Gastrointest Radiol 16:5-10 (1991)
Gastrointestinal
Radiology 9 Springer-VerlagNewYorkInc.1991
Primary Small Cell Carcinoma of the Esophagus: Case Presentation and Review of the Literature Linda D. Mulder, Geoffrey A. Gardiner, and Douglas A. Weeks Departments of Radiology and Pathology, Loma Linda University Medical Center, Loma Linda, California, USA
Abstract. A case of primary small cell carcinoma of the esophagus is presented. The clinical, radiologic, and pathologic findings of our case and 72 other cases were reviewed. The most common presenting symptoms were weight loss and dysphagia. Eighty percent were larger than 4 cm at presentation and 97% were in the mid to distal esophagus. The esophageal tumors were identical histologically to small cell carcinoma of the lung. Esophageal luminal widening on esophagram has been found to be more common in nonsquamous cell carcinomas. While rare, small cell carcinoma should be considered in the differential diagnosis of primary esophageal tumors, particularly in the presence of these findings. Key words: Esophagus - Small cell c a r c i n o m a Oat cell.
Primary carcinoma of the esophagus is most frequently squamous cell, or if distal, adenomatous in histologic type. In recent years, however, a number of cases of primary small cell carcinoma of the esophagus have been reported. The first two cases were described by McKeown in 1952 [1] and since then 70 other cases have been reported in the English literature. Because of confusion regarding the true nature and histogenesis of this tumor, it has been reported variously as small cell carcinoma [2-4], anaplastic carcinoma [5], oat cell carcinoma with argyrophilia and/or neurosecretory granules [1, 6-13], argyrophil cell carcinoma [14], apudoma [9, 10, 14], oat cell carcinoma with squamous Address offprint requests to: Linda D. Mulder, M.D., Department, of Radiology, Loma Linda University Medical Center, 11234 Anderson Street, Loma Linda, CA 92354, U S A
cell carcinoma [1], small cell anaplastic carcinoma [7], and small cell epidermoid carcinoma [15]. Table 1 lists the primary features of 72 cases reported in the English literature including the current case. The incidence is difficult to estimate because most reports have presented single cases. American authors report an incidence of up to 2%. Turnbull et al. [7] found one case of small cell carcinoma of the esophagus in a total of 1918 cases of esophageal carcinoma reviewed. Olmsted et al. [16] reviewed 150 cases of epithelial esophageal malignancies and found two cases of primary small cell carcinoma. Reyes et al. [17] found 16 cases among a total of 928 primary esophageal cancers reviewed. Japanese authors report a higher incidence ranging up to 9% [3]. It has been suggested that the actual incidence of this malignancy may be higher than that reported and that as recognition of this entity improves, the reported incidence may more closely approximate the true incidence [2]. Most of the previously presented cases are found in the pathology and oncology literature and few have described the radiologic findings. We present the clinical, radiologic, and pathologic findings of a new case and review the others found in the English literature.
Case Report An 83-year-old man presented with a 3.5-month history of 45 pound weight loss and dysphagia for both solids and liquids. On physical exam he appeared cachectic, mildly volume depleted, and was found to have guaiac positive stools. No hepatosplenomegaly or lymphadenopathy was noted. Liver function tests were normal. The admission chest x-ray demonstrated cardiomegaly, arteriosclerotic changes in the aorta, and evidence of early congestive heart failure. Barium esophagram revealed an ulcerated fungating mass involving the distal third of the esophagus with a shelving defect proximally (Fig. 1). It measured 12 cm in cephalocaudad dimensions and up to 8 cm in
6
L.D. Mulder et al. : Primary Small Cell Carcinoma
Table 1. Cases of small cell carcinoma of the esophagus reported in the English literature Author/year
Age/sex
Symptoms
Location/gross
Microscopic
Hormones
Metastases
Treatment/lifespan a
68M
Anorexia, chest pain
Distal 1/3, 2" fungating encircling lumen
Small cell ca
?
W
None/5 days
60M
Dysphagia, hoarseness
Middle 1/3, 3" ulcerated mass
Small cell ca and squamous cell ca
?
W
None/died during work-up
2. Turnbull et al. (1973)
55F
?
Distal 1/3
Small cell ca
?
W
Resected/18 months
3. Rosen et al. (1975)
67F
Dysphagia, weight loss
Middle 1/3, 5 x 3 x 5.1 cm, elevated, ulcerated
Small cell ca and squamous cell ca
?
W
None/5 days
4. Cook et al. (1976)
73F
Weight loss, interscapular pain with swallowing
Distal 1/3, 4.5 cm, Small cell ca and irregular mucosa, squamous cell ca proximal part stenotic
?
W
Resected/died of postop complications
5. Matsusaka et al. (1976)
67M
?
Distal 1/3, polypoid
Small cell ca
?
W
None/1 month of another cause
62M
Dysphagia
Middle 1/3, elevated ulcer
Small cell ca with squamous cell ca in situ
?
W
Chemotherapy via hepatic artery to liver/3 months
70M
Hoarseness, hemoptysis
Middle 1/3, polypoid Small cell ca
?
W
None/died shortly after admission
58M
?
Distal 1/3, 2.5 x 2 cm, ulcerated
Small cell ca
( + ) Calcitonin
W
Resected/8 months
1. McKeown (1952)
6. Horai et al. (1978) b
64M
?
?
Small cell ca
?
?
?
54M
?
?
Small cell ca
?
?
?
57M
?
?
Small ceil ca
(+)ACTH
?
62M
?
Small cell ca
(+)ACTH W
Resected/3 months
72M
?
Distal 1/3, I x 1 cnl, fungating/polypoid ?
Small cell ca
?
?
52M
?
?
Small cell ca
?
?
?
?
?
W
Resection and chemotherapy/ 6 months
7. lmai et al. (1978)
60M
Dysphagia
Middle 1/3, polypoid Small cell ca with glandular differentiation
(-)
8. Kelson et al. (1980)
76F
Dysphagia, weight loss
Middle 1/3
Small cell ca
?
W
Chemotherapy/ 9 months
9. Reid et al. (1980)
60F
Epigastric pain
Distal 1/3, 3 x i x 0 . 5 cm, ulcerated
Small cell ca
?
W
Resection and chemotherapy/ 8 months
60% middle 1/3, 27% distal 1/3, 13 % upper 1/3, avg. diam. 5.4 cm
Small cell ca, 10, pure; 6, " m i x e d "
1 case ( - ) PTH
?
?/1-6 months, avg. 2 months
10. Reyes et al. (1980)
16 cases, 75% weight all M, loss, 69% 29-74 years, dysphagia mean 58 years
11. Chaudhry et al. 77F (1981)
Abdominal bloating, anorexia, eructation
Distal 1/3, bulky, partial obstruction of lumen
Small cell ca
?
W
Radiation/8 months
12. Rivera et al. (1981)
62M
Dysphagia, piercing pain
Middle 1/3
Small cell ca
?
LN
Resected/1 week
13. Sarma (1982)
59M
Weight loss, hematemisis
Middle 1/3, hemorrhagic, ulcerated
Small cell ca
?
W
None/l month
L.D. Mulder et al. : Primary Small Cell Carcinoma Table 1. (continued) Author/year
Age/sex
Symptoms
Location/gross
Microscopic
Hormones
Metastases
Treatment/lifespan a
14. Olmsted et al. (1983)
62
?
> 4 cm, lumen expanded, scalloped edges
Small cell ca
?
?
?
77
?
> 4 cm, lumen expanded, scalloped edges
Small cell ca
?
?
9
15. Briggs et al. (1983)
23 cases, 95% dysphagia (15)F, (8)M, 51-88 years, mean 69.8 years
78% distal 1/3, 22% middle 1/3, range 2.5-14.5 cm
Small cell ca ; 17, pure; ? 3, foci of carcinoid; 2, foci of squamous cell; 1, loci glandular tissue
48% LN ?/91% _< 13 months 3% W 4% 14 months 4% ?
16. Doherty et al. (1984)
76F
Dysphagia, weight loss
Distal 1/3
Small cell ca
?
W
Radiation/10 weeks
70M
Dysphagia, weight loss
Middle 1/3, 8 cm, esophageal narrowing
Small cell ca
?
?
Radiation/5 months
83F
Dysphagia, Middle 1/3, coughing spasm irregular narrowing
Small cell ca
?
W
Radiation/1 month of another cause
69M
Comatose
Distal 1/3, 5 cm, narrowed lumen
Small cell ca
?
W
None/4.5 h
74F
Anorexia, weight loss
Mid to distal 1/3
Small cell ca
?
W
Radiation/2 months
69F
Dysphagia, weight loss
Mid to distal 1/3, polypoid
Small cell ca
?
W
Radiation/3 months
63M
Dysphagia
Distal 1/3, small ulcerated
Small cell ca and ? squamous cell ca with mucous secretion
?
Resected/?
62M
Dysphagia
Middle and distal 1/3s, fungating
Small cell and squamous cell ca
?
?
Palliative dilatation/?
63M
Achalasia 10 years, 3 months worsening dysphagia
Distal i/3, polypoid
Small cell ca
?
?
Chemotherapy/?
18. Ignacio et al. (1987)
60M
Weight loss, vomitting
Middle and distal 1/3s, 6 cm, varicoid
Small cell ca
?
W
None/died before therapy could be given
19. Mulder et al. (1989)
83M
Weight loss, dysphagia
Middle and distal 1/3s, 12 cm, ulcerated, fungating
Small cell ca
?
LN
Palliative laser therapy/22 days
17. Ho et al. (1984)
Ca, carcinoma; W, widespread metastatic disease to multiple organs; LN, metastasis to lymph nodes only. " Lifespan after diagnosis made. b Tateishi et al. [14] and Horai et al. [2] both reviewed 79 cases of esophageal malignancies resected at The Center for Adult Diseases, Osaka, Japan. Small cell carcinoma was found in six cases by Tateishi et al. and in seven cases by Horai et al. It is unclear whether both studies evaluated the same patients. Only the seven cases reported by Horai et al. have been included.
greatest transverse dimensions. Contrast appeared to filter slowly through the mass within the lumen. The esophageal lumen near the gastroesophageal junction was narrowed. Computed tomography of the chest revealed a large left-sided paraesophageal mass beginning at the level of the left pulmonary artery (Fig. 2). It surrounded the esophagus as it extended distally and terminated at the gastroesophageal junction. The
esophageal lumen was narrowed eccentrically and the walls were markedly thickened by the mass. Additionally, a nonhomogeneous mass of lymph nodes was seen in the gastrohepatic ligament region displacing the stomach anteriorly (Fig. 3). There was no evidence of tumor involving the lung. Esophagoduodenoscopy revealed an exophytic, necrotic mass in the distal esophagus, partially obstructing the lumen. No tumor was seen
8
Fig. 1. Barium esophagram reveals a bulky mass in the distal esophagus with apparent luminal widening. Fig. 2. CT scan through the mid chest demonstrates a large esophageal soft tissue mass with distortion of the lumen. Fig. 3. CT scan through the upper abdomen reveals a nonhomogeneous collection of enlarged lymph nodes in the gastrohepatic ligament region. Fig. 4. Photomicrograph of biopsy tissue shows infiltration by nests and masses of small neoplastic cells with hyperchromatic nuclei and scant cytoplasm. Hematoxylin-eosin, original magnification, x 200.
L.D. Mulder et al. : Primary Small Cell Carcinoma
in the stomach; however, a 2.5 cm lobulated polyp was removed from the antrum. Histologic study of biopsies of the esophageal mass revealed infiltration of esophageal tissue by a high-grade cellular neoplasm composed of irregular masses and nests of closely packed tumor cells exhibiting hyperchromatic nuclei and scant to minimal amounts of amphophilic staining cytoplasm (Fig. 4). Numerous mitotic figures were seen. Immunoperoxidase staining for leukocyte common antigen was negative; a stain for low molecular weight cytokeratin showed weak positivity in a few tumor cells. An immunoperoxidase reaction for neuronspecific enolase showed moderately bright staining within tumor cell cytoplasm. The histologic and immunocytochemical findings were interpreted as diagnostic of small cell anaplastic carcinoma of neuroendocrine origin. Tissue was not available
L.D. Mulder et al. : Primary Small Cell Carcinoma for ultrastructural studies. The polypoid lesion in the gastric antrum proved to be a benign adenomatous polyp. Because of his poor nutritional status, the patient was placed on peripheral total parenteral nutrition. Palliative treatment included laser ablation of the tumor to enlarge the esophageal lumen. On the second attempt at laser therapy, a large pulsatile tumor cavity in the left lateral wall of the esophagus was noted suggesting close proximity to the aorta. Following this discovery, no further laser therapy was performed. Radiation therapy was not considered an option. At this point, the patient declined further therapy. His clinical condition continued to deteriorate and he died 22 days after initial presentation. Unfortunately, permission to perform an autopsy was not obtained.
Discussion
Primary small cell carcinoma involving the esophagus is a relatively recently described entity. The majority of cases have been reported in men, with a male to female ratio of 2:1. The tumor most commonly occurs during the sixth to eighth decades. Microscopically, small cell carcinoma of the esophagus is identical in appearance to small cell carcinoma of the lung. McKeown [1] suggested that primary " o a t cell" carcinoma of the esophagus may arise from persistent islands of embryonic ciliated columnar entodermal epithelium in the esophagus after the separation of the esophagus and trachea. Most authors now believe that these tumors originate from esophageal neuroendocrine cells [2, 6, 9-12, 14]. They are sometimes referred to as "Kultschitzky" or " A P U D " (amine precursor uptake and decarboxylase) cells and have been described as argyrophil cells due to their silverstaining characteristics. More recently, the argyrophil stain has been replaced by immunoperoxidase stains for neuron-specific enolase and other markers of neural and neuroendocrine differentiation. Argyrophil cells have been found in human esophageal mucosa [18], as well as in human bronchi [19]. If indeed small cell carcinomas orginate from argyrophilic neuroendocrine cells, it is not surprising that they occur in the esophagus. Macroscopically, several methods have been used to evaluate these lesions, including esophagram, esophagoscopy, and postmortem examination. Unfortunately, not all modalities were used, or the findings were not reported; thus, many incomplete descriptions have been given. Sixty-six of the 73 cases reviewed specify tumor location in the esophagus: two were located in the upper esophagus and the remainder were roughly equally divided between the middle and distal thirds. Among the 24 cases grossly described, 11 were ulcerated, seven were fungating, six were polypoid, five were elevated, and two were small lesions with
9
only stricture and mucosal irregularity. Thirty-one cases included dimensions with 25 tumors being greater than 4 cm in size. In seven cases the lumen was described, with narrowing in five and widening in two. In our case, the lumen was markedly compressed and narrowed by the fungating mass in the distal esophagus. Olmsted et al. [16] reviewed the radiologic findings on the esophagrams of 22 large bulky esophageal malignancies which produced widening of the esophageal lumen. Four tumor types were found including 15 spindle cell carcinomas, two carcinosarcomas, three squamous cell carcinomas, and two small cell carcinomas. The authors concluded that no definite distinction among the four tumor types could be made by evaluating configuration or expansion of the esophageal lumen. However, it is of interest that despite the overwhelming predominance of squamous cell carcinoma among tumors of the esophagus, it is only represented by three cases in Olmsted's series. This study suggests that the presence of luminal widening on esophagram should raise the index of suspicion for a nonsquamous cell malignancy of the esophagus. Histologically, these tumors have been found to be composed of small round-, oval-, polygonal-, or spindle-shaped cells with intensely hyperchromatic nuclei and scant cytoplasm. The cells are typically arranged in sheets, ribbons, streaming patterns, or, occasionally, rosettes. Numerous mitoses are the rule. Cytoplasmic argyrophilia is frequently noted but is not essential for making the diagnosis [12]. Briggs et al. [20] reviewed 23 cases of esophageal small cell carcinoma and found argyrophilia in only 13%. Several authors have reported a mixed morphologic pattern with squamous cell carcinoma [1, 4, 5, 8, 15] or adenocarcinoma [4] intermingled with the small cell pattern. Theories attempting to explain these lesions include dual origin from endocrine and sqamous cells [8, 11] or divergent lines of differentiation in a tumor derived from a single cell type [4, 8, 11]. The ultrastructural morphology of small cell carcinoma in the lung was studied by Bensche et al. [21]. The most characteristic feature of cells comprising these tumors were numerous electron-dense neurosecretory-type granules scattered throughout the cytoplasm. Subsequently, neurosecretory granules were identified in cells of primary esophageal small cell carcinoma. The identification of these granules is felt to be essential for establishing the diagnosis of extrapulmonary small cell carcinoma by some authors [2, 4, 15]. However, others feel the presence of these granules aid in confirming the diagnosis but should not be an essential criteri-
10
on [12]. Briggs et al. [20] demonstrated these granules in only 22% of cases. Biochemicalty, small cell carcinomas of the lung are often associated with ectopic hormone secretion. Using bioassay or radioimmunoassay, ACTH activity has been detected in three cases of small cell carcinoma of the esophagus [14]. One case of calcitonin production by rumor cells has been reported [2]. Clinical signs or symptoms of abnormal hormone production have not been present in any of these cases. The aggressive nature of this lesion is similar to small cell carcinoma of the lung with rapid tumor growth and spread. Most of the patients had widely disseminated metastatic disease at death. In untreated patients, all died of the tumor within 1 month of diagnosis. In treated cases, therapy included resection, radiation therapy, and chemotherapy with a mean survival of 8, 2.5, and 8 months, respectively. Twenty-four months is the longest reported survival in a patient treated with resection only. Most tumors originating in the lung are treated with radiation and chemotherapy because response to surgical resection is poor. Kelsen et al. [3] evaluated treatment by chemotherapy alone and found that small cell carcinoma of the esophagus was as responsive as its counterpart in the lung. Conclusion Small cell carcinoma of the esophagus generally presents with dysphagia and weight loss, and by the time of presentation is usually a large tumor of the mid to distal esophagus. In this regard it is similar to squamous cell carcinoma which is also large at presentation. There do not appear to be any specific distinguishing characteristics in the radiographic presentation of this tumor, although several cases have shown luminal widening on esophagram. While there are not enough complete descriptions in the literature to determine if this occurs more often in small cell carcinoma than in other tumors of the esophagus, this remains an intriguing possibility. Clearly, more cases with detailed radiographic descriptions are needed before any trend can be determined. The cases presented by Olmsted et al. suggest that luminal widening on the esophagram should raise the question of a nonsquamous cell malignancy of the esophagus. More generally, primary small cell carcinoma of the esophagus should be taken into consideration in the differential diagnosis of esophageal mass lesions. Recognition that this tumor may occur pri-
L.D. Mulder et al. : Primary Small Cell Carcinoma
marily in the esophagus may in certain cases prevent an erroneous diagnosis of advanced small cell carcinoma of the lung. References 1. McKeown F: Oat cell carcinoma of the esophagus. J Pathol Bacteriol 64: 889-891, 1952 2. Horai T, Kobayashi A, Tateishi R, et al : A cytologic study on small cell carcinoma of the esophagus. Cancer 41 : 1890-1896, 1978 3. Kelsen DP, Weston E, Kurtz R, Critkovic E, Lieberman P, Golbey RB: Small cell carcinoma of the esophagus: Treatment by chemotherapy alone. Cancer 45:1558-1561, 1980 4. Ho K, Herrera GA, Jones JM, Alexander CB: Small cell carcinoma of the esophagus: Evidence for a unified histogenesis. Hum Pathol 15:460468, 1984 5. Matsusaka T, Watanabe H, Enjoji M: Anaplastic carcinoma of the esophagus: Report of three cases and their histogenetic consideration. Cancer 37:1352-1358, 1976 6. Sarma DP: Oat cell carcinoma of the esophagus. J Surg Oncol 19:145-150, 1982 7. Turnbull AD, Rosen P, Goodner JT, Beattie EJ: Primary malignant tumors of the esophagus other than typical epidermoid carcinoma. Ann Thoracic Surg 15: 463-473, 1973 8. Cook MG, Eusebi V, Betts CM: Oat cell carcinoma of the oesophagus : A recently recognized entity. J Clin Pathol 29:1068-1073, 1976 9. Imai T, Sannohe Y, Okano H: Oa~ cell carcinoma (apudoma) of the esophagus. Cancer 41: 358-364, 1978 10. Chaudhry AP, Satchidanand S, Prezyna A, Adler RH: Oat cell carcinoma (apudoma) of esophagus. N Y State J Med 8:1212-1217, 1981 11. Reid HAS, Richardson WW, Corrin B: Oat cell carcinoma of the esophagus. Cancer 45:2342-2347, 1980 12. Doherty MA, MeIntyre M, Arnott SJ: Oat cel[ car:inoma of esophagus: A report of six British patients with a review of the literature. J Radiat Oncol Biol Phys 10:147-152, 1984 13. Ignacio AG, Chintapalli K, Choi H: Primary oat cell carcinoma of the esophagus. Am J Gastroentero182: 78-81, 1987 14. Tateishi R, Taniguchi K, Horai T, et al: Argyrophil cell carcinoma (apudoma) of the esophagus. Virchows Arch [A] 371 : 283-294, 1976 15. Rosen Y, Moon S, Kim B: Small cell epidermoid carcinoma of the esophagus. Cancer 36:1042-1049, 1975 16. Olmsted WW, Lichtenstein JE, Hyams VJ: Polypoid epithelial malignancies of the esophagus. A JR 140: 921-925, 1983 17. Reyes CV, Wellington J, Gould VE: Neuro-endocrine carcinomas of the esophagus. Ultrastruct Pathol 1 : 367-376, 1980 18. Tateishi R, Taniguchi H, Wada A, Horai T, Tanignchi K: Argyrophil cells and melanocytes in esophageal mucosa. Arch Patho198: 87-89, 1974 19. Tateishi R: Distribution of argyrophil cells in adult human lungs. Arch Patho196:198-202, 1973 20. Briggs JC, Ibrahim NBN: Oat cell carcinoma of oesophagus: A clinico-pathological study of 23 cases. Histopathology 7:261-277, 1983 21. Bensch KG, Corrin B, Pariente R, Spencer H: Oat cell carcinoma of lung. Cancer 22:1163-1172, 1968 22. Rivera F, Matilla A, Fernandez-Sanz J, Galera H: Oat cell carcinoma of the oesophagus. Virchows Arch 391:332344, 1981 Received: May I, 1990; accepted: June 3, 1990
Gastrointestinal
Radiology 9 Springer-VerlagNewYorkInc.1991
Primary Small Cell Carcinoma of the Esophagus: Case Presentation and Review of the Literature Linda D. Mulder, Geoffrey A. Gardiner, and Douglas A. Weeks Departments of Radiology and Pathology, Loma Linda University Medical Center, Loma Linda, California, USA
Abstract. A case of primary small cell carcinoma of the esophagus is presented. The clinical, radiologic, and pathologic findings of our case and 72 other cases were reviewed. The most common presenting symptoms were weight loss and dysphagia. Eighty percent were larger than 4 cm at presentation and 97% were in the mid to distal esophagus. The esophageal tumors were identical histologically to small cell carcinoma of the lung. Esophageal luminal widening on esophagram has been found to be more common in nonsquamous cell carcinomas. While rare, small cell carcinoma should be considered in the differential diagnosis of primary esophageal tumors, particularly in the presence of these findings. Key words: Esophagus - Small cell c a r c i n o m a Oat cell.
Primary carcinoma of the esophagus is most frequently squamous cell, or if distal, adenomatous in histologic type. In recent years, however, a number of cases of primary small cell carcinoma of the esophagus have been reported. The first two cases were described by McKeown in 1952 [1] and since then 70 other cases have been reported in the English literature. Because of confusion regarding the true nature and histogenesis of this tumor, it has been reported variously as small cell carcinoma [2-4], anaplastic carcinoma [5], oat cell carcinoma with argyrophilia and/or neurosecretory granules [1, 6-13], argyrophil cell carcinoma [14], apudoma [9, 10, 14], oat cell carcinoma with squamous Address offprint requests to: Linda D. Mulder, M.D., Department, of Radiology, Loma Linda University Medical Center, 11234 Anderson Street, Loma Linda, CA 92354, U S A
cell carcinoma [1], small cell anaplastic carcinoma [7], and small cell epidermoid carcinoma [15]. Table 1 lists the primary features of 72 cases reported in the English literature including the current case. The incidence is difficult to estimate because most reports have presented single cases. American authors report an incidence of up to 2%. Turnbull et al. [7] found one case of small cell carcinoma of the esophagus in a total of 1918 cases of esophageal carcinoma reviewed. Olmsted et al. [16] reviewed 150 cases of epithelial esophageal malignancies and found two cases of primary small cell carcinoma. Reyes et al. [17] found 16 cases among a total of 928 primary esophageal cancers reviewed. Japanese authors report a higher incidence ranging up to 9% [3]. It has been suggested that the actual incidence of this malignancy may be higher than that reported and that as recognition of this entity improves, the reported incidence may more closely approximate the true incidence [2]. Most of the previously presented cases are found in the pathology and oncology literature and few have described the radiologic findings. We present the clinical, radiologic, and pathologic findings of a new case and review the others found in the English literature.
Case Report An 83-year-old man presented with a 3.5-month history of 45 pound weight loss and dysphagia for both solids and liquids. On physical exam he appeared cachectic, mildly volume depleted, and was found to have guaiac positive stools. No hepatosplenomegaly or lymphadenopathy was noted. Liver function tests were normal. The admission chest x-ray demonstrated cardiomegaly, arteriosclerotic changes in the aorta, and evidence of early congestive heart failure. Barium esophagram revealed an ulcerated fungating mass involving the distal third of the esophagus with a shelving defect proximally (Fig. 1). It measured 12 cm in cephalocaudad dimensions and up to 8 cm in
6
L.D. Mulder et al. : Primary Small Cell Carcinoma
Table 1. Cases of small cell carcinoma of the esophagus reported in the English literature Author/year
Age/sex
Symptoms
Location/gross
Microscopic
Hormones
Metastases
Treatment/lifespan a
68M
Anorexia, chest pain
Distal 1/3, 2" fungating encircling lumen
Small cell ca
?
W
None/5 days
60M
Dysphagia, hoarseness
Middle 1/3, 3" ulcerated mass
Small cell ca and squamous cell ca
?
W
None/died during work-up
2. Turnbull et al. (1973)
55F
?
Distal 1/3
Small cell ca
?
W
Resected/18 months
3. Rosen et al. (1975)
67F
Dysphagia, weight loss
Middle 1/3, 5 x 3 x 5.1 cm, elevated, ulcerated
Small cell ca and squamous cell ca
?
W
None/5 days
4. Cook et al. (1976)
73F
Weight loss, interscapular pain with swallowing
Distal 1/3, 4.5 cm, Small cell ca and irregular mucosa, squamous cell ca proximal part stenotic
?
W
Resected/died of postop complications
5. Matsusaka et al. (1976)
67M
?
Distal 1/3, polypoid
Small cell ca
?
W
None/1 month of another cause
62M
Dysphagia
Middle 1/3, elevated ulcer
Small cell ca with squamous cell ca in situ
?
W
Chemotherapy via hepatic artery to liver/3 months
70M
Hoarseness, hemoptysis
Middle 1/3, polypoid Small cell ca
?
W
None/died shortly after admission
58M
?
Distal 1/3, 2.5 x 2 cm, ulcerated
Small cell ca
( + ) Calcitonin
W
Resected/8 months
1. McKeown (1952)
6. Horai et al. (1978) b
64M
?
?
Small cell ca
?
?
?
54M
?
?
Small cell ca
?
?
?
57M
?
?
Small ceil ca
(+)ACTH
?
62M
?
Small cell ca
(+)ACTH W
Resected/3 months
72M
?
Distal 1/3, I x 1 cnl, fungating/polypoid ?
Small cell ca
?
?
52M
?
?
Small cell ca
?
?
?
?
?
W
Resection and chemotherapy/ 6 months
7. lmai et al. (1978)
60M
Dysphagia
Middle 1/3, polypoid Small cell ca with glandular differentiation
(-)
8. Kelson et al. (1980)
76F
Dysphagia, weight loss
Middle 1/3
Small cell ca
?
W
Chemotherapy/ 9 months
9. Reid et al. (1980)
60F
Epigastric pain
Distal 1/3, 3 x i x 0 . 5 cm, ulcerated
Small cell ca
?
W
Resection and chemotherapy/ 8 months
60% middle 1/3, 27% distal 1/3, 13 % upper 1/3, avg. diam. 5.4 cm
Small cell ca, 10, pure; 6, " m i x e d "
1 case ( - ) PTH
?
?/1-6 months, avg. 2 months
10. Reyes et al. (1980)
16 cases, 75% weight all M, loss, 69% 29-74 years, dysphagia mean 58 years
11. Chaudhry et al. 77F (1981)
Abdominal bloating, anorexia, eructation
Distal 1/3, bulky, partial obstruction of lumen
Small cell ca
?
W
Radiation/8 months
12. Rivera et al. (1981)
62M
Dysphagia, piercing pain
Middle 1/3
Small cell ca
?
LN
Resected/1 week
13. Sarma (1982)
59M
Weight loss, hematemisis
Middle 1/3, hemorrhagic, ulcerated
Small cell ca
?
W
None/l month
L.D. Mulder et al. : Primary Small Cell Carcinoma Table 1. (continued) Author/year
Age/sex
Symptoms
Location/gross
Microscopic
Hormones
Metastases
Treatment/lifespan a
14. Olmsted et al. (1983)
62
?
> 4 cm, lumen expanded, scalloped edges
Small cell ca
?
?
?
77
?
> 4 cm, lumen expanded, scalloped edges
Small cell ca
?
?
9
15. Briggs et al. (1983)
23 cases, 95% dysphagia (15)F, (8)M, 51-88 years, mean 69.8 years
78% distal 1/3, 22% middle 1/3, range 2.5-14.5 cm
Small cell ca ; 17, pure; ? 3, foci of carcinoid; 2, foci of squamous cell; 1, loci glandular tissue
48% LN ?/91% _< 13 months 3% W 4% 14 months 4% ?
16. Doherty et al. (1984)
76F
Dysphagia, weight loss
Distal 1/3
Small cell ca
?
W
Radiation/10 weeks
70M
Dysphagia, weight loss
Middle 1/3, 8 cm, esophageal narrowing
Small cell ca
?
?
Radiation/5 months
83F
Dysphagia, Middle 1/3, coughing spasm irregular narrowing
Small cell ca
?
W
Radiation/1 month of another cause
69M
Comatose
Distal 1/3, 5 cm, narrowed lumen
Small cell ca
?
W
None/4.5 h
74F
Anorexia, weight loss
Mid to distal 1/3
Small cell ca
?
W
Radiation/2 months
69F
Dysphagia, weight loss
Mid to distal 1/3, polypoid
Small cell ca
?
W
Radiation/3 months
63M
Dysphagia
Distal 1/3, small ulcerated
Small cell ca and ? squamous cell ca with mucous secretion
?
Resected/?
62M
Dysphagia
Middle and distal 1/3s, fungating
Small cell and squamous cell ca
?
?
Palliative dilatation/?
63M
Achalasia 10 years, 3 months worsening dysphagia
Distal i/3, polypoid
Small cell ca
?
?
Chemotherapy/?
18. Ignacio et al. (1987)
60M
Weight loss, vomitting
Middle and distal 1/3s, 6 cm, varicoid
Small cell ca
?
W
None/died before therapy could be given
19. Mulder et al. (1989)
83M
Weight loss, dysphagia
Middle and distal 1/3s, 12 cm, ulcerated, fungating
Small cell ca
?
LN
Palliative laser therapy/22 days
17. Ho et al. (1984)
Ca, carcinoma; W, widespread metastatic disease to multiple organs; LN, metastasis to lymph nodes only. " Lifespan after diagnosis made. b Tateishi et al. [14] and Horai et al. [2] both reviewed 79 cases of esophageal malignancies resected at The Center for Adult Diseases, Osaka, Japan. Small cell carcinoma was found in six cases by Tateishi et al. and in seven cases by Horai et al. It is unclear whether both studies evaluated the same patients. Only the seven cases reported by Horai et al. have been included.
greatest transverse dimensions. Contrast appeared to filter slowly through the mass within the lumen. The esophageal lumen near the gastroesophageal junction was narrowed. Computed tomography of the chest revealed a large left-sided paraesophageal mass beginning at the level of the left pulmonary artery (Fig. 2). It surrounded the esophagus as it extended distally and terminated at the gastroesophageal junction. The
esophageal lumen was narrowed eccentrically and the walls were markedly thickened by the mass. Additionally, a nonhomogeneous mass of lymph nodes was seen in the gastrohepatic ligament region displacing the stomach anteriorly (Fig. 3). There was no evidence of tumor involving the lung. Esophagoduodenoscopy revealed an exophytic, necrotic mass in the distal esophagus, partially obstructing the lumen. No tumor was seen
8
Fig. 1. Barium esophagram reveals a bulky mass in the distal esophagus with apparent luminal widening. Fig. 2. CT scan through the mid chest demonstrates a large esophageal soft tissue mass with distortion of the lumen. Fig. 3. CT scan through the upper abdomen reveals a nonhomogeneous collection of enlarged lymph nodes in the gastrohepatic ligament region. Fig. 4. Photomicrograph of biopsy tissue shows infiltration by nests and masses of small neoplastic cells with hyperchromatic nuclei and scant cytoplasm. Hematoxylin-eosin, original magnification, x 200.
L.D. Mulder et al. : Primary Small Cell Carcinoma
in the stomach; however, a 2.5 cm lobulated polyp was removed from the antrum. Histologic study of biopsies of the esophageal mass revealed infiltration of esophageal tissue by a high-grade cellular neoplasm composed of irregular masses and nests of closely packed tumor cells exhibiting hyperchromatic nuclei and scant to minimal amounts of amphophilic staining cytoplasm (Fig. 4). Numerous mitotic figures were seen. Immunoperoxidase staining for leukocyte common antigen was negative; a stain for low molecular weight cytokeratin showed weak positivity in a few tumor cells. An immunoperoxidase reaction for neuronspecific enolase showed moderately bright staining within tumor cell cytoplasm. The histologic and immunocytochemical findings were interpreted as diagnostic of small cell anaplastic carcinoma of neuroendocrine origin. Tissue was not available
L.D. Mulder et al. : Primary Small Cell Carcinoma for ultrastructural studies. The polypoid lesion in the gastric antrum proved to be a benign adenomatous polyp. Because of his poor nutritional status, the patient was placed on peripheral total parenteral nutrition. Palliative treatment included laser ablation of the tumor to enlarge the esophageal lumen. On the second attempt at laser therapy, a large pulsatile tumor cavity in the left lateral wall of the esophagus was noted suggesting close proximity to the aorta. Following this discovery, no further laser therapy was performed. Radiation therapy was not considered an option. At this point, the patient declined further therapy. His clinical condition continued to deteriorate and he died 22 days after initial presentation. Unfortunately, permission to perform an autopsy was not obtained.
Discussion
Primary small cell carcinoma involving the esophagus is a relatively recently described entity. The majority of cases have been reported in men, with a male to female ratio of 2:1. The tumor most commonly occurs during the sixth to eighth decades. Microscopically, small cell carcinoma of the esophagus is identical in appearance to small cell carcinoma of the lung. McKeown [1] suggested that primary " o a t cell" carcinoma of the esophagus may arise from persistent islands of embryonic ciliated columnar entodermal epithelium in the esophagus after the separation of the esophagus and trachea. Most authors now believe that these tumors originate from esophageal neuroendocrine cells [2, 6, 9-12, 14]. They are sometimes referred to as "Kultschitzky" or " A P U D " (amine precursor uptake and decarboxylase) cells and have been described as argyrophil cells due to their silverstaining characteristics. More recently, the argyrophil stain has been replaced by immunoperoxidase stains for neuron-specific enolase and other markers of neural and neuroendocrine differentiation. Argyrophil cells have been found in human esophageal mucosa [18], as well as in human bronchi [19]. If indeed small cell carcinomas orginate from argyrophilic neuroendocrine cells, it is not surprising that they occur in the esophagus. Macroscopically, several methods have been used to evaluate these lesions, including esophagram, esophagoscopy, and postmortem examination. Unfortunately, not all modalities were used, or the findings were not reported; thus, many incomplete descriptions have been given. Sixty-six of the 73 cases reviewed specify tumor location in the esophagus: two were located in the upper esophagus and the remainder were roughly equally divided between the middle and distal thirds. Among the 24 cases grossly described, 11 were ulcerated, seven were fungating, six were polypoid, five were elevated, and two were small lesions with
9
only stricture and mucosal irregularity. Thirty-one cases included dimensions with 25 tumors being greater than 4 cm in size. In seven cases the lumen was described, with narrowing in five and widening in two. In our case, the lumen was markedly compressed and narrowed by the fungating mass in the distal esophagus. Olmsted et al. [16] reviewed the radiologic findings on the esophagrams of 22 large bulky esophageal malignancies which produced widening of the esophageal lumen. Four tumor types were found including 15 spindle cell carcinomas, two carcinosarcomas, three squamous cell carcinomas, and two small cell carcinomas. The authors concluded that no definite distinction among the four tumor types could be made by evaluating configuration or expansion of the esophageal lumen. However, it is of interest that despite the overwhelming predominance of squamous cell carcinoma among tumors of the esophagus, it is only represented by three cases in Olmsted's series. This study suggests that the presence of luminal widening on esophagram should raise the index of suspicion for a nonsquamous cell malignancy of the esophagus. Histologically, these tumors have been found to be composed of small round-, oval-, polygonal-, or spindle-shaped cells with intensely hyperchromatic nuclei and scant cytoplasm. The cells are typically arranged in sheets, ribbons, streaming patterns, or, occasionally, rosettes. Numerous mitoses are the rule. Cytoplasmic argyrophilia is frequently noted but is not essential for making the diagnosis [12]. Briggs et al. [20] reviewed 23 cases of esophageal small cell carcinoma and found argyrophilia in only 13%. Several authors have reported a mixed morphologic pattern with squamous cell carcinoma [1, 4, 5, 8, 15] or adenocarcinoma [4] intermingled with the small cell pattern. Theories attempting to explain these lesions include dual origin from endocrine and sqamous cells [8, 11] or divergent lines of differentiation in a tumor derived from a single cell type [4, 8, 11]. The ultrastructural morphology of small cell carcinoma in the lung was studied by Bensche et al. [21]. The most characteristic feature of cells comprising these tumors were numerous electron-dense neurosecretory-type granules scattered throughout the cytoplasm. Subsequently, neurosecretory granules were identified in cells of primary esophageal small cell carcinoma. The identification of these granules is felt to be essential for establishing the diagnosis of extrapulmonary small cell carcinoma by some authors [2, 4, 15]. However, others feel the presence of these granules aid in confirming the diagnosis but should not be an essential criteri-
10
on [12]. Briggs et al. [20] demonstrated these granules in only 22% of cases. Biochemicalty, small cell carcinomas of the lung are often associated with ectopic hormone secretion. Using bioassay or radioimmunoassay, ACTH activity has been detected in three cases of small cell carcinoma of the esophagus [14]. One case of calcitonin production by rumor cells has been reported [2]. Clinical signs or symptoms of abnormal hormone production have not been present in any of these cases. The aggressive nature of this lesion is similar to small cell carcinoma of the lung with rapid tumor growth and spread. Most of the patients had widely disseminated metastatic disease at death. In untreated patients, all died of the tumor within 1 month of diagnosis. In treated cases, therapy included resection, radiation therapy, and chemotherapy with a mean survival of 8, 2.5, and 8 months, respectively. Twenty-four months is the longest reported survival in a patient treated with resection only. Most tumors originating in the lung are treated with radiation and chemotherapy because response to surgical resection is poor. Kelsen et al. [3] evaluated treatment by chemotherapy alone and found that small cell carcinoma of the esophagus was as responsive as its counterpart in the lung. Conclusion Small cell carcinoma of the esophagus generally presents with dysphagia and weight loss, and by the time of presentation is usually a large tumor of the mid to distal esophagus. In this regard it is similar to squamous cell carcinoma which is also large at presentation. There do not appear to be any specific distinguishing characteristics in the radiographic presentation of this tumor, although several cases have shown luminal widening on esophagram. While there are not enough complete descriptions in the literature to determine if this occurs more often in small cell carcinoma than in other tumors of the esophagus, this remains an intriguing possibility. Clearly, more cases with detailed radiographic descriptions are needed before any trend can be determined. The cases presented by Olmsted et al. suggest that luminal widening on the esophagram should raise the question of a nonsquamous cell malignancy of the esophagus. More generally, primary small cell carcinoma of the esophagus should be taken into consideration in the differential diagnosis of esophageal mass lesions. Recognition that this tumor may occur pri-
L.D. Mulder et al. : Primary Small Cell Carcinoma
marily in the esophagus may in certain cases prevent an erroneous diagnosis of advanced small cell carcinoma of the lung. References 1. McKeown F: Oat cell carcinoma of the esophagus. J Pathol Bacteriol 64: 889-891, 1952 2. Horai T, Kobayashi A, Tateishi R, et al : A cytologic study on small cell carcinoma of the esophagus. Cancer 41 : 1890-1896, 1978 3. Kelsen DP, Weston E, Kurtz R, Critkovic E, Lieberman P, Golbey RB: Small cell carcinoma of the esophagus: Treatment by chemotherapy alone. Cancer 45:1558-1561, 1980 4. Ho K, Herrera GA, Jones JM, Alexander CB: Small cell carcinoma of the esophagus: Evidence for a unified histogenesis. Hum Pathol 15:460468, 1984 5. Matsusaka T, Watanabe H, Enjoji M: Anaplastic carcinoma of the esophagus: Report of three cases and their histogenetic consideration. Cancer 37:1352-1358, 1976 6. Sarma DP: Oat cell carcinoma of the esophagus. J Surg Oncol 19:145-150, 1982 7. Turnbull AD, Rosen P, Goodner JT, Beattie EJ: Primary malignant tumors of the esophagus other than typical epidermoid carcinoma. Ann Thoracic Surg 15: 463-473, 1973 8. Cook MG, Eusebi V, Betts CM: Oat cell carcinoma of the oesophagus : A recently recognized entity. J Clin Pathol 29:1068-1073, 1976 9. Imai T, Sannohe Y, Okano H: Oa~ cell carcinoma (apudoma) of the esophagus. Cancer 41: 358-364, 1978 10. Chaudhry AP, Satchidanand S, Prezyna A, Adler RH: Oat cell carcinoma (apudoma) of esophagus. N Y State J Med 8:1212-1217, 1981 11. Reid HAS, Richardson WW, Corrin B: Oat cell carcinoma of the esophagus. Cancer 45:2342-2347, 1980 12. Doherty MA, MeIntyre M, Arnott SJ: Oat cel[ car:inoma of esophagus: A report of six British patients with a review of the literature. J Radiat Oncol Biol Phys 10:147-152, 1984 13. Ignacio AG, Chintapalli K, Choi H: Primary oat cell carcinoma of the esophagus. Am J Gastroentero182: 78-81, 1987 14. Tateishi R, Taniguchi K, Horai T, et al: Argyrophil cell carcinoma (apudoma) of the esophagus. Virchows Arch [A] 371 : 283-294, 1976 15. Rosen Y, Moon S, Kim B: Small cell epidermoid carcinoma of the esophagus. Cancer 36:1042-1049, 1975 16. Olmsted WW, Lichtenstein JE, Hyams VJ: Polypoid epithelial malignancies of the esophagus. A JR 140: 921-925, 1983 17. Reyes CV, Wellington J, Gould VE: Neuro-endocrine carcinomas of the esophagus. Ultrastruct Pathol 1 : 367-376, 1980 18. Tateishi R, Taniguchi H, Wada A, Horai T, Tanignchi K: Argyrophil cells and melanocytes in esophageal mucosa. Arch Patho198: 87-89, 1974 19. Tateishi R: Distribution of argyrophil cells in adult human lungs. Arch Patho196:198-202, 1973 20. Briggs JC, Ibrahim NBN: Oat cell carcinoma of oesophagus: A clinico-pathological study of 23 cases. Histopathology 7:261-277, 1983 21. Bensch KG, Corrin B, Pariente R, Spencer H: Oat cell carcinoma of lung. Cancer 22:1163-1172, 1968 22. Rivera F, Matilla A, Fernandez-Sanz J, Galera H: Oat cell carcinoma of the oesophagus. Virchows Arch 391:332344, 1981 Received: May I, 1990; accepted: June 3, 1990
