S a group of lung cancers that were characteristically

Transcription

1 PERIPHERAL LUNG CANCERS ARISING IN SCARS HIDEJIRO YOKOO, M.D., AND EARL E. SUCKOW, M.D. INCE Rossles and Friedrich4 first described S a group of lung cancers that were characteristically associated with scars in the lungs, and called them scar or cicatrical cancer of the lung, other papers have appeared on this subject, mainly those by Raeburn and Spencer? and Liiders and Themel.5 We have observed a number of peripheral lung cancers associated with scars and wish to add 7 cases to the literature. The 7 cases presented here were seen at the Laboratory Service, Veterans Administration Research Hospital, Chicago, Ill., in the period from January, 1960, to August, Of these 7 cases, 4 were found among surgically excised specimens, and 3 were obtained from autopsy material. The total number of lung cancers found during the same period was 10 among surgical specimens and 31 among autopsy material. All the tumors were completely sectioned, and at least 2 sections were cut from each paraffin block and stained by hematoxylin and eosin. Additional mucicarmine and elastic stains were used on selected sections. CASE REPORTS Case A-66. This 48-year-old white man was admitted to the Veterans Administration Research Hospital, Chicago, Ill., on Jan. 29, 1960, because of frontal headaches for 3 to 4 weeks. Physical findings were normal, but a neurological examination showed an intracranial lesion. A chest roentgenogram on admission to the hospital was reported as normal. The patient underwent a craniotomy, and a metastatic adenocarcinoma was removed. In view of these findings, an extensive unsuccessful medical work-up was performed in search of the primary tumor. The patient died on March 9, Autopsy Findings. The lungs exhibited foci of acute bronchopneumonia, and there was a 1.-cm. subpleural tumor nodule in the right upper lobe over the posterior aspect and near the apex. The pleura over the tumor showed marked depression and puckering. No tumor Fmm the departments of Pathology, Veterans Administration Research Hospital and Northwestern University Medical School, Chicago, Ill. Received for publication Dec. 7, other than residual metastatic tumor in the brain was found. Microscopically, the pleura over the tumor was thickened, and there was an old hyalinized scar just beneath the pleura (Fig. 1A). Surrounding the scar was a tumor arranged in an alveolar pattern lined by 1 layer of tall columnar epithelial cells that resembled those of the terminal bronchioli (Fig. IB). The mucin stain exhibited the presence of mucin within the cytoplasm as well as in the lumina. The tumor cells showed occasional cilia-like cytoplasmic projections and in some areas suggested phagocytic activity. Histological Diagnosis. Bronchiolar carcinoma (peripheral scar cancer) with metastasis to brain. Case A-207. This 63-year-old white man entered the Veterans Administration Research Hospital on Sept. 18, 1959, because of severe pain over the upper back for the past 8 months. On Oct. 7, 1959, he suddenly developed complete paraplegia with cord bladder. The myelographic examination indicated a complete obstruction at the level of T8 and 9. A laminectomy was performed, and an extra: dural metastatic tumor was excised. After recovery, the patient was subjected to an extensive search for the primary tumor without any findings. He was dismissed and returned on June 28, Terminally he developed acute bronchopneumonia and died on Aug. 17, Autopsy Findings. The right lung weighed 650 gm. On sectioning, there were occasional minute gray discrete nodules in the parenchyma in addition to focal areas of acute bronchopneumonia in all lobes. The lymph nodes around the right main bronchus were enlarged. The left lung weighed 500 gm. There was a fibrous adhesion over the lateral aspect, bridging the upper and lower lobes. Posterior to this adhesion, and in the superior segment of the lower lobe, was a prominent pleural depression and puckering resembling a healed scar. Section through this area revealed a gray hard nodule located subpleurally, measuring 2. cm. in greatest diameter (Fig. 2A). The nodule was rich in anthracotic pigment. Elsewhere, the apex was thickened, and both lobes contained scattered gray minute nodules, measuring up to 0.3 cm. in diameter. There were 1205

2 1206 CANCER November-December 1961 Vol. 14 FIG. 1. Case 1. A, Photomicrograph of the tumor. Note the pleural depression, subpleural scar, and carcinoma at the periphery of the scar. (H. & E. ~6.) B, Photomicrograph showing tumor arranged in an alveolar pattern. (H. & E. X200.) focal areas of acute bronchopneumonia throughout both lobes. The lymph nodes around the main bronchus contained small gray nodules. Metastatic foci were found in the thoracic vertebrae and cerebellum. Other organs were not remarkable. No other tumor was found. Microscopically, the nodule of the left lower lobe consisted of a centrally located dense hyalinized scar with tumor infiltrating the peripheral zone of the scar tissue. The center of the scar tissue was free of tumor tissue but contained small arteries, anthracotic pigment, foci of osteogenesis, and several dilated tenninal bronchioli lined by normal-appearing columnar epithelium. Obliterated arteries were noted, some of which were invaded by tumor cells. Tumor cells were arranged in 1 layer with large vesicular basally located nuclei with prominent nucleoli. The cytoplasm of the tumor cells was acidophilic and granular. Transition of normal bronchiolar lining epithelium to neoplastic cells was noted (Fig. 2C). Mitotic figures were rare, and there were frequent tumor cells with gigantic or multiple nuclei. Some tumor cells showed a few cilia-like cytoplasmic processes and suggestive phagocytic activities. Intraluminal mucin was weakly positive, and intracytoplasmic mucin was rarely encountered. Elastic stains of the scar tissue revealed the presence of haphazardly arranged elastic fibers, suggesting an old healed infarct (Fig. 2B). Scattered, discrete, minute nodules throughout both lungs exhibited tumor deposits mainly around the blood vessels and bronchial tree. The lymph nodes contained fibrotic nodules and multiple tumor deposits bilaterally. Diagnosis. Bronchiolar carcinoma (peripheral scar cancer) with metastases to regional lymph nodes, thoracic vertebrae, and cerebellum. Case A2 16. This 63-year-old colored man entered the Veterans Administration Research Hospital on April 16, He had

3 No. 6 PERIPHERAL LUNG CANCERS ARISING IN SCARS - Yokoo Q Suckow 1207 been in good health until April 1, 1960, when he developed a dull aching pain in the left hip which was aggravated by movement. In June, 1960, he developed sharp pain in the left upper anterior chest. Approximately 1 month prior to admission to the hospital, he developed shortness of breath and a moderate cough, productive of 2 to 3 teaspoons of white to gray sputum per day. The patient smoked 1 pack of cigarettes per day. Positive physical findings were precordial friction rubs, mild generalized expiratory wheezes, and a few rhonchi in the left base. Roentgenograms showed a pathological fracture of the left anterior sixth rib, and erosion of the vertebral bones. On Aug. 25, 1960, the patient became fe- brile and chest roentgenograms revealed consolidation of the right middle lobe. The patient continued a febrile course in spite of therapy and died on Aug. 28, Autopsy Findings. The right lung weighed 900 gm. Large pulmonary arteries on the right side were filled with thromboemboli, and the middle and lower lobes showed recent hemorrhagic infarction with fibrinous exudate over the pleural surface. The upper lobe revealed apical pleural thickening and marked ernphysema. The left lung weighed 700 gm. There was a markedly puckered, depressed lesion near the apex, resembling an old healed scar (Fig. 3). Section through this lesion showed a subpleurally located gray, hard nodule, measuring FIG. 2. Case 2. A, Gross appearance of the tumor. There is marked depression of the pleural surface, and the underlying scar contains abundant anthracotic pigment. The tumor surrounding the scar appears grayish white. B, Elastic stain of scar. Elastic fibers are abundant and haphazardly arranged, snggesting that the scar is the result of an old healed infarct. (Modified Himes and Moriber stain. ~200.) C, Photomicrograph of the tumor. There is transition of normal-appearing bronchiolar epithelium to neoplastic cells. (H. & E. ~200.)

4 1208 CANCER November-December 1961 Vol cm. in diameter, which was rich in anthracotic pigment. There were two ill defined, grayish, hard nodular foci subjacent to the aforementioned nodule. They measured up to 1. cm. in greatest diameter. Elsewhere the lung parenchyma showed marked emphysematous changes. The pericardial sac contained 520 cc. of blood-tinged fluid and there was an acute fibrinous pericarditis. The heart was not remarkable except for the aforementioned pericarditis. Metastatic tumor deposits were found in the lumber vertebrae and left sixth rib. The other organs showed no evidence of tumor. Microscopically the nodule of the right upper lobe revealed a subpleural old hyalinized scar (Fig. 4A), containing a moderate amount of anthracotic pigment, cholesterol clefts, and hyalinized arteries (Fig. 4B). Some arteries contained tumor cell clusters. The center of the scar was free of tumor tissue, and the elastic stain exhibited the presence of haphazardly Fic. 3. Case 3. Gross appearance of the tumor. There is marked depression and puckering of the pleura over arranged fibers suggesting an Old the tumor. healed infarct. The peripheral zone of the scar FIG. 4. Case 3. A, Photomicrograph of the entire tumor. The inset refers to the photomicrograph seen in Fig. 6A. (H. & E. X8.) B, Photomicrograph of scar showing a completely obliterated medium-sized artery within the scar. There is anthracotic deposit around the artery. The lumen of the artery is filled with loose connective tissue. (H. & E. ~30.)

5 No. 6 PERIPHERAL LUNG CANCERS ARISING IN SCARS - Yokoo & Suckow 1209 was infiltrated by tumor tissue, the cells of which were arranged in an alveolar pattern. Many of these cells had a large vesicular nucleus, which was frequently located at the base and contained an acidophilic nucleolus (Fig. 5). The cytoplasm was acidophilic and granular. Mitotic figures were occasionally seen. Cilia-like cytoplasmic processes were noted in a few instances, and there was suggestive phagocytic activity by tumor cells. Intralumirlal and intracytoplasmic mucin was weakly positive. Blood vessels and lymphatics were invaded by tumor cells in many areas. Transition of normal bronchiolar epithelium to the neoplastic cells was demonstrated in 2 instances (Fig. 6A). The ill-defined nodular areas subjacent to the tumor appeared to be direct extension of the tumor, and there was no scar tissue present in those lesions. Small tumor deposits were found throughout both lungs, many of them being within lymphatics, around blood vessels, and within the pleura. Right and left bronchial and carynal lymph nodes showed metastatic deposits. One of the right bronchial lymph nodes contained a small hyalinized scar. It is interesting to note that small tumor cell clusters were found within the lymphatics of the left main bronchial wall (Fig. 6B). The lining epithelium of the bronchus did not show atypical changes. The right middle and lower lobes showed extensive hemorrhagic infarction. The pericardium was infiltrated by tumor tissue with an associated acute fibrinous pericardi t is. Diagnosis. Bronchiolar carcinoma (peripheral scar cancer) with metastases to regional lymph nodes, pericardium, lumbar vertebrae, and rib. Case S-3. The patient was a 60-year-old white man, who was found to have a lung lesion at another hospital in March, 1959, when he underwent bronchoscopy with negative findings. He was admitted to our hospital in December, 1959, and roentgeno<graphic examinations of the chest revealed a mass in the leet upper lung field. A left pneumonectomy was performed in January, 1960, following the frozen section diagnosis of carcinoma. The postoperative course was uneventful. The patient died in another Veterans Administration hospital after a cerebral vascular accident in March, hto autopsy was performed. Gross Appearance. The specimen was an entire left lung, weighing 383 gm. and measuring 21.x15.x4. cm. The upper lobe was covered by fibrofatty tissue on the posterolatera1 aspect. There was a slight depression over the pleural surface in the superior segment of the lower lobe. Section through this area revealed a well circumscribed, ovoid tumor, 3.5 FIG. 5. Case 3. Photomicrograph of tumor. (H. & E. XZOO.) cm. in greatest diameter. The tumor was mottled dark gray and black. The rest of the lung parenchyma showed moderately severe emphysematous changes throughout. The bronchi were not involved by the tumor. Microscopic Appearance. The pleura was thickened over the tumor. There was a dense hyalinized scar beneath the pleura, containing abundant anthracotic pigment. Tumor immediately adjacent to the scar showed tubular structures lined by 1 or more layers of cuboidal epithelial cells with eosinophilic cytoplasm. Occasional tumor cells contained mucin-positive material within the cytoplasm. In 1 area a bronchiole was partly lined by tumor cells. Mitotic figures were frequently encountered. At the periphery of the tumor, the cells were arranged in clusters or nests, giving an appearance of epidermoid or undifferentiated carcinoma, although keratinization or intercellular bridges were not seen. The bronchial epithelium showed no abnormality. The bronchial lymph nodes contained a large amount of anthracotic pigment, but there were no metastatic deposits or granuloma. Histological Diagnosis. Undifferentiated carcinoma (peripheral scar cancer).

6 1210 CANCER Novem ber-decem ber 1961 Vol. 14 FIG. 6. Case 3. A, Magnified from the same area as the box in Fig. 4A, and showing the transition of normalappearing bronchiolar epithelium to neoplastic cells. (H. & E. ~200.) B. Photomicrograph of the left main bronchial wall. There are tumor cell clusters within the lymphatics. (H. & E. X200.) Case This 64-year-old white man was admitted to the Veterans Administration Research Hospital because of failing vision. Physical examination was normal except for a marked decrease in vision secondary to cataract, and a chest roentgenogram showed a round opacity, approximately 2 cm. in diameter, present in the periphery of the right second and third intercostal space. An exploratory thoracotomy was performed in January, 1960, and a small lesion in the right upper lobe and a small nodule in the right lower lobe were noted. A right pneumonectomy was performed following the frozen section diagnosis of carcinoma. The postoperative course was essentially uneventful. He was completely asymptomatic 8 months after operation. Gross Appearance. The specimen consisted of an entire right lung, weighing 421 gm. and measuring 24.~14.~3. cm. At the apex, the pleura was slightly depressed and puckered in appearance. Section through this area revealed a well defined, dark gray nodule measuring 2. cm. in diameter. Another nodule similar to the one just described was present in the medial aspect of the lower lobe close to the hilum; it measured 1.5~ 1.ZX 1. cm. Microscopic Appearance. Sections of both nodules were quite similar. The covering pleura was thickened, and there was an old hyalinized scar just beneath the pleura. The scar contained an increased amount of anthracotic pigment. Surrounding the scar and spreading outward was a tumor arranged in alveolar structures lined by 1 layer of columnar neoplastic epithelial cells. Mucin stains showed occasional tumor cells containing mucin-positive material within the cytoplasm. The intraluminal material was also positive for mucicarmine stain. The bronchial lymph nodes contained metastatic deposits. Histological Diagnosis. Bronchiolar carcinoma (peripheral scar cancer) with regionai lymph node metastasis. Case This 61-year-old white man entered the Veterans Administration Research Hospital on Feb. 29, 1960, complaining of upper abdominal pain since December, He had slight exertional dyspnea with a hack-

7 No. 6 PERIPHERAL LUNG CANCERS ARISING IN SCARS * Yokoo & Suckow 1211 ing cough for 2 weeks prior to admission, with production of small amounts of white sputum. Chest roentgenograms revealed an opacity in the right middle lung field associated with a smaller, rounded opacity superiorly. Intravenous pyelography, cholecystography, and roentgenographic examination of the entire alimentary tract were negative for tumor. Skeletal bone survey revealed no evidence of metastasis. In view of these findings, an exploratory thoracotomy was done on March 15, Frozen section revealed a carcinoma of the right upper lung. A right upper lobectomy was done. The postoperative course was uneventful. On April 4, 1960, he underwent a transurethral resection of the prostate. The prostatic tissue was negative for a tumor, revealing only nodular hyperplasia. The patient was asymptomatic 6 months after operation. Gross Appearance. The specimen was an upper lobe of right lung, weighing 166 gm. and measuring 18.XlO.x3. cm. There were patchy pleural thickenings and a few emphysematous bullae. Over the posteromedial aspect of the lobe the pleura was slightly depressed and puckered, beneath which was a well defined, dark-gray, hard tumor nodule measuring 1.3 cm. in diameter. The posterolateral aspect of the lobe contained a tumor mass, just beneath the pleura, measuring 4. cm. in greatest diameter. Microscopic Appearance. Sections of both tumors were identical to each other. The overlying pleura was thickened, and immediately beneath it there was an old hyalinized scar containing abundant anthracotic pigment and old thrombosed arteries. At the periphery of the scar were clumps of large anaplastic tumor cells. Mucin stain was negative. Bronchial lymph nodes showed no tumor metastasis, but there was an old hyalinized granuloma in 1 of the nodes. Histological Diagnosis. Undifferentiated carcinoma (peripheral scar cancer). Case no. TABLE 1 PERSONAL CASES OF SCAR CANCER Case S-732. A 70-year-old white man was admitted to the Veterans Administration Research Hospital on April 14, 1960, because of a progressively enlarging chest lesion found in a previous admission to this hospital in October, The patient experienced slight cough and blood-streaked sputum on 2 occasions before admission. On April 25, 1960, the patient underwent exploratory thoracotomy, and a left pneumonectomy was performed following the frozen section diagnosis of carcinoma. Two days after operation the patient developed chest pain with electrocardiographic changes suggestive of an acute myocardial infarction. He was placed on anticoagulants, and there were no further complications. The patient returned to the outpatient clinic in September, There was no sign of recurrent tumor. Gross Appearance. The first specimen submitted for frozen section was a piece of lung tissue measuring 7.~3.~3. cm. There was a 1.5-cm. nodule that was located about 0.5 cm. beneath the pleural surface. The second specimen was an entire left upper lobe with many emphysematous bullae at the apex. Otherwise, the specimen showed no significant pathological changes. Microscopic Appearance. Sections of the nodule showed a centrally located, old hyalinized scar that contained abundant anthracotic pigment and a large, completely thrombosed artery invaded in 1 area by the tumor. The center of the scar was free of tumor cells. The periphery of the scar was infiltrated by tumor cells that were arranged in an alveolar pattern. They exhibited abundant pale cytoplasm, positive for mucicarmine stain. Intraluminal material was also strongly positive for mucin. Regional lymph nodes were negative for metastatic deposits, but there was a healed, old granuloma in 1 of the nodes. Histological Diagnosis. Bronchiolar carcinoma (peripheral scar cancer). Pt. Pt. Location Size age, yr. sex tumor* tumor, cm. Histol. diag. Metastasis 1 48 M RUL 1.0 Bronchiolar ca. Brain 2 63 M LLL 2.0 Bronchiolar ca. Lymph node, brain, bone 3 63 M LUL 1.3 Bronchiolar ca. Lymph node, pericardium, bone 4 60 M I.LL 3.5 Undiff. ca M RUL 2.0 Bronchiolar ca. Lymph node RLL 1.5 Bronchiolar ca M RUL 4.0 Undiff. ca ? 7 70 M LUL 1.5 Bronchiolar ca.... *The symbols indicate the following locations: RUL, right upper lobe; RLL, right lower lobe; LUL, left upper lobe; LLL, left lower lobe.

8 1212 CANCER November-December 1961 Vol. 14 Author Friedrich4 Rossles Luders & Theme16 Raeburn & Spencer7 TABLE 2 DATA FOR 56 CASES OF SCAR CANCER TAKEN Mean age Sex pt. Location tumor, no.* Size tumor, cm. NO. pt., cases yr. M F RUL RML RLL LUL LLL Apex 53 >3 Unkn t _ TOTAL *The symbols indicate the following locations: RUL, right upper lobe; RML, right middle lobe; RLL, right tin 1 patient the sex was not stated. DISCUSSION The summary of our cases is presented in Table 1. In addition to analyzing our own material, the cases described by Friedri~h,~ Rossle,s Liiders and Themel,5 and Raeburn and Spencer? were tabulated in Table 2 and the data were compared with our findings. Friedrich's last 6 cases were omitted from the analysis because of uncertainty of the diagnosis expressed by the author. Age. In our series of cases the mean age of the patients was 61.3 years and that of the patients in the series of collected cases was 60.6 years. Sex. All the patients in our series were men, reflecting the predominant male population in our hospital. Table 2 shows that the ratio between male and female in the collected cases is 4.5 to 1. Duration of Cancer. As noted in the case history, the patient in case 4 had the lesion as shown by chest roentgenogram for at least 8 months before operation, and likewise the patient in case 7 had roentgenographic evidence of the chest lesion for at least 6 months prior to operation. There is no way of estimating the duration of the disease in the remaining 5 cases because the lesions were found either on admission (cases 5 and 6), or at the time of autopsy, although the symptoms due to the metastatic tumors were present from several weeks to 19 months (cases 1, 2, and 3). Clinical Symptoms. The patient in case 3 presented a history of productive cough for about 1 month prior to admission to the hospital. In case 6 there was a history of dyspnea, hacking cough, and expectoration. The patient in case 7 experienced slight cough and blood-streaked sputum on 2 occasions before admission. The other 4 patients showed no clinical symptoms attributable to lung cancer. Absence of clinical symptoms is not surprising, since the tumors were found incidentally on roentgenographic examination of the chest or at the time of autopsy. Clinical symptoms were not analyzed in the collected cases because the stages of the tumors are not comparable among these cases. Location of Tumor. The right upper lobe was involved in 3 cases (cases 1, 5, and 6). The right lower lobe was involved once (case 5). The left lower lobe was involved twice (cases 2 and 4). The left upper lobe was involved twice (cases 3 and 7). Table 2 shows that in the 56 cases collected from the literature, 39 cases occurred in the upper lobes, and the right upper lobe was involved 22 times. As has been observed frequently by the previous investigators,4,5,7,* a majority of the tumors were located subpleurally, and the pleural surfaces directly over the tumors often showed a depressed, puckered appearance, very much like old healed scars. This has been observed in 6 of our 7 cases. Only case 7 did not show this characteristic appearance, as the scar was located 0.5 cm. beneath the pleura. Size of Tumor. In all of our cases the tumors were small. In 5 instances they were less than 3. cm. in diameter. In case 6, in which there were 2 separate primary tumors, the larger one measured 4. cm. in diameter and the smaller one 1.3 cm. in diameter. In case 4 the lesion measured 3.5 cm. in diameter. In Table 2, the collected cases are divided into 2 groups according to the size of the tumors. In 6 cases the size of the tumor was not stated, but in the remaining cases more than two-thirds were

9 No. 6 FROM THE LITERATURE PERIPHERAL LUNG CANCERS ARISING IN SCARS * Histological diagnosis, no. Un- Bron- Bron- Poly- Squam. Adeno- diff. cho- chiol. gon. cell ca. ca. gen. ca. ca. cell ca. Unkn lower lobe; LUL, left upper lobe; LLL, left lower lobe. not more than 3. cm. in diameter, suggesting that scar is more likely found in small carcinomas, or conversely, advanced carcinomas obscure the presence of such findings. Metastasis. In case 5, metastatic deposits were demonstrated in the bronchial lymph nodes. In case 1, the tumor produced early metastasis to the brain, which caused the death of the patient. In case 2, there were metastases to the bronchial lymph nodes, brain, and bone, and in case 3, the bronchial lymph nodes, pericardium, and bones were involved. Among the collected cases, those described by Raeburn and Spencer7 are different from the others, which represented mostly small carcinomas found incidentally at autopsy, measuring up to 3. cm. in diameter. Yet, nearly half of the cases produced metastasis, either locally, distantly, or both. The other cases showed tumor metastasis in about one-third of those in which the lesions were not more than 3. cm. in diameter and in about three-fourths of those in which the lesions were larger than 3. cm. Etiology of Scar in Relation to the Development of Tumor. In the previous reports, the scars that were associated with the carcinomas were predominantly subpleural in location. Various causes have been suggested for the scar formation by those authors. In Raeburn and Spencer s cases7 there were at least 3 tuberculous lesions, 1 tuberculous cavity, 2 probable healed infarcts, 1 probable bronchiectatic cavity, 1 probable chronic lung abscess and bronchiectasis with an old bullet wound. In 2 of the remaining cases there were thrombosed arteries present in the scars. Liiders and Theme15 considered most of the scars to be due to tuberculosis (4 tuberculous Yokoo cb Suckow 1213 scars and 17 tuberculous reinfections), but the remaining 3 cases in their series were classified as old healed infarcts. In many cases, healed infarction was also considered by other investigators because of the subpleural location of the scars and the presence of obliterated artery within them. Balo et al.1 ob6erved 2 cases of alveolar tell carcinoma associated with organized thrombosed pulmonary artery. Studying 50 cases of pulmonary infarcts, they noted that the proliferation of alveolar epithelium frequently occurs on the border of pulmonary infarcts and this alveolar epithelial proliferation can form stratified epithelium through metaplasia. They believed that lung cancer can develop from the epithelial proliferation at the site of infarcts and that this can be either alveolar cell carcinoma or squamous cell Carcinoma. Anoxemia and the effect of irritative substances liberated at the site of tissue necrosis were considered to play an important role in the epithelial proliferation. In our series the nature of the scars could not be stated with certainty. All showed a central hyalinized area but no caseation necrosis or other specific changes suggesting a possible etiology. In cases 2, 3, 6, and 7, the regional lymph nodes contained an old healed granuloma suggesting a primary tuberculous complex. Completely thrombosed, medium4 zed arteries that had given an impression of old healed infarction to the previous investigators were found in all cases except case 5. In cases 1 and 7, these arteries were also invaded by tumor cells. According to Castleman,3 old healed infarct is frequently overlooked at autopsy and difficult to differentiate microscopically from healed tuberculosis, organized pneumonia, or other healed infections. However, elastic stain of these lesions reveal differences as to the amount and arrangement a elastic fibers. In all our cases, elastic stains were done in selected sections containing scars, and the slides were evaluated according to the criteria given by Castleman.3 The results were inconclusive. Most of the scars were devoid of elastic fibers, but in cases 2 and 3 the arrangement of elastic fibers within the scars was haphazard, suggesting healed infarcts, and in case 4, the elastic fibers were arranged in an alveolar pattern at the periphery of a hyaline scar that was devoid of elastic fibers, thus suggesting a healed abscess. Increased amounts of anthracotic pigment

10 1214 CANCER November-December 1961 Vol. 14 were found in every instance. No bacteriological studies were done in any of our cases. Histological Characteristics of Scar Cancers. Five of our 7 cases were diagnosed as bronchiolar carcinoma. The remaining 2 (cases 4 and 6) were undifferentiated. In Table 2, the histological diagnoses of the collected cases are listed. Squamous cell carcinoma was diagnosed most frequently, totaling 14 cases. As is shown in the table, bronchiolar carcinoma was never diagnosed in Friedrich s4 series and once in Raeburn and Spencer s7 series although they listed 6 adenocarcinomas and 1 mucinproducing polygonal-celled carcinoma, some of which might represent bronchiolar carcinomas. At any rate, 13 cases were diagnosed as bronchiolar carcinoma, followed in order of frequency by 11 cases of undifferentiated carcinoma, 7 of adenocarcinoma, 4 of polygonalcelled carcinoma, 3 of bronchogenic carcinoma, and 4 cases in which the histological diagnosis was not known. It is interesting to note that Liiders and Themel s series5 contained 11 cases of bronchiolar carcinoma in the total of 24. Beaver and Shapiroz reported 7 cases of bronchiolar carcinoma (alveolar cell carcinoma) associated with localized chronic inflammatory disease in the lung. They collected 121 cases of bronchiolar carcinoma from the literature, in 6201, of which the patients had a history of previous lung disease and in 84% of which there was gross or microscopic evidence of chronic infection or prior inflammatory disease with adhesions, fibrosis, bronchiectasis, chronic or organizing pneumonia, and lipoid pneumonia. Storey, Knudtson, and Lawrence9 analyzed the cases of bronchiolar carcinoma collected from the literature and their own material and found that in 26% of 153 cases the tumors appeared first as a solitary peripheral nodule on roentgenographic examination. This suggests that at least in a certain percentage of the cases bronchiolar carcinomas do arise as a solitary nodule and disseminate by way of lymphatics and blood stream. One of their patients had a lesion evidenced by roentgenographic examination 4 years before it was excised and proved to be a bronchiolar carcinoma. At the time of operation the tumor was still small and localized. The known duration of bronchiolar carcinoma has been many years and in some cases it was estimated up to 15 years. In our opinion, this fact suggests that the lesions, shown on earlier roentgenograms in those cases, might have represented scars in which a bronchiolar carcinoma subsequently developed. Two cases in our series (cases 5 and 7) diagnosed as bronchiolar carcinoma appear to represent an early stage, if not the earliest, of bronchiolar carcinoma, yet the regional lymph nodes were already involved in case 5. The other 3 autopsied cases exhibited either distant, or both local and distant metastases, although the sizes of the primary tumors remained extremely small. All these tumors arose as a peripheral (subpleural), solitary nodule associated with scar except for case 5, which contained 2 small peripheral nodules with identical histological appearances, suggesting a multicentric origin. The finding of scar in the center of these tumors seems to have a significant bearing as regards the etiological connection with the development of lung cancers, particularly those situated at the periphery, including the bronchiolar carcinoma. Being aware of the difficulty in differentiating bronchiolar carcinoma from metastatic adenocarcinoma in a surgically excised lung, it is our working hypothesis that the presence of a scar surrounded by adenocarcinomatous tissue favors the diagnosis of bronchiolar carcinoma, provided the usual criteria of this tumor are met. Incidence of Scar Cancer. The exact incidence of scar cancer is not known until sufficient data become available. Luders and Theme15 stated that more than one-third of the lung cancers observed by them were located in the periphery of the lungs and were practically identical with scar cancers. Raeburn and Spencer6 studied small cancers of the lung found incidentally at autopsy that were thought to represent earliest stages of development of this neoplasm. Of 15 cases collected by them, 11 were located in the periphery of the lungs, representing more than two-thirds of the total cases. These peripheral tumors were diagnosed as adenocarcinoma, mixed oat-celled and round-celled carcinoma, and mixed polygonal and squamoid-celled carcinoma, many of which were arranged in a tubular pattern. The remaining 4 cases were located in main lobar bronchi, and histologically all of them were multifocal intraepithelial squamous carcinoma. TheyS pointed out that most lung cancers have been customarily assumed to have arisen from main bronchi and their immediate branches, but they emphasized the fact that

11 No. 6 PERIPHERAL LUNG CANCERS ARISING IN SCARS - peripheral cancer may produce early metastatic deposits in the lymphatic system around the larger bronchi, thus simulating the appearance of bronchogenic carcinoma in advanced stages. We concur with this opinion and feel that advanced cases seen at autopsy or large cancers of the lung removed surgically are not suitable for tracing the origin of the tumor or finding the presence of scar within the tumor. Raeburn and Spencer s cases6 are valuable in this respect, although admittedly, tumors located in the periphery of the lung are much more easily detected. It is our impression that the earlier the surgical excision of lung cancer is performed, the more frequently peripheral cancer of the lung may be diagnosed, and whether or not peripheral cancers are identical to scar cancers may then become clarified. SUMMARY AND CONCLUSIONS 1. Seven cases of peripheral lung cancers arising in scars were presented, in which the 1. BAL~, J.; JUHASZ, E., and TEMES, J.: Pulmonary infarcts and pulmonary carcinoma. Cancer 9: , BFAVER, D. I.., and SHAPIRO, J. L.: Consideration of chronic pulmonaiy parenchymal inflammation and alveolar cell carcinoma with regard to possible etiologic relationship. Am. J. Med. 21: , CASTLEMAN, B.: Healed pulmonary infarcts. Arch. Path. 30: , FRIEDRICH, G.: Periphere Lungenkrebse auf dem Boden pleuranaher Narben. Virchows Arch. path. Anat. 304: , LUDERS, C. J., and THEMEL, K. G.: Die Narben- REFERENCES Yokoo h+ Suckow 1215 histological characteristics suggested a close relationship between the development of cancer and scar in the lung. 2. Literature concerning scar cancer of the lung was reviewed and pertinent points were discussed. 3. A high incidence of bronchiolar carcinoma was observed among these peripheral tumors arising in scar tissue. Since normal bronchiolar epithelium as well as bronchiolar carcinoma seem to possess a wide range of morphological variations through metaplasia, the undifferentiated carcinoma or squamous cell carcinoma found in our series and those of others may possibly be of a bronchiolar origin. The histogenesis of scar carcinoma requires further investigation. 4. The importance of studying small carcinomas of the lung to elucidate the natural history of lung carcinomas in general was emphasized, and it was felt that carcinomas of bronchogenic origin have been too frequently made on the assumption that most lung carcinomas arise in the larger bronchi, a situation which seems to require re-evaluation. krebse der Lungen als Beitrag zur Pathogenese des peripheren Lungencarcinoms. Virchows Arch. path. Anat. 325: , RAEBURN, C., and SPENCER, H.: Study of origin and developmerlt of lung cancer. Thorax 8: 1-10, RAEBURN, C., and SPENCER, H.: Lung scar cancers. Brit. J. Tuherc. 51: , ROSSLE, R.: Die Narbenkrebse der Lungen. Schiueiz. med. Wchnschr. 73: , STOREY, C. F.; KNUDTSON, K. P., and LAWRE:NCE, B. J.: Rronchiolar ( alveolar cell ) carcinoma of lung. J. Thoracic Surg. 26: , 1953.