Mixed Anaplastic Small-Cell and Squamous-Cell Carcinoma of the Lung HARMAR D. BRERETON, M.D.; MARY M. MATHEWS, M.D.; JOSE COSTA, M.D.; C. HARRY KENT, M.D.; and RALPH E. JOHNSON, M.D. Radiation Oncology and Pathology Branches, National Cancer Institute; Bethesda, Maryland; and Veterans Administration Medical Onocology Branch, National Cancer Institute; Washington, D.C. T H E PLEOMORPHISM OF LUNG CANCER is well known
and the appearance of histologically well and poorly differentiated areas within a tissue specimen, or even the coexistence of multiple discreet histologic subtypes, is not uncommon. The association, however, of small-cell anaplastic and squamous-cell lung cancer has been rarely noted, and we report here a 24% prevalence of this association in an autopsy series. Fifty consecutive previously untreated patients with biopsyproven small-cell carcinoma of the lung were studied between November 1974 and May 1975. Each diagnostic biopsy conBrief Reports
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805
Figure 1 Top. Cohesive sheets of fusiform t o "lymphocyte-like" cells in the diagnostic biopsy of Case 3. Bottom. Nests of malignant squamous cells in a vertebral metastasis found at autopsy in Case 3. (Hematoxylin and eosin; original magnification, x 3 0 0 . )
tained only small-cell anaplastic elements. All patients were evaluated with sequential chest radiographs, whole lung tomography, radioisotopic bone, brain, liver and gallium scans, and bilateral posterior iliac-crest bone-marrow aspirate and biopsy. Patients were treated with cyclic intravenous combination chemotherapy, irradiation to the bulky chest disease, and prophylactic whole-brain irradiation as previously reported (1). All pretreatment biopsy and autopsy material has been independently reviewed by two of us (JC, MM). Of the 50 patients involved in this study, 34 have died. Autopsies were done on 21 of these patients. Five who died during therapy had no tumor identified at autopsy. Eleven patients had only small-cell anaplastic tumor at autopsy. The remaining five patients had as least some foci of squamous-cell carcinoma identified at autopsy. Of these five patients, one had squamous-cell nests discretely centered within islands of small-cell tumor in the lung and mediastinal lymph nodes located within the field of irradiation. All other metastases in this case were of a classic lymphocyte-like type. A second patient had similar changes in tumor involving the serosa of the esophagus; the esophageal mucosa remained intact. A third patient had nests of well-differentiated squamous cells, discrete and separate from the small-cell tumor in a field of irradiated vertebral bone (Figure 1), and the fourth pa8 0 6
June 1978 • Annals of Internal Medicine • Volume 88 • Number 6
Downloaded from https://annals.org by Tulane University user on 01/19/2019
tient had well-differentiated squamous-cell scalp metastases. The fifth patient had a typical small-cell anaplastic carcinoma diagnosed with a bronchoscopic biopsy; however, during the course of treatment well-differentiated neoplastic squamous cells were identified in the sputum, and at autopsy only well-differentiated squamous cell tumor was identified. The demonstration of both squamous- and small-cell elements within the same tumor has been alluded to infrequently with the conclusion that the cases represented double primary tumors and that such a phenomenon occurs rarely (2, 3). Larsson and Zettergren (4), however, described 25 cases of small-cell carcinoma that went on to excisional surgery; two of these cases were classified as squamous-cell carcinoma on the basis of the resected specimens. The high prevalence (five of 21) of squamous-cell carcinoma in our series is similar to the experience noted by Bates and associates (5); they described six patients with biopsy-proven small-cell lung cancer, who had squamous cell carcinoma identified in the resected specimen after preoperative irradiation. This represented one fourth of their cases. Both our experience and Bates' suggest that treatment may be important to the appearance of squamous-cell elements within small-cell anaplastic tumors either by causing the differentiation of anaplastic cells to squamous cells or by selecting out the resistant elements of a tumor with multiple histologies. It is impossible to guess which of these mechanisms is correct; however, either hypothesis could support the concept that in some cases both tumor types are derived from a common cell. More important, however, is that the simultaneous appearance of both small-cell anaplastic and squamous-cell elements within the same lung tumor raises important therapeutic questions. Curative therapy for squamouscell lung cancer is based on adequate surgical resection; curative therapy for small-cell anaplastic lung cancer will depend on chemotherapy for control of known or presumed distant metastatic disease and, perhaps, radiation therapy for control of disease locally or in sanctuary sites unaccessable to chemotherapeutic agents. Thus, the important questions posed to the clinician are: How extensive an examination of tumor histology should be undertaken before deciding upon a specific therapy? Will the surgeon play more than a diagnostic role in small-cell lung cancer, particularly in cases with mixed histology? Will patients who apparently have small-cell anaplastic carcinoma and achieve remission then be at risk to develop squamous-cell carcinoma and vice versa? Answers to these questions await a more accurate estimate of the true prevalence of mixed histologies in lung cancer both before treatment and at autopsy, and will also depend on the efficacy of treatment for the component histologies and tumor stage. REFERENCES 1. JOHNSON RE, B R E R E T O N H D , K E N T CH: Small-cell carcinoma of the
lung: attempt to remedy causes of past therapeutic failure. Lancet 2:289291, 1976 2. AZZOPARDI JG: Oat-cell carcinoma of the bronchus. J Pathol Bacteriol 78:513-519, 1959 3. M A T T H E W S MJ: Problems in morphology and behavior of bronchopulmonary malignant disease, in Lung Cancer, Natural History, Prognosis and Therapy, edited by ISRAEL L, CHAHINIAN AP. London, Academic Press, 1976, pp. 23-62 4. LARSSON S, ZETTERGREN L: Histological typing of lung cancer. Acta Pathol Microbiol Scand [A] 84:529-537, 1976 5. BATES M, LENISON V, H U R T R, S U T T O N G: Treatment of oat-cell carci-
noma of bronchus by preoperative radiotherapy and surgery. 1:1134-1135, 1974 © 1 9 7 8 American College of Physicians
Lancet
and the appearance of histologically well and poorly differentiated areas within a tissue specimen, or even the coexistence of multiple discreet histologic subtypes, is not uncommon. The association, however, of small-cell anaplastic and squamous-cell lung cancer has been rarely noted, and we report here a 24% prevalence of this association in an autopsy series. Fifty consecutive previously untreated patients with biopsyproven small-cell carcinoma of the lung were studied between November 1974 and May 1975. Each diagnostic biopsy conBrief Reports
Downloaded from https://annals.org by Tulane University user on 01/19/2019
805
Figure 1 Top. Cohesive sheets of fusiform t o "lymphocyte-like" cells in the diagnostic biopsy of Case 3. Bottom. Nests of malignant squamous cells in a vertebral metastasis found at autopsy in Case 3. (Hematoxylin and eosin; original magnification, x 3 0 0 . )
tained only small-cell anaplastic elements. All patients were evaluated with sequential chest radiographs, whole lung tomography, radioisotopic bone, brain, liver and gallium scans, and bilateral posterior iliac-crest bone-marrow aspirate and biopsy. Patients were treated with cyclic intravenous combination chemotherapy, irradiation to the bulky chest disease, and prophylactic whole-brain irradiation as previously reported (1). All pretreatment biopsy and autopsy material has been independently reviewed by two of us (JC, MM). Of the 50 patients involved in this study, 34 have died. Autopsies were done on 21 of these patients. Five who died during therapy had no tumor identified at autopsy. Eleven patients had only small-cell anaplastic tumor at autopsy. The remaining five patients had as least some foci of squamous-cell carcinoma identified at autopsy. Of these five patients, one had squamous-cell nests discretely centered within islands of small-cell tumor in the lung and mediastinal lymph nodes located within the field of irradiation. All other metastases in this case were of a classic lymphocyte-like type. A second patient had similar changes in tumor involving the serosa of the esophagus; the esophageal mucosa remained intact. A third patient had nests of well-differentiated squamous cells, discrete and separate from the small-cell tumor in a field of irradiated vertebral bone (Figure 1), and the fourth pa8 0 6
June 1978 • Annals of Internal Medicine • Volume 88 • Number 6
Downloaded from https://annals.org by Tulane University user on 01/19/2019
tient had well-differentiated squamous-cell scalp metastases. The fifth patient had a typical small-cell anaplastic carcinoma diagnosed with a bronchoscopic biopsy; however, during the course of treatment well-differentiated neoplastic squamous cells were identified in the sputum, and at autopsy only well-differentiated squamous cell tumor was identified. The demonstration of both squamous- and small-cell elements within the same tumor has been alluded to infrequently with the conclusion that the cases represented double primary tumors and that such a phenomenon occurs rarely (2, 3). Larsson and Zettergren (4), however, described 25 cases of small-cell carcinoma that went on to excisional surgery; two of these cases were classified as squamous-cell carcinoma on the basis of the resected specimens. The high prevalence (five of 21) of squamous-cell carcinoma in our series is similar to the experience noted by Bates and associates (5); they described six patients with biopsy-proven small-cell lung cancer, who had squamous cell carcinoma identified in the resected specimen after preoperative irradiation. This represented one fourth of their cases. Both our experience and Bates' suggest that treatment may be important to the appearance of squamous-cell elements within small-cell anaplastic tumors either by causing the differentiation of anaplastic cells to squamous cells or by selecting out the resistant elements of a tumor with multiple histologies. It is impossible to guess which of these mechanisms is correct; however, either hypothesis could support the concept that in some cases both tumor types are derived from a common cell. More important, however, is that the simultaneous appearance of both small-cell anaplastic and squamous-cell elements within the same lung tumor raises important therapeutic questions. Curative therapy for squamouscell lung cancer is based on adequate surgical resection; curative therapy for small-cell anaplastic lung cancer will depend on chemotherapy for control of known or presumed distant metastatic disease and, perhaps, radiation therapy for control of disease locally or in sanctuary sites unaccessable to chemotherapeutic agents. Thus, the important questions posed to the clinician are: How extensive an examination of tumor histology should be undertaken before deciding upon a specific therapy? Will the surgeon play more than a diagnostic role in small-cell lung cancer, particularly in cases with mixed histology? Will patients who apparently have small-cell anaplastic carcinoma and achieve remission then be at risk to develop squamous-cell carcinoma and vice versa? Answers to these questions await a more accurate estimate of the true prevalence of mixed histologies in lung cancer both before treatment and at autopsy, and will also depend on the efficacy of treatment for the component histologies and tumor stage. REFERENCES 1. JOHNSON RE, B R E R E T O N H D , K E N T CH: Small-cell carcinoma of the
lung: attempt to remedy causes of past therapeutic failure. Lancet 2:289291, 1976 2. AZZOPARDI JG: Oat-cell carcinoma of the bronchus. J Pathol Bacteriol 78:513-519, 1959 3. M A T T H E W S MJ: Problems in morphology and behavior of bronchopulmonary malignant disease, in Lung Cancer, Natural History, Prognosis and Therapy, edited by ISRAEL L, CHAHINIAN AP. London, Academic Press, 1976, pp. 23-62 4. LARSSON S, ZETTERGREN L: Histological typing of lung cancer. Acta Pathol Microbiol Scand [A] 84:529-537, 1976 5. BATES M, LENISON V, H U R T R, S U T T O N G: Treatment of oat-cell carci-
noma of bronchus by preoperative radiotherapy and surgery. 1:1134-1135, 1974 © 1 9 7 8 American College of Physicians
Lancet
