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Simultaneous onset of systemic sclerosis (scleroderma) and lung cancer: A case report and histologic analysis of fibrogenic peptides
BRIEF CLINICAL
There was a marked reduction in circulating T lymphocytes (CDll+, 0.25 X log/L; T4:T8 ratio 1.9). Results of other tests done in an attempt to exclude underlying malignancy or infection were all negative. With the lumps waxing and waning, the diagnosis was only made 3 months later, from a biopsy of the fat in the abdominal wall, shown to be grossly abnormal on computed tomographic (CT) scan. Ultrasonography also suggested fatty infiltration of the liver. Two months of treatment with nonsteroidal antiinflammatory drugs and prednisone 60 mg daily achieved only a transient improvement in his fever. His abdomen became so distended and hard that he was unable to touch his knees. Weight gain totaled 20 kg and he developed respiratory difficulty with tightness about his throat. Eight months after the patient’s presentation, therapy with cyclosporin was commenced at a dose of 600 mg/d orally (approximately 6.5 mg/kg), and over the subsequent 4 months his abdomen softened, he lost 10 kg, and results of ultrasonography and CT scanning were normal. His cyclosporin dose was adjusted to maintain his blood levels (monitored weekly initially) within the therapeutic range of 150 to 350 nmol/L. After a year of treatment, we reduced the cyclosporin dose to 300 mg/d orally, maintaining his levels at approximately 70 nmol/L for 1 year (levels were checked every 3 weeks). He is now back at work and active in sports. CDll+ cell counts have improved (0.91 X log/L; T4:T8 ratio of 1.4) with normal phytohemagglutinin and pokeweed mitogen responses. For the past 6 months he has not required any treatment, and has remained well and asymptomatic. The rationale for using cyclosporin is the involvement of the T lymphocyte in the disease process [2], and the two previously reported cases of panniculitis that have responded to this treatment [3,4]. Although one of these patients had severe systemic panniculitis [4], in neither case was the histology reported as cytophagic. The etiology of cytophagic panniculitis is unknown and there is no previous specific therapy, with many patients dying despite aggressive chemotherapy [2]. The sustained remission achieved with cyclosporin in our patient provides further evidence for the role of the T lymphocyte in the pathologic process. Our results suggest that a trial of this drug is warranted in other patients with cytophagic panniculitis.
1. Crotty cytopenia, tol 1981: 2. Alegre Dermatol 3. Entzian Christian 4. Kusuki Christian Submitted
OBSERVATIONS
CP, Winkelmann RK. Cytophagic histiocytic panniculitis with fever, liver failure and terminal haemorrhagic diathesis. J Am Acad Derma4: 181-94. VA, Winkelmann RK. Histiocytic cytophagic panniculitis. J Am Acad 1989: 20: 177-85. P, Barth J, Monig H, Ohnhaus EE, Kirch W. Treatment of Weberpanniculitis with cyclosporin A. Rheumatol Int 1987; 7: 181. A, Kitamura K. Urabe A, Takaku F. Successful treatment of Weberdisease by cyclosporin. Am J Med 1988; 85: 277-8. June 5, 1991. and accepted
in revised form November
14, 1991
ACKNOWLEDGMENT: The histology was reviewed by Dr. R. K. Winkelmann, Dermatopathologist. Mayo Clinic. Thanks to Sandoz Pharmaceutical N.Z. Ltd. for providing the cyclosporin for this patient.
SIMULTANEOUSONSET OF SYSTEMIC SCLEROSIS(SCLERODERMA)AND LUNG CANCER:A CASEREPORTAND HISTOLOGIC ANALYSISOF FIBROGENICPEPTIDES
Primary neoplasms of the lungs developing in patients with systemic sclerosis (scleroderma) are well documented [l-lo]. Alveolar cell carcinoma has received particular attention in this regard [l], although all histologic types have been observed. The risk of developing lung cancer in individuals with scleroderma may be increased over that in the general population, with relative risks calculated from available data between 4.4 and 16.5 [6]. The concurrent development of lung cancer and scleroderma has been extremely rare; most cases of coincidence have been related to breast carcinoma [ll-131. We report a patient who developed systemic sclerosis immediately after the diagnosis of adenocarcinoma of the lung. This case is reminiscent of the relationship of polymyositis-dermatomyositis and cancer, and suggests that causal biologic relationships may exist. Therefore, the production and deposition of fibrogenic peptides or fibroblast growth factors by the neoplastic cells that potentially might stimulate dermal fibroblasts were explored by immunohistologic techniques. Case Report. A 50-year-old woman with a 30 pack-year history of cigarette smoking noted the onset of Raynaud’s phenomenon and episodic pain in her proximal interphalangeal and metacarpophalangeal joints 18 months prior to presentation. Four months later, subacute pleuritic chest pain and dyspnea prompted hospitalization. Chest radiographs and a computed tomographic scan reGORDONROYLE, M.Med.sc.,F.R.c.P.A. vealed a right upper lobe mass with extension into North Shore Hospital Auckland, New Zealand the pleura. After surgical excision, a diagnosis of HILARYBLACKLOCK,F.R.A.C.P.,F.R.C.P.A. adenosquamous carcinoma with tumor-free marMARY MILLER, F.R.C.P.A. gins was rendered. No further therapy was recomMiddlemore Hospital Auckland, New Zealand mended. Over the following months, the patient June
1992
The American
Journal
of Medicine
Volume
92
705
BRIEF CLINICAL
OBSERVATIONS
Figure 1. Left. Sclerodactyly involving all the digits with tightening of the skin leading to flexion contractures as well as a shallow ulceration over the fourth proximal interphalangeal joint. Note also the telangiectasia on the distal aspect of the third digit. Right. Limited scleroderma involving the skin distal to the wrists of both hands and in the perioral region of the face. Note the puckering of the skin around the mouth, multiple facial telangiectasias, and the ulcerations over several proximal interphalangeal joints. The severe flexion contractures involving the hands can also be observed in this photograph.
experienced increasing skin tightness, swelling, and pain involving the digits, wrist, and lower forearm bilaterally associated with severe Raynaud’s phenomenon of both the feet and hands (Figure 1, left). This was associated with pitting of several digits along with prominent telangiectasias on her face and hands. Mild tightening of the skin on her face and neck with perioral puckering developed over the next 12 months after the diagnosis of lung cancer (Figure 1, right). Tendon friction rubs were palpable at the wrists. Serologic testing revealed the presence of an antinuclear antibody with an atypical discrete speckled pattern at a titer of 1:2,560 and typical speckled pattern at a titer of 1:320, and a latex fixation of 1:2,560. An anticentromere antibody was not seen. Antibody to Scl-70 (topoisomerase I) was absent. Radiographs of the chest, hands, and wrists were unremarkable. Pulmonary function testing revealed a severe reduction in the carbon monoxide diffusing capacity (24% of predicted), but the results were otherwise unremarkable. The presence of rapidly progressive skin tightening (despite its limited distribution), tendon friction rubs, and digital pitting all suggested a more generalized form of systemic sclerosis. Followup for more than 6 months still fails to indicate any evidence of recurrent malignancy. Immunohistologic Studies. The routinely processed surgical lung tissue was reviewed and the diagnosis of adenosquamous carcinoma was confirmed. Furthermore, the surrounding parenchyma was notable for the absence of interstitial fibrosis. The excised tumor and surrounding lung tissue
706
June
1992
The American
Journal
of Medicine
Volume
92
were subjected to immunohistologic analysis for growth factors using a panel of antibodies directed against TGF-a (Peninsula Labs, Belmont, CA), TGF-@ (R&D Systems, Minneapolis, MN), PDGFAA and PDGF-BB, bFGF, and EGF (Genzyme, Boston, MA) with the appropriate secondary antibody biotinylated and the tertiary antibody coupled to Strepavidin-peroxidase. The intensity of staining was compared to normal control lung tissue obtained at autopsy and to three other cases of adenosquamous lung carcinoma without associated scleroderma. Strong staining for all the peptide growth factors was observed within scattered macrophages, blood vessels, and the tumor cells themselves (Figure 2). The control lung showed essentially no staining, while the other three cases of squamous adenocarcinoma were indistinguishable from our index case. Comments. The occurrence of a neoplasm and a connective tissue disease within an individual raises the suspicion of a common underlying pathogenetic mechanism, especially when a temporal relationship is observed. This event, nonetheless, is extremely uncommon and has been documented previously in scleroderma only in association with breast carcinoma, the esophagus, multiple myeloma, and several cases of lung cancer [1,2,5,7,11-151. The reported cases of lung cancer (or other neoplasms) have occurred in the setting of long-standing scleroderma, usually with extensive pulmonary fibrosis [3,4,8,9]. As stated in one textbook, “carcinoma of the lung never occurs in scleroderma in the absence of pulmonary fibrosis” [16]. In this regard,
BRIEF CLINICAL
the current reported case of simultaneous occurrence of scleroderma and lung cancer is unique and represents an important observation. Although the possibility exists that the development of lung cancer and scleroderma in this patient was a chance event or perhaps related to her long history of cigarette smoking, the data from two recent studies suggest otherwise [8,9]. These reports clearly establish scleroderma itself as an independent risk factor for the development of malignancy. However, these authors reported on the development of neoplasms in the setting of scleroderma of many years’ duration. Relative risks for the development of lung cancer in established scleroderma were estimated in the above studies at 4.4 and 16.5, although the overall number of cases observed was small. Previous surveys failed to document an increased prevalence of malignancy in scleroderma, although the relative risks were not calculated [l,lO]. Furthermore, alveolar cell carcinomas, which have received most of the attention in case series and standard textbooks, were not observed in the two recent studies [8,9]. The presentation of cancer coincident with scleroderma raised the possibility that the sclerosis was a paraneoplastic manifestation of the underlying malignancy. The development of malignancy at or near the onset of scleroderma is reminiscent of polymyositis-dermatomyositis and its presumed relationship to cancer. Many of the speculations concerning a pathophysiologic relationship would be applicable in this patient. Substances elaborated by the transformed cells may act in a hormonal fashion to stimulate fibroblast activity and/or damage endothelial cells. Current concepts in the pathogenesis of scleroderma have focused on various growth factors and cytokines that, under appropriate conditions, might transform fibroblasts into a profibrotic phenotype [17]. It is of interest that many of these soluble factors, such as TGF-/3, have been previously implicated in the neoplastic transformation of normal host cells. It is conceivable that the individual described in this report developed scleroderma secondary to dysregulation of similar growth factors or cytokines. For this reason, we decided to survey the tumor tissue for an array of fibrogenic peptides. The malignant cells displayed intense cytoplasmic staining for the aforementioned factors, along with surrounding tissue. However, no fibrosis was observed in this immediate vicinity associated with these fibrogenic peptides. Furthermore, the control cases of malignancy (in the absence of scleroderma) stained equally intense. Therefore, two conclusions become evident. First, a simple paracrine effect of these peptides
OBSERVATIONS
Figure 2. Photomicrograph of a representative area of the resected lung tumor showing strong positive immunoperoxidase staining with anti-TGF-jS antibody in the cytoplasm of the transformed cells (arrow) and adjacent macrophages (arrowhead). (Original magnification X400, reduced by 30%.)
was not observed on the tissue immediately surrounding the tumor. It is likely that these factors enter the circulation and may act in an endocrine fashion to activate the dermal fibroblasts, leading to sclerosis. Second, the index case was not unique in the elaboration of these factors. From this we are left with the speculation that the patient’s fibroblasts are unusually reactive to one or more of these factors. However, several questions remain unanswered: for example, why certain target tissue fibroblasts were activated while others are seemingly spared and why this patient’s fibroblasts were susceptible to the effects of these peptides while the other three cases showed no evidence of activation. Perhaps this relates to genetic or other predisposing influences in our index case. Also, the other three patients died shortly after diagnosis, leaving little time for the potential development of a chronic connective tissue disease. Lastly, it is conceivable that a tumor-specific fibrogenic product different from the factors studied above was elaborated by this patient. Nonetheless, the data provided above lend strong support to the theory that the pathogenesis involves end-organ hyperreactivity rather than specific factors hypersecreted by the tumor cells. BARRYL. GRVBER,M.D. FREDERICKMILLER, M.D. LEE D. KAUFMAN, M.D. Health Sciences Center State University of New York Stony Brook, New York 1. Duncan S. Winkelmann R. Cancer and scleroderma. Arch Dermatol 1979; 115: 950-5. 2. Mattingly P, Mowat A. Rapidly progressive scleroderma associated with carcinoma of the esophagus. J Rheum Dis 1979; 38: 177-8.
June
1992
The American
Journal
of Medicine
Volume
92
707
BRIEF CLINICAL
OBSERVATIONS
3. Twersky J, Twersky N, Lehr C. Scleroderma and carcinoma of the lung. Clin Radio1 1976; 27: 203-9. 4. Talbott J. Barrocas M. Progressive systemic sclerosis (PSS) and malignancy, pulmonary and non-pulmonary. Medicine (Baltimore) 1979; 58: 182-207. 5. Talbott J, Barrocas M. Carcinoma of the lung in progressive systemic sclerosis: a tabular review of the literature and a detailed report of the roentgenographic changes in two cases: Semin Arthritis Rheum 1980; 9: 191-217. 6. Medsger TJ. Systemic sclerosis and malignancy-are they related? J Rheumatol 1985; 12: 1041-3. 7. Enzenauer R. McKay J, Riel M. Case report: rapidly progressive systemic sclerosis
associated
with carcinoma
of the lung. Milit Med 1989; 154: 574-
7. 6. Peters-Golden M. Wise R, Hochberg M, Stevens M. Wigley F. Incidence of lung cancer in systemic sclerosis. J Rheumatol 1985; 12: 1136-9. 9. Roumm A, Medsger TJ. Cancer and systemic sclerosis. An epidemiologic study. Arthritis Rheum 1985; 28: 1336-40. 10. Black K, Zilko P, Dawkins R, Armstrong B, Mastaglia G. Cancer in connective tissue disease. Arthritis Rheum 1982; 25: 1130-3. 11. Matzner MJ, Trachtman B, Mandelbaum R. Coexistent carcinoma and scle-
708
June
1992
The American
Journal
of Medicine
Volume
92
roderma of esophagus. Am J Gastroenterol 1963; 39: 31-41. 12. Lee P, Alderdice C. Wilkinson S, Keystone E, Urowitz M, Gladman D. Malignancy in progressive systemic sclerosis-association with breast carcinoma. J Rheumatol 1983; 10: 665-6. 13. Forbes AM, Woodrow JC, Verbov JL, Graham RM. Carcinoma of the breast and scleroderma: four further cases and a literature review. Br J Rheumatol 1989; 28: 65-9. 14. Bielefeld P. Besancenot J, Cortet P, Couillaut G. Sclerodermie generalisee et hemopathies malignes. Rev Rhum 1990; 57: 235-6. 15. Dupond J, Humbert P. Fest T, de Wazieres B. Sclerodermie, syndrome de gougerot-sjbgren et leucemie myelomonocytaire. Rev Rhum 1989; 56: 425-6. 16. Dunnill MS. Pulmonary pathology. Edinburgh: Churchill Livingstone, 1982:
322. 17. LeRoy
EC, Smith EA. Kahaleh MB, Trojanowska M, Silver RM. Current comment: a strategy for determining the pathogenesis of systemic sclerosis: is transforming growth factor beta the answer? Arthritis Rheum 1989; 32: 817-25. Submitted
September
14, 1991, and accepted
October
4, 1991
There was a marked reduction in circulating T lymphocytes (CDll+, 0.25 X log/L; T4:T8 ratio 1.9). Results of other tests done in an attempt to exclude underlying malignancy or infection were all negative. With the lumps waxing and waning, the diagnosis was only made 3 months later, from a biopsy of the fat in the abdominal wall, shown to be grossly abnormal on computed tomographic (CT) scan. Ultrasonography also suggested fatty infiltration of the liver. Two months of treatment with nonsteroidal antiinflammatory drugs and prednisone 60 mg daily achieved only a transient improvement in his fever. His abdomen became so distended and hard that he was unable to touch his knees. Weight gain totaled 20 kg and he developed respiratory difficulty with tightness about his throat. Eight months after the patient’s presentation, therapy with cyclosporin was commenced at a dose of 600 mg/d orally (approximately 6.5 mg/kg), and over the subsequent 4 months his abdomen softened, he lost 10 kg, and results of ultrasonography and CT scanning were normal. His cyclosporin dose was adjusted to maintain his blood levels (monitored weekly initially) within the therapeutic range of 150 to 350 nmol/L. After a year of treatment, we reduced the cyclosporin dose to 300 mg/d orally, maintaining his levels at approximately 70 nmol/L for 1 year (levels were checked every 3 weeks). He is now back at work and active in sports. CDll+ cell counts have improved (0.91 X log/L; T4:T8 ratio of 1.4) with normal phytohemagglutinin and pokeweed mitogen responses. For the past 6 months he has not required any treatment, and has remained well and asymptomatic. The rationale for using cyclosporin is the involvement of the T lymphocyte in the disease process [2], and the two previously reported cases of panniculitis that have responded to this treatment [3,4]. Although one of these patients had severe systemic panniculitis [4], in neither case was the histology reported as cytophagic. The etiology of cytophagic panniculitis is unknown and there is no previous specific therapy, with many patients dying despite aggressive chemotherapy [2]. The sustained remission achieved with cyclosporin in our patient provides further evidence for the role of the T lymphocyte in the pathologic process. Our results suggest that a trial of this drug is warranted in other patients with cytophagic panniculitis.
1. Crotty cytopenia, tol 1981: 2. Alegre Dermatol 3. Entzian Christian 4. Kusuki Christian Submitted
OBSERVATIONS
CP, Winkelmann RK. Cytophagic histiocytic panniculitis with fever, liver failure and terminal haemorrhagic diathesis. J Am Acad Derma4: 181-94. VA, Winkelmann RK. Histiocytic cytophagic panniculitis. J Am Acad 1989: 20: 177-85. P, Barth J, Monig H, Ohnhaus EE, Kirch W. Treatment of Weberpanniculitis with cyclosporin A. Rheumatol Int 1987; 7: 181. A, Kitamura K. Urabe A, Takaku F. Successful treatment of Weberdisease by cyclosporin. Am J Med 1988; 85: 277-8. June 5, 1991. and accepted
in revised form November
14, 1991
ACKNOWLEDGMENT: The histology was reviewed by Dr. R. K. Winkelmann, Dermatopathologist. Mayo Clinic. Thanks to Sandoz Pharmaceutical N.Z. Ltd. for providing the cyclosporin for this patient.
SIMULTANEOUSONSET OF SYSTEMIC SCLEROSIS(SCLERODERMA)AND LUNG CANCER:A CASEREPORTAND HISTOLOGIC ANALYSISOF FIBROGENICPEPTIDES
Primary neoplasms of the lungs developing in patients with systemic sclerosis (scleroderma) are well documented [l-lo]. Alveolar cell carcinoma has received particular attention in this regard [l], although all histologic types have been observed. The risk of developing lung cancer in individuals with scleroderma may be increased over that in the general population, with relative risks calculated from available data between 4.4 and 16.5 [6]. The concurrent development of lung cancer and scleroderma has been extremely rare; most cases of coincidence have been related to breast carcinoma [ll-131. We report a patient who developed systemic sclerosis immediately after the diagnosis of adenocarcinoma of the lung. This case is reminiscent of the relationship of polymyositis-dermatomyositis and cancer, and suggests that causal biologic relationships may exist. Therefore, the production and deposition of fibrogenic peptides or fibroblast growth factors by the neoplastic cells that potentially might stimulate dermal fibroblasts were explored by immunohistologic techniques. Case Report. A 50-year-old woman with a 30 pack-year history of cigarette smoking noted the onset of Raynaud’s phenomenon and episodic pain in her proximal interphalangeal and metacarpophalangeal joints 18 months prior to presentation. Four months later, subacute pleuritic chest pain and dyspnea prompted hospitalization. Chest radiographs and a computed tomographic scan reGORDONROYLE, M.Med.sc.,F.R.c.P.A. vealed a right upper lobe mass with extension into North Shore Hospital Auckland, New Zealand the pleura. After surgical excision, a diagnosis of HILARYBLACKLOCK,F.R.A.C.P.,F.R.C.P.A. adenosquamous carcinoma with tumor-free marMARY MILLER, F.R.C.P.A. gins was rendered. No further therapy was recomMiddlemore Hospital Auckland, New Zealand mended. Over the following months, the patient June
1992
The American
Journal
of Medicine
Volume
92
705
BRIEF CLINICAL
OBSERVATIONS
Figure 1. Left. Sclerodactyly involving all the digits with tightening of the skin leading to flexion contractures as well as a shallow ulceration over the fourth proximal interphalangeal joint. Note also the telangiectasia on the distal aspect of the third digit. Right. Limited scleroderma involving the skin distal to the wrists of both hands and in the perioral region of the face. Note the puckering of the skin around the mouth, multiple facial telangiectasias, and the ulcerations over several proximal interphalangeal joints. The severe flexion contractures involving the hands can also be observed in this photograph.
experienced increasing skin tightness, swelling, and pain involving the digits, wrist, and lower forearm bilaterally associated with severe Raynaud’s phenomenon of both the feet and hands (Figure 1, left). This was associated with pitting of several digits along with prominent telangiectasias on her face and hands. Mild tightening of the skin on her face and neck with perioral puckering developed over the next 12 months after the diagnosis of lung cancer (Figure 1, right). Tendon friction rubs were palpable at the wrists. Serologic testing revealed the presence of an antinuclear antibody with an atypical discrete speckled pattern at a titer of 1:2,560 and typical speckled pattern at a titer of 1:320, and a latex fixation of 1:2,560. An anticentromere antibody was not seen. Antibody to Scl-70 (topoisomerase I) was absent. Radiographs of the chest, hands, and wrists were unremarkable. Pulmonary function testing revealed a severe reduction in the carbon monoxide diffusing capacity (24% of predicted), but the results were otherwise unremarkable. The presence of rapidly progressive skin tightening (despite its limited distribution), tendon friction rubs, and digital pitting all suggested a more generalized form of systemic sclerosis. Followup for more than 6 months still fails to indicate any evidence of recurrent malignancy. Immunohistologic Studies. The routinely processed surgical lung tissue was reviewed and the diagnosis of adenosquamous carcinoma was confirmed. Furthermore, the surrounding parenchyma was notable for the absence of interstitial fibrosis. The excised tumor and surrounding lung tissue
706
June
1992
The American
Journal
of Medicine
Volume
92
were subjected to immunohistologic analysis for growth factors using a panel of antibodies directed against TGF-a (Peninsula Labs, Belmont, CA), TGF-@ (R&D Systems, Minneapolis, MN), PDGFAA and PDGF-BB, bFGF, and EGF (Genzyme, Boston, MA) with the appropriate secondary antibody biotinylated and the tertiary antibody coupled to Strepavidin-peroxidase. The intensity of staining was compared to normal control lung tissue obtained at autopsy and to three other cases of adenosquamous lung carcinoma without associated scleroderma. Strong staining for all the peptide growth factors was observed within scattered macrophages, blood vessels, and the tumor cells themselves (Figure 2). The control lung showed essentially no staining, while the other three cases of squamous adenocarcinoma were indistinguishable from our index case. Comments. The occurrence of a neoplasm and a connective tissue disease within an individual raises the suspicion of a common underlying pathogenetic mechanism, especially when a temporal relationship is observed. This event, nonetheless, is extremely uncommon and has been documented previously in scleroderma only in association with breast carcinoma, the esophagus, multiple myeloma, and several cases of lung cancer [1,2,5,7,11-151. The reported cases of lung cancer (or other neoplasms) have occurred in the setting of long-standing scleroderma, usually with extensive pulmonary fibrosis [3,4,8,9]. As stated in one textbook, “carcinoma of the lung never occurs in scleroderma in the absence of pulmonary fibrosis” [16]. In this regard,
BRIEF CLINICAL
the current reported case of simultaneous occurrence of scleroderma and lung cancer is unique and represents an important observation. Although the possibility exists that the development of lung cancer and scleroderma in this patient was a chance event or perhaps related to her long history of cigarette smoking, the data from two recent studies suggest otherwise [8,9]. These reports clearly establish scleroderma itself as an independent risk factor for the development of malignancy. However, these authors reported on the development of neoplasms in the setting of scleroderma of many years’ duration. Relative risks for the development of lung cancer in established scleroderma were estimated in the above studies at 4.4 and 16.5, although the overall number of cases observed was small. Previous surveys failed to document an increased prevalence of malignancy in scleroderma, although the relative risks were not calculated [l,lO]. Furthermore, alveolar cell carcinomas, which have received most of the attention in case series and standard textbooks, were not observed in the two recent studies [8,9]. The presentation of cancer coincident with scleroderma raised the possibility that the sclerosis was a paraneoplastic manifestation of the underlying malignancy. The development of malignancy at or near the onset of scleroderma is reminiscent of polymyositis-dermatomyositis and its presumed relationship to cancer. Many of the speculations concerning a pathophysiologic relationship would be applicable in this patient. Substances elaborated by the transformed cells may act in a hormonal fashion to stimulate fibroblast activity and/or damage endothelial cells. Current concepts in the pathogenesis of scleroderma have focused on various growth factors and cytokines that, under appropriate conditions, might transform fibroblasts into a profibrotic phenotype [17]. It is of interest that many of these soluble factors, such as TGF-/3, have been previously implicated in the neoplastic transformation of normal host cells. It is conceivable that the individual described in this report developed scleroderma secondary to dysregulation of similar growth factors or cytokines. For this reason, we decided to survey the tumor tissue for an array of fibrogenic peptides. The malignant cells displayed intense cytoplasmic staining for the aforementioned factors, along with surrounding tissue. However, no fibrosis was observed in this immediate vicinity associated with these fibrogenic peptides. Furthermore, the control cases of malignancy (in the absence of scleroderma) stained equally intense. Therefore, two conclusions become evident. First, a simple paracrine effect of these peptides
OBSERVATIONS
Figure 2. Photomicrograph of a representative area of the resected lung tumor showing strong positive immunoperoxidase staining with anti-TGF-jS antibody in the cytoplasm of the transformed cells (arrow) and adjacent macrophages (arrowhead). (Original magnification X400, reduced by 30%.)
was not observed on the tissue immediately surrounding the tumor. It is likely that these factors enter the circulation and may act in an endocrine fashion to activate the dermal fibroblasts, leading to sclerosis. Second, the index case was not unique in the elaboration of these factors. From this we are left with the speculation that the patient’s fibroblasts are unusually reactive to one or more of these factors. However, several questions remain unanswered: for example, why certain target tissue fibroblasts were activated while others are seemingly spared and why this patient’s fibroblasts were susceptible to the effects of these peptides while the other three cases showed no evidence of activation. Perhaps this relates to genetic or other predisposing influences in our index case. Also, the other three patients died shortly after diagnosis, leaving little time for the potential development of a chronic connective tissue disease. Lastly, it is conceivable that a tumor-specific fibrogenic product different from the factors studied above was elaborated by this patient. Nonetheless, the data provided above lend strong support to the theory that the pathogenesis involves end-organ hyperreactivity rather than specific factors hypersecreted by the tumor cells. BARRYL. GRVBER,M.D. FREDERICKMILLER, M.D. LEE D. KAUFMAN, M.D. Health Sciences Center State University of New York Stony Brook, New York 1. Duncan S. Winkelmann R. Cancer and scleroderma. Arch Dermatol 1979; 115: 950-5. 2. Mattingly P, Mowat A. Rapidly progressive scleroderma associated with carcinoma of the esophagus. J Rheum Dis 1979; 38: 177-8.
June
1992
The American
Journal
of Medicine
Volume
92
707
BRIEF CLINICAL
OBSERVATIONS
3. Twersky J, Twersky N, Lehr C. Scleroderma and carcinoma of the lung. Clin Radio1 1976; 27: 203-9. 4. Talbott J. Barrocas M. Progressive systemic sclerosis (PSS) and malignancy, pulmonary and non-pulmonary. Medicine (Baltimore) 1979; 58: 182-207. 5. Talbott J, Barrocas M. Carcinoma of the lung in progressive systemic sclerosis: a tabular review of the literature and a detailed report of the roentgenographic changes in two cases: Semin Arthritis Rheum 1980; 9: 191-217. 6. Medsger TJ. Systemic sclerosis and malignancy-are they related? J Rheumatol 1985; 12: 1041-3. 7. Enzenauer R. McKay J, Riel M. Case report: rapidly progressive systemic sclerosis
associated
with carcinoma
of the lung. Milit Med 1989; 154: 574-
7. 6. Peters-Golden M. Wise R, Hochberg M, Stevens M. Wigley F. Incidence of lung cancer in systemic sclerosis. J Rheumatol 1985; 12: 1136-9. 9. Roumm A, Medsger TJ. Cancer and systemic sclerosis. An epidemiologic study. Arthritis Rheum 1985; 28: 1336-40. 10. Black K, Zilko P, Dawkins R, Armstrong B, Mastaglia G. Cancer in connective tissue disease. Arthritis Rheum 1982; 25: 1130-3. 11. Matzner MJ, Trachtman B, Mandelbaum R. Coexistent carcinoma and scle-
708
June
1992
The American
Journal
of Medicine
Volume
92
roderma of esophagus. Am J Gastroenterol 1963; 39: 31-41. 12. Lee P, Alderdice C. Wilkinson S, Keystone E, Urowitz M, Gladman D. Malignancy in progressive systemic sclerosis-association with breast carcinoma. J Rheumatol 1983; 10: 665-6. 13. Forbes AM, Woodrow JC, Verbov JL, Graham RM. Carcinoma of the breast and scleroderma: four further cases and a literature review. Br J Rheumatol 1989; 28: 65-9. 14. Bielefeld P. Besancenot J, Cortet P, Couillaut G. Sclerodermie generalisee et hemopathies malignes. Rev Rhum 1990; 57: 235-6. 15. Dupond J, Humbert P. Fest T, de Wazieres B. Sclerodermie, syndrome de gougerot-sjbgren et leucemie myelomonocytaire. Rev Rhum 1989; 56: 425-6. 16. Dunnill MS. Pulmonary pathology. Edinburgh: Churchill Livingstone, 1982:
322. 17. LeRoy
EC, Smith EA. Kahaleh MB, Trojanowska M, Silver RM. Current comment: a strategy for determining the pathogenesis of systemic sclerosis: is transforming growth factor beta the answer? Arthritis Rheum 1989; 32: 817-25. Submitted
September
14, 1991, and accepted
October
4, 1991