Diagnostic Radiology
Hypertrophic Pulmonary Osteoarthropathy in Pulmonary Metastases 1 Hossein Firooznla, M.D., Gustav Seliger, M.D., Nancy B. Genieser, M.D., and Eugene Barasch, M.D. Hypertrophic pulmonary osteoarthropathy is most commonly encountered in association with bronchogenic carcinoma and tumors of the pleura. Its association with pulmonary metastases from extrathoracic neoplasms is rare, with only 44 documented cases in the literature. Three additional cases are reported. Nearly half of the reported cases have been sarcomas, mainly of bone and soft tissues; among the rest are tumors of the nasopharynx and uterus and cervix. It has recently been noted that symptoms can be dramatically relieved by intrathoracic or cervical vagotomy. INDEX TERMS: Bones, abnormalities secondary to disturbances of extraskeletal systerns. Lung Neoplasms, metastases. Nerves, vagus • Osteoarthropathy, hypertrophic pulmonary. Sarcoma, metastases Radiology 115:269-274, May 1975
OSTEOARTHROPATHY, an established clinical syndrome, is associated with a large and diverse number of conditions involving the lungs, pleura, mediastinum, and the digestive system (2, 3, 7, 10, 15, 17,20,37,38,40). Currently, it is most commonly seen with intrathoracic neoplasms, both bronchogenic carcinoma and primary benign and malignant tumors of the pleura (10, 15, 40). Osteoarthropathy is said to occur in 0.7 to 12 % of patients with bronchogenic carcinoma (1, 14, 18-20, 36-38, 42-44). This frequency is in sharp contrast to the rarity of the association of hypertrophic osteoarthropathy with hematogenous metastasis to the lungs from extrathoracic neoplasms. To date, only 44 instances of such an association have been recorded, to our knowledge (2, 10, 15, 45). The purpose of this communication is to add three additional cases and to review and analyze the literature. YPERTROPHIC
H
CASE REPORTS CASE I: A 51-year-old white woman was admitted to the hospital because of painful swelling of the knees, ankles, right elbow, and hands of three months duration. One year prior to admission, she had undergone a total hysterectomy for leiomyosarcoma of the uterus. Clinical findings on admission included exquisite tenderness and swelling of the wrists, knees, legs, and feet. Prominent clubbing of the fingers was noted. Laboratory studies included a complete blood count, latex fixation test, and uric acid determination; all values were within normal limits. Admission chest films showed several pulmonary nodules, some of which contained cavities (Fig. 1, A). Lung biopsy revealed metastatic leiomyosarcoma. While the patient was in the hospital, a pelvic mass was discovered. Surgical exploration disclosed recurrence of the uterine tumor with extrinsic invasion of the pelvic colon. Radiographs of the extremities (Fig. 1, B) showed typical findings of hypertrophic osteoarthropathy at the wrists, metacarpals, fingers, and around the knees, ankles, and feet. The patient died four months later. No autopsy was performed.
CASE II: A 14-year-old black girl noted the gradual onset of pain and swelling of the left knee. Radiographs showed a destructive lesion of the distal left femur, which, on biopsy, proved to be an osteogenic sarcoma. The patient had no other complaint, and there were no other findings. Chest radiographs were normal. A skeletal survey revealed no abnormality except for the destructive lesion of the left femur. Laboratory values were within normal limits. After a left hip disarticulation, the patient was discharged in fair condition. The patient was readmitted four months later for evaluation of weakness, low-grade fever, and pain and swelling of the extremities. On this admission, prominent swelling of the right leg and foot was noted. The right knee and both forearms were moderately swollen and tender to the touch. Clubbing of the fingers was noted. The chest radiographs now disclosed extensive metastatic disease to the lungs and pleura (Fig. 2, A). A survey of the extremities revealed hypertrophic osteoarthropathy of the hands, wrists, elbow, right knee, and right ankle (Fig. 2, B and C). No bony lesions indicative of metastasis were found. Death eight months later followed a downhill course. CASE III: A 70-year-old white woman was admitted to the hospital because of weight loss, shortness of breath, weakness, and progressively worsening pain and swelling of the knees, ankles, elbows, and wrists of several weeks duration. Nineteen months earlier she had undergone a total hysterectomy for uterine adenocarcinoma. Physical examination on admission disclosed swelling of the knees, shins, ankles, and feet. Clubbing of the fingers and toes was noted. The legs were extremely tender to the touch. Laboratory values were noncontributory. Admission chest films demonstrated several pulmonary masses indicative of metastases (Fig. 3, A). Radiographs of the extremities showed the characteristic changes of hypertrophic pulmonary osteoarthropathy involving the knees, tibiae, fibulae, ankles, feet, and hands (Fig. 3, B). The patient died six months later. At necropsy, metastatic uterine adenocarcinoma to the lungs, pleura, liver, and brain was found.
DISCUSSION
Hypertrophic pulmonary osteoarthropathy consists of (a) painful swelling and tenderness of the distal third of
1 From the New York University Medical Center (H. F., G. S., N. B. G., Associate Professors of Radiology; E. B., Resident in Radiology), New York, N. Y. Accepted for publication in October 1974. ah
269
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HOSSEIN FIROOZNIA AND OTHERS
L Fig. 1. A. The chest radiograph shows multiple nodular pulmonary lesions. with cavitation present in several nodules. B. Note the periosteal new. bone formation along the medial side of the shaft of the distal left tibia.
Fig. 2. A. The left lung is involved by metastases. and one nodule is seen in the right lung. There is a considerable amount of pleural fluid. and the heart and the mediastinal contents have shifted into the right hemithorax. Band C. Extensive periosteal new bone has formed along the shaft of the humerus. in the ulna and the radius around the right elbow. and around the left wrist and metacarpal bones.
the arms and legs and the adjacent joints, (b) clubbing of the fingers and toes, (c) joint effusion, and (d) periosteal new bone formation along the shafts of the tubular bones of the extremities, particularly in the vicinity of the joints. These findings tend to be symmetrical and are more pronounced in the distal parts of the limbs, i.e., the hands and feet. The knees and elbows are also
commonly affected. However, involvement of the hips and shoulders is rare. In some patients gynecomastia is present (10, 11, 17,40). Clubbing of the fingers and toes, unaccompanied by the other manifestations of this condition, is commonly encountered in association with diseases causing hypertrophic osteoarthropathy (10). Clubbing developed in
HYPERTROPHIC PULMONARY OSTEOARTHROPATHY IN PULMONARY METASTASES
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Fig. 3. A. The multiple masses in the lungs are indicative of metastases. B. Note the periosteal new bone formation along the shafts of the femur and tibia around the left knee.
255 (26 %) of 959 patients with bronchogenic carcinoma seen at the Mount Sinai Hospital, New York (1). While the association of clubbing of the fingers and hypertrophic osteoarthropathy has been known for years, only recently has it been realized that the two conditions are intimately related. There is general agreement now that the bone and joint changes represent a further extension of the clubbing process (40). Clubbing usually precedes the onset of osteoarthropathy by several months, but it may occur simultaneously with or on rare occasions even be preceded by osteoarthropathy (10, 40,43). An idiopathic form of hypertrophic osteoarthropathy, called pachydermoperiostosis, has also been described. This is an heredofamilial disorder seen in males and mediated by a recessive or an incompletely dominant gene (21). The condition usually begins at or about the time of puberty and is characterized by an insidious and progressive occurrence of clubbing and nontender enlargement of the joints, especially the wrists and the lower parts of the legs and ankles. Not uncommonly it is accompanied by sterile joint effusions. The sites most usually involved with periosteal changes are the distal third of the tibiae, fibulae, radii, ulnae, and humeri. In these locations, periosteal new bone formation and thickening of the cortical bone are present (21). Clinically, malaise, profuse sweating, sebaceous gland overactivity (especially over the face), and marked thickening and furrow-
ing of the skin of the face, forehead, scalp, hands, and feet are prominent. Myelofibrosis and myeloid metaplasia in two brothers affected by this disorder have also been reported (33). No pulmonary disease has been described as a causative factor of this condition. In the past, chronic inflammatory pulmonary diseases, such as lung abscesses and empyema, were the commonest intrathoracic diseases encountered in association with this condition (3, 7, 10, 15, 17, 40). Pulmonary tuberculosis, although often associated with clubbing (10), is rarely seen with the full clinical picture of hypertrophic pulmonary osteoarthropathy (45). Other intrathoracic conditions accompanying this syndrome include cyanotic congenital heart defects (7), pleural tumors (7, 9, 27, 36, 43, 44), and even "pseudotumors" in the thorax, such as esophageal dilatation secondary to achalasia or carcinoma (15, 35). Several extrathoracic diseases are also occasionally encountered in association with this condition, such as portal (6) and biliary (18) cirrhosis, or tumors of the upper gastrointestinal system (23, 41). Hypertrophic pulmonary osteoarthropathy is currently most commonly encountered in association with intrathoracic neoplasms (10, 15), with bronchogenic carcinoma accounting for more than 80 % of the cases in adults. Pleural tumors account for 100/0, and other intrathoracic and mediastinal malignant growths account for 5 % (10). As noted earlier, the incidence of hypertro-
272
HOSSEIN FIROOZNIA AND OTHERS
Table I: Extrathoracic Neoplasms with Pulmonary Metastases Associated with Hypertrophic Osteoarthropathy in 47 Patients (2, 28, 39, 42, 45) Location
-------
Histology
No.
Musculoskeletal Osteosarcoma-periosteal sarcoma system and soft Soft-tissue sarcoma tissues Fibrosarcoma Malignant melanoma Chondrosarcoma Malignant giant-cell tumor (bone) Metastasizing giant-cell tumor (tendon) Myxoma
10 4
3 2 1 1 1 1
23 Nasopharynx
Carcinoma Lymphoepithelioma Transitional-cell
Uterus and cervix
Carcinoma Leiomyosarcoma Chorioepithelioma
5 3 2
10 4 3 1
8 Others Breast Esophagus and stomach Prostate Kidney
Carcinoma Carcinoma
2 2
Carcinoma Carcinoma
1 1 {)
Total
47
phic pulmonary osteoarthropathy complicating bronchogenic carcinoma varies from 0.7 to 12 % . In children as in adults the chronic suppurative inflammatory diseases of the Chest were the leading cause of this condition in the past. At present, cyanotic congenital heart defects are the most frequent underlying cause (7). Hypertrophic osteoarthropathy secondary to hematogenous metastases to the lungs from extrathoracic neoplasms is very rare (2, 15, 32, 45). In a 1967 review of the literature, Yacoub and Simon (45) collected 38 cases, to which they added three of their own. In our review of the literature since 1967 we found three additional cases. These were metastases to the lungs from uterine carcinoma (42), prostatic carcinoma (39), and esophageal carcinoma (28). An analysis of the 47 cases, including the three described in this report, reveals some interesting observations (TABLE I). Patients suffering from bronchogenic carcinoma complicated by osteoarthropathy are usually in the sixth or seventh decade of life, while those with pulmonary metastases and osteoarthropathy are as a rule much younger. The mean age of the 47 patients who comprise the basis for this report was only 38 years. The commonest extrathoracic neoplasms with hematogenous metastases to the lungs complicated by osteoarthropathy are those arising from mesenchymal tissues having a predominantly fibrous tissue stroma, such as osteosarcoma and fibrosarcoma. These tumors account for nearly half of all the reported Cases in the literature. It is of interest that fibrous tumors of the lung and visceral pleura (fibroma, fibrosarcoma, and mesothelioma) are also frequently associated with osteoar-
May 1975
thropathy. Wierman (44) reported 14 cases of pleural mesothelioma, in eight of which (57 0/0) osteoarthropathy developed. Polley (36) reported 24 cases of localized fibrous mesothelioma of the pleura. Articular symptoms were noted in 18 of these, and in 10 there was the full picture of hypertrophic osteoarthropathy. In four of six cases of visceral pleural fibrous tumors (fibroma and fibrosarcoma) reported by Thomas and Drew (43), osteoarthropathy developed. In these patients the osteoarthropathy was a most dramatic and striking feature. In three the articular symptoms antedated those referable to the chest by several years. Other published case reports show the same link between osteoarthropathy and fibrous tumors of the lung or pleura (5, 9, 27). No other neoplasm is as constantly associated with osteoarthropathy as are these fibrosarcomatous tumors (43). The factors responsible for this frequent association of osteoarthropathy and fibrosarcomato us tumors of the lung and pleura, either primary or metastatic, are not known. According to Yacoub, the fibrous-tissue stroma, which is present in all these tumors, may in itself be responsible in some unknown way for initiating the reflex responsible for osteoarthropathy. This is supported by the fact that oat-cell carcinoma, which lacks a fibroustissue stroma, is never associated with osteoarthropathy (45). The second largest group of tumors in these 'patients are nasopharyngeal neoplasms, which account for 21 % of the cases. The relationship between pulmonary metastases from tumors of the nasopharynx and osteoarthropathy has been pointed out by several authors (12, 25, 34, 45). The patients in this group are young, with a mean age of 23 years, whereas the mean age in all other reported cases is 42 years. Papavasiliou (34) reported 35 cases of carcinoma of the nasopharynx, in six of which the patient Was under 25 years of age. In four of this latter group pulmonary metastases developed, and in three of these osteoarthropathy subsequentlyappeared. Tumors of the uterus and cervix are responsible for 16 % of the cases; and it is significant that leiomyosarcoma accounts for 3 out of 8 cases in these patients. The exact pathogenesis of osteoarthropathy is not known. Recent reports have suggested that its incidence may depend on the location of the pulmonary neoplasm. In 13 of their 14 cases, Ray and Fisher (37) found peripheral lung cancer. Others have felt that central necrosis or cavitation of such peripheral lesions may be a contributing factor (38, 40, 44). Mendlowitz and Leslie produced hypertrophic osteoarthropathy in dogs by anastomosing the left pulmonary artery to the left auricle (30-32). This resulted in a shunt simulating the conditions in cyanotic congenital heart disease. Mendlowitz (29) also found an abnormally high blood flow in clubbed fingers secondary to heart and lung disease in humans. It was further demonstrated by Charr and Swenson (8) that a regional increase in the number and caliber of the arterioles covering the ungual phalanx
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of the clubbed fingers occurs in these patients. The increase in blood flow and its relationship to osteoarthropathy and clubbing (40) have been established by later investigators (3, 22, 38). It is stated that the increased blood flow produces periosteal hyperemia with a subperiosteal serous effusion in which the new bone is deposited (38). Similar vascular changes also explain the associated subcutaneous tissue edema and joint effusion. How this increased vascularity is mediated by the pulmonary lesion is not definitely known. It has been recently postulated that a neural reflex, initiated by the affected lung and mediated by the vagus nerve, causes the peripheral hypervascularity and associated changes (12, 16, 22). The theory of vagal reflex mechanism is strongly supported by the fact that the symptoms can be dramatically relieved by intrathoracic or cervical vagotomy (12, 13, 22, 26). This finding was first described by Brea (4) in 1959 and later confirmed by Flavell (13) and Diner (12). Following vagotomy, the structural abnormalities of the limbs regress gradually, although in some patients they remain unaltered and may even progress (3). Symptoms do not recur if metastases of malignant lesions arise postoperatively (3). The dramatic results following section of the vagus nerve have led to the postulate that the important. part of the resection may well be the severance of the nerves supplying that part (3). It should be recalled that the pleural surfaces have a more abundant nerve supply than the lung parenchyma itself; this may account .for the more common association of osteoarthropathy with lesions involving the pleural surfaces (24) than with those in the center of the lung tissue. This may also explain why such conditions as a dilated esophagus, mediastinal tumors, and lesions of the ribs may cause the Same syndrome (3). University Hospital 560 First Ave. New York, N. Y. 10016
REFERENCES 1. Aufses AH: Primary carcinoma of the lung: a 14-year survey. J Mt Sinai Hosp NY 20:212-228, Sep-Oct 1953 2. Aufses AH t Aufses BH: Hypertrophic osteoarthropathy in association with pulmonary metastases from extrathoracic malignancies. Dis Chest 38:399'-402, Oct 1960 3. Barclay Nt Ogbeide M, Grillo IA: Gross hypertrophic pulmonary osteoarthropathy in a 7-year-old child. Thorax 25:484-489, Jul 1970 4. Brea MM, Martinez y G JL, Alvarez H: SindrOme de Bamberger-Marie. Desnervacibn pulmonar. 801 Soc Tisiol Repub Argent, 1959, p 47. Quoted by Diner (12) 5. Bryan L: Secondary hypertrophic osteo-arthropathy with metastatic sarcoma of the lung. Am J Roentgenol 7:286-288, Jun 1920 6. Buchan DJ. Mitchell OM: Hypertrophic osteoarthropathy in portal cirrhosis. Ann Intern Med 66: 130-135, Jan 1967 7. Cavanaugh JJ, Holman GH: Hypertrophic osteoarthropathy in childhood. J Pedlatr 66:27-40, Jan 1965 8. Charr R, Swenson PC: Clubbed fingers. Am J Roentgenol 55:325-330, Mar 1946 9. Clagett OT, McDonald JR, Schmidt HW: Localized fibrous
Diagnostic Radiology
mesothelioma of the pleura. J Thorac Surg 24:213-230, Sep 1952 10. Coury C:- Hippocratic fingers and hypertrophic osteoarthropathy: study of 350 cases. Br J Dis Chest 54:202-209, Jul 1960 11 . Craig JW: Hypertrophic pulmonary osteoarthropathy as the first symptom of pulmonary neoplasm. Br Med J 1:750-752, 10 Apr 1937 12. Diner WC: Hypertrophic osteoarthropathy: relief of symptoms by vagotomy in a patient with pulmonary metastases from a lympho-epttheuorna of the nasopharynx. JAMA 181:555-557, 11 Aug 1962 13. Flavell G: Reversal of pulmonary hypertrophic osteoarthropathy by vagotomy. Lancet 1:260-262, 11 Feb 1956 14. Flavell G: Some unusual manifestations of bronchial carcinoma. Br J Tuberc Dis Chest 47 (Suppl): 135-141,1953 15. Gibbs DO, Schiller KF, Stovin PG: Lung metastases heraided by hypertrophic pulmonary osteoarthropathy. Lancet 1:623625, 19 Mar 1960 16. Ginsburg J: Observations on the peripheral circulation in hypertrophic pulmonary osteoarthropathy. J Med 27:335-352, Jul 1958 17. Hammarsten JF, O'Leary J: The features and significance of hypertrophic osteoarthropathy. Arch Intern Med 99:431-441, Mar 1957 18. Han SY, Collins LC: Hypertrophic osteoarthropathy in cirrhosis of the liver: report of two cases. Radiology 91:795-796, Oct 1968 19. Hansen JL: Bronchial carcinoma presenting as arthralgia. Acta Med Scand (Suppl 266): 467-472, 1952 20. Harper FA, Patterson LT: Osteoarthropathy in carcinoma of the lung. Arch Surg 70:643-646, May 1955 21. Herman MA, Massaro D, Katz 5, et al: Pachydermoperiostosis: clinical spectrum. Arch Intern Med 116:918-923, Dec 1965 22. Holling HE, Brodey RS, Boland He: Pulmonary hypertrophic osteoarthropathy. Lancet 2: 1269-1274, 9 bee 1961 23. Hollis we: Hypertrophic osteoarthropathy secondary to upper gastro-intestinal tract neoplasm. Case report and review. Ann Intern Med 66: 125-130, Jan 1967 24. Huckstep RL, Bodkin PE: Vagotomy in hypertrophic pulmonary osteoarthropathy associated with bronchial carcinoma. Lancet 2:343-345, 16 Aug 1958 25. Martin CL: Complications produced by malignaht tumors of the nasopharynx. Am J RoentgenoI41:377-390, Mar 1939 26. Mason RW: Bronchial carcinoma presenting as polyneuritis. Lancet 1:203-206, 7 Feb 1948 27. Massachusetts General Hospital, Case 31271: Fibrosarcoma of lung (hypertrophic osteoarthropathy). N Engl J Med 233: 1822. 5 Jul 1945 28. Maurice-Williams RS, Wilson RJ: Hypertrophic osteoarthropathy associated with carcinoma of the oesophagus. Postgrad Med J 45:743-744, Nov 1969 29. Mendlowitz M: Measurements of blood flow and blood pressure in clubbed fingers. J Clin Invest 20: 113-117, Mar 1941 30. Mendlowitz M, Leslie A: Cyanosis produced by anastomosis of pulmonary artery to left auricle. Proc Soc Exp Bioi Med 44: 501, Jun 1940 31. Mendlowitz M t Leslie A: Experimental simulation in the dog of cyanosis and hypertrophic osteoarthropathy which are associated with congenital heart disease. Am Heart J 24: 141-152, Aug 1942 32. Mendlowitz M, Leslie A: Pulmonary artery to left auricle anastomosis with hypertrophic osteoarthropathy (abst). Am J Pathol 17:458, May 1941 33. Metz EN, Dowell A: Bone marrow failure in hypertrophic osteoarthropathy. Arch Intern Med 116:759-764, Nov 1965 34. Papavasiliou CG: Pulmonary metastases from cancer of the nasopharynx associated with hypertrophic osteoarthropathy. Br J RadioI36:680-684, Sep 1963 35. Peyman MA: Achalasia of cardia, carcinoma of oesophagus. and hypertrophic pulmonary osteoarthropathy. Br Med J 1:2325, 3 Jan 1959 36. Polley HF, Clagett OT, McDonald JR, et al: Articular reactions associated with localized fibrous mesothelioma of the pleura. Ann Rheum Dis 11:314, Dec 1952 37. Ray ESt Fisher HP Jr: Hypertrophic osteoarthropathy in pulmonary malignancies. Ann Intern Med 38:239-246, Feb 1953
a
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38. Semple T, McCluskie RA: Generalized hypertrophic osteoarthropathy in association with bronchial carcinoma. A review, based on 24 cases. Br Med J 1:754-759, 26 Mar 1955 39. Serre H, Simon L, Roques J-M: Seropositive rheumatoid arthritis combined with secondary hypertrophic osteoarthropathy in the course of metastasizing cancer of the prostate (abst no. 2719). Arthritis Rheum Dis Abst 4:491, Sep 1968 (from Rev Rhum 35: 134-138, Mar 1968) 40. Shapiro M: Hypertrophic osteoarthropathy. Arch Intern Med 98:700-711, Dec 1956 41. Singh A, Jolly S8, Bansal BB: Hypertrophic osteoarthropathy associated with carcinoma of the stomach. Br Med J 2:581-582, Aug 1960
May 1975
42. Stevanovic DV: Malignant acanthosis nigricans and secondary hypertrophic osteoarthropathy (abst no. ·2720). Arthritis Rheum Dis Abst 4:491, Sep 1968 (from Derm Wschr 154: 414-417, 4 May 1968) 43. Thomas CP, Drew CE: Fibroma of the visceral pleura. Thorax 8: 180-188, Sep 1953 44. Wierman WH, Clagett OT, McDonald JR: Articular manifestations in pulmonary diseases: an analysis of their occurrence in 1,024 cases in which pulmonary resection was performed. JAMA 155:1459-1463,21 Aug 1954 45. Yacoub MH, Simon G, Ohnsorge J: Hypertrophic pulmonary osteoarthropathy in association with pulmonary metastases from extrathoracic tumours. Thorax 22:226-231, May 1967
Hypertrophic Pulmonary Osteoarthropathy in Pulmonary Metastases 1 Hossein Firooznla, M.D., Gustav Seliger, M.D., Nancy B. Genieser, M.D., and Eugene Barasch, M.D. Hypertrophic pulmonary osteoarthropathy is most commonly encountered in association with bronchogenic carcinoma and tumors of the pleura. Its association with pulmonary metastases from extrathoracic neoplasms is rare, with only 44 documented cases in the literature. Three additional cases are reported. Nearly half of the reported cases have been sarcomas, mainly of bone and soft tissues; among the rest are tumors of the nasopharynx and uterus and cervix. It has recently been noted that symptoms can be dramatically relieved by intrathoracic or cervical vagotomy. INDEX TERMS: Bones, abnormalities secondary to disturbances of extraskeletal systerns. Lung Neoplasms, metastases. Nerves, vagus • Osteoarthropathy, hypertrophic pulmonary. Sarcoma, metastases Radiology 115:269-274, May 1975
OSTEOARTHROPATHY, an established clinical syndrome, is associated with a large and diverse number of conditions involving the lungs, pleura, mediastinum, and the digestive system (2, 3, 7, 10, 15, 17,20,37,38,40). Currently, it is most commonly seen with intrathoracic neoplasms, both bronchogenic carcinoma and primary benign and malignant tumors of the pleura (10, 15, 40). Osteoarthropathy is said to occur in 0.7 to 12 % of patients with bronchogenic carcinoma (1, 14, 18-20, 36-38, 42-44). This frequency is in sharp contrast to the rarity of the association of hypertrophic osteoarthropathy with hematogenous metastasis to the lungs from extrathoracic neoplasms. To date, only 44 instances of such an association have been recorded, to our knowledge (2, 10, 15, 45). The purpose of this communication is to add three additional cases and to review and analyze the literature. YPERTROPHIC
H
CASE REPORTS CASE I: A 51-year-old white woman was admitted to the hospital because of painful swelling of the knees, ankles, right elbow, and hands of three months duration. One year prior to admission, she had undergone a total hysterectomy for leiomyosarcoma of the uterus. Clinical findings on admission included exquisite tenderness and swelling of the wrists, knees, legs, and feet. Prominent clubbing of the fingers was noted. Laboratory studies included a complete blood count, latex fixation test, and uric acid determination; all values were within normal limits. Admission chest films showed several pulmonary nodules, some of which contained cavities (Fig. 1, A). Lung biopsy revealed metastatic leiomyosarcoma. While the patient was in the hospital, a pelvic mass was discovered. Surgical exploration disclosed recurrence of the uterine tumor with extrinsic invasion of the pelvic colon. Radiographs of the extremities (Fig. 1, B) showed typical findings of hypertrophic osteoarthropathy at the wrists, metacarpals, fingers, and around the knees, ankles, and feet. The patient died four months later. No autopsy was performed.
CASE II: A 14-year-old black girl noted the gradual onset of pain and swelling of the left knee. Radiographs showed a destructive lesion of the distal left femur, which, on biopsy, proved to be an osteogenic sarcoma. The patient had no other complaint, and there were no other findings. Chest radiographs were normal. A skeletal survey revealed no abnormality except for the destructive lesion of the left femur. Laboratory values were within normal limits. After a left hip disarticulation, the patient was discharged in fair condition. The patient was readmitted four months later for evaluation of weakness, low-grade fever, and pain and swelling of the extremities. On this admission, prominent swelling of the right leg and foot was noted. The right knee and both forearms were moderately swollen and tender to the touch. Clubbing of the fingers was noted. The chest radiographs now disclosed extensive metastatic disease to the lungs and pleura (Fig. 2, A). A survey of the extremities revealed hypertrophic osteoarthropathy of the hands, wrists, elbow, right knee, and right ankle (Fig. 2, B and C). No bony lesions indicative of metastasis were found. Death eight months later followed a downhill course. CASE III: A 70-year-old white woman was admitted to the hospital because of weight loss, shortness of breath, weakness, and progressively worsening pain and swelling of the knees, ankles, elbows, and wrists of several weeks duration. Nineteen months earlier she had undergone a total hysterectomy for uterine adenocarcinoma. Physical examination on admission disclosed swelling of the knees, shins, ankles, and feet. Clubbing of the fingers and toes was noted. The legs were extremely tender to the touch. Laboratory values were noncontributory. Admission chest films demonstrated several pulmonary masses indicative of metastases (Fig. 3, A). Radiographs of the extremities showed the characteristic changes of hypertrophic pulmonary osteoarthropathy involving the knees, tibiae, fibulae, ankles, feet, and hands (Fig. 3, B). The patient died six months later. At necropsy, metastatic uterine adenocarcinoma to the lungs, pleura, liver, and brain was found.
DISCUSSION
Hypertrophic pulmonary osteoarthropathy consists of (a) painful swelling and tenderness of the distal third of
1 From the New York University Medical Center (H. F., G. S., N. B. G., Associate Professors of Radiology; E. B., Resident in Radiology), New York, N. Y. Accepted for publication in October 1974. ah
269
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HOSSEIN FIROOZNIA AND OTHERS
L Fig. 1. A. The chest radiograph shows multiple nodular pulmonary lesions. with cavitation present in several nodules. B. Note the periosteal new. bone formation along the medial side of the shaft of the distal left tibia.
Fig. 2. A. The left lung is involved by metastases. and one nodule is seen in the right lung. There is a considerable amount of pleural fluid. and the heart and the mediastinal contents have shifted into the right hemithorax. Band C. Extensive periosteal new bone has formed along the shaft of the humerus. in the ulna and the radius around the right elbow. and around the left wrist and metacarpal bones.
the arms and legs and the adjacent joints, (b) clubbing of the fingers and toes, (c) joint effusion, and (d) periosteal new bone formation along the shafts of the tubular bones of the extremities, particularly in the vicinity of the joints. These findings tend to be symmetrical and are more pronounced in the distal parts of the limbs, i.e., the hands and feet. The knees and elbows are also
commonly affected. However, involvement of the hips and shoulders is rare. In some patients gynecomastia is present (10, 11, 17,40). Clubbing of the fingers and toes, unaccompanied by the other manifestations of this condition, is commonly encountered in association with diseases causing hypertrophic osteoarthropathy (10). Clubbing developed in
HYPERTROPHIC PULMONARY OSTEOARTHROPATHY IN PULMONARY METASTASES
Vol. 115
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~
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.~:,..\.'
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~
'j~~
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0"'
') -
/
!-, _
l-
/
Fig. 3. A. The multiple masses in the lungs are indicative of metastases. B. Note the periosteal new bone formation along the shafts of the femur and tibia around the left knee.
255 (26 %) of 959 patients with bronchogenic carcinoma seen at the Mount Sinai Hospital, New York (1). While the association of clubbing of the fingers and hypertrophic osteoarthropathy has been known for years, only recently has it been realized that the two conditions are intimately related. There is general agreement now that the bone and joint changes represent a further extension of the clubbing process (40). Clubbing usually precedes the onset of osteoarthropathy by several months, but it may occur simultaneously with or on rare occasions even be preceded by osteoarthropathy (10, 40,43). An idiopathic form of hypertrophic osteoarthropathy, called pachydermoperiostosis, has also been described. This is an heredofamilial disorder seen in males and mediated by a recessive or an incompletely dominant gene (21). The condition usually begins at or about the time of puberty and is characterized by an insidious and progressive occurrence of clubbing and nontender enlargement of the joints, especially the wrists and the lower parts of the legs and ankles. Not uncommonly it is accompanied by sterile joint effusions. The sites most usually involved with periosteal changes are the distal third of the tibiae, fibulae, radii, ulnae, and humeri. In these locations, periosteal new bone formation and thickening of the cortical bone are present (21). Clinically, malaise, profuse sweating, sebaceous gland overactivity (especially over the face), and marked thickening and furrow-
ing of the skin of the face, forehead, scalp, hands, and feet are prominent. Myelofibrosis and myeloid metaplasia in two brothers affected by this disorder have also been reported (33). No pulmonary disease has been described as a causative factor of this condition. In the past, chronic inflammatory pulmonary diseases, such as lung abscesses and empyema, were the commonest intrathoracic diseases encountered in association with this condition (3, 7, 10, 15, 17, 40). Pulmonary tuberculosis, although often associated with clubbing (10), is rarely seen with the full clinical picture of hypertrophic pulmonary osteoarthropathy (45). Other intrathoracic conditions accompanying this syndrome include cyanotic congenital heart defects (7), pleural tumors (7, 9, 27, 36, 43, 44), and even "pseudotumors" in the thorax, such as esophageal dilatation secondary to achalasia or carcinoma (15, 35). Several extrathoracic diseases are also occasionally encountered in association with this condition, such as portal (6) and biliary (18) cirrhosis, or tumors of the upper gastrointestinal system (23, 41). Hypertrophic pulmonary osteoarthropathy is currently most commonly encountered in association with intrathoracic neoplasms (10, 15), with bronchogenic carcinoma accounting for more than 80 % of the cases in adults. Pleural tumors account for 100/0, and other intrathoracic and mediastinal malignant growths account for 5 % (10). As noted earlier, the incidence of hypertro-
272
HOSSEIN FIROOZNIA AND OTHERS
Table I: Extrathoracic Neoplasms with Pulmonary Metastases Associated with Hypertrophic Osteoarthropathy in 47 Patients (2, 28, 39, 42, 45) Location
-------
Histology
No.
Musculoskeletal Osteosarcoma-periosteal sarcoma system and soft Soft-tissue sarcoma tissues Fibrosarcoma Malignant melanoma Chondrosarcoma Malignant giant-cell tumor (bone) Metastasizing giant-cell tumor (tendon) Myxoma
10 4
3 2 1 1 1 1
23 Nasopharynx
Carcinoma Lymphoepithelioma Transitional-cell
Uterus and cervix
Carcinoma Leiomyosarcoma Chorioepithelioma
5 3 2
10 4 3 1
8 Others Breast Esophagus and stomach Prostate Kidney
Carcinoma Carcinoma
2 2
Carcinoma Carcinoma
1 1 {)
Total
47
phic pulmonary osteoarthropathy complicating bronchogenic carcinoma varies from 0.7 to 12 % . In children as in adults the chronic suppurative inflammatory diseases of the Chest were the leading cause of this condition in the past. At present, cyanotic congenital heart defects are the most frequent underlying cause (7). Hypertrophic osteoarthropathy secondary to hematogenous metastases to the lungs from extrathoracic neoplasms is very rare (2, 15, 32, 45). In a 1967 review of the literature, Yacoub and Simon (45) collected 38 cases, to which they added three of their own. In our review of the literature since 1967 we found three additional cases. These were metastases to the lungs from uterine carcinoma (42), prostatic carcinoma (39), and esophageal carcinoma (28). An analysis of the 47 cases, including the three described in this report, reveals some interesting observations (TABLE I). Patients suffering from bronchogenic carcinoma complicated by osteoarthropathy are usually in the sixth or seventh decade of life, while those with pulmonary metastases and osteoarthropathy are as a rule much younger. The mean age of the 47 patients who comprise the basis for this report was only 38 years. The commonest extrathoracic neoplasms with hematogenous metastases to the lungs complicated by osteoarthropathy are those arising from mesenchymal tissues having a predominantly fibrous tissue stroma, such as osteosarcoma and fibrosarcoma. These tumors account for nearly half of all the reported Cases in the literature. It is of interest that fibrous tumors of the lung and visceral pleura (fibroma, fibrosarcoma, and mesothelioma) are also frequently associated with osteoar-
May 1975
thropathy. Wierman (44) reported 14 cases of pleural mesothelioma, in eight of which (57 0/0) osteoarthropathy developed. Polley (36) reported 24 cases of localized fibrous mesothelioma of the pleura. Articular symptoms were noted in 18 of these, and in 10 there was the full picture of hypertrophic osteoarthropathy. In four of six cases of visceral pleural fibrous tumors (fibroma and fibrosarcoma) reported by Thomas and Drew (43), osteoarthropathy developed. In these patients the osteoarthropathy was a most dramatic and striking feature. In three the articular symptoms antedated those referable to the chest by several years. Other published case reports show the same link between osteoarthropathy and fibrous tumors of the lung or pleura (5, 9, 27). No other neoplasm is as constantly associated with osteoarthropathy as are these fibrosarcomatous tumors (43). The factors responsible for this frequent association of osteoarthropathy and fibrosarcomato us tumors of the lung and pleura, either primary or metastatic, are not known. According to Yacoub, the fibrous-tissue stroma, which is present in all these tumors, may in itself be responsible in some unknown way for initiating the reflex responsible for osteoarthropathy. This is supported by the fact that oat-cell carcinoma, which lacks a fibroustissue stroma, is never associated with osteoarthropathy (45). The second largest group of tumors in these 'patients are nasopharyngeal neoplasms, which account for 21 % of the cases. The relationship between pulmonary metastases from tumors of the nasopharynx and osteoarthropathy has been pointed out by several authors (12, 25, 34, 45). The patients in this group are young, with a mean age of 23 years, whereas the mean age in all other reported cases is 42 years. Papavasiliou (34) reported 35 cases of carcinoma of the nasopharynx, in six of which the patient Was under 25 years of age. In four of this latter group pulmonary metastases developed, and in three of these osteoarthropathy subsequentlyappeared. Tumors of the uterus and cervix are responsible for 16 % of the cases; and it is significant that leiomyosarcoma accounts for 3 out of 8 cases in these patients. The exact pathogenesis of osteoarthropathy is not known. Recent reports have suggested that its incidence may depend on the location of the pulmonary neoplasm. In 13 of their 14 cases, Ray and Fisher (37) found peripheral lung cancer. Others have felt that central necrosis or cavitation of such peripheral lesions may be a contributing factor (38, 40, 44). Mendlowitz and Leslie produced hypertrophic osteoarthropathy in dogs by anastomosing the left pulmonary artery to the left auricle (30-32). This resulted in a shunt simulating the conditions in cyanotic congenital heart disease. Mendlowitz (29) also found an abnormally high blood flow in clubbed fingers secondary to heart and lung disease in humans. It was further demonstrated by Charr and Swenson (8) that a regional increase in the number and caliber of the arterioles covering the ungual phalanx
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273
HYPERTROPHIC PULMONARY OSTEOARTHROPATHY IN PULMONARY METASTASES
of the clubbed fingers occurs in these patients. The increase in blood flow and its relationship to osteoarthropathy and clubbing (40) have been established by later investigators (3, 22, 38). It is stated that the increased blood flow produces periosteal hyperemia with a subperiosteal serous effusion in which the new bone is deposited (38). Similar vascular changes also explain the associated subcutaneous tissue edema and joint effusion. How this increased vascularity is mediated by the pulmonary lesion is not definitely known. It has been recently postulated that a neural reflex, initiated by the affected lung and mediated by the vagus nerve, causes the peripheral hypervascularity and associated changes (12, 16, 22). The theory of vagal reflex mechanism is strongly supported by the fact that the symptoms can be dramatically relieved by intrathoracic or cervical vagotomy (12, 13, 22, 26). This finding was first described by Brea (4) in 1959 and later confirmed by Flavell (13) and Diner (12). Following vagotomy, the structural abnormalities of the limbs regress gradually, although in some patients they remain unaltered and may even progress (3). Symptoms do not recur if metastases of malignant lesions arise postoperatively (3). The dramatic results following section of the vagus nerve have led to the postulate that the important. part of the resection may well be the severance of the nerves supplying that part (3). It should be recalled that the pleural surfaces have a more abundant nerve supply than the lung parenchyma itself; this may account .for the more common association of osteoarthropathy with lesions involving the pleural surfaces (24) than with those in the center of the lung tissue. This may also explain why such conditions as a dilated esophagus, mediastinal tumors, and lesions of the ribs may cause the Same syndrome (3). University Hospital 560 First Ave. New York, N. Y. 10016
REFERENCES 1. Aufses AH: Primary carcinoma of the lung: a 14-year survey. J Mt Sinai Hosp NY 20:212-228, Sep-Oct 1953 2. Aufses AH t Aufses BH: Hypertrophic osteoarthropathy in association with pulmonary metastases from extrathoracic malignancies. Dis Chest 38:399'-402, Oct 1960 3. Barclay Nt Ogbeide M, Grillo IA: Gross hypertrophic pulmonary osteoarthropathy in a 7-year-old child. Thorax 25:484-489, Jul 1970 4. Brea MM, Martinez y G JL, Alvarez H: SindrOme de Bamberger-Marie. Desnervacibn pulmonar. 801 Soc Tisiol Repub Argent, 1959, p 47. Quoted by Diner (12) 5. Bryan L: Secondary hypertrophic osteo-arthropathy with metastatic sarcoma of the lung. Am J Roentgenol 7:286-288, Jun 1920 6. Buchan DJ. Mitchell OM: Hypertrophic osteoarthropathy in portal cirrhosis. Ann Intern Med 66: 130-135, Jan 1967 7. Cavanaugh JJ, Holman GH: Hypertrophic osteoarthropathy in childhood. J Pedlatr 66:27-40, Jan 1965 8. Charr R, Swenson PC: Clubbed fingers. Am J Roentgenol 55:325-330, Mar 1946 9. Clagett OT, McDonald JR, Schmidt HW: Localized fibrous
Diagnostic Radiology
mesothelioma of the pleura. J Thorac Surg 24:213-230, Sep 1952 10. Coury C:- Hippocratic fingers and hypertrophic osteoarthropathy: study of 350 cases. Br J Dis Chest 54:202-209, Jul 1960 11 . Craig JW: Hypertrophic pulmonary osteoarthropathy as the first symptom of pulmonary neoplasm. Br Med J 1:750-752, 10 Apr 1937 12. Diner WC: Hypertrophic osteoarthropathy: relief of symptoms by vagotomy in a patient with pulmonary metastases from a lympho-epttheuorna of the nasopharynx. JAMA 181:555-557, 11 Aug 1962 13. Flavell G: Reversal of pulmonary hypertrophic osteoarthropathy by vagotomy. Lancet 1:260-262, 11 Feb 1956 14. Flavell G: Some unusual manifestations of bronchial carcinoma. Br J Tuberc Dis Chest 47 (Suppl): 135-141,1953 15. Gibbs DO, Schiller KF, Stovin PG: Lung metastases heraided by hypertrophic pulmonary osteoarthropathy. Lancet 1:623625, 19 Mar 1960 16. Ginsburg J: Observations on the peripheral circulation in hypertrophic pulmonary osteoarthropathy. J Med 27:335-352, Jul 1958 17. Hammarsten JF, O'Leary J: The features and significance of hypertrophic osteoarthropathy. Arch Intern Med 99:431-441, Mar 1957 18. Han SY, Collins LC: Hypertrophic osteoarthropathy in cirrhosis of the liver: report of two cases. Radiology 91:795-796, Oct 1968 19. Hansen JL: Bronchial carcinoma presenting as arthralgia. Acta Med Scand (Suppl 266): 467-472, 1952 20. Harper FA, Patterson LT: Osteoarthropathy in carcinoma of the lung. Arch Surg 70:643-646, May 1955 21. Herman MA, Massaro D, Katz 5, et al: Pachydermoperiostosis: clinical spectrum. Arch Intern Med 116:918-923, Dec 1965 22. Holling HE, Brodey RS, Boland He: Pulmonary hypertrophic osteoarthropathy. Lancet 2: 1269-1274, 9 bee 1961 23. Hollis we: Hypertrophic osteoarthropathy secondary to upper gastro-intestinal tract neoplasm. Case report and review. Ann Intern Med 66: 125-130, Jan 1967 24. Huckstep RL, Bodkin PE: Vagotomy in hypertrophic pulmonary osteoarthropathy associated with bronchial carcinoma. Lancet 2:343-345, 16 Aug 1958 25. Martin CL: Complications produced by malignaht tumors of the nasopharynx. Am J RoentgenoI41:377-390, Mar 1939 26. Mason RW: Bronchial carcinoma presenting as polyneuritis. Lancet 1:203-206, 7 Feb 1948 27. Massachusetts General Hospital, Case 31271: Fibrosarcoma of lung (hypertrophic osteoarthropathy). N Engl J Med 233: 1822. 5 Jul 1945 28. Maurice-Williams RS, Wilson RJ: Hypertrophic osteoarthropathy associated with carcinoma of the oesophagus. Postgrad Med J 45:743-744, Nov 1969 29. Mendlowitz M: Measurements of blood flow and blood pressure in clubbed fingers. J Clin Invest 20: 113-117, Mar 1941 30. Mendlowitz M, Leslie A: Cyanosis produced by anastomosis of pulmonary artery to left auricle. Proc Soc Exp Bioi Med 44: 501, Jun 1940 31. Mendlowitz M t Leslie A: Experimental simulation in the dog of cyanosis and hypertrophic osteoarthropathy which are associated with congenital heart disease. Am Heart J 24: 141-152, Aug 1942 32. Mendlowitz M, Leslie A: Pulmonary artery to left auricle anastomosis with hypertrophic osteoarthropathy (abst). Am J Pathol 17:458, May 1941 33. Metz EN, Dowell A: Bone marrow failure in hypertrophic osteoarthropathy. Arch Intern Med 116:759-764, Nov 1965 34. Papavasiliou CG: Pulmonary metastases from cancer of the nasopharynx associated with hypertrophic osteoarthropathy. Br J RadioI36:680-684, Sep 1963 35. Peyman MA: Achalasia of cardia, carcinoma of oesophagus. and hypertrophic pulmonary osteoarthropathy. Br Med J 1:2325, 3 Jan 1959 36. Polley HF, Clagett OT, McDonald JR, et al: Articular reactions associated with localized fibrous mesothelioma of the pleura. Ann Rheum Dis 11:314, Dec 1952 37. Ray ESt Fisher HP Jr: Hypertrophic osteoarthropathy in pulmonary malignancies. Ann Intern Med 38:239-246, Feb 1953
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38. Semple T, McCluskie RA: Generalized hypertrophic osteoarthropathy in association with bronchial carcinoma. A review, based on 24 cases. Br Med J 1:754-759, 26 Mar 1955 39. Serre H, Simon L, Roques J-M: Seropositive rheumatoid arthritis combined with secondary hypertrophic osteoarthropathy in the course of metastasizing cancer of the prostate (abst no. 2719). Arthritis Rheum Dis Abst 4:491, Sep 1968 (from Rev Rhum 35: 134-138, Mar 1968) 40. Shapiro M: Hypertrophic osteoarthropathy. Arch Intern Med 98:700-711, Dec 1956 41. Singh A, Jolly S8, Bansal BB: Hypertrophic osteoarthropathy associated with carcinoma of the stomach. Br Med J 2:581-582, Aug 1960
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42. Stevanovic DV: Malignant acanthosis nigricans and secondary hypertrophic osteoarthropathy (abst no. ·2720). Arthritis Rheum Dis Abst 4:491, Sep 1968 (from Derm Wschr 154: 414-417, 4 May 1968) 43. Thomas CP, Drew CE: Fibroma of the visceral pleura. Thorax 8: 180-188, Sep 1953 44. Wierman WH, Clagett OT, McDonald JR: Articular manifestations in pulmonary diseases: an analysis of their occurrence in 1,024 cases in which pulmonary resection was performed. JAMA 155:1459-1463,21 Aug 1954 45. Yacoub MH, Simon G, Ohnsorge J: Hypertrophic pulmonary osteoarthropathy in association with pulmonary metastases from extrathoracic tumours. Thorax 22:226-231, May 1967
