Digital Ischemia as a Manifestation of Malignancy

LLOYD M. TAYLOR, JR., M.D., MICHAEL G. HAUTY, M.D., JAMES M. EDWARDS, M.D., and JOHN M. PORTER, M.D.

The association of malignancy with thrombotic disorders of thearterial and venous systems is well described. To date, how-ever, there are only 23 published case reports of digital gan-grene associated with malignancy. During a prospective evalu-ation of over 700 patients with finger ischemia, there were fivepatients with finger gangrene associated with malignancy. De-tailed clinical and laboratory evaluation, including detailed im-munologic survey and hand angiography, allowed establish-ment of the precise mechanisms responsible for vascular oc-clusions in each patient. Three mechanisms were identified:arteritis, hyperviscosity, and hypercoagulability. Digital gan-grene associated with malignancy is a rare condition, themechanism for which can be deduced by careful diagnosticevaluation.

Tn HE OCCASIONAL ASSOCIATION ofdiseases of thevascular system with systemic neoplasia hasbeen recognized for over a century. The earliest

reported paraneoplastic syndrome involving the vascu-lar system was Trousseau's description in 1865 of femo-ral vein thrombosis, which he termed phlegmasia albadolens, and occult carcinoma.' Venous thrombosis as-sociated with carcinoma has been reported subse-quently, frequently being termed "thrombophlebitismigrans."2-4

Descriptions ofthe remote effects ofneoplasms on thearterial system have increased in frequency and varietyin the past several decades.5 6 Hairy cell leukemia hasbeen associated with classic polyarteritis nodosa.7Symptoms of central nervous system granulomatousangiitis have preceded the diagnosis of Hodgkin's dis-

Supported in part from Grant RR00334 from the General ClinicalResearch Center Branch, Division of Research Resources, NationalInstitutes of Health, Bethesda, Maryland.

Reprint requests: John M. Porter, M.D., Department of Surgery,The Oregon Health Sciences University, 3181 S.W. Sam Jackson ParkRoad, Portland, OR 97201.Submitted for publication: December 31, 1986.

From the Division of Vascular Surgery, Oregon HealthSciences University, Portland, Oregon

ease in at least several patients.89 Johnson et al.'0 havedescribed vasculitis involving nutrient arteries of nerves,which may explain the frequently observed relationshipof mononeuritis monoplex with small cell carcinomaand lymphoma. Ischemic tissue necrosis, possiblycaused by hyperviscosity, has been reported in a patientwith chronic granulocytic leukemia." Cryoglobuline-mia and multiple myeloma associated with Raynaud'ssyndrome were reported as early as 1933.12,13The coexistence of digital ischemia and carcinoma

was first reported in 1884 by O'Connor. He described amiddle-aged woman with breast cancer and presumedleft supraclavicular metastases who had gangrenous fin-gertips.'4 Seven years later, Fagge and Pye-Smith de-scribed a young woman with digital ischemia who wasfound to have a locally infiltrating tumor mass involvingthe first dorsal sympathetic nerve at necropsy. The pa-tient died within 1 year of onset of symptoms. The au-thors hypothesized that the digital ischemia was causedby local tumor invasion or metastases to the cervicalsympathetic trunk.'"To our knowledge there have been 23 published case

reports linking digital ischemia and malignant disease.The ischemic changes have been generally bilateral,symmetric, and have involved the upper extremities.Most of the reports have described single patients, withvariable, usually sparse, accompanying laboratory data.These reports are summarized in Table 1.

In the past 15 years during a prospective evaluation ofover 700 patients with upper extremity ischemia, wefound five patients to have finger gangrene occurring inassociation with systemic malignancy. Each of these pa-tients had detailed evaluation, including magnification

62

DIGITAL ISCHEMIA AS A MANIFESTATION OF MALIGNANCY

TABLE 1. Case Reports Associating Digital Ischemia with Malignancy

CaseDate Author Sex Age Malignancy Type Symptoms Course

1 1866 Fagge and Pye-Smith"5

2 1884 O'Connor'4

3 1901 Pasteur andPrice-Jones33

4 1920 Hamilton3

5 1928 Bennett andPoulton23

6 1961 Domz andChapman27

7 1963 Nielson andPetri24

8 1959 Hawley et al.(1967)35

9 ? Hawley et al.(1967)31

10 1964-1965 Hawley et al.(1967)35

11 1957 Hawley et al.(1967)31

12 1965-1966 Hawley et al.(1967)35

13 1953-1954 Hawley et al.(1967)35

14 1965-1967 Friedman et al.25

15 1966 Friedman et al.25

17 1970 Powell (1973)36

18 1974 Palmer andVedi6,37

19 1974 Palmer andVedi6'37

20 1974 Palmer andVedi6'37

21 1976-1977 O'Donnell et al.(1980)28

22 1978-1977 O'Donnell et al.(1980)28

23 1983 Wytock et al.38

F "young" CNS metastases, 1st Blue, cold, painful Died within 1 yeardorsal nerve and fingerssympathetic trunkmetastases

F "middle Breast carcinoma Gangrene: fingertips Left supraclavicular metastasisaged"

M 61 Gastric carcinoma Cold, blue extremities, ?Raynaud's

M 54 Esophageal carcinoma Typical Raynaud's ?syndrome

M 61 Occult gastric Raynaud's syndrome Died during cervicalcarcinoma sympathectomy

F 56 Adenocarcinoma right Digital ischemia, Symptoms resolved withlung, myelofibrosis, gangrene fingertips tumor resectioncryoglobulins

F 77 Colon carcinoma, Symmetrical Diedcervical gangrene: fingerssympathetic andstellate ganglionmetastasis

F 59 Anaplastic carcinoma Painful, numb, Died in 4 monthsof maxillary antrum gangrene digits

F 54 Hypernephroma Cold, numb, painful Return of pulses, healing offingers lesions, died within months

F 45 Rectal/colon Raynaud's syndrome Died within 11 months ofcarcinoma, cystic symptoms despite tumorovarian tumor resection

F 45 Adenopapillary Numb, cold hands Radiation therapy, symptomsovarian carcinoma resolvedwith metastasis

F 58 Pancreatic/ovariancarcinoma

F 42 Hodgkin's disease

F 32 Epidermoidcarcinoma, cervix,stage 1, ankylosingspondylitis

57 Anaplastic breastcarcinoma withnodes

7 Acute lymphocyticleukemia

F 62 Reticulum cellsarcoma

F 74 Intra-abdominalcarcinoma

F 66 Gastric carcinoma

M 9 Acute myelocyticleukemia

M 52 Poorly differentiatedadenocarcinoma,Buerger's disease

F 59 Adenocarcinoma ofileum

Pain, numb, pallor: Died in 8 monthsfingers

Pain, tingling, blue Chemotherapy, radiationfingers

Raynaud's syndrome, Symptoms improved withright leg gangrene excision and radiationupper extremity therapy

Ischemia and Symptoms resolved 22gangrene fingers months after mastectomyand feet, bilateralthigh amputation

Raynaud's syndrome Remission ofsymptoms afterchemotherapy andradiation therapy

Finger cyanosis, Death months after onset ofbilateral splinter symptomshemorrhages

Numbness, tingling Death months after onset ofand cyanosis symptomsbilateral fingers

Cold, blue fingers Symptoms resolved afterresection

Foot necrosis 9/76 Died 11/77: right mainpulmonary artery thrombus

Claudication, great Died 1/79toe necrosis,brachial arterythrombosis

Digital ischemia Resolution of symptoms,resection x 5 years

hand arteriography and skin biopsy in three of the five five patients. Our experience with the diagnosis andpatients and detailed laboratory screening for collagen management of these patients forms the basis for thisvascular disease and coagulation abnormalities in all report.

63Vol. 206 * No. I

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64 TAYLOR AND OTHERS

TABLE 2. Laboratory Testsfor Patients with Severe Digital Ischemia

Complete blood count Platelet countProthrombin time Serum triglyceridesPartial thromboplastin time Serum cholesterolSedimentation rate Blood viscosityHepatitis B antigen/antibody Urine proteinSerum protein electrophoresis Cold agglutininsImmunoglobulin electrophoresis CryoglobulinRheumatoid factor CryofibrinogenAntinuclear antibody Anti-DNAExtractable nuclear antigenRaji cell immune complex assay*Complement (C3, C4, C19 binding assay)Anticardiolipin antibody*

* Not routinely obtained.

Diagnostic Evaluation

Our approach to the diagnostic evaluation of patientswith severe finger ischemia is standardized and has beenpreviously reported.'6-'9 Each patient has had pharma-codynamic magnification hand arteriography and/ornoninvasive digital vascular examinations to identifyand quantitate digital arterial obstruction and/or vaso-spasm. Biopsy specimens of affected tissue were ob-tained for routine histologic examination and immuno-fluorescent staining. In addition, a standard panel oflaboratory tests as outlined in Table 2 was obtained.

Case ReportsCase IThis 53-year-old woman had a history of 11 years ofepisodic digital

color changes with cold exposure. There was a family and personalhistory of neurofibromatosis, with multiple skin lesions having beenremoved. There was no history of collagen vascular disease. She wasfound to have a large fixed breast mass and had modified radicalmastectomy with postoperative irradiation. Pathologic examinationshowed an infiltrating ductal carcinoma with 15 of 21 nodes positive.The patient's digital ischemic symptoms worsened and gangrenouslesions of multiple fingers developed. Complete serologic evaluationincluding antinuclear antibody, rheumatoid factor, immunoglobulinelectrophoresis, complement determination, cold agglutinins, andcryoglobulins were normal. Arteriography showed numerous digitalartery occlusions with associated cold-induced vasospasm. Treatmentwith guanethidine gave some symptomatic relief. She had persistentdigital ischemia for 2 years at which time she was found to haveabdominal metastatic disease and was treated with hormonal therapyand chemotherapy. She died 7 months later of metastatic disease.

Case 2A 49-year-old woman noted the onset of bilateral finger pain and

cyanosis at the time of a modified radical mastectomy for infiltratingductal carcinoma. No axillary lymph node involvement was present.The symptoms continued for 6 months, associated with progressivedigital dysesthesia and fingertip gangrene. An arteriogram showed oc-clusion of most named palmar and digital arteries with associatedvasospasm. The digital ischemia improved slightly after brachial arteryinjections of tolazoline and reserpine. Chest x-ray showed pulmonarymetastases, and chemotherapy was begun. The digital ischemia per-sisted but did not worsen. Serologic tests showed a low-titer antinuclear

Ann. Surg. * July 1987

antibody and nonspecific mild immunoglobulin elevations. Upper ex-

tremity nerve conduction showed diffuse neuropathic changes. Thepatient died 2 months after the initiation of chemotherapy. At nec-

ropsy she was found to have extensive metastatic carcinoma to theviscera. Pathologic examination of the radial artery and involved skinshowed no evidence of inflammatory vasculitis, immune deposits, orthrombosis.

Case 3This 75-year-old man with a life-long history of mild, stable Rayn-

aud's syndrome was found to have chronic lymphocytic leukemia(CLL) in 1977. He received chemotherapy and was in remission. Fiveyears later he had an abrupt onset ofblanching ofboth hands and feet,followed in several days by gangrenous changes of most toes andfingers. These lesions persisted despite treatment with antibiotics, cor-ticosteroids, and pentoxifylline. A skin biopsy specimen showed lym-phocytic infiltration, believed to be secondary to his CLL. He wastreated with LeukeranO for 6 months and the digital lesions healed.Four months later ischemic finger lesions again developed. Evaluationrevealed an exacerbation of the leukemia, with a leukocyte count of120,000/uL and gangrene of multiple fingertips. Digit plethysmog-raphy showed decreased pulsatile flow to the affected digits. The onlyabnormal laboratory finding was a small amount of plasma cryofi-brinogen. His evaluation is summarized in Tables 2 and 3. The digitallesions improved somewhat with the initiation ofleukemia chemother-apy, but the patient died 3 weeks later of septic complications.

Case 4A 63-year-old woman noted the precipitous onset of cold-induced

tenderness and blanching of her fingers followed by cyanosis andrubor. Within 3 weeks, small ulcerations and gangrenous changes ofthe tips of the thumbs, index, and middle fingers ofthe right hand andthe index and middle fingers ofthe left hand developed. Magnificationhand angiography showed widespread palmar and digital arterial ob-struction (Fig. 1). The abnormal findings ofher evaluation are summa-rized in Table 3, and included a striking elevation of IgG to 2,800mg/dL. Hematuria led to renal angiography, which revealed an avas-cular mass in the upper pole ofthe left kidney. A radical nephrectomywas done and the mass was found to be a sarcomatoid renal adenocar-cinoma, with metastasis to hilar, periaortic, and mesenteric nodes.After operation the digital ischemia improved with healing of the le-sions over the next 2 months, associated with a decrease of IgG tonormal levels. She received a short course of chemotherapy. Over thenext 3 years she continued to have Raynaud's attacks and recurrentdigital ulcerations. She had no evidence of metastases at this time,although the carcinoembryonic antigen (CEA) remained elevated. Shewas treated medically for her Raynaud's syndrome. She returned 3months later with a large epigastric mass and died soon thereafter ofrecurrent tumor.

Case 5A 43-year-old man was found to have gastric adenocarcinoma with

extension to regional nodes and hepatic metastases. He was treatedwith chemotherapy with 5-fluorouracil and developed lower extremitydeep vein thrombosis. He was anticoagulated with heparin followed bywarfarin. Six months later while therapeutically anticoagulated withwarfarin, right axillary vein thrombosis developed followed by therapid onset of hand ischemia progressing to gangrene of the rightthumb, index, middle, and ring fingers. Digit plethysmography con-firmed absent arterial flow in these four fingers with preservation ofnormal pulsatile flow in the fifth finger and normal palpable radial andulnar pulses (Fig. 2). Ten days later despite heparin treatment, deep

DIGITAL ISCHEMIA AS A MANIFESTATION OF MALIGNANCY

TABLE 3. Summary ofClinical Courses ofDescribed Patients

CaseNumber 1 2 3 4 5

Malignancy

Metastases

Treatment

Smoking history

Associated diseasesPrevious Raynaud'ssyndrome

Digital lesions

Angiography

Skin biopsy

Treatment ofdigital lesions

Outcome

Autopsy

Outcome of digitallesions

Breast, infiltratingductal

15 of 21 axillarynodes, ovarian,iliac, mesentericnodes

L MRM 1969XRT 1969Oophorectomy

1976XRT/CTX 197680 pack years

Neurofibromatosis1-year historycold-inducedpain andcyanoticchanges

Ulcerations,cyanosis andgangrenouschanges overmultiple fingers(bilateral)

Multiple digitalarteryocclusions,markedvasoconstrictionwith iceimmersion,relieved withreserpine

Not done

Good response toreserpine orallyand intra-arterial

Died withextensivemetastases 1976

Extensiveabdominalmetastases

Acrocyanosis andseveralulcerations attime of death

Breast, infiltratingductal

0 of 14 axillarynodes,pulmonarymetastasis

R MRM 1983CTX 1984

Moderate, none1980

NoneNone

Dysesthesias andpunctateulcerations andseveralgangrenousareas over 7fingertips

Bilateral radialarteryocclusion withmultiple digitalarteryocclusions;someimprovementwith tolazoline

No cutaneousvasculitis orinflammation(at autopsy)

Some relief withintra-arterialreserpine/tolazoline/dextran IV;mild relief withnifedipine andprednisone

Died of septiccomplicationsofCTX forpulmonarymetastasis 1984

Metastases tolung and liver,radial arterypatent, noevidence ofvasculitis

Acrocyanosis,petechiae, andsinglegangrenousulcer

Chronic lymphocyticleukemia

Remission1977-1982

Chlorambucil CTX-1977

Chlorambucil 1982-1985

CTX 198580 pack years, none

since 1966NoneCold-induced painand blanchingsince adolescence

Purpura, ulcerationswith gangrenouslesions over 19fingers and toes

Not done

1. Vasocentriclymphohistiocyticinfiltrate

2. Discoid lupus V.chilblains

Initial relief withchlorambucil,local wound careand CTX withrecurrence

Died of septiccomplications ofCTX 1985

Not done

Great improvementand healing ofulcerations

Renal adenocarcinoma

Recurrent peritonealnodes

L radicalCTX 1974

Unknown

NoneNone

Ulcerations andgangrenous changesover 5 fingers(bilateral)

Left hand multiplearterial irregularitieswith narrowing, no

improvement withreserpine

Mild leukocytoclasticangiitis

Increased symptomsfollowing initialslight relief withguanethidine andphenoxybenzaminewith recurrence

Died with recurrenttumor 1977

Not done

Painful red hands withminimal ulcerations

Gastric carcinoma

Mediastinal andlymphatic metastases

Laparotomy, CTX

>100 pack years

NoneNone

Gangrene of fingers anddistal palm

Not done

No arteritis, widespreadvenous and arterialthrombosis

Amputation

Died 2 months afterdiagnosis

Not done

No new lesions

MRM = modified radical mastectomy.XRT = radiation therapy.

CTX = chemotherapy.

65Vol. 206 * No. I

TAYLOR AND OTHERS

ischemic symptoms including gangrenous changes donot constitute Raynaud's syndrome as currently de-fined. Clearly, however, patients with severe digital isch-emia may also have episodic symptoms that are prop-erly termed Raynaud's syndrome. The patients de-scribed in this report all reported symptoms ofRaynaud's syndrome accompanying their severe digitalischemia, and in two ofthe patients (Cases 1 and 3) thesesymptoms preceded the development of severe digitalischemia by years. The relationship between fixed digitalarterial obstruction and Raynaud's syndrome has beendescribed previously.'6

Patients with Raynaud's syndrome may be conve-niently divided into two groups, which we have termedspastic and obstructive with the differential point beingthe presence of fixed obstruction to flow in the palmarand digital arteries. Patients with spastic Raynaud's syn-drome have symptoms as a result of an exaggerated va-sospastic response to cold or emotional stimuli. Patientswith obstructive Raynaud's syndrome have symptoms

Digital PlethysmographyRIG,TII

t71 1141IIi

I4

-r

LaEFT

I

r=_~~~~I

FIG. 1. Magnification hand arteriogram demonstrating widespreadpalmar and digital arterial obstruction (Case 4).

vein thrombosis recurred in the right leg. The patient died 2 monthsafter limited hand amputation. Pathologic examination of the in-volved arteries showed no evidence of vasculitis. The details ofthe casehistories are summarized in Table 3.

Discussion

Patients with episodic digital ischemic syndromeshave been classically said to have Raynaud's disease ifthe condition exists alone and Raynaud's phenomenonif the ischemic symptoms exist in the presence of anassociated disease process, frequently collagen vasculardiseases.20 Since neither of these terms describes a spe-cific diagnosis, many authorities have abandoned themin favor of the term Raynaud's syndrome, used to de-scribe the symptom complex ofepisodic digital ischemiain response to cold or emotional stimuli.'6 Fixed digital

j

go

FIG. 2. Digital plethysmography demonstrating absence of pulsatileflow in right hand fingers 1-4 with normal pulsatile flow in left handfingers (Case 5).

66

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NI., v \11- II

V V 11 N!

N'll

I

Ann. Surg * July 1987

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1 -I

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DIGITAL ISCHEMIA AS A MANIFESTATION OF MALIGNANCY 67from digital artery closure caused by a normal vasocon-strictive response acting on an obstructed vessel.2' Al-though spastic Raynaud's symptoms may be symptom-atically severe, it has never in our experience causeddigital gangrene. The latter has occurred only in thepresence of diffuse palmar and digital arterial fixed ob-structive disease.'7 The five patients with digital gan-grene described in this report all had extensive fixedarterial obstructive disease in the hand and finger arter-ies as demonstrated by arteriography in three patientsand digital plethysmography in the remainder. Threepatients had a history ofRaynaud's syndrome before thedevelopment of digital gangrene, and each patient hadmoderate improvement of ischemic symptoms afterintra-arterial injection of vasodilators. Spastic Rayn-aud's syndrome preceding by years the development offixed arterial obstruction and digital gangrene has beenrepeatedly noted by us and by others.'6"17'22

Previous observers have postulated multiple mecha-nisms to explain the digital vasospasm and the digitalartery obstruction producing digital ischemic symptomsin association with malignancy. Vasospasm has beenattributed to sympathetic hyperactivity and to arteritis.Arterial obstruction has been attributed to arteritis, tohyperviscosity caused by elevated levels of a variety ofserum proteins or of the formed elements of the blood,and to hypercoagulability associated with malignancy.The earliest reports of digital ischemia associated with

malignancy hypothesized vasospasm caused by meta-static tumor invasion of sympathetic nerves. Bennettand Poulton described in 1928 the case of a 61-year-oldman with an occult gastric carcinoma who died during acervical sympathectomy for relief of digital ischemicpain. In 1963, Nielson and Petri reported a 77-year-oldwoman with bilateral digital gangrene and occult coloncancer with metastases to the cervical sympathetic chainand stellate ganglion.24 None of the five patients de-scribed in this report had metastases detected to thesympathetic nerves to the upper extremity. The exis-tence ofbilaterally symmetrical symptoms in four ofourfive patients and in 22 ofthe 23 patients listed in Table 1likewise mitigates against a local infiltrative process asthe cause of this syndrome.

Arteritis of diverse etiologies has been clearly asso-ciated with digital artery vasospasm, as well as with digi-tal artery obstruction producing finger ischemia andfinger gangrene.'6"17'25 Several of the existing reports oftumor-associated digital ischemia have noted changesconsistent with arteritis in the affected vessels, occasion-ally in association with circulating immune com-plexes.26 The cause of the arteritis is unknown but maybe related to tumor antigen-antibody complexes withsubsequent complement activation in contact with thearterial wall.

Viscosity abnormalities have also been proposed as amechanism of ischemia. An increase in blood viscositymay result from an increase in numbers of circulatingblood cells as was noted by Hild and Myers who re-ported a case of ischemic necrosis of the fingertips,which they attributed to a severely elevated whole bloodviscosity (Oswald viscosity: 7.1) in a patient withchronic granulocytic leukemia." This mechanism ap-pears to have resulted in digital ischemia in Case 3 inthis series, in whom the granulocyte count was elevatedto 120,000/tL at the time of severe symptoms. Hyper-viscosity may also be caused by an increase in circulat-ing blood proteins as was described by Domz and Chap-man who related the 1961 case of a 56-year-old womanwith adenocarcinoma of the lung who had elevatedcryoglobulin levels and "pseudo-Raynaud's disease"progressing to gangrene. Tumor resection and concom-mitant decrease in circulating cryoglobulin level was as-sociated with healing ofthe digital lesions and resolutionof pain. Cryoglobulins were postulated to produce local-ized thrombosis and eventual infarction by precipitatingprothrombin and accessory clotting factors.27

Hyperviscosity caused by cryoglobulinemia and ar-teritis may coexist.28 In Case 4 described in this report,cryoglobulinemia was present in association with se-verely elevated IgG levels during the period of maximaldigital ischemia. In this case the ischemia resolved andulcerative lesions healed after resection ofa sarcomatoidrenal adenocarcinoma. Elevated gamma-globulin level,IgG immunofluorescence of tumor cells, and electron-dense deposits lining the endothelium of the tumor mi-crovasculature were seen, suggesting the presence of im-mune complex deposition in vessel walls. Moore andCupps in their review ofthe neurologic complications ofvasculitis postulate immune complex deposition as thecause of both hypersensitivity vasculitis and systemicnecrotizing vasculitis.8 They cite the isolation of solubleimmune complexes in experimental models, micro-scopic demonstration ofimmunologically mediated vas-cular destruction, and resolution of findings with im-muno§uppressants as justification for their conclusions.

Hypercoagulability in the absence of arteritis or hy-perviscosity has been detected in 50-90% of patientswith malignant tumors, especially those with metas-tases.29'30 In as many as 15% of these patients, throm-botic events may be clinically apparent.3' Case 5 de-scribed in this report had widespread venous and arterialthrombosis that progressed rapidly despite anticoagu-lant therapy. The relative resistance to treatment of thisform of hypercoagulability has been well described.32The fixed digital artery obstruction in these patients

appeared to be caused by hyperviscosity in two patients.Arteritis was documented by pathologic findings andpresumably caused the obstruction in two additional

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68 TAYLOR AND OTHERS Ann. Surg. *July 1987

patients. In the final patient, diffuse digital artery ob-struction resulted from thrombotic occlusion caused byhypercoagulability.Four of the five patients described in this report had

considerable symptomatic improvement after treatmentdirected at their primary neoplasms, emphasizing theability of the hands and fingers to recover from severeischemia, presumably through the development of col-lateral arterial channels.'7 Although antitumor therapyis of primary importance in treatment of these patients,the administra¶ion of vasodilators, currently calciumchannel blockers, may result in moderate symptomaticimprovement in those patients with an underlying vaso-spastic component ihi addition to the fixed arterial ob-struction.

Digital gangrene in association with malignancy, al-though uncommon, is not rare and is being recognizedwith increasing frequency. The judicious application ofangiography and plethysmography, serologic testing,and biopsy should permit accurate definition of whichmechanism(s) of ischemia is (are) most important in theindividual patient and permit selection of optimaltherapy.

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l'Hotel Dieu de Paris, 3rd ed. Paris: J.B. Bailliere et Fils, 1868;657-659.

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9. Cupps TR, Fauci AS. The Vasculitides. Philadelphia: WBSaunders 1981; 116-118.

10. Johnson PC, Rolak LA, Hamilton RH, et al. Paraneoplastic vas-culitis of a nerve: a remote effect of cancer. Ann Neurol 1979;5:437-444.

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12. Bohrod MG. Plasmacytosis and cryoglobulinemia in cancer.JAMA 1957; 164:18-21.

13. Gorevic PD, Kassab HJ, Levo Y, et al. Mixed cryoglobulinemia:clinical aspects and long term followup of 40 patients. Am JMed 1980; 69:287-308.

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book of the Principle and Practice of Medicine, Vol. 2, 3rd ed.London: J & A Churchill, 1891; 115-119.

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17. Taylor LM Jr, Baur GM, Porter JM. Finger gangrene caused bysmall artery occlusive disease. Ann Surg 1981; 193:543-561.

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21. Hirai M. Cold sensitivity of the hand in arterial occlusive disease.Surgery 1979; 85:140.

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28. O'Donnell JR, Keaveny TV, O'Connell LG. Digital arteritis as apresenting feature of malignant disease. Irish J Med Sci 1980;149(10):326-390.

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31. Sun NCJ, McAfee WM, Hum GJ, et al. Hemostatic abnormalitiesin malignancy, a prospective study of one hundred patients.Am J Clin Pathol 1979; 71:10-16.

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33. Pasteur W, Price-Jones C. A case of cancer of the stomach withunusual vascular and blood changes. Trans Clin Soc London1901; 34:160-164.

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36. Powell KR. Raynaud's phenomenon preceding acute lymphocyticleukemia. J Pediatr 1973; 82:539-540.

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38. Wytock DH, Bartholomew LG, Sheps SG. Digital ischemia asso-ciated with small bowel malignancy. Gastroenterology 1983;84:1025-1027.