Ann Otol 88 :1979
SMALL CELL UNDIFFERENTIATED CARCINOMA OF THE LARYNX GLENN D. JOHNSON, MD V. PATRICK MAHATAPHONGSE, MD
ARTHUR B. ABT, MD GEORGE H. CONNER, MD
HERSHEY, PENNSYLVANIA
A patient with a small cell, undifferentiated carcinoma of the larynx is described. The tumor appeared to arise in close association with subglottic minor salivary glands. Ultrastructural study of the tumor cells showed neurosecretory granules similar to those seen in normal Kulchitsky cells and pulmonary oat cell carcinomas. Bronchogenic oat cell carcinoma and small cell undifferentiated carcinoma of minor salivary gland tissue probably originate from the same cell type. The aggressive behavior of this tumor suggests the need for early systemic treatment including combination chemotherapy.
Small cell undifferentiated carcinoma of the lung (oat cell carcinoma) is a common tumor. Extrapulmonary tumors histologically similar to the oat cell carcinoma have been described in many organs. Primary oat cell carcinoma of the larynx is exceedingly rare,' and of the five previously reported cases,':" ultrastructural studies have been performed on only one." A patient with a primary small cell carcinoma of the subglottic larynx is presented. OASE REPORT
A 68-year-old Caucasian female presented to the emergency room in December 1976, with acute respiratory distress. She had a three-month history of a chronic, nonproductive cough. One week prior to admission she developed hoarseness, followed by progressive dyspnea. She had smoked three packs of cigarettes per day since early adulthood. Indirect laryngoscopy revealed an erythematous mass on the right side of the subglottic larynx with extensive crusting. The vocal cords appeared normal with full mobility. There were no palpable neck nodes. The remainder of the physical examination was within normal limits. Xerolaminograms of the larynx showed a subglottic mass just below the vocal cords with an inferior extension of 1.5 em and marked narrowing of the subglottic airway. Following
tracheostomy, direct laryngoscopy was performed revealing a submucosal mass arising from the right side of the subglottic larynx, extending superiorly to the inferior surface of the right true vocal cord. The mass extended laterally from the anterior to the posterior commissure. The biopsy showed a small cell undifferentiated carcinoma. A negative search for another primary tumor included a metastatic survey, bronchoscopy, 1251 thyroid imaging, chest x-ray, lung tomograms, and liver and spleen imaging. A total laryngectomy with right thyroid lobectomy was performed. Postoperative radiation therapy consisting of 5100 rads to the upper and lower neck bilaterally was started three weeks later. Ten months after her laryngectomy she was readmitted, severely ill with multiple problems including hyperglycemia, hypokalemic metabolic alkalosis, pancytopenia, pneumonia, hypoxia, sepsis, renal failure, hypothyroidism, hypotension, and ileus. A bone marrow aspirate showed metastatic oat cell carcinoma. Despite intensive therapy, her clinical condition rapidly deteriorated and she died eight days after admission. An autopsy was performed. METHODS AND MATERIALS Tissue from the laryngeal biopsy, laryngectomy specimen and autopsy was fixed in 4% buffered formaldehyde. Paraffin-embedded
From the Department of Surgery, Division of Otorhinolaryngology and the Department of Pathology, Milton E. Hershey Medical Center, Pennsylvania State University, Hershey, Pennsylvania. Presented in part at the meeting of the Pennsylvania Academy of Ophthalmology and Otolaryngology, Bedford Springs, Pennsylvania, May 20, 1977.
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Fig. 2. Several tumor cells (arrows) contain dark staining cytoplasmic granules. (Sevier-Munger, x2,OOO) Fig. 1. The tumor is composed of cells with round to oval nuclei. Mitotic figures are prominent. (H & E, x830) sections were stained with hematoxylin and eosin, Hamperl-Masson stain for argentaffin granules, and the Sevier-Munger stain for argyrophilia, Tissue for electron microscopical study was obtained from the biopsy specimen. This material was fixed in 4% gluteraldehyde, The tissue was postfixed in osmium tetroxide, stained with uranyl acetate, and embedded in a mixture of resins (Epon@ 812) after dehydration in graded alcohol. Thin sections cut on an ultramicrotome were placed on uncoated copper grids, stained with lead citrate, and examined in an electron microscope.
PATHOLOGIC FINDINGS
The initial laryngeal biopsy consisted of multiple fragments of soft, pale yellow tissue. On histologic examination the tumor was composed of irregular nests of small cells surrounded by a fibrous stroma. Tumor was seen infiltrating the overlying squamous mucosa, but the mucosa showed no evidence of dysplasia. The tumor nests were composed of cells with round to oval nuclei and scant cytoplasm (Fig. 1). Cytoplasmic borders were ill defined and mitotic figures were numerous. The nuclei were either hyperchromatic or exhibited fine granular chromatin. Nucleoli were not prominent. Salivary gland tissue was not demonstrated in this biopsy specimen. Argy-
rophilic granules were seen within some tumor cells with the Sevier-Munger stain (Fig. 2). While some cells contained numerous granules, most tumor cells exhibited either a scant or negative reaction. The argentaffin stain was negative. The ultrastructural studies demonstrated tumor cells with irregular nuclei and chromatin clumping near the nuclear membrane. The cytoplasm contained a moderate number of mitochondria and prominent endoplasmic reticulum. Scattered through the cytoplasm of most cells were spherical granules composed of an electron-dense core (Fig. 3). A single limiting membrane was separated from the dense core by a clear space. These granules measured from 100-270 nm in diameter. The surgically-excised larynx demonstrated an intact laryngeal mucosa. A depressed area was located 0.9 em below the right vocal cord. This area measured less than 1 em in diameter. The vocal cords were unremarkable. On sectioning through the depressed area, a yellow-white, relatively well-demarcated tumor nodule was noted (Fig. 4). Histologic examination revealed a tumor identical to that seen in the biopsy specimen obtained 12 days earlier. The tumor was admixed with minor salivary glands. The overlying laryngeal mucosa showed no atypia. Portions of thyroid,
Downloaded from aor.sagepub.com at UNIV OF MIAMI on June 28, 2015
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parathyroid, skeletal muscle, and skin excised with the laryngectomy specimen showed no significant abnormality. Cervical lymph nodes were not excised. An autopsy, metastatic, small cell carcinoma was found bilaterally within cervicallymph nodes, in the bone marrow, spleen, liver, pancreas, adrenals, left lobe of thyroid, anterior pituitary and apices of both lungs. Histologically, the tumor was identical to that seen in the original laryngeal specimen. DISCUSSION
Undifferentiated small cell carcinoma of the larynx was first described in 1972 by Olofsson and von Nostrand.' To date
there are five reported cases in the English Iiterature.':" All five patients were in their 60s or 70s. Two of the tumors were subglottic masses. One tumor was confined to the epiglottis. The other two were large, extensive lesions extending outside the larynx. Oat cell carcinomas have been reported in many areas of the head and neck. Kos et all described 14 cases arising in minor salivary gland tissue of the head and neck region including one which involved the epiglottis. Cells similar to the Kulchitsky cells of the intestinal tract and lung have been described in human salivary glands as well as in the salivary glands of dogs and rats.?"
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The intimate association of our patient's tumor with subglottic salivary gland tissue suggests a similar origin. The histologic and ultrastructural features of this laryngeal tumor, the presence of argyrophilic granules and a negative argentaffin reaction, all support this tumor's relationship with other foregut carcinoids. As such, it appears that this is another malignant neoplasm related to the amine precursor uptake and decarboxvlation (APUD) system." While many authors have accepted the hypothesis of a common precursor cell for carcinoids and oat cell carcinomas," a recent epidemiologic study of pulmonary carcinoids and oat cell carcinomas'? argues against this concept.
Fig. 4. Whole mount from the right side of the larynx shows the subglottic tumor (short arrows). The ventricle and vocal cords (long arrows) are uninvolved. The association of salivary gland and tumor is seen in the inset. (H & E, xlO, inset x190)
An understanding of the natural history of laryngeal oat cell carcinoma has been limited by the infrequency of this tumor. The clinical course of our patient suggests that laryngeal oat cell carcinoma is as aggressive as the more familiar pulmonary tumor. Early metastasis mitigates against tumor extirpation by localIv aggressive measures. Combination chemotherany and radiation therapy has improved the survival of patients with bronchogenic oat cell carcinoma over radiation therapy alone.!' Since laryngeal and bronchogenic oat cell carcinomas appear to arise from the same cell. it would be reasonable for them to exhibit similar clinical behavior. Of the five previously published cases, three were dead of their disease in less than one year (two were treated with surgery and irradiation, one with only surgery) .1.3 One patient had extensive neck disease at the time of initial surgery" and one was alive and well 2~ years after surgery and irradiation." With our current knowledge of the metastatic potential of laryngeal oat cell carcinoma, a combination of chemotherapy, irradiation and surgery should be considered in the initial treatment of future patients.
REFERENCES
1. Koss LG, Spiro RH, Hadju S: Small cell (oat cell) carcinoma of minor salivary gland origin. Cancer 30:737-741, 1972 2. Benisch BM, Tawfik B, Breitenbach EE: Primary oat cell carcinoma of the larynx: An ultrastructural study. Cancer 36: 145-148, 1975
3. Gelot R, Rhee TR, Lapidot A: Primary oat-cell carcinoma of head and neck. Ann Otol Rhinol Laryngol 84:238-244, 1975 4. Olofsson J, van Nostrand AWP: Anaplastic small cell carcinoma of larynx: Case report. Ann Otol Rhinol Laryngol 81 :284-287, 1972
Downloaded from aor.sagepub.com at UNIV OF MIAMI on June 28, 2015
JOHNSON ET AL
778
5. Ferlito A: Oat cell carcinoma of the larynx. Ann Otol Rhinol Laryngol 83:254256, 1974
8. Pearse AGE: The APUD cell concept and its implications in pathology. Pathol Annu 9:27-41, 1974
6. Ho1l6si K: A nyalmirigyek chromaffinargentaffin sejtjeinek feny-es elektron-mikroszkopos vizsgalata: Adatok e sajatos sejtalak functionalis szerepenek kerdesehez ( A light and electron microscopic investigation of chromaffin-argentaffin cells of the large salivary glands. A contribution to the function of these peculiar cells) . Morphol Igazsagugyi Orv Sz 7:241-247, 1967
9. Bensch KG, Corrin B, Pariente R, et al: Oat-cell carcinoma of the lung: Its origin and relationship to bronchial carcinoid. Cancer 22:1163-1172, 1968
10. Godwin JD, Brown CC: Comparative epidemiology of carcinoid and oat-cell tumors of the lung. Cancer 40:1671-1673, 1977
7. Godlowski ZZ, Calandra JC: Argentaffine cells in the submaxillary glands of dogs. IAnat Rec 140:45-57,1961
11. Nixon D, Carey RW, Suit HD, et al: Combination chemotherapy in oat cell carcinoma of the lung. Cancer 36:867-872, 1975
REPRINTS -
Arthur B. Abt, MD, Division of Anatomic Pathology, Milton S. Hershey Med-
ical Center, Pensylvania State University, Hershey, PA 17033.
LURIE LIBRARY FUND Many inquiries have been made about a memorial fund to which friends and colleagues of Dr. Moses Hyman Lurie could contribute. Shortly before his death Dr. Lurie established a modest fund for the purchase of books in Otolaryngology for the Library at the Massachussetts Eye and Ear Infirmary. The Library Committee of the Infirmary has verified that donations can be made in memory of Dr. Lurie to this fund. Contributions may be sent to the "Lurie Library Fund," in care of Mr. Charles Snyder, Librarian, Massachusetts Eye and Ear Infirmary, 243 Charles St., Boston, MA 02114.
-INTERNATIONAL SYMPOSIUM PATHOGENESIS, DIAGNOSIS AND TREATMENT OF MENI:i1:RE'S DISEASE Symposium will be held May 12-14, 1980 in Duesseldorf, Germany. Faculty will include internationally known basic scientists and clinicians. Limited number of free papers will be ac~ cepted for presentation. Inquiries may be sent to Dr. Claus Morgenstern, HNO Klinik, University of Duesseldorf, Germany or Dr. E. K. Juhn, Dept. of Otolaryngology, University of Minnesota, USA.
Downloaded from aor.sagepub.com at UNIV OF MIAMI on June 28, 2015
SMALL CELL UNDIFFERENTIATED CARCINOMA OF THE LARYNX GLENN D. JOHNSON, MD V. PATRICK MAHATAPHONGSE, MD
ARTHUR B. ABT, MD GEORGE H. CONNER, MD
HERSHEY, PENNSYLVANIA
A patient with a small cell, undifferentiated carcinoma of the larynx is described. The tumor appeared to arise in close association with subglottic minor salivary glands. Ultrastructural study of the tumor cells showed neurosecretory granules similar to those seen in normal Kulchitsky cells and pulmonary oat cell carcinomas. Bronchogenic oat cell carcinoma and small cell undifferentiated carcinoma of minor salivary gland tissue probably originate from the same cell type. The aggressive behavior of this tumor suggests the need for early systemic treatment including combination chemotherapy.
Small cell undifferentiated carcinoma of the lung (oat cell carcinoma) is a common tumor. Extrapulmonary tumors histologically similar to the oat cell carcinoma have been described in many organs. Primary oat cell carcinoma of the larynx is exceedingly rare,' and of the five previously reported cases,':" ultrastructural studies have been performed on only one." A patient with a primary small cell carcinoma of the subglottic larynx is presented. OASE REPORT
A 68-year-old Caucasian female presented to the emergency room in December 1976, with acute respiratory distress. She had a three-month history of a chronic, nonproductive cough. One week prior to admission she developed hoarseness, followed by progressive dyspnea. She had smoked three packs of cigarettes per day since early adulthood. Indirect laryngoscopy revealed an erythematous mass on the right side of the subglottic larynx with extensive crusting. The vocal cords appeared normal with full mobility. There were no palpable neck nodes. The remainder of the physical examination was within normal limits. Xerolaminograms of the larynx showed a subglottic mass just below the vocal cords with an inferior extension of 1.5 em and marked narrowing of the subglottic airway. Following
tracheostomy, direct laryngoscopy was performed revealing a submucosal mass arising from the right side of the subglottic larynx, extending superiorly to the inferior surface of the right true vocal cord. The mass extended laterally from the anterior to the posterior commissure. The biopsy showed a small cell undifferentiated carcinoma. A negative search for another primary tumor included a metastatic survey, bronchoscopy, 1251 thyroid imaging, chest x-ray, lung tomograms, and liver and spleen imaging. A total laryngectomy with right thyroid lobectomy was performed. Postoperative radiation therapy consisting of 5100 rads to the upper and lower neck bilaterally was started three weeks later. Ten months after her laryngectomy she was readmitted, severely ill with multiple problems including hyperglycemia, hypokalemic metabolic alkalosis, pancytopenia, pneumonia, hypoxia, sepsis, renal failure, hypothyroidism, hypotension, and ileus. A bone marrow aspirate showed metastatic oat cell carcinoma. Despite intensive therapy, her clinical condition rapidly deteriorated and she died eight days after admission. An autopsy was performed. METHODS AND MATERIALS Tissue from the laryngeal biopsy, laryngectomy specimen and autopsy was fixed in 4% buffered formaldehyde. Paraffin-embedded
From the Department of Surgery, Division of Otorhinolaryngology and the Department of Pathology, Milton E. Hershey Medical Center, Pennsylvania State University, Hershey, Pennsylvania. Presented in part at the meeting of the Pennsylvania Academy of Ophthalmology and Otolaryngology, Bedford Springs, Pennsylvania, May 20, 1977.
774 Downloaded from aor.sagepub.com at UNIV OF MIAMI on June 28, 2015
SMALL CELL LARYNGEAL CANCER
775
Fig. 2. Several tumor cells (arrows) contain dark staining cytoplasmic granules. (Sevier-Munger, x2,OOO) Fig. 1. The tumor is composed of cells with round to oval nuclei. Mitotic figures are prominent. (H & E, x830) sections were stained with hematoxylin and eosin, Hamperl-Masson stain for argentaffin granules, and the Sevier-Munger stain for argyrophilia, Tissue for electron microscopical study was obtained from the biopsy specimen. This material was fixed in 4% gluteraldehyde, The tissue was postfixed in osmium tetroxide, stained with uranyl acetate, and embedded in a mixture of resins (Epon@ 812) after dehydration in graded alcohol. Thin sections cut on an ultramicrotome were placed on uncoated copper grids, stained with lead citrate, and examined in an electron microscope.
PATHOLOGIC FINDINGS
The initial laryngeal biopsy consisted of multiple fragments of soft, pale yellow tissue. On histologic examination the tumor was composed of irregular nests of small cells surrounded by a fibrous stroma. Tumor was seen infiltrating the overlying squamous mucosa, but the mucosa showed no evidence of dysplasia. The tumor nests were composed of cells with round to oval nuclei and scant cytoplasm (Fig. 1). Cytoplasmic borders were ill defined and mitotic figures were numerous. The nuclei were either hyperchromatic or exhibited fine granular chromatin. Nucleoli were not prominent. Salivary gland tissue was not demonstrated in this biopsy specimen. Argy-
rophilic granules were seen within some tumor cells with the Sevier-Munger stain (Fig. 2). While some cells contained numerous granules, most tumor cells exhibited either a scant or negative reaction. The argentaffin stain was negative. The ultrastructural studies demonstrated tumor cells with irregular nuclei and chromatin clumping near the nuclear membrane. The cytoplasm contained a moderate number of mitochondria and prominent endoplasmic reticulum. Scattered through the cytoplasm of most cells were spherical granules composed of an electron-dense core (Fig. 3). A single limiting membrane was separated from the dense core by a clear space. These granules measured from 100-270 nm in diameter. The surgically-excised larynx demonstrated an intact laryngeal mucosa. A depressed area was located 0.9 em below the right vocal cord. This area measured less than 1 em in diameter. The vocal cords were unremarkable. On sectioning through the depressed area, a yellow-white, relatively well-demarcated tumor nodule was noted (Fig. 4). Histologic examination revealed a tumor identical to that seen in the biopsy specimen obtained 12 days earlier. The tumor was admixed with minor salivary glands. The overlying laryngeal mucosa showed no atypia. Portions of thyroid,
Downloaded from aor.sagepub.com at UNIV OF MIAMI on June 28, 2015
776
JOHNSON ET AL
parathyroid, skeletal muscle, and skin excised with the laryngectomy specimen showed no significant abnormality. Cervical lymph nodes were not excised. An autopsy, metastatic, small cell carcinoma was found bilaterally within cervicallymph nodes, in the bone marrow, spleen, liver, pancreas, adrenals, left lobe of thyroid, anterior pituitary and apices of both lungs. Histologically, the tumor was identical to that seen in the original laryngeal specimen. DISCUSSION
Undifferentiated small cell carcinoma of the larynx was first described in 1972 by Olofsson and von Nostrand.' To date
there are five reported cases in the English Iiterature.':" All five patients were in their 60s or 70s. Two of the tumors were subglottic masses. One tumor was confined to the epiglottis. The other two were large, extensive lesions extending outside the larynx. Oat cell carcinomas have been reported in many areas of the head and neck. Kos et all described 14 cases arising in minor salivary gland tissue of the head and neck region including one which involved the epiglottis. Cells similar to the Kulchitsky cells of the intestinal tract and lung have been described in human salivary glands as well as in the salivary glands of dogs and rats.?"
Downloaded from aor.sagepub.com at UNIV OF MIAMI on June 28, 2015
SMALL CELL LARYNGEAL CANCER
777
The intimate association of our patient's tumor with subglottic salivary gland tissue suggests a similar origin. The histologic and ultrastructural features of this laryngeal tumor, the presence of argyrophilic granules and a negative argentaffin reaction, all support this tumor's relationship with other foregut carcinoids. As such, it appears that this is another malignant neoplasm related to the amine precursor uptake and decarboxvlation (APUD) system." While many authors have accepted the hypothesis of a common precursor cell for carcinoids and oat cell carcinomas," a recent epidemiologic study of pulmonary carcinoids and oat cell carcinomas'? argues against this concept.
Fig. 4. Whole mount from the right side of the larynx shows the subglottic tumor (short arrows). The ventricle and vocal cords (long arrows) are uninvolved. The association of salivary gland and tumor is seen in the inset. (H & E, xlO, inset x190)
An understanding of the natural history of laryngeal oat cell carcinoma has been limited by the infrequency of this tumor. The clinical course of our patient suggests that laryngeal oat cell carcinoma is as aggressive as the more familiar pulmonary tumor. Early metastasis mitigates against tumor extirpation by localIv aggressive measures. Combination chemotherany and radiation therapy has improved the survival of patients with bronchogenic oat cell carcinoma over radiation therapy alone.!' Since laryngeal and bronchogenic oat cell carcinomas appear to arise from the same cell. it would be reasonable for them to exhibit similar clinical behavior. Of the five previously published cases, three were dead of their disease in less than one year (two were treated with surgery and irradiation, one with only surgery) .1.3 One patient had extensive neck disease at the time of initial surgery" and one was alive and well 2~ years after surgery and irradiation." With our current knowledge of the metastatic potential of laryngeal oat cell carcinoma, a combination of chemotherapy, irradiation and surgery should be considered in the initial treatment of future patients.
REFERENCES
1. Koss LG, Spiro RH, Hadju S: Small cell (oat cell) carcinoma of minor salivary gland origin. Cancer 30:737-741, 1972 2. Benisch BM, Tawfik B, Breitenbach EE: Primary oat cell carcinoma of the larynx: An ultrastructural study. Cancer 36: 145-148, 1975
3. Gelot R, Rhee TR, Lapidot A: Primary oat-cell carcinoma of head and neck. Ann Otol Rhinol Laryngol 84:238-244, 1975 4. Olofsson J, van Nostrand AWP: Anaplastic small cell carcinoma of larynx: Case report. Ann Otol Rhinol Laryngol 81 :284-287, 1972
Downloaded from aor.sagepub.com at UNIV OF MIAMI on June 28, 2015
JOHNSON ET AL
778
5. Ferlito A: Oat cell carcinoma of the larynx. Ann Otol Rhinol Laryngol 83:254256, 1974
8. Pearse AGE: The APUD cell concept and its implications in pathology. Pathol Annu 9:27-41, 1974
6. Ho1l6si K: A nyalmirigyek chromaffinargentaffin sejtjeinek feny-es elektron-mikroszkopos vizsgalata: Adatok e sajatos sejtalak functionalis szerepenek kerdesehez ( A light and electron microscopic investigation of chromaffin-argentaffin cells of the large salivary glands. A contribution to the function of these peculiar cells) . Morphol Igazsagugyi Orv Sz 7:241-247, 1967
9. Bensch KG, Corrin B, Pariente R, et al: Oat-cell carcinoma of the lung: Its origin and relationship to bronchial carcinoid. Cancer 22:1163-1172, 1968
10. Godwin JD, Brown CC: Comparative epidemiology of carcinoid and oat-cell tumors of the lung. Cancer 40:1671-1673, 1977
7. Godlowski ZZ, Calandra JC: Argentaffine cells in the submaxillary glands of dogs. IAnat Rec 140:45-57,1961
11. Nixon D, Carey RW, Suit HD, et al: Combination chemotherapy in oat cell carcinoma of the lung. Cancer 36:867-872, 1975
REPRINTS -
Arthur B. Abt, MD, Division of Anatomic Pathology, Milton S. Hershey Med-
ical Center, Pensylvania State University, Hershey, PA 17033.
LURIE LIBRARY FUND Many inquiries have been made about a memorial fund to which friends and colleagues of Dr. Moses Hyman Lurie could contribute. Shortly before his death Dr. Lurie established a modest fund for the purchase of books in Otolaryngology for the Library at the Massachussetts Eye and Ear Infirmary. The Library Committee of the Infirmary has verified that donations can be made in memory of Dr. Lurie to this fund. Contributions may be sent to the "Lurie Library Fund," in care of Mr. Charles Snyder, Librarian, Massachusetts Eye and Ear Infirmary, 243 Charles St., Boston, MA 02114.
-INTERNATIONAL SYMPOSIUM PATHOGENESIS, DIAGNOSIS AND TREATMENT OF MENI:i1:RE'S DISEASE Symposium will be held May 12-14, 1980 in Duesseldorf, Germany. Faculty will include internationally known basic scientists and clinicians. Limited number of free papers will be ac~ cepted for presentation. Inquiries may be sent to Dr. Claus Morgenstern, HNO Klinik, University of Duesseldorf, Germany or Dr. E. K. Juhn, Dept. of Otolaryngology, University of Minnesota, USA.
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