide hormone that stimulates megakaryocyte proliferation and platelet production. The etiology of thrombocytosis has not been established in most cases.

Patients with thrombocytosis are nearly all asymptomatic. Thrombocytosis is not clearly linked to thrombosis in patients with

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ONCOLOGIC EMERGENCIES

Pressureorobstruc<on

Metabolicorhormonalproblems

Treatment-related

complica<ons

SUPERIOR VENA CAVA SYNDROME

PATHOPHYSIOLOGY ASSOCIATEDTUMORS CLINICALMANIFESTATIONS

Superiorvenacava(SVC)obstruc<on,withseverereduc<oninvenousreturnfromthehead,neck,&upperextremi<es

–Lung(smallcell,squamouscell)–Lymphoma(esp.inyoungadults)–Metasta<ctumorstothemedia<nallymphnodes(tes<cular,breast)

–Neck&facialswelling–Dyspnea–Cough–Othersymptoms:Hoarseness,tongueswelling,headaches,nasalconges<on,epistaxis,hemoptysis,dysphagia,pain,dizziness,syncope,lethargy–Dilatedneckveins–Increasednumberofanteriorchestwallcollateralveins–Cyanosis–Edema&plethoraoftheface,arms,&chest–Moreseverecases:Proptosis,glossal&laryngealedema,obtunda<on


§  The diagnosis of SVCS is a clinical one.

§  Widening of the superior mediastinum – most significant chest radiographic finding o  Normal chest radiograph – still

compatible with the diagnosis if other characteristic findings are present

o  Pleural effusion – occurs in only 25% of patients

§  CT scan – most reliable view of the mediastinal anatomy o  Diminished or absent opacification of central venous structures

with prominent collateral venous circulation

§  Endobronchial or esophageal ultrasound-guided needle aspiration – may establish the diagnosis safely

§  For patients with a known cancer, a detailed workup usually is not necessary, and appropriate treatment may be started after obtaining a CT scan of the thorax.

§  Tracheal obstruction – the one potentially life-threatening complication of a superior mediastinal mass



MANAGEMENT REMARKS

DiureNcswithalow-saltdiet

Mayproducetemporarysymptoma<crelief

HeadelevaNon

Oxygen

GlucocorNcoids Maybeusefulatshrinkinglymphomamasses,butareofNObenefitinpa<entswithlungcancer

RadiaNontherapy PrimarytreatmentforSVCScausedbynon-small-celllungcancer&othermetasta<csolidtumors

Chemotherapy Effec<vewhentheunderlyingcancerissmallcellcarcinomaofthelung,lymphoma,orgermcelltumor

Intravascularself-expandingstents

Maybenecessaryinpa<entswithseveresymptoms

PERICARDIAL EFFUSION


Pericardialmetastasis –Lung–Breast–Leukemias–Lymphomas

–Asymptoma<c(mostcommon)–Dyspnea,orthopnea–Cough–Chestpain–Weakness–Pleuraleffusion–Sinustachycardia–Jugularvenousdisten<on–Hepatomegaly–Peripheraledema–Cyanosis


§  Chest radiographs and electrocardiogram (ECG) – reveal abnormalities in 90% of patients

§  Echocardiography – most helpful diagnostic test

§  CT scan findings suggestive of a malignant pericardial effusion: o  Irregular pericardial thickening o  Mediastinal lymphadenopathy


§  Cytologic examination of pericardial fluid – diagnostic in most patients o May be serous, serosanguineous, or hemorrhagic o  Positive cytology – very poor survival (about 7

weeks)

§  Combination of cytology, pericardial and epicardial biopsy, and guided pericardioscopy – best diagnostic yield

MANAGEMENT REMARKS

Pericardiocentesiswithorwithoutsclerosingagents

Acutepericardialtamponadewithlife-threateninghemodynamicinstabilityrequiresimmediatedrainageoffluid.Pericardialwindow/

pericardiotomy

Completepericardialstripping

CardiacirradiaNon

Systemicchemotherapy


SPINAL CORD COMPRESSION


Compressionofthespinalcord&/orcaudaequinabyanextraduraltumormass,producingedema&ischemiaDirectextensionofaparavertebrallesionthroughtheintervertebralforamen

–Mostcommon:Lung–Breast–Prostate–Mul<plemyeloma–Lesscommon:Lymphomas,melanoma,renal,genitourinary

–Localizedbackpain&tenderness(mostcommon)–Radicularpain–Lossofbowelorbladdercontrol(late)–Paininducedbystraightlegraising,neckflexion,orvertebralpercussion–Numbness&paresthesias,withtheupperlimitofthezoneofsensorylossoXen1or2vertebraelower–Weakness,spas<city,abnormalmusclestretching,extensorplantarreflex,hyperreflexia–Absenceoftheanalwinkreflexorthebulbocavernosusreflex(confirmscordinvolvement)–Autonomicdysfunc<on


§  Thoracic spine – most common site (70%) o  Lumbosacral spine (20%) o  Cervical spine (10%) o  Multiple sites – most frequent in patients

with breast and prostate carcinoma

§  Erosion of the pedicles (“winking owl” sign) – earliest radiologic finding of vertebral tumor

§  A normal appearance on plain films of the

spine does not exclude the diagnosis of cancer.


§  MRI – imaging procedure of choice o  Indentation of the theca at the level of clinical features –

minimum radiologic evidence for cord compression

§  In patients with cord compression and an unknown primary tumor, a simple workup including the following usually reveals the underlying malignancy: o  Chest radiography o  Mammography o  Measurement of prostate-specific antigen (PSA) o  Abdominal CT scan


CHAPTER 331Oncologic Emergencies

1791and a distended bladder. The absence of the anal wink reflex or the bulbocavernosus reflex confirms cord involvement. In doubtful cases, evaluation of postvoiding urinary residual volume can be helpful. A residual volume of >150 mL suggests bladder dysfunction. Autonomic dysfunction is an unfavorable prognostic factor. Patients with progres-sive neurologic symptoms should have frequent neurologic examina-tions and rapid therapeutic intervention. Other illnesses that may mimic cord compression include osteoporotic vertebral collapse, disk disease, pyogenic abscess or vertebral tuberculosis, radiation myelopa-thy, neoplastic leptomeningitis, benign tumors, epidural hematoma, and spinal lipomatosis.

Cauda equina syndrome is characterized by low back pain; dimin-ished sensation over the buttocks, posterior-superior thighs, and peri-neal area in a saddle distribution; rectal and bladder dysfunction; sex-ual impotence; absent bulbocavernous, patellar, and Achilles’ reflexes; and variable amount of lower-extremity weakness. This reflects com-pression of nerve roots as they form the cauda equina after leaving the spinal cord. The majority of cauda equine tumors are primary tumors of glial or nerve sheath origin; metastases are very rare.

Patients with cancer who develop back pain should be evaluated for spinal cord compression as quickly as possible (Fig. 331-2). Treatment is more often successful in patients who are ambulatory and still have sphincter control at the time treatment is initiated. Patients should have a neurologic examination and plain films of the spine. Those whose physical examination suggests cord compression should receive dexamethasone (6 mg intravenously every 6 h), starting immediately.

Erosion of the pedicles (the “winking owl” sign) is the earliest radiologic finding of vertebral tumor. Other radiographic changes include increased intrapedicular distance, vertebral destruction, lytic or sclerotic lesions, scalloped vertebral bodies, and vertebral body col-lapse. Vertebral collapse is not a reliable indicator of the presence of tumor; about 20% of cases of vertebral collapse, particularly those in

older patients and postmenopausal women, are due not to cancer but to osteoporosis. Also, a normal appearance on plain films of the spine does not exclude the diagnosis of cancer. The role of bone scans in the detection of cord compression is not clear; this method is sensitive but less specific than spinal radiography.

The full-length image of the cord provided by MRI is the imaging procedure of choice. Multiple epidural metastases are noted in 25% of patients with cord compression, and their presence influences treat-ment plans. On T1-weighted images, good contrast is noted between the cord, cerebrospinal fluid, and extradural lesions. Owing to its sen-sitivity in demonstrating the replacement of bone marrow by tumor, MRI can show which parts of a vertebra are involved by tumor. MRI also visualizes intraspinal extradural masses compressing the cord. T2-weighted images are most useful for the demonstration of intra-medullary pathology. Gadolinium-enhanced MRI can help to delineate intramedullary disease. MRI is as good as or better than myelography plus postmyelogram CT scan in detecting metastatic epidural disease with cord compression. Myelography should be reserved for patients who have poor MRIs or who cannot undergo MRI promptly. CT scan in conjunction with myelography enhances the detection of small areas of spinal destruction.

In patients with cord compression and an unknown primary tumor, a simple workup including chest radiography, mammography, measurement of prostate-specific antigen, and abdominal CT usually reveals the underlying malignancy.

TREATMENT SPINAL CORD COMPRESSIONThe treatment of patients with spinal cord compression is aimed at relief of pain and restoration/preservation of neurologic func-tion (Fig. 331-2). Management of MSCC requires a multidisciplinary approach.

Symptomatic therapy

Back pain

Neurologic exam

Plain spine x-ray

High-dosedexamethasone

MRI of spine

Bone metastases butno epidural metastases

Symptomatic therapy ±radiation therapy

Epidural metastases No metastases

Surgery followed byradiation therapy orradiation therapy alone

Symptomatic therapy

Pain crescendo patternLhermitte’s signPain aggravated with cough,Valsalva, and recumbency

Abnormal

Normal

Normal Suspicious formyelopathy

FIGURE 3312 Management of cancer patients with back pain.

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§  Goals of treatment: o  Relief of pain o  Restoration/preservation of neurologic function

§  Treatment is more often successful in patients who are ambulatory and still have sphincter control at the time treatment is initiated. o  Patients should have a neurologic examination and plain

films of the spine. o  Those whose physical examination suggests cord

compression should immediately receive dexamethasone.

MANAGEMENT REMARKS

RadiaNontherapyplusglucocorNcoids

Ini<altreatmentofchoice;upto75%ofpa<entstreatedwhens<llambulatoryremainambulatory,butonly10%ofpa<entswithparaplegiarecoverwalkingcapacity

SurgicalintervenNon Indica<ons:–Unknowne<ology–Failureofradia<ontherapy–Radioresistanttumortype(e.g.,melanomaorrenalcellcancer)–Pathologicfracturedisloca<on–Rapidlyevolvingneurologicsymptoms

Chemotherapy Mayhavearoleinpa<entswithchemosensi<vetumorswhohavehadpriorradiotherapytothesameregion&whoarenotcandidatesforsurgery


INCREASED INTRACRANIAL PRESSURE


Tumormassandsurroundingedemamaycauseobstruc<onofthecircula<onofcerebrospinalfluid,withresul<nghydrocephalus

–Mostcommon:Lung,breast,melanoma–Melanoma–Germcelltumors–Renal

–Headache,nausea,vomi<ng,behavioralchanges,seizures,&focal,progressiveneurologicchanges–Occasionallywithabruptonset,resemblingastroke,usuallyduetohemorrhageintothemetastasis–Papilledemawithvisualdisturbances&necks<ffness–Hernia<onsyndromes

§  Chest/abdominal CT scans and brain MRI as the initial diagnostic studies can identify a biopsy site in most patients.

§  CT scan and MRI are equally effective in the diagnosis of brain metastases. o  CT scan with contrast should be used as a screening

procedure, which may show multiple enhancing lesions of various sizes with surrounding areas of low-density edema.

o  Gadolinium-enhanced MRI is better in the following circumstances: –  Single lesion or no metastases visualized by CT scan –  Meningeal involvement –  Small lesions, particularly in the brainstem or cerebellum


MANAGEMENT REMARKS

Dexamethasone Bestini<altreatmentforallsymptoma<cpa<entswithbrainmetastases

Whole-brainradiaNontherapy(WBRT)

Forpa<entswithmul<plelesions

SurgicalexcisionfollowedbyWBRT

Forpa<entswithasinglebrainmetastasis&withcontrolledextracranialdisease,esp.iftheyare<60years

SurgicalresecNon Forradioresistanttumors

StereotacNcradiosurgery(SRS)

Recommendedinpa<entswithalimitednumberofbrainmetastases(1-4)whohavestable,systemicdiseaseorreasonablesystemictreatmentop<ons,&forpa<entswhohaveasmallnumberofmetasta<clesionsinwhomWBRThasfailed

Shuntplacement,ventriculotomy,craniotomy

Forsomepa<entswithhydrocephalusinwhomneurologicdeteriora<onisnotreversedwithmedicaltherapy


TUMOR LYSIS SYNDROME


Destruc<onofalargenumberofrapidlyprolifera<ngneoplas<ccells

–Mostcommon:BurkiV’slymphoma,acutelymphoblas<cleukemia,otherrapidlyproliferat-inglymphomas–Chronicleukemias–Rare:Solidtumors

–Hyperuricemiafromtheturnoverofnucleicacids–Hyperkalemiafromthereleaseofintracellularpotassium,whichmaycauseventriculararrhythmias&suddendeath–Hyperphosphatemiafromthereleaseofintracellularphosphatepools–Reciprocalhypocalcemia,whichcausessevereneuromuscularirritability&tetany–Lac<cacidosis–Acuterenalfailurefromtherenalprecipita<onofuricacid,calciumphosphatedeposi<on,&hyperphos-phatemia

§  Usually occurs during or shortly (1-5 days) after chemotherapy o  Rarely, spontaneous necrosis of malignancies causes TLS.

§  The likelihood that TLS will occur is related to the tumor burden and renal function. o  Also correlated with hyperuricemia and high serum levels of

lactate dehydrogenase (LDH >1500 U/L), which reflect total tumor burden

§  Pretreatment evaluations should include a complete blood count, serum chemistry evaluation, and urinalysis.

§  Risk stratification and prevention are the most important steps in the management of this syndrome.


Critical Care MedicinePART 12

1796 monocytes/macrophages and T and B lymphocytes. Severe reactions from rituximab have occurred with high numbers (>50 × 109 lymphocytes) of circulating cells bearing the target antigen (CD20) and have been associated with a rapid fall in circulating tumor cells, mild electrolyte evidence of TLS, and very rarely, death. In addition, increased liver enzymes, D-dimer, and LDH and prolongation of the prothrombin time may occur. Diphenhydramine, hydrocortisone, and acetaminophen can often prevent or suppress the infusion-related symptoms. If they occur, the infu-sion is stopped and restarted at half the initial infu-sion rate after the symptoms have abated. Severe CRS may require intensive support for acute respiratory distress syndrome (ARDS) and resistant hypotension.

HEMOLYTICUREMIC SYNDROMEHemolytic-uremic syndrome (HUS) and, less com-monly, thrombotic thrombocytopenic purpura (TTP) (Chap. 341) may rarely occur after treatment with antineoplastic drugs, including mitomycin, gem-citabine, cisplatin, and bleomycin, and with VEGF inhibitors. It occurs most often in patients with gastric, lung, colorectal, pancreatic, and breast car-cinoma. In one series, 35% of patients were without evident cancer at the time this syndrome appeared. Secondary HUS/TTP has also been reported as a rare but sometimes fatal complication of bone marrow transplantation.

HUS usually has its onset 4–8 weeks after the last dose of chemotherapy, but it is not rare to detect it several months later. HUS is characterized by micro-angiopathic hemolytic anemia, thrombocytopenia, and renal failure. Dyspnea, weakness, fatigue, oligu-ria, and purpura are also common initial symptoms and findings. Systemic hypertension and pulmonary edema frequently occur. Severe hypertension, pul-monary edema, and rapid worsening of hemoly-sis and renal function may occur after a blood or blood product transfusion. Cardiac findings include

atrial arrhythmias, pericardial friction rub, and pericardial effusion. Raynaud’s phenomenon is part of the syndrome in patients treated with bleomycin.

Laboratory findings include severe to moderate anemia associ-ated with red blood cell fragmentation and numerous schistocytes on peripheral smear. Reticulocytosis, decreased plasma haptoglobin, and an LDH level document hemolysis. The serum bilirubin level is usually normal or slightly elevated. The Coombs’ test is negative. The white cell count is usually normal, and thrombocytopenia (<100,000/μL) is almost always present. Most patients have a normal coagulation profile, although some have mild elevations in thrombin time and in levels of fibrin degradation products. The serum creatinine level is elevated at presentation and shows a pattern of subacute worsening within weeks of the initial azotemia. The urinalysis reveals hematuria, proteinuria, and granular or hyaline casts; and circulating immune complexes may be present.

The basic pathologic lesion appears to be deposition of fibrin in the walls of capillaries and arterioles, and these deposits are similar to those seen in HUS due to other causes. These microvascular abnor-malities involve mainly the kidneys and rarely occur in other organs. The pathogenesis of cancer treatment–related HUS is not completely understood, but probably the most important factor is endothelial damage. Primary forms of HUS/TTP are related to a decrease in pro-cessing of von Willebrand factor by a protease called ADAMTS13.

The case fatality rate is high; most patients die within a few months. There is no consensus on the optimal treatment for chemotherapy-induced HUS. Treatment modalities for HUS/TTP including immu-nocomplex removal (plasmapheresis, immunoadsorption, or exchange transfusion), antiplatelet/anticoagulant therapies, immunosuppressive

during laboratory monitoring of the patient with TLS. Samples must be cooled immediately to deactivate the urate oxidase. Despite aggressive prophylaxis, TLS and/or oliguric or anuric renal failure may occur. Care should be taken to prevent worsening of symptom-atic hypocalcemia by induction of alkalosis during bicarbonate infu-sion. Administration of sodium bicarbonate may also lead to urinary precipitation of calcium phosphate, which is less soluble at alkaline pH. Dialysis is often necessary and should be considered early in the course. Hemodialysis is preferred. Hemofiltration offers a gradual, continuous method of removing cellular by-products and fluid. The prognosis is excellent, and renal function recovers after the uric acid level is lowered to ≤10 mg/dL.

HUMAN ANTIBODY INFUSION REACTIONSThe initial infusion of human or humanized antibodies (e.g., ritux-imab, gemtuzumab, trastuzumab, alemtuzumab, panitumumab, bren-tuximab vedotin) is associated with fever, chills, nausea, asthenia, and headache in up to half of treated patients. Bronchospasm and hypotension occur in 1% of patients. Severe manifestations including pulmonary infiltrates, acute respiratory distress syndrome, and cardio-genic shock occur rarely. Laboratory manifestations include elevated hepatic aminotransferase levels, thrombocytopenia, and prolongation of prothrombin time. The pathogenesis is thought to be activation of immune effector processes (cells and complement) and release of inflammatory cytokines, such as tumor necrosis factor α, interferon gamma, interleukin 6, and interleukin 10 (cytokine release syndrome [CRS]). Although its origins are not completely understood, CRS is believed to be due to activation of a variety of cell types including

Serum uric acid >8 mg/dLSerum creatinine >1.6 mg/dL

Maintain hydration by administration of normal or 1/2 normal saline at 3000 mL/m2 per day–/+ Keep urine pH at 7.0 or greater by administration of sodium bicarbonate*Administer allopurinol at 300 mg/m2 per dayMonitor serum chemistry

PREVENTION AND TREATMENT OF TUMOR LYSIS SYNDROME

If, after 24–48 h

Serum uric acid >8 mg/dLSerum creatinine >1.6 mg/dL

Correct treatable renal failure(obstruction)

Start rasburicase 0.2 mg/kgdaily

Serum uric acid ≤8.0 mg/dLSerum creatinine ≤1.6 mg/dL

Urine pH ≥7.0

Delay chemotherapy iffeasible or start hemodialysis

± chemotherapy

Start chemotherapyDiscontinue bicarbonate administration*Monitor serum chemistry every 6–12 h

If serum potassium >6 meq/LSerum uric acid >10 mg/dLSerum creatinine >10 mg/dLSerum phosphate >10 mg/dL or increasingSymptomatic hypocalcemia present

Begin hemodialysis

FIGURE 3314 Management of patients at high risk for the tumor lysis syndrome. *See text.

HPIM19_Part12_p1729-p1798.indd 1796 2/9/15 3:34 PM


MANAGEMENT REMARKS

AggressivehydraNon

Allopurinol Decreasesuricacidlevels

Rasburicase(recombinanturateoxidase)

Actsrapidly(withinhours);canbeeffec<ve,par<cularlywhenrenalfailureispresent

UrinaryalkalizaNonwithsodiumbicarbonate

Controversial;increasesuricacidsolubility,butdecreasescalciumphosphatesolubility

Dialysis OXennecessaryandshouldbeconsideredearlyinthecourse


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PARANEOPLASTIC SYNDROMES & ONCOLOGIC EMERGENCIES

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