DIAGNOSIS IN ONCOLOGY

Some Unusual Paraneoplastic Syndromes

CASE 1. METASTATIC SQUAMOUS CELL ESOPHAGEAL CANCER TO THE THUMB

A 56-year-old white male was received in our outpatient clinic because of slight pain and swelling on the thumb of his left hand. The patient reported a history of trauma with a shhook 3 days earlier but recognized that the nger was already swollen for a week. The symptoms were conned to the distal phalanx of the thumb, and on examination, it had an inammatory aspect (Fig 1). He had been diagnosed 3 months earlier with squamous cell esophageal carcinoma with metastatic supraclavicular lymph nodes. He was treated with palliative radiotherapy and cisplatin-uorouracil chemotherapy. A complete regression of the supraclavicular nodes and a resolution of the dysphagia were obtained. A radiograph of the thumb (Fig 2) showed destruction of the distal phalanx with soft-tissue tumor and lytic lesions in the proximal phalanx. A biopsy was performed, revealing metastatic squamous cell carcinoma. Recurrence of the esophageal tumor was detected by endoscopic examination, and it was the only evidence of disease relapse after work-up. The pain was controlled with nonsteroidal analgesics, but the patient developed recurrent dysphagia and started second-line chemotherapy. Bone metastases are frequent in cancer patients; however, acrometastases or metastases to the hand and foot are rare. Acrometastases have been reported in a variety of malignancies, such as breast, lung, gastrointestinal, and genitourinary tract, especially renal cell carcinoma.1 In some cases, it can be the rst manifestation of an occult cancer.2,3 A biopsy must be performed to conrm the diagnosis because many cases are often mistaken for benign processes, such as infection or inammatory arthritis. David Aguiar Bujanda, Uriel Bohn Sarmiento, and Jose Aguiar Morales Servicio de Oncologia Medica, Hospital de Gran Canaria Dr. Negrin, Las Palmas de Gran Canaria, Spain Copyright 2003 American Society of Clinical Oncology

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Fig 1.

Inammation of the distal phalanx of the thumb.

Fig 2. A radiograph of the thumb showing destruction of the distal phalanx with soft-tissue tumor and lytic lesions in the proximal phalanx.

REFERENCES
1. Troncoso A, Ro JY, Grignon DJ, et al: Renal cell carcinoma with acrometastasis: Report of two cases and review of the literature. Mod Pathol 4:66-69, 1991 2. Janne PA, Datta MW, Johnson BE: Lung cancer presenting with solitary bone metastases. Case 2: Acrometastasis as an initial presentation of nonsmall-cell lung carcinoma. J Clin Oncol 17:2998-3001, 1999 3. Healey JH, Turnbull AD, Miedema B, et al: Acrometastases: A study of twenty-nine patients with osseous involvement of the hands and feet. J Bone Joint Surg Am 68:743-746, 1986

EDITORS NOTE

See also Acrometastasis as an Initial Presentation of NonSmall-Cell Lung Carcinoma Janne P, et al: J Clin Oncol 17:2998-3001, 1999.
DOI: 10.1200/JCO.2003.06.074

CASE 2. DIGITAL ULCERATION AS A PARANEOPLASTIC SYNDROME IN OVARIAN CANCER

A 62-year-old woman presented in early November 1999 with a 12-week history of painful, pale ngers and toes of both hands and feet, worsening with exposure to cold, and cutaneous lesions on both hands. She also had an 8-week history of malaise,

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Journal of Clinical Oncology, Vol 21, No 13 (July 1), 2003: pp 2620-2625

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nausea, dizziness, diarrhea, unspecied weight loss, fatigue, and a periodically distended abdomen. There was no history of Raynauds phenomenon, vascular or connective tissue disease, or hyperlipidemia. Previous history was unremarkable. Physical examination revealed a pale, tired-looking afebrile woman with paronychia on digits two and four of both hands and feet and some bruising. Both the ngers and toes were pale, cool, and painful to touch. Peripheral pulses were present and symmetric. Livedo reticularis was visible on the ventral side of both legs. The abdomen was not distended or painful, and there was no shifting dullness. The physical examination was otherwise unremarkable. Laboratory results at that time were normal, except for mild thrombocytosis. In December 1999, while the analysis of dermal symptoms was still ongoing, she was diagnosed with pulmonary embolism arising from the deep venous thrombosis of the right femoral vein. Additional investigation, focused on malignancy, revealed a poorly differentiated adenocarcinoma of the right ovary, International Federation of Gynecology and Obstetrics classication stage IIIC, grade 3, which was subsequently treated with debulking surgery and six courses of chemotherapy. Evaluation of the skin lesions by immunouorescence for immunoglobulin (Ig) G, IgA, IgM, and complement C1q and C3c were negative, as were tests for autoimmune disease, cryoglobulins, and paraprotein. Magnetic resonance imaging of the hands did not show osseous abnormalities. Biopsy of the dermis revealed no epidermal abnormalities or signs of inammation, and there were no signs of vasculitis or tumor emboli. By exclusion of other possible diagnoses, we concluded that the skin condition was most likely a paraneoplastic syndrome. Treatment with nifedipine did not stop progression of the cutaneous symptoms, which deteriorated even though a clinical remission of the ovarian cancer was demonstrated after surgery and the rst courses of chemotherapy in March 2000 (Fig 1 and Fig 2, showing small necrotic ulcers with red indurated spots). It was then decided to start iloprost (Ilomedin; Schering AG, Berlin, Germany) 2 ng/kg over 6 hours intravenously for 5 days, with continuation of oral nifedipine. Instant clinical improvement was seen, with healing of the ulcers and disappearance of Raynaud complaints. Although iloprost treatment was administered for 5 days only, improvement continued for months, with almost complete disappearance of the dermatosis leaving only a few crusts on the proximal and distal interphalangeal joints and on the cuticles. The skin condition remained in remission until February 2001, when a mild relapse of symptoms occurred without clinical or biologic proof of tumor progression. The symptoms again responded to a short course of iloprost treatment. In May 2001, progression of the dermal symptoms coincided with tumor recurrence, and this time, the ulcers also appeared on the feet. The patient decided against palliative chemotherapy. Iloprost was administered, but this time, no effect was observed. The patient died from progressive ovarian cancer.

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Fig 1. spots.

Photograph of patient showing small necrotic ulcers with red indurated

Fig 2. spots.

Photograph of patient showing small necrotic ulcers with red indurated

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AGRAWAL ET AL

Paraneoplastic dermal manifestations in ovarian cancer are uncommon.1,2 The physiopathology of most paraneoplastic syndromes remains elusive, and to date, no standard treatment has been dened. The distinct cutaneous paraneoplastic syndrome in our patient is extremely rare, and to our knowledge, only three similar cases have been reported.3-5 No specic diagnostic tools are available; therefore, the diagnosis of the dermatosis was conrmed by the clinical morphology of the lesions, by the temporal relationship with malignant disease, and by exclusion of other diagnoses.6 Unfortunately, biopsy is inconclusive,5 as was the case in our patient. Corticosteroids are mostly ineffective in these lesions,5 and therefore, in this patient, a symptom-directed policy was chosen with continuous intravenous infusion of the prostacyclin analog iloprost. Iloprost has vasodilating and platelet-inhibitory effects, and it is known to be effective in patients with peripheral arterial occlusive disease or with Raynauds phenomenon.7 Moreover, iloprost can produce signicant healing of digital ulcers.8 Treatment of a cutaneous paraneoplastic syndrome with iloprost has not been described before. It is of interest to note that, although treatment of the malignancy was not sufcient to induce a remission of the dermal manifestations in our patients, iloprost administration could not achieve improvement without treatment of the tumor. Wendela G. Pronk, Jan P. Baars, Paul Chr. de Jong, and Anneke M. Westermann Academic Medical Center, Amsterdam; Flevo Hospital, Almere; and St Anthonius Hospital, Nieuwegein, the Netherlands Copyright 2003 American Society of Clinical Oncology
REFERENCES
1. Ashour AA, Verschraegen CF, Kudelka AP, et al: Paraneoplastic syndromes of gynecologic neoplasms. J Clin Oncol 15:1272-1282, 1997 2. Sabir S, James WD, Schuchter LM: Cutaneous manifestations of cancer. Curr Opin Oncol 11:139-144, 1999 3. Hawley PR, Johnston AW, Rankin JT: Association between digital ischaemia and malignant disease. BMJ 3:208-212, 1967 4. Freundlich B, Makover D, Maul GG: A novel antinuclear antibody associated with a lupus-like paraneoplastic syndrome. Ann Intern Med 109:295-297, 1988 5. Chow SF, McKenna CH: Ovarian cancer and gangrene of the digits: Case report and review of the literature. Mayo Clin Proc 71:253-258, 1996 6. Cohen PR, Kurzrock R: Mucocutaneous paraneoplastic syndromes. Semin Oncol 24:334-359, 1997 7. Black CM, Halkier-Sorensen L, Belch JJF, et al: Oral iloprost in Raynauds phenomenon secondary to systemic sclerosis: A multicenter, placebo-controlled dose-comparison study. Br J Rheumatol 37:952-960, 1998 8. Wigley FM, Seibold JR, Wise RA, et al: Intravenous iloprost in the treatment of Raynauds phenomenon and ischaemic ulcers secondary to systemic sclerosis. J Rheumatol 19:1407-1414, 1992

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EDITORS NOTE

See also Iamandi C, Dietemann A, Grosshans E, et al: Unusual presentations of lung cancer. Case 3: Paraneoplastic digital necrosis in a patient with small-cell lung cancer. J Clin Oncol 20:4600-4601, 2002
DOI: 10.1200/JCO.2003.07.099

CASE 3. METASTATIC PULMONARY CALCIFICATION CAUSING HYPOXEMIA IN MALE BREAST CANCER

A 56-year-old white male with previous left mastectomy for breast cancer and skeletal metastatic disease of a duration of 2 years was hospitalized with a history of nonproductive cough and dyspnea for 4 days. Physical examination revealed an afebrile, normotensive individual with a regular heart rate of 110 beats/min, respiratory rate of 20 beats/min, and fracture of the left tibia. Laboratory values were calcium 16.1 mg/dL, alkaline phosphatase 252 IU/L (normal 38 to 126 IU/L), creatinine 3.5 mg/dL, blood urea nitrogen 58 mg/dL, and phosphorus 4.8 mg/dL. Arterial blood gases on 40% oxygen by facemask showed a pH of 7.36, p02 of 46 mmHg, pC02 of 35 mmHg, HCO3 of 18 mEq/dL, and oxygen saturation of 80%. ECG showed sinus tachycardia. Chest radiograph (Fig 1) was normal except for blastic bone metastases on admission, showing, 48 hours later, diffuse bilateral pulmonary inltrates and consolidation with obliteration of the left heart border (Fig 2). Differential diagnosis included pulmonary edema, congestive heart failure, pneumonitis, lymphangitic metastases, and intrapulmonary hemorrhage. Two-dimensional echocardiogram showed a left-ventricular ejection fraction in the range of 25% and wall-motion abnormality consistent with coronary artery disease. Swan-Ganz catheterization showed pulmonary artery peak-systolic and end-diastolic pressures of 35 and 16 mmHg, respectively, and a pulmonary capillary wedge pressure of 12 mmHg, which was not consistent with a cardiac cause of pulmonary inltrates. Ventilation-perfusion nuclear study was unremarkable. The patient was initially treated with subcutaneous enoxaparin, intravenous imipenem, erythromycin, corticosteroids, calcitonin-salmon, and hemodialysis for oliguria. Although serum calcium, creatinine, and blood urea nitrogen slowly normalized, the diffuse pulmonary inltrates and dyspnea persisted. High-resolution computed tomography (HRCT; Fig 3) demonstrated several geographic areas of faint ground-glass density throughout both lungs, with focal areas of alveolar consolidation. Finally, bronchoscopic lung biopsy showed calcied lesions (Fig 4) of various shapes and sizes, primarily located in the thickened broproliferative interstitium of the lungs. Diffuse pulmonary calcication (also called metastatic calcication) will often have a benign etiology. It is most frequently encountered in chronic renal failure patients undergoing hemodialysis. Other causes, including hypervitaminosis D, primary

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Fig 1.

Chest radiograph of patient showing blastic bone metastases.

Fig 2. Chest radiograph showing diffuse bilateral pulmonary inltrates and consolidation with obliteration of the left heart border.

hyperparathyroidism, milk-alkali syndrome, and orthotopic hepatic transplantation, are much less common. Metastatic pulmonary calcication is occasionally associated with various malignancies. The underlying disturbance is an elevated serum calcium with or without an increased calcium-phosphate product. Hypercalcemia in a malignant disorder results from either skeletal metastases or humoral effects on the skeleton. Pulmonary calcication may lead to slowly diminishing diffusion capacity, and hypoxemia may ensue.1 In such cases, the patient may die from progressive respiratory failure.2,3 In other cases, the respiratory failure is rapid and rather acute.4,5 Two reported patients, one with B-cell lymphoma and the other with multiple myeloma, developed hypercalcemia and subsequent acute respiratory distress syndrome.5 Autopsy studies showed disseminated alveolar calcium deposition and diffuse alveolar damage. The standard chest x-ray is relatively insensitive to detect diffuse parenchymal pulmonary calcication. In addition, inltrates often cannot be distinguished from other intrapulmonary processes. Bone scintigraphy and HRCT scan with

Fig 3. High-resolution computed tomography demonstrating several geographic areas of faint ground-glass density throughout both lungs, with focal areas of alveolar consolidation.

Fig 4.

Bronchoscopic lung biopsy showing calcied lesions.

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EBERT, SHAFFER, AND RENNKE

mediastinal images are both superior to the standard chest x-ray in detecting pulmonary calcication. Pulmonary calcication is often misinterpreted as pneumonitis or pulmonary edema both on chest x-ray and computed tomography scan. Bone scintigraphy with bone-avid radiotracer 99mtechnetium-methylene diphosphate helps to resolve these equivocal cases. Twenty-four patients with positive pulmonary bone scintigraphy and hypercalcemia caused by hyperparathyroidism but without chest radiographic evidence of calcication have been described.6 A critical but often overlooked use of bone scintigraphy and HRCT is in the early and accurate recognition of pulmonary calcication in cases of unexplained and persistent inltrates. These tests further obviate the need for more invasive procedures, such as lung biopsy. In the right clinical setting, metastatic pulmonary calcication should be considered in the differential diagnosis of lung inltrates of both acute nature and, as in this case, chronic nature. Ravi S. Agrawal, Jaya R. Agrawal, Bharat L. Agrawal, Amaresh R. Nath, Asha R. Agrawal, J.C. Gaddipat and Richard F. Garnett, Jr Cancer and Blood Disease Center, and Department of Medicine, Reid Hospital & Health Care Services, Richmond, IN Copyright 2003 American Society of Clinical Oncology
REFERENCES
1. Khaf RA, DeLima C, Silverberg A, et al: Calciphylaxis and systemic calcinosis: Collective review. Arch Intern Med 150:956-959, 1990 2. McLachlan MSF, Wallace M, Seneviratne C: Pulmonary calcication in renal failure: Report of three cases. Br J Radiol 41:99-106, 1968 3. Davidson RC, Pendros JP: Calcium related cardio-respiratory death in chronic hemodialysis. Trans Am Soc Artif Intern Organs 13:36-40, 1967 4. Morii H, Ohnishi Y, Oko-moto T, et al: A case of B cell lymphoma complicated by hypercalcemia and acute respiratory insufciency. Osaka City Med J 29:75-85, 1983 5. Poe RH, Kamath C, Bauer MA, et al: Acute respiratory distress syndrome with pulmonary calcication in two patients with B cell malignancies. Respiration 56:127-133, 1989 6. Coolens JL, Devos P, De Roo M: Diffuse pulmonary uptake of 99m Tc bone-imaging agents: Case report and survey. Eur J Nucl Med 11:36-42, 1985 Downloaded from jco.ascopubs.org on May 1, 2012. For personal use only. No other uses without permission. Copyright 2003 American Society of Clinical Oncology. All rights reserved.

DOI: 10.1200/JCO.2003.09.104

CASE 4. PARANEOPLASTIC NEPHROTIC SYNDROME IN A PATIENT WITH LUNG CANCER

A 69-year-old man with a 100 pack/year history of cigarette smoking was noted to have a lung mass on screening chest x-ray. A chest computed tomography (CT) revealed a 4 3 cm right lower-lobe (RLL) lung mass and a 1-cm precarinal node. Nonsmall-cell lung cancer was diagnosed by CT-guided biopsy of the pulmonary mass. A head CT and bone scan were negative for metastases. He was asymptomatic, and he chose to defer treatment of his lung cancer for 3 months until after his daughters marriage. Four months after diagnosis and before any therapy, he developed hemoptysis, worsening dyspnea, and bilateral lower-extremity edema. He noted that his urine had become extremely frothy. On physical examination, he had decreased breath sounds in the right lung base, abdominal distension, and 3 lower-extremity edema. A chest CT showed progression of his malignancy with RLL collapse, mediastinal adenopathy up to 3 cm in size, and a left upper-lobe nodule. Laboratory studies were signicant for a serum albumin of 2.3 mg/dL and a creatinine unchanged at 1.4 mg/dL. Urinalysis showed 3 protein, and a 24-hour urine collection contained 10.2 grams of protein. His serum cholesterol level was elevated at 308 mg/dL. A serum protein electrophoresis, antinuclear antibody (ANA), and renal ultrasound were unremarkable. He was treated with concomitant chemotherapy and radiation therapy consisting of 3,750 Gy of radiation to the RLL in 15 fractions, as well as weekly carboplatin at an area under the curve of 2 and taxol 50 mg/m2 for 5 weeks. Hemoptysis and dyspnea resolved in the rst month of treatment. Lower-extremity edema and abdominal distension improved gradually over 3 months. According to CT scans, his RLL mass decreased in size, and his RLL collapse resolved and remained stable over the subsequent 9 months (Fig 1). His blood pressure was controlled with lisinopril (Zestril; AstraZeneca, London, United Kingdom) and hydrochlorothiazide. His albumin increased to 3.7 gm/dL, his proteinuria decreased to 540 mg/24 hours, and his creatinine remained stable (Fig 2). Lung cancer is among the malignancies most commonly associated with a paraneoplastic nephrotic syndrome.1-3 Membranous nephropathy is most commonly associated with solid malignancies, whereas minimal change disease is seen most often in patients with Hodgkins disease.1,2,4 Presentation with nephrotic syndrome occurs before the diagnosis of cancer in approximately 40% of patients, at the time of diagnosis in 40% of patients, and after diagnosis in 20% of patients.2 Treatment of the neoplasm is associated with improvements in proteinuria.3,5 The pathogenesis of this paraneoplastic syndrome has been attributed to the production of cancer-related antigens, with subsequent damage to the glomerular basement membrane by antigen-antibody complexes.6 An alternative hypothesis is that an autoantibody, produced in response to the malignancy, may cross-react with and damage the glomerular basement membrane.

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Fig 1.

Computed tomography scan showing decreased right lower lobe mass. Fig 2. Graphs showing (A) 24-hour urine total protein, (B) serum albumin, and (C) serum creatinine.

Hypoalbuminemia is common in patients with lung cancer. A small subset of these patients will have nephrotic syndrome because of a paraneoplastic process. Benjamin Ebert, Kitt Shaffer, and Helmut Rennke Dana-Farber Cancer Institute, Brigham and Womens Hospital, and Harvard Medical School, Boston, MA Copyright 2003 American Society of Clinical Oncology
REFERENCES
1. Lee JC, Yamauchi H, Hopper J: The association of cancer and the nephrotic syndrome. Ann Intern Med 64:41-51, 1965 2. Burstein DM, Korbet SM, Schwartz MM: Membranous glomerulonephritis and malignancy. Am J Kidney Dis 22:5-10, 1993 3. Shikata Y, Hayashi Y, Yamazaki H, et al: Effectiveness of radiation therapy in nephrotic syndrome associated with advanced lung cancer. Nephron 83:160-164, 1999 4. Davison AM: Renal diseases associated with malignancies. Nephrol Dial Transplant 16:13-14, 2001 (suppl 6) 5. Boon ES, Vrij AA, Nieuwhof C, et al: Small cell lung cancer with paraneoplastic nephrotic syndrome. Eur Respir J 7:1192-1193, 1994 6. Costanza ME, Pinn V, Schwartz RS, et al: Carcinoembryonic antigenantibody complexes in a patient with colonic carcinoma and nephrotic syndrome. N Engl J Med 289:520-522, 1973

DOI: 10.1200/JCO.2003.11.021