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ORIGINAL ARTICLES |
From the Departments of Surgery (JMK, JBFH, HO, JJBV) and Pathology (GJAO, FJWT), Academic Medical Center, Amsterdam, The Netherlands.
Correspondence: Address correspondence and reprint requests to: Joost M. Klaase, MD, Department of Surgery, Medisch Spectrum Twente, Haaksbergerstraat 55, 7500 KA Enschede, The Netherlands; Fax: 0031-53-4872526; E-mail: j.klaase{at}ziekenhuis-mst.nl
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Methods: To get more insight into the unusual pathologic variants, patients were selected from our computer-assisted database containing data from 426 consecutive patients treated with esophageal resection or enucleation at our institute during 1993 to 2000.
Results: Uncommon variants of esophageal neoplasms were encountered in 23 patients (5.3%). The following unusual histopathologic variants were seen: basaloid squamous cell carcinoma (n = 3), small-cell carcinoma (n = 1), leiomyoma (n = 5), gastrointestinal stromal tumor (n = 2), leiomyosarcoma (n = 1), adenosquamous carcinoma (n = 5), carcinosarcoma (n = 4), collision tumor (n = 1), and melanoma (n = 1). Presentation, histopathologic characteristics, treatment, and prognosis are described in reference to the existing literature.
Conclusions: Survival data of the unusual pathologic variants seem to be comparable to those of the most frequently encountered neoplasms. Only in case of small-cell carcinoma does there seem to be a definite role for chemotherapy, especially in a multimodality treatment protocol.
Key Words: Esophageal neoplasms • Histopathological characteristics • Unusual variants • Small-cell carcinoma
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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From the 429 esophageal operations, the pathologic diagnosis was adenocarcinoma in 262 patients (61%), squamous cell carcinoma in 128 patients (30%), high-grade dysplasia in Barrett’s mucosa in 15 patients (3.5%), and high-grade dysplasia in squamous mucosa in 1 patient (.2%).3 An unusual histopathologic diagnosis was seen in 23 patients (5.3%). For this article, the last group of 23 patients was subjected to a detailed analysis. All pathologic specimens were reviewed by a gastrointestinal pathologist (G.J.A.O.).
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Carcinomas (Basaloid Squamous Cell Carcinoma and Small-Cell Carcinoma)
Four patients were treated for an unusual carcinoma of the esophagus. Three patients with basaloid squamous cell carcinoma were found in our database. Two patients are alive without disease 7 and 24 months after operation, and one patient died from brain metastases 3 months after surgery. The latter patient had a proximal esophageal tumor.
The patient with a small-cell carcinoma of the distal esophagus had limited disease and was postoperatively treated with chemotherapy (six courses of cyclophosphamide, doxorubicin, and etoposide). He died 13 months after esophagectomy as a result of distant metastases.
Mesenchymal Tumors (Leiomyoma, GIST, and Leiomyosarcoma)
Eight patients had a mesenchymal neoplasm. In three patients, the diagnosis of leiomyoma was made beforehand, on the basis of the size of the tumor and the specific endosonographic features. Those three patients were treated with simple enucleation and are disease free 40, 42, and 84 months after operation. In four patients, an esophageal resection was performed because a GIST or leiomyosarcoma was expected or could not be excluded. In another patient, esophageal resection was performed because of local recurrence after enucleation of the tumor elsewhere. Histopathologic examination showed that two of the five patients treated with esophageal resection had a leiomyoma. They are disease free 6 and 15 months after operation. Two patients had a GIST that was histologically considered to be malignant on the basis of the size of the lesion and the mitotic activity. One patient is still alive 14 months after surgery, and one patient died 44 months after esophagectomy as a result of recurrent disease. One patient had a leiomyosarcoma and was treated very recently.
Mixed Tumors (Adenosquamous Carcinoma, Carcinosarcoma, and Collision Tumor)
Ten patients had a mixed esophageal neoplasm. In the database, five patients with adenosquamous carcinoma were found. Two patients are still alive with no evidence of disease 9 and 24 months after esophagectomy. Three patients died from distant metastases within 1 year after operation. One of these patients participated in a neoadjuvant chemotherapy trial and did not respond to two courses of cisplatin and etoposide. Because a coin lesion in the right lung was considered to be a primary lung tumor, besides transthoracic esophageal resection, exploration of the right lung was performed, and two tumors were removed from the upper lobe. These tumors turned out to be one squamous cell metastasis and one adenocarcinoma metastasis of esophageal cancer. The patient died 10 months after operation with multiple bone metastases. Four patients with a carcinosarcoma were identified in our database, all with a mid esophageal tumor. Three of the four patients died 2, 4, and 11 months after surgery, and one is alive 2 months after surgery. One patient was identified with a collision tumor. He was treated, according to a neoadjuvant chemotherapy trial protocol for squamous cell carcinoma, with two courses of cisplatin and etoposide. A transhiatal esophagectomy was performed, and at histopathologic examination the tumor consisted of a squamous cell carcinoma in the distal esophagus collapsing with an adenocarcinoma at the esophagogastric junction (Fig. 1). The survival after surgery was only 6 months.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Carcinomas (Basaloid Squamous Cell Carcinoma and Small-Cell Carcinoma)
Basaloid Squamous Cell Carcinoma
Basaloid squamous cell carcinoma is an uncommon variant of squamous cell carcinoma that is mainly seen in the head and neck region, such as the larynx, pharynx, and base of the tongue, but can also be found in the esophagus.4–6 Basaloid squamous cell carcinoma of the esophagus mainly affects men in the sixth and seventh decades of life. Basaloid squamous cell carcinoma in the esophagus usually presents as high-stage disease. Wain et al.7 first described the histopathologic features of basaloid squamous cell carcinoma in detail in a study of 10 cases arising in the tongue, hypopharynx, and larynx. The major histopathologic feature of this tumor is a basaloid pattern intimately associated with squamous cell carcinoma or dysplasia. The solid growth of basaloid cells, resembling that of basal-cell carcinoma of the skin, with microcystic spaces positive for periodic acid-Schiff and/or Alcian blue staining, is considered the most important criterion in differentiating basaloid squamous cell carcinoma from typical squamous cell carcinoma, as was the case in our three patients (Fig. 2). Basaloid squamous cell carcinoma should be distinguished from small-cell carcinoma and adenoid cystic carcinoma on the basis of light microscopic, immunohistochemical, and electron microscopic findings.
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Small-Cell Carcinoma
Because of confusion regarding the true nature and histogenesis of small-cell carcinoma, it has been reported as anaplastic carcinoma, oat cell carcinoma with argyrophilia and/or neurosecretory granules, argyrophil cell carcinoma, apudoma, oat cell carcinoma with squamous cell carcinoma, small-cell anaplastic carcinoma, and small-cell epidermoid carcinoma.
In a review reporting the data of >70 patients with small-cell esophageal carcinoma, 97% of the carcinomas were in the mid or distal part of the esophagus, and 80% were >4 cm at presentation.8 At the time of diagnosis, 31% to 90% of the patients already have metastatic disease.9 Small-cell carcinoma of the esophagus is histologically identical to small-cell carcinoma of the lung. It has been suggested that small-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 the trachea.8 Most authors now think that these tumors originate from esophageal neuroendocrine cells. Its aggressive nature is similar to that of small-cell carcinoma of the lung, with rapid tumor growth and spread. Small-cell lung cancer is treated with chemotherapy and radiotherapy, and it is suggested that small-cell carcinoma of the esophagus might also be responsive to these treatment modalities.8,10,11 The discussion remains whether surgery should be one of the treatment modalities. Long-term survival after resection for small-cell carcinoma of the esophagus has been reported.12 Our patient had limited disease and underwent esophagectomy. He was postoperatively treated with six courses of multichemotherapy but died from distant metastases 13 months after operation. Recently, we saw another two patients with small-cell carcinoma of the esophagus who were referred to our hospital for treatment. They had limited disease. We decided to treat them with chemotherapy and radiation treatment instead of esophagectomy (they were therefore excluded from this series) on the basis of a recent review that showed no advantage in terms of survival for the surgery-treated patients compared with the chemoradiation-treated patients.9 In a series of eight patients with esophageal small-cell carcinoma from the M. D. Anderson Cancer Center, four patients with limited disease underwent esophagectomy after neoadjuvant chemotherapy.10 Two patients also had radiation treatment. None of the four patients had a complete remission at histopathologic examination of the esophagectomy specimen. It was therefore suggested that surgery should be part of the multimodality treatment. The median survival for the group of eight patients in the M. D. Anderson series was 12.5 months (range, 5–57 months). There is an emerging consensus that chemotherapy should be the cornerstone of treatment. Radiation or surgery should be offered to manage local disease. Which of these local procedures is more effective can, however, not be definitively established because of the paucity of cases.11
Mesenchymal Tumors (Leiomyoma, GIST, and Leiomyosarcoma)
Leiomyoma
Leiomyomas are the most commonly encountered mesenchymal tumors of the esophagus.13–15 Leiomyomas are benign lesions and are rarely seen elsewhere in the gastrointestinal tract. The male:female ratio is 2:1. The peak incidence for both men and women is between 30 and 59 years. Most leiomyomas are seen in the middle and distal third of the esophagus. Dysphagia is the most commonly reported symptom, followed by pain. Endoscopic ultrasonography is essential for the diagnosis. Leiomyomas are typically described as hypoechoic tumors located in the submucosa, with a smooth contour and clear margins, and arising within the muscularis propria or occasionally the muscularis mucosae.14,15 Biopsy is contraindicated because of the risk of damage to the mucosa when enucleation (which is the preferred treatment for intramural leiomyoma), without opening the mucosa, is attempted. An esophageal resection is indicated for all large (>5 cm) or anular-shaped tumors because in these patients, a malignant GIST or leiomyosarcoma cannot be excluded.
At histopathologic examination, leiomyomas resemble normal smooth muscle cells. Leiomyomas are paucicellular to moderately cellular tumors with eosinophilic cytoplasm. Leiomyomas are positive for the smooth muscle markers desmin and actin, and immunohistochemically they are negative for CD34 and CD117.14
GIST
Most gastrointestinal mesenchymal tumors belong to the group of specific GISTs.14,15 GISTs are most common in the stomach (65%), followed by the small intestine (30%–35%), and are rare in the colon and rectum. Occasionally they are seen in the esophagus. GISTs have a peak incidence in the fifth and sixth decades of life. GISTs are cellular spindle or epithelioid tumors that show rudimentary, if any, smooth muscle differentiation and were previously called cellular leiomyoma, leiomyoblastoma, and leiomyosarcoma.14,15 Their origin has been thought to be the interstitial cells of Cajal in the intestinal wall, which are pacemaker cells that are involved in the regulation of motility of the gastrointestinal tract. GISTs show a higher overall cellularity than leiomyomas, creating a basophilic appearance of a hematoxylin and eosin-stained slide. GISTs are negative for the smooth muscle markers desmin and actin and are immunohistochemically positive for CD34 and CD117 (Fig. 3). The differential diagnosis of GISTs includes, besides the typical smooth muscle tumors, schwannomas, inflammatory fibroid polyps, Kaposi sarcomas, and esophageal carcinosarcoma.
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Leiomyosarcoma
Esophageal leiomyosarcomas are extremely rare. At endoscopic ultrasonography, leiomyosarcomas are moderately hyperechogenic, homogeneous masses arising from the muscle layer of the esophagus.14 They are defined as tumors showing smooth muscle cell markers such as desmin and actin but are immunohistochemically negative for CD34 and CD117. Leiomyosarcomas have a high mitotic activity and are high-grade malignant tumors.
Mixed Tumors (Adenosquamous Carcinoma, Carcinosarcoma, and Collision Tumor)
Adenosquamous Carcinoma
The nomenclature for adenosquamous carcinoma has been confusing. Other terms used for adenosquamous carcinoma are squamous cell carcinoma with mucin-secreting component and mucoepidermoid carcinoma.16–18
Adenosquamous carcinoma of the esophagus does not differ significantly in presentation, degree of tumor extension, or response to surgical therapy from either squamous cell carcinoma or adenocarcinoma.16 Generally, the location in the esophagus is comparable to that of squamous cell carcinoma.
Adenosquamous carcinoma is a mixed-cell tumor with both adenocarcinomatous and squamous components, which are intermingled with each other. There are several theories about its origin. Collision of an adenocarcinoma and squamous cell carcinoma has been mentioned, although the term collision tumor nowadays is reserved for morphologically different neighboring neoplasms that do not intermingle. Also, an origin as a mucoepidermoid cancer from the submucosal salivary glands of the esophagus has been postulated. Finally, squamous differentiation in Barrett’s carcinoma can be encountered.
In the review of Fegelman et al.,16 no 5-year survivors were documented. In our series, it is surprising that in one patient two distinct metastases were found in the upper lobe of the right lung (one adenosquamous and one squamous cell metastasis). A primary lung carcinoma was less probable because there were two small peripheral lesions with different pathologic diagnoses.
Carcinosarcoma
Polypoid tumors of the esophagus with both epithelial and sarcomatoid differentiation are rare lesions, representing .5% to 2.8% of all esophageal tumors.19,20 The histogenesis of the sarcomatous component is generally considered to result from metaplasia of carcinomatous cells toward mesenchymal differentiation. This spindle cell component is an expression of the bidirectional differentiation within a single neoplasm. First it was believed that only the epithelial component had a metastatic potential, but cases of metastases of the sarcomatous component in patients with carcinosarcoma have been reported.20 On the basis of a clinicopathologic review, it has been realized that carcinosarcoma and pseudosarcoma of the esophagus are probably two names for one disease.20 In previous reports it was suggested that carcinosarcoma has a better prognosis than squamous carcinoma, but this could not be confirmed by Iascone and Barreca20 in their review of 183 patients. Our three patients all died within a few months after surgery.
Collision Tumor
Collision tumors are synchronous, morphologically different neighboring neoplasms that expand into each other. In the literature, the coincidence of squamous cell carcinoma and mesenchymal tumors such as leiomyoma, leiomyosarcoma, and lipoma has been reported in several case reports.21 In these reports, it was postulated that when a tumor causes esophageal stenosis, it may also induce or promote malignant transformation in the overlying epithelium. In our patient, there was a true collision of squamous cell carcinoma in the esophagus and adenocarcinoma located at the esophagogastric junction (Fig. 1). This case could be differentiated from an adenosquamous carcinoma because in the latter case the adenomatous and squamous parts are intermingled with each other.
Melanoma
Primary melanoma of the esophagus is rare.22 It accounts for only .1% to .2% of all esophageal malignancies. Although it was once thought that primary melanoma could not arise in the esophagus because of a lack of precursor cells, it has since been shown in autopsy series that 4% to 8% of individuals have melanoblasts in the esophageal mucosa. Melanoma of the esophagus is twice as common in men as in women, occurs in the sixth and seventh decades of life, and is most commonly located in the middle or distal third of the esophagus. Much more frequent than primary melanoma, metastatic melanoma is found in the esophagus. In autopsy series, gastrointestinal metastatic melanoma has been found in almost 50% of patients dying from melanoma. These metastases are most frequently found in the small intestine and less often in the stomach and colon.23 In 4% of patients who die of melanoma, metastases in the esophagus can be found. Primary and metastatic melanomas of the esophagus usually present as a polypoid mass and give symptoms such as dysphagia, weight loss, and pain. Other polypoid tumors include leiomyosarcoma, carcinosarcoma, and, rarely, adenocarcinoma. The prognosis for patients with primary melanoma of the esophagus is dismal. Synchronous metastases are present in almost half of the patients. After resection, the 5-year survival rate ranges from 0% to 4%, with a median survival of 5 to 7 months. Although at histopathologic examination no differentiation can be made between a primary and metastatic melanoma, the esophageal melanoma was considered a primary tumor in our patient because no primary tumor was identified elsewhere and because there were no signs of metastatic disease elsewhere in the gastrointestinal tract.
Primary Lymphoma and Carcinoid
Primary Lymphoma
Primary esophageal lymphoma is an extremely rare tumor, with <20 cases documented in the literature.24,25 Gastrointestinal involvement by lymphomas occurs in approximately 20% of patients with lymphoma and frequently involves the stomach, small bowel, and colon, but rarely the esophagus. Esophageal lymphomas are usually secondary to adjacent lymph node invasion or contiguous spread from gastric lymphoma. Here chemotherapy, radiotherapy, or both are the treatment of choice. Primary esophageal lymphoma is defined by the presence of isolated involvement of the esophageal wall and adjacent lymph nodes without evidence of lymphoma elsewhere. The presence of "B" symptoms in patients with an esophageal mass should raise the suspicion for Hodgkin’s or non-Hodgkin’s lymphoma. The endoscopic appearance of non-Hodgkin’s disease of the esophagus, mostly located in the distal part of the esophagus, is indistinguishable from the usual esophageal malignancies, whereas Hodgkin’s lymphoma most often presents as ulcerated intraluminal lesions in the proximal or mid esophagus. Endoscopic biopsies may be unsuccessful because of the submucosal origin of the tumors, and diagnosis may be postponed until esophageal resection has been performed; however, the treatment should consist of chemotherapy and radiotherapy, with a reported 5-year survival of 66% for esophageal Hodgkin’s lymphoma and 40% for non-Hodgkin’s lymphoma.24,25
Carcinoid
Esophageal carcinoid tumors are exceedingly rare neoplasms, with <15 patients reported in the literature.26 They usually occur in the lower esophagus of men who present with dysphagia. Survival statistics are limited but seem best correlated with stage of disease. For isolated carcinoids of the esophagus, there seems to be a role for esophagectomy.
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CONCLUSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Footnotes |
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Received for publication May 28, 2002. Accepted for publication October 10, 2002.
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