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Background

Squamous cell carcinoma of the esophagus is a devastating disease. It is usually detected in the late stages when a cure is no longer possible. The most common presentation is dysphagia (difficulty swallowing). Weight loss and hypercalcemia may also ensue.

OUTLINE

Epidemiology  
Disease Associations  
Pathogenesis  
Laboratory/Radiologic/Other Diagnostic Testing  
Gross Appearance and Clinical Variants  
Histopathological Features and Variants  
Special Stains/
Immunohistochemistry/
Electron Microscopy
 
Differential Diagnosis  
Prognosis  
Treatment  
Commonly Used Terms  
Internet Links  

EPIDEMIOLOGY CHARACTERIZATION
SYNONYMS Squamous cell carcinoma
INCIDENCE 310,400 new cases per year
AGE-RANGE AND MEDIAN 55-74 years
SEX (MALE:FEMALE) 3:1
GEOGRAPHIC DISTRIBUTION Worldwide, more common in developing countries esp. China, northeast Iran, and temparate S. America
More common among blacks
EPIDEMIOLOGIC ASSOCIATIONS CHARACTERIZATION
Alcohol abuse 25x increased risk
Tobacco Not as great a risk as alcohol
Nitrosamines May be produced by some fungi which can contaminate some grains
Zinc and vitamin A deficiency May be carcinogenic cofactors

DISEASE ASSOCIATIONS CHARACTERIZATION
Tylosis palmaris et plantaris Hereditary autosomal dominant with palmoplantar keratoderma
Human papilloma virus (HPV) May be important in some geographic regions but not in US
HPV types 16 and 18 incidence ranged up to 20% of cases
Esophagitis May be more important in high-risk populations
Achalasia Low risk about 0.41/1000 patients in USA
Plummer-Vincent (Patterson-Kelly) syndrome (Siderophagic dysphagia)

Most common in postmenopausal women with:
Cervical esophageal webs
Iron deficiency anemia
Poor nutrition

10% develop carcinoma, also in hypopharynx and mouth

Acid and lye burns CA occurs after long latency of 30 or more years
Strictures develop in the upper esophagus

 

PATHOGENESIS CHARACTERIZATION
APC GENE  
Microsatellite analysis of the APC gene and immunoexpression of E-cadherin, catenin, and tubulin in esophageal squamous cell carcinoma.

Nair KS, Naidoo R, Chetty R.

Pfizer Molecular Biology Research Facility, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban 4013, South Africa.


Hum Pathol. 2006 Feb;37(2):125-34. Abstract quote  

The histological features that accompany the development and progression of solid tumors are known to be controlled by a distinct cascade of molecular events.

One such event is the inactivation of tumor suppressor genes, such as the adenomatous polyposis coli (APC) gene. Disruption of the cadherin-catenin cell adhesion complex also plays a role in the initial steps of cancer invasion and metastasis whereas alterations in cell structural molecules, such as tubulin, may contribute to the cancer phenotype. The understanding of the status of these molecules in ESSC may provide novel markers that could impact on management of the disease.

The present study examined alterations in the microsatellite sequence of the APC gene via fluorescent-based polymerase chain reaction in 100 cases of primary esophageal squamous cell carcinoma. In addition, the expression of E-cadherin, alpha- and beta-catenin, and alpha- and beta-tubulin was analyzed using immunohistochemistry. These data were then statistically compared with each other as well as the relevant clinicopathologic data. Although the APC markers (D5S210, D5S346, D5S299, and D5S82) tested did show an overall high frequency of allelic imbalance/loss of heterozygosity (62.48%) and microsatellite instability (41.27%), they did not show prognostic significance in the study cohort and were not correlated with the immunohistochemical data. The tubulin proteins showed no significant change in expression in the tumor tissue The decreased immunoreactivity of E-cadherin was statistically correlated with the presence of lymph node metastases (P = .0180).

Although alpha- and beta-catenin as well as E-cadherin showed no direct prognostic value, E-cadherin may warrant further investigation as an indirect prognostic indicator by allowing more accurate prediction of lymph node metastases.
APOPTOSIS  

Expression of Bax and Apoptosis-Related Proteins in Human Esophageal Squamous Cell Carcinoma Including Dysplasia

Atsushi Kurabayashi, Mutsuo Furihata, Manabu Matsumoto, Yuji Ohtsuki, Shiro Sasaguri and Shohei Ogoshi

Departments of Pathology II (AKMF, MM, YO) and Surgery II (AK, SS), and Vice President (SO), Kochi Medical School, Nankoku, Kochi, Japan

Mod Pathol 2001;14:741-747 Abstract quote

The rate of tumor growth depends on the balance between proliferation and death of tumor cells. It is known that Bax, caspase-3, and p53 proteins are death-promoting factors, whereas Bcl-2 protein is a death antagonist.

We immunohistochemically examined the expression of Bax and apoptosis-related proteins such as caspase-3, p53, and Bcl-2 in 76 patients with human esophageal squamous cell carcinoma (SCC) including dysplasia to determine the relationship of expression of each protein to tumor behavior and patientsí prognosis.

No significant relationships in immunopositivity were found among these proteins in SCCs. Cytoplasmic Bax expression was exhibited in 63 cases of SCCs (82.9%). The apoptotic index of caspase-3-positive lesions was significantly higher than that of caspase-3-negative lesions in both dysplasia and SCC (P = .016, P = .012). On the other hand, the apoptotic index (1.18%) was significantly correlated with Bax overexpression in dysplasia (P = .006), but not in SCC lesions (P = .129). The patients with Bax-positive SCCs were found to have a poor prognosis by the Kaplan-Meier method (P = .043).

These findings suggested that Bax expressed in dysplasia may play a role as an apoptotic factor, but that it may be functionally inactive in some cancerous lesions and thus not contribute to suppression of the tumor progression in some cases of human esophageal SCCs.

CHROMOSOMAL ALTERATIONS  

Chromosomal aberrations in esophageal squamous cell carcinoma among chinese: Gain of 12p predicts poor prognosis after surgery.

Kwong D, Lam A, Guan X, Law S, Tai A, Wong J, Sham J.
Hum Pathol 2004;35:309-316 Abstract quote

Sixty primary esophageal squamous cell carcinomas (ESCCs) were evaluated for cytogenetic changes by comparative genomic hybridization (CGH). Recurrent chromosomal aberrations were correlated with stage and clinical outcome after esophagectomy to identify cytogenetic changes that are of prognostic significance.

Chromosomal aberrations were found in 52 (86.7%) cases. The most frequently detected chromosomal gains involved 3q (67.3%), 8q (57.7%), 5p (51.9%), 7q (28.8%), 15q (28.8%), 20p (21.2%), 20q (28.8%), 1q (26.9%), 7p (26.9%), 2p (23.1%), and 12p (23.1%). Chromosome 12p was most frequently involved in high-level amplification. Six of the 12 cases with gain in 12p showed high-level amplification and the minimum overlapping region localized to 12pter-p13. The most frequently detected chromosomal loss involved 3p (46.2%), 4q (26.9%), 4p (23.1%), 3q (19.2%), 9p (17.3%), 19p (17.3%), and whole 13 (15.4%). No significant correlation was found between the recurrent chromosomal aberrations and pathological stage of ESCC. Univariate analysis demonstrated that late pathological stage (III and IV), gain in 12p, and loss in 3p are associated with poor relapse-free survival. Multivariate analysis confirmed gain in 12p as independent prognosticator for relapse-free survival after esophagectomy besides pathological stage.

We conclude that chromosomal aberrations are common in ESCC. Gain in 12p is indicative of poor prognosis after esophagectomy, and combined modality therapy would be indicated in these patients.
p63  

Expression of p53-related protein p63 in the gastrointestinal tract and in esophageal metaplastic and neoplastic disorders

Jonathan N. Glickman, MD, PhD
Annie Yang, BS
Aliakbar Shahsafaei, MSc
Frank McKeon, PhD
Robert D. Odze, MD, FRCP

Hum Pathol 2001;32:1157-116 Abstract quote

p63 is a p53-related DNA-binding protein that helps regulate differentiation and proliferation in epithelial progenitor cells. Its expression has never been evaluated in the human gastrointestinal tract.

The aim of this study was to evaluate the expression of p63 in the esophagus and related metaplastic and neoplastic disorders to gain insight into the pathogenesis of these processes.
Of particular interest was the expression of p63 in Barrett esophagus (BE) and in BE-associated multilayered epithelium. Multilayered epithelium has been postulated to represent an early precursor to the development of BE primarily because it shares morphologic and immunophenotypic features of both squamous and columnar epithelium, and has been shown prospectively to be highly associated with BE. Routinely processed mucosal biopsy or resection specimens that contained normal esophageal squamous epithelium (n = 20), squamous dysplasia (n = 4), squamous cell carcinoma (n = 7), BE (n = 10), BE-associated multilayered epithelium (n = 13), esophageal mucosal gland ducts (n = 10), BE-associated dysplasia (n = 12), and BE-associated adenocarcinoma (n = 7) were immunostained for p63 to determine the extent and location of staining. p63 staining was compared with the staining patterns observed for p53, Ki 67 (proliferation marker), and cytokeratins (CKs) 13 (squamous marker), 14 (basal squamous marker), 8/18 (columnar marker), and 19 (basal/columnar marker). Expression of p63 messenger RNA (mRNA) isoforms was also analyzed by reverse-transcription polymerase chain reaction of freshly isolated tissues.

In the normal esophagus, p63 was expressed in the basal and suprabasal layers of the squamous epithelium and in basal cells that line the mucosal gland ducts but was negative in all other epithelia of the gastrointestinal tract, including the stomach, small intestine, and colon. Similarly, p63 was not expressed in BE, but it, was present in the basal layer of multilayered epithelium in 9 of 13 cases (69%). p63-positive cells in multilayered epithelium and in the mucosal gland duct epithelium were positive for CK8/18 (100%) and CK13 (67% and 30%, respectively) and negative for CK14 (0%), in contrast to p63-positive cells in squamous epithelium, which were positive for CK14 and CK13 (100%) but negative for CK8/18.

In neoplastic tissues, p63 was diffusely expressed in all cases of esophageal squamous cell dysplasia and carcinoma but was negative in all cases of esophageal and colorectal adenocarcinoma. The N isoform of p63 mRNA predominated in all benign and neoplastic squamous tissues examined. p63 may represent a marker of 2 distinct epithelial progenitor cells (basal squamous epithelium and gland duct epithelium) in the esophagus. P63 is upregulated in squamous neoplastic conditions and in this manner may play a role in squamous carcinogenesis.

These data also indicate that multilayered epithelium is phenotypically similar to, and may share a lineage relationship with, mucosal gland duct epithelium.

 

LABORATORY/
RADIOLOGIC/
OTHER TESTS
CHARACTERIZATION
Hypercalcemia Hypercalcemia of malignancy

 

GROSS APPEARANCE/CLINICAL VARIANTS CHARACTERIZATION
Superficial squamous cell carcinoma Polypoid
Plateau-like
Flat (erosive, ulcerative, and mixed)
Deeply invasive squamous cell carcinoma

Fungating
Ulcerative
Infiltrative

Often present in the middle and lower portions of the thoracic esophagus

 

HISTOLOGICAL TYPES CHARACTERIZATION
DYSPLASIA AND CARCINOMA IN SITU Preinvasive histological change, may be 8x more common in high risk areas
More likely to be found when cancer is low stage and small
Some advocate dividing into low and high grade dysplasia though reproducibility is poor
Architectural and cytologic abnormalities with enlarged and hyperchromatic nuclei and increased mitotic figures, confined to the mucosa
SUPERFICIAL Carcinoma limited to the submucosa
DEEPLY INVASIVE Invasion of the submucosa and deeper, often with deep and circumferential expansion
VARIANTS  
ADENOID CYSTIC Uniform basaloid cells with smal nuclei and rare mitoses
Grows in cords, cribriform, tubules, and solid nests surrounded by hyalinized basement membrane
Recurrence frequent
Metastases in 50%, usually to lungs
BASALOID Aggressive deeply invasive and rapidly fats
Large basaloid cells with high grade nuclei and numerous mitoses
Basaloid squamous cell carcinoma of the esophagus with or without adenoid cystic features.

Li TJ, Zhang YX, Wen J, Cowan DF, Hart J, Xiao SY.

Department of Oral Pathology, Peking University School of Stomatology, Beijing, People's Republic of China.
Arch Pathol Lab Med. 2004 Oct;128(10):1124-30. Abstract quote  

CONTEXT: Basaloid squamous cell carcinoma (BSCC) of the esophagus is a rare malignant tumor that morphologically could bear some resemblance to adenoid cystic carcinoma (ACC) originating from salivary glands.

OBJECTIVE:The purpose of this study is to describe the histologic, immunohistochemical, and ultrastructural findings of BSCCs of the esophagus, with an emphasis on comparing tumors with or without adenoid cystic features.

DESIGN: We reviewed 239 cases of primary esophageal carcinoma and detected 12 cases (5%) of BSCC. The light and electron microscopic findings and immunocytochemical localization of various antigens, including cytokeratins (AE1, AE3), carcinoembryonic antigen, epithelial membrane antigen, S100, smooth muscle actin, and p53, were examined in these BSCC cases.

RESULTS: Histologically, all BSCCs were composed of solid lobules or nests of basaloid cells with well-demarcated outlines surrounded by a fibrous stroma. Seven of 12 tumors showed areas of ACC-like features, that is, cribriform-like pseudoglandular lumina formation and hyaline material surrounding the tumor nests, whereas the remaining 5 tumors were apparently pure basaloid carcinomas. These 2 groups of tumors were histologically and immunohistochemically identical in many aspects, namely, high-grade nuclei of the tumor cells with frequent mitoses, abundant comedo-type necrosis, focal areas of concomitant squamous differentiation, consistent immunoreactivity for cytokeratins, and poor or absent staining for S100 and smooth muscle actin. Ultrastructurally, the basaloid tumor cells exhibited relatively undifferentiated cellular characteristics and undeveloped cell organelles.

CONCLUSION: Basaloid squamous cell carcinomas of the esophagus frequently have an intimate association with ACC-like patterns, but their histologic, immunocytochemical, and ultrastructural features correspond more to poorly differentiated squamous cell carcinoma than to salivary gland ACC. This distinction is important because genuine ACC is much less aggressive than BSCC.
CARCINOMA CUNNICULATUM  
Carcinoma cuniculatum of the esophagus.

De Petris G, Lewin M, Shoji T.

Department of Pathology, Mayo Clinic Scottsdale, Scottsdale, AZ 85259, USA.
Ann Diagn Pathol. 2005 Jun;9(3):134-8. Abstract quote

AIMS: Extremely well-differentiated squamous cell carcinoma with the features of so-called carcinoma cuniculatum (CC) is a rare neoplasm. We describe the clinicopathologic findings of the first 2 cases of CC of the esophagus.

METHODS AND RESULTS: Two elderly men presented with symptoms and clinical signs of esophageal malignancy. Repeated endoscopic biopsies of their esophageal tumors were inconclusive. Resection revealed CC of the esophagogastric junction in both cases. The tumors extended into the adventitia but no lymph node metastases were present. In situ hybridization for human papillomavirus HPV subtypes was negative.

CONCLUSION: Carcinoma cuniculatum is reported for the first time in the esophagus. The diagnosis of this tumor variant is difficult by means of cytological examination or by endoscopic biopsies alone. Carcinoma cuniculatum in this location shows biologic features similar to verrucous carcinoma (deep penetration, no lymph nodes metastases, and location at one end of the esophagus). No evidence of human papillomavirus could be demonstrated.
SARCOMATOID (spindle cell carcinoma, carcinosarcoma) Squamous cell carcinoma mixed with a sarcomatous-like stroma
Same profile as deeply invasive squamous cell carcinomas
May be very large, 10 cm or more, usually polypoid mass
Better prognosis since most are polypoid and remain at low stage

Loss of heterozygosity analysis shows monoclonal evolution with frequent genetic progression and divergence in esophageal carcinosarcoma.

Matsumoto T, Fujii H, Arakawa A, Yamasaki S, Sonoue H, Hattori K, Kajiyama Y, Hirose S, Tsurumaru M.
Hum Pathol 2004;35:322-327 Abstract quote

Carcinosarcoma (spindle cell carcinoma) of the esophagus is a rare neoplasm that shows squamous cell carcinoma (SCC) with a variable component of spindle cell sarcoma. Clinical and pathologic features of this neoplasm have been well documented, but the histogenesis has long been a matter of speculation and dispute.

In an attempt to clarify the clonality and genetic relationships in the evolution of this neoplasm, we microdissected a total of 36 carcinomatous and sarcomatous foci from six esophageal carcinosarcoma (CS) and analyzed the allelic status with 25 microsatellite markers on chromosomal arms 3p, 5q, 6q, 8p, 9p, 11q, 13q, 17p, and 18q. In all cases, we found multiple and homogenous allelic losses in both the carcinomatous and sarcomatous components, strongly supporting the concept of monoclonal origin for this neoplasm. Homogeneous allelic losses were detected most frequently on 17p (5 cases), a chromosomal arm that included the p53 locus, followed by 3p, 11q, and 13q (3 cases); 9p (2 cases); and 8p and 18q (1 case). Moreover, five of the six cases showed additional or divergent allelic losses at more than one chromosomal locus at some of the microdissected foci, indicating genetic progression (2 cases) or genetic progression and divergence (3 cases).

In four cases, the genetic changes indicated that an original clone of a pure SCC apparently acquired carcinosarcomatous or sarcomatous phenotype by successive genetic changes.

On the other hand, we saw no evidence for tumors in which a sarcoma appeared to give rise to a carcinosarcomatous or carcinomatous subclone in the examined cases.

In conclusion, our data support the concept that esophageal CS is derived from a single clone originating from a SCC. Furthermore, we showed genetic heterogeneity to accompany the phenotypic divergence, with patterns of genetic alterations that are consistent with both progression and divergence within individual tumors.
SMALL CELL CARCINOMA  

Primary esophageal small cell carcinoma with concomitant invasive squamous cell carcinoma or carcinoma in situ.

Yamamoto J, Ohshima K, Ikeda S, Iwashita A, Kikuchi M.

Department of Pathology, Fukuoka University School of Medicine, Japan.
Hum Pathol. 2003 Nov;34(11):1108-15 Abstract quote.  

Esophageal small cell carcinoma (SmCC) is a rarer, more highly aggressive, and more rapidly growing neoplasm than esophageal squamous cell carcinoma (SqCC). SmCC and SqCC also differ in terms of chemotherapy of choice, response to therapy, and prognosis. Accordingly, it is important to differentiate the 2 carcinomas.

We studied the histology and immunohistochemical profiles of 6 cases of esophageal SmCC to elucidate the correct diagnosis of this tumor. We performed immunohistochemical analysis antibodies against cytokeratins (CKAE1/AE3, CKCAM5.2, CK34betaE12, CK7, CK8, CK10/13, and CK19), epithelial membrane antigen (EMA), neural cell adhesion molecule (NCAM; CD56), neuron-specific enolase (NSE), chromogranin-A, S-100 protein, carcinoembryonic antigen (CEA), E-cadherin, thyroid transcription factor-1 (TTF-1), and p53. In 3 of the 6 SmCCs, heterogeneous components of in situ or invasive SqCC were observed. SqCC was found in the mucosa adjacent to the main SmCC, and the boundary between SmCC and SqCC was distinct, with no transitional features. Staining for NCAM, NSE, and chromogranin-A was positive in SmCCs, but negative in SqCCs. Both SmCCs and SqCCs were positive for CKAE1/AE3, CKCAM5.2, CK8, and EMA, but only SqCCs were positive for CK34betaE12 and CK19. Moreover, SmCCs containing SqCC components were positive for CEA and E-cadherin, whereas SmCCs without SqCC were negative.

Our study suggests that NCAM and NSE are useful markers in diagnosing esophageal SmCC, and CK34betaE12 and CK19 are useful for differentiating SqCC components from SmCC.
VERRUCOUS Malignant papillay tumor with well-differentiated squamous epithelium with minimal cytologic atypia growing with a pushing margin
Locally aggressive but usually do not metastasize

 

SPECIAL STAINS/
IMMUNOPEROXIDASE/
OTHER
CHARACTERIZATION
Cytokeratin positive  

 

DIFFERENTIAL DIAGNOSIS CHARACTERIZATION
HYPERPLASTIC POLYP  

Hyperplastic Polyps of the Esophagus and Esophagogastric Junction Histologic and Clinicopathologic Findings

Susan C. Abraham, M.D.; Vikesh K. Singh, M.D.; John H. Yardley, M.D.; Tsung-Teh Wu, M.D., Ph.D.

From the Division of Gastrointestinal/Liver Pathology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, U.S.A.

Am J Surg Pathol 2001;25:1180-1187 Abstract quote

Hyperplastic polyps of the esophagus and esophagogastric junction region (EGJ) are uncommon lesions characterized by hyperplastic epithelium (foveolar-type, squamous, or both) with variable amounts of inflamed stroma. They have been reported almost exclusively in the radiologic and clinical literature as occurring predominantly in association with gastroesophageal reflux disease (GERD). Comprehensive histologic and clinicopathologic evaluation of these polyps, their association with background mucosal pathology, and their association with Barrett's esophagus has not been previously performed.

We studied 30 hyperplastic polyps from 27 patients and characterized the histologic, endoscopic, and clinical features of both the polyps and the background esophagus. Hyperplastic polyps were most common in the region of the EGJ (67%), followed by the distal esophagus (30%) and mid-esophagus (3%). Most (80%) were composed of predominantly cardiac-type mucosa, predominantly squamous mucosa (17%), or an admixture (3%). Intestinal metaplasia of the polyp was present in only 7% and low-grade dysplasia in only 3%. In the majority of cases (67%) hyperplastic polyps were associated with concurrent or recent ulcers or erosive esophagitis. In most cases (48%) esophageal injury was associated with GERD, but other potential etiologies included medications, infection, anastomotic or polypectomy sites, vomiting, and photodynamic therapy. Four patients (15%) had Barrett's esophagus, three of whom had or developed dysplastic Barrett's mucosa.

These results underscore the pathogenesis of esophageal/EGJ region hyperplastic polyps as a mucosal regenerative response to surrounding mucosal injury. Careful clinical history and biopsy of the nonpolypoid mucosa are essential for determining the clinicopathologic context in which the polyps have developed.

REGENERATIVE HYPERPLASIA  
Atypical regenerative hyperplasia of the esophagus in endoscopic biopsy: a mimicker of squamous esophagic carcinoma.

Arista-Nasr J, Rivera I, Martinez-Benitez B, Bornstein-Quevedo L, Orozco H, Lugo-Guevara Y.

Department of Pathology, Instituto Nacional de Ciencias Medicas y Nutricion, Salvador Zubiran (INCMNSZ), Mexico City, Mexico.
Arch Pathol Lab Med. 2005 Jul;129(7):899-904. Abstract quote  

CONTEXT: Atypical regeneration can mimic carcinoma in various epithelia. On endoscopic biopsies, atypical regenerative hyperplasia of the esophagus may show pleomorphism and atypia, simulating esophageal squamous cell carcinoma.

OBJECTIVE: To establish the most useful histologic features to distinguish atypical regenerative hyperplasia from esophageal carcinoma in endoscopic biopsies.

DESIGN: To study the frequency and histologic appearance of atypical regenerative hyperplasia, which simulate carcinoma, we reviewed 600 endoscopic biopsies (555 with chronic esophagitis and 45 with carcinomas of the esophagus). We selected those cases in which the differential diagnosis included regenerative atypical hyperplasia versus esophageal carcinoma and cases of atypical regenerative hyperplasia that were mistaken for carcinoma. For comparative purposes, we studied 10 cases of esophageal carcinoma from endoscopic biopsies that were confirmed by esophagectomy.

RESULTS: Among the cases with chronic esophagitis, we found 10 biopsies (1.8%) in which atypical regenerative hyperplasia mimicked carcinoma. In 7 cases, there were 4 to 12 years of follow-up, and no patient developed esophageal neoplasm. The remaining 3 patients were submitted to esophagectomy. None of these patients had carcinoma or dysplasia in the esophageal resection (false-positive biopsies). The most useful architectural changes in squamous carcinoma included stromal infiltration by nests, cords, or thin prongs of neoplastic keratinocytes, palisading desmoplasia, and in situ carcinoma in the adjacent epithelium. Malignant keratinocytes showed variable degrees of differentiation with differently shaped and sized cells, squamous epithelial pearls, individual keratinization, and atypical mitosis. In contrast, biopsies with atypical hyperplasia showed detached nests or irregular fragments without stroma and were made up of immature and relatively monotonous medium or small keratinocytes that were intermixed with inflammatory cells. Individual keratinization was rare, and no squamous pearls were seen. Other features of atypical hyperplasia included granulated tissue with atypical endothelial cells, nonatypical mitosis, lymphoid hyperplasia, and the absence of dysplasia or carcinoma in situ. Two biopsies showed stromal pseudoinfiltration as a result of tangential sectioning and were characterized by thick, round prongs composed of keratinocytes that penetrated regions with granulation or the inflamed tissues of esophageal ulcers.

CONCLUSIONS: Atypical esophageal regenerative hyperplasia may mimic carcinoma in a small percentage of esophageal biopsies. If the histologic changes are not sufficient to establish an accurate diagnosis, medical treatment and subsequent biopsies should be performed, particularly if there are no endoscopic or radiologic data to support the presence of a neoplasm.

 

PROGNOSIS CHARACTERIZATION
Prognostic Factors Stage is most important
Lymph node inolvement regardless of the size of primary tumor is poor prognosis
5 Year Survival Overall 6-9% survival
If tumor extends to adventitia, 10-20%
Early superficial carcinoma is potentially curable with 86% survival

Prognosis of early esophageal cancer. Comparison between adeno- and squamous cell carcinoma.

Holscher AH, Bollschweiler E, Schneider PM, Siewert JR.

Department of Surgery, Technische Universitat Munchen, Germany.

Cancer 1995 Jul 15;76(2):178-86 Abstract quote

BACKGROUND. The purpose of this study was to compare the prognosis of patients with T1 squamous cell carcinoma (SCC) with those with T1 adenocarcinoma of the esophagus and to explain prognostic differences by an analysis of clinicopathologic characteristics.

METHODS. Seventy-seven patients with early esophageal cancer who underwent esophagectomy and lymphadenectomy from 1982 to 1993 were included in the study. Clinical and histopathologic characteristics, patterns of lymph node metastasis, results of surgery, and long term prognosis of 47 patients with SCC were compared with 30 patients with adenocarcinoma; a multivariate analysis of various prognostic factors was performed.

RESULTS. The groups with adenocarcinoma and SCC were comparable regarding age, postoperative 90-day mortality (6.6% vs. 8.5%), infiltration of submucosa (74.5% vs. 80%), and rate of lymph node metastasis (17% vs. 16.6%). Cancer limited to the mucosa was not associated with lymph node metastasis in either group, whereas submucosal spread showed lymph node involvement in 21% of patients with adenocarcinoma and 26% of those with SCC. The 5-year survival rate of patients with complete tumor removal was superior for those with adenocarcinoma (82.5%) compared with those with SCC (59.2%) (P < 0.03). Multivariate analysis indicated that the histopathologic type (adenocarcinoma vs. SCC) was the only independent prognostic factor. The unfavorable prognosis of patients with T1 SCC was due to a higher recurrence rate and the more frequent development of second primary tumors (21% vs. 0%).

CONCLUSIONS. The prognosis of patients with early esophageal cancer depends on the histologic tumor type. Patients with T1 SCC should be examined for another primary cancer before surgery and during follow-up.

E-CADHERIN  
E-Cadherin Expression in Patients With Esophageal Squamous Cell Carcinoma
Promoter Hypermethylation, Snail Overexpression, and Clinicopathologic Implications

Shinsuke Takeno, MD, PhD, Tsuyoshi Noguchi, MD, PhD, Shoichi Fumoto, MD, Yasuhiko Kimura, MD, Tomotaka Shibata, MD, and Katsunobu Kawahara, MD, PhD

Am J Clin Pathol 2004;122:78-84 Abstract quote

Hypermethylation in the E-cadherin promoter region and expression of the transcription factor Snail were analyzed in 41 cases of esophageal squamous cell carcinoma (ESCC) and paired normal squamous epithelium by methylation-specific polymerase chain reaction (PCR) and reverse transcription–polymerase chain reaction (RT-PCR) to clarify the mechanism regulating E-cadherin deletion; 93 cases of ESCC were analyzed immunohistochemically to determine the clinicopathologic impact of E-cadherin deletion.

Hypermethylation of the E-cadherin promoter and Snail overexpression were detected in 25 cases (61%) by methylation-specific PCR and 34 cases (83%) by RT-PCR, respectively. Reduced E-cadherin expression, observed immunohistochemically in 55 cases (59%), correlated with hypermethylation (P = .0011) but not Snail overexpression (P = .685). Hypermethylation and Snail overexpression correlated significantly with E-cadherin deletion (P = .0018). Snail overexpression was unrelated to clinicopathologic factors. Reduced E-cadherin expression correlated with tumor invasion (P = .019) and vascular invasion (P = .052) but not other factors. E-cadherin deletion had prognostic impact in univariate (P = .023) and multivariate (P = .034) analyses.

E-cadherin deletion was regulated by hypermethylation and Snail expression. Examination of reduced E-cadherin expression is important for assessing biologic behavior, including clinical outcome, in patients with ESCC.
Metastasis

Regional lymph nodes most common site
Liver and lung most common visceral organ
Local recurrences in 35% without adjuvant therapy

Mucosal squamous cell carcinoma of the esophagus: a clinicopathologic study of 30 cases.

Natsugoe S, Baba M, Yoshinaka H, Kijima F, Shimada M, Shirao K, Kusano C, Fukumoto T, Mueller J, Aikou T.

First Department of Surgery, Kagoshima University School of Medicine, Japan.

Oncology 1998 May-Jun;55(3):235-41 Abstract quote

A clinicopathologic study was carried out on 30 patients with mucosal esophageal cancer (MEC).

The depth of cancer invasion was subdivided histologically into three categories: m1 = carcinoma in situ (intraepithelial carcinoma) or carcinoma with questionable invasion beyond the basal membrane; m2 = cancer invasion confined to the lamina propria, and m3 = cancer reaching to or infiltrating into the muscularis mucosae. Lymph node metastases and lymphatic invasion were found only in the tumors reaching or infiltrating the muscularis mucosae (m3). The maximum histologic vertical extent of the tumors was more than 1 mm in 4 of 5 patients with lymph node metastasis or lymphatic invasion. None of the patients died of recurrent esophageal disease, and 3 of the 6 patients who had a second primary tumor died of this other malignancy.

It is critical to distinguish between m1, m2 and m3 tumors to plan a treatment strategy, including an endoscopic mucosal resection.

Prognostic factors after extended esophagectomy for squamous cell carcinoma of the thoracic esophagus.

Tachibana M, Kinugasa S, Dhar DK, Kotoh T, Shibakita M, Ohno S, Masunaga R, Kubota H, Kohno H, Nagasue N.

Second Department of Surgery, Shimane Medical University, Shimane, Japan.

J Surg Oncol 1999 Oct;72(2):88-93 Abstract quote

BACKGROUNDS AND OBJECTIVES: In Japan, extended esophagectomy with extensive lymphadenectomy has become the standard surgical procedure for carcinoma of the thoracic esophagus. Although mortality and morbidity rates after such extensive esophagectomy have been acceptable, the long-term outcomes are not necessarily satisfactory.

METHODS: Among 235 patients with primary squamous cell carcinoma of the thoracic esophagus between June 1981 and March 1998, 143 patients (60.9%) underwent extended esophagectomy with extensive lymphadenectomy. To exclude the effects of surgery-related postoperative complications, 14 patients who died within 90 days after operation were excluded. Thus, clinicopathological characteristics and prognostic factors of 129 patients were retrospectively investigated.

RESULTS: Sixty-three patients were alive and free of cancer. Sixty-six patients died: 37 of recurrence of the esophageal cancer and 29 of other causes. The 1-, 3-, 5-, and 10-year overall survival rates in the 129 patients were 78.8%, 53.5%, 45.8%, and 30.9%, respectively, and the disease-specific survival rates were 85.7%, 69.1%, 67.9%, and 56.2%, respectively. The factors influencing the disease-specific survival rate were tumor location (upper third vs. non-upper third), Borrmann classification (0, 1 vs. 2, 3), size of tumor (3.0 cm), depth of invasion (T1, 2 vs. T3, 4), number of lymph node metastases (0 or 1 vs. >/=2), time of operation (420 min), amount of blood transfused (/=3 U), lymph vessel invasion (marked vs. not marked), and blood vessel invasion (marked vs. not marked). Among those significant variables, independent prognostic factors for survival determined by multivariate analysis were number of lymph node metastases (P < 0.001), amount of blood transfusions (P = 0.0016), and tumor location (P = 0.0382).

CONCLUSIONS: Patients with a single metastatic node after extended esophagectomy should be considered to have excellent prognosis, like patients with pN0 tumors. Patients with multiple involved nodes should receive aggressive postoperative adjuvant treatments. Reduced blood loss during extended esophagectomy and minimal blood transfusions might improve the outcome of curative esophageal resections.

Prognostic factors in T1 and T2 squamous cell carcinoma of the thoracic esophagus.

Tachibana M, Kinugasa S, Dhar DK, Tabara H, Masunaga R, Kotoh T, Kubota H, Nagasue N.

Second Department of Surgery, Shimane Medical University, Izumo, Japan.

Arch Surg 1999 Jan;134(1):50-4 Abstract quote

BACKGROUND: Prognostic indicators in patients with T2 tumor have not been fully understood.

OBJECTIVE: To clarify the clinicopathologic characteristics and long-term results of T1 and T2 squamous cell carcinomas of the thoracic esophagus.

DESIGN: Consecutive case series.

SETTING: Department of surgery in a university hospital.

PATIENTS: Of 234 patients with primary squamous cell carcinoma of the thoracic esophagus, 142 patients underwent esophagectomy with curative intent: 97 patients had pT1 and pT2 tumors.

INTERVENTIONS: Investigated were clinicopathologic characteristics of 65 of 97 patients with pT1 and pT2 tumors; excluded were 7 patients who died of postoperative complications and another 25 patients who died of causes other than esophageal cancer.

MAIN OUTCOME MEASURES: Clinicopathologic characteristics and long-term results.

RESULTS: Pathologic tumor stages were pT1 N0 in 23 patients, pT1 N(+) in 7 patients, pT2 N0 in 15 patients, and pT2 N(+) in 20 patients. Fifty patients are alive and free of cancer and 15 patients died of tumor recurrence (1 patient with pT1 N0 tumor, 1 patient with pT1 N[+][+] tumor, 1 patient with pT2 N0 tumor, and 12 patients with pT2 N[+] tumor). The sites of metastatic nodes in 6 survivors with pT1 N(+) tumor were a solitary perigastric node in 4 patients, a solitary mediastinal node in 1 patient, and 2 mediastinal nodes in 1 patient. The 5-year survival rates of patients with pT1 N0, pT1 N(+), and pT2 N0 tumors all exceeded 85%, and the rate of those with pT2 N(+) tumor was 33.9% (pT2 N[+] vs. others: pT1 N0, pT1 N[+], and pT2 N0; P = .003). The factors affecting survival rate by univariate analysis were Borrmann classification (0, 1 vs. 2, 3, 4), tumor size (<4.0 vs. > or =4.0 cm), combined T, N factor (pT2 N[+] vs. others), time of operation (< or =420 vs. >420 minutes), estimated blood loss (<1000 vs. > or =1000 mL), and lymph vessel invasion (marked vs. not marked). Stage pT2 N(+) tumor became a single independent prognostic factor for survival as determined by multivariate analysis (pT2 N[+] vs. others; P = .008).

CONCLUSIONS: Stage pT1 N(+) tumors with a few diseased nodes and pT2 N0 tumors are considered to be a group with an excellent prognosis, similar to pT1 N0 tumors. Patients with pT2 N(+) diseases had worse prognoses and thus should have meticulous lymph node dissection and extensive adjuvant therapy.

Prognostic significance of perioperative blood transfusions in resectable thoracic esophageal cancer.

Tachibana M, Tabara H, Kotoh T, Kinugasa S, Dhar DK, Hishikawa Y, Masunaga R, Kubota H, Nagasue N.

Second Department of Surgery, Shimane Medical University, Izumo, Japan.

Am J Gastroenterol 1999 Mar;94(3):757-65 Abstract quote

OBJECTIVE: The perioperative blood transfusions have been associated with tumor recurrence and decreased survival in various types of alimentary tract cancer. There exist, however, contradictory studies showing no relationship between blood transfusions and survival. For patients with esophageal cancer, only one report suggested that blood transfusions did not by itself decrease the chance of cure after esophagectomy.

METHODS: Among 235 patients with primary squamous cell carcinoma of the thoracic esophagus between December 1979 and March 1998, 143 patients (60.9%) underwent esophagectomy with curative intent (RO). To exclude the effects of surgery-related postoperative complications, 14 patients who died within 90 days during the hospital stay were excluded. Thus, clinicopathological characteristics and prognostic factors were retrospectively investigated between patients with no or few transfusions (< or = 2 units) (n = 58), and much transfused patients (> or = 3 units) (n = 71).

RESULTS: Sixty-three patients are alive and free of cancer, and 66 patients are dead. A total of 98 patients (76%) received blood transfusions, whereas 31 patients (24%) had no transfusion. The amount of blood transfused was 1 or 2 units in 27 patients (27.6%), 3 or 4 units in 33 (33.7%), 5 or 6 units in 20 (20.4%), and > or = 7 units in 18 (18.4%). The 5-yr survival rate for patients with no or few transfusions was 69%, whereas that for much transfused patients was 31.7% (p < 0.0001). The much transfused patients had more prominent ulcerative tumor, longer time of operation, more estimated blood loss, and more marked blood vessel invasion than the group with no or few transfusions. The factors influencing survival rate were tumor location, Borrmann classification, size of tumor, depth of invasion, number of lymph node metastases, time of operation, amount of blood transfusions, lymph vessel invasion, and blood vessel invasion. Among those nine significant variables verified by univariate analysis, independent prognostic factors for survival determined by multivariate analysis were number of lymph node metastasis (0 or 1 vs > or = 2, p < 0.0001), amount of blood transfusions (< or = 2 units vs > or = 3 units, p < 0.0001), and blood vessel invasion (marked vs non-marked, p = 0.0207).

CONCLUSIONS: There is an association between high amount of blood transfusions and decreased survival for patients with resectable esophageal cancer. To improve the prognosis, surgeons must be careful to reduce blood loss during esophagectomy with extensive lymph node dissection and subsequently must minimize blood transfusions.

Prognostic factors in node-negative squamous cell carcinoma of the thoracic esophagus.

Tachibana M, Kinugasa S, Dhar DK, Shibakita M, Ohno S, Masunaga R, Kotoh T, Kubota H, Nagasue N.

Second Department of Surgery, Shimane Medical University, Izumo, Japan.

Int J Surg Investig 2000;1(5):389-95 Abstract quote

BACKGROUNDS: Among several clinicopathological factors influencing the outcome of patients with esophageal carcinoma, the presence or absence of lymph node metastasis is the most important. Prognostic indicators, however, in patients without lymph node involvement have not been fully understood.

MATERIALS AND METHODS: Out of 247 patients with primary squamous cell carcinoma of the thoracic esophagus between February 1981 and December 1998, 154 patients (62.3%) underwent esophagectomy with curative intent; 78 patients (50.6%) had no lymph node metastasis. Clinicopathological characteristics of those node-negative 78 patients were investigated.

RESULTS: Pathological tumor stages (pT) were pT1 in 44 patients, pT2 in 24 patients, pT3 in 9 patients, and pT4 in one patient. Forty-six patients are alive free of cancer and another one with pT2N0 tumor is alive with recurrence. Four patients died of recurrence; one in pT1 and three in pT3. The remaining 27 patients died of miscellaneous causes other than esophageal cancer. The 1-, 3-, 5-, and 10-year overall survival rates of all 78 patients including in-hospital mortality were 86.3%, 73%, 66.5%, and 34.6%, respectively. The 3- and 5-year survival rates were 75.4% and 67.7% for those with pT1, T2 tumor (n = 68) and 57.1% and 57.1% for those with pT3, T4 tumor (n = 10) (p = 0.0151). The factors influencing overall survival rate were patient age (< 65 vs. > or = 65), depth of invasion (pT1,T2 vs. pT3, T4), time of operation (< or = 420 min vs. > 420 min), and estimated blood loss (< or = 810 ml vs. > 810 ml). More elderly patients died of unrelated causes to esophageal cancer than younger patients. Among those four variables, the patient age (p = 0.0114) and depth of invasion (p = 0.0443) were independent prognosticators for survival determined by multivariate analysis.

CONCLUSION: For follow-up of elderly patients with node-negative esophageal cancer, evaluation of medical problems is more important than detection of recurrence. pT2N0 stage tumors should be considered a group with an excellent prognosis like pT1N0 tumors.

Prediction of prognosis by the extent of lymph node involvement in squamous cell carcinoma of the thoracic esophagus.

Hsu CP, Chen CY, Hsia JY, Shai SE.

Division of Thoracic Surgery, Department of Surgery, Taichung Veterans General Hospital, #160, Section 3, Taichung-Kang Road, Taichung, Taiwan.

Eur J Cardiothorac Surg 2001 Jan;19(1):10-3 Abstract quote

OBJECTIVES: Current criteria of the N-category in the TNM staging system for carcinoma of the esophagus needs further subgrouping due to its simplicity in mixing together patients with different prognosis.

METHOD: A retrospective cohort study of 186 patients (176 men and ten women; mean age, 59.9 years) with squamous cell carcinoma (SCC) of the thoracic esophagus who underwent esophagectomy followed by two-field lymphadenectomy and cervical lymph node sampling between 1992 and 1999 was conducted. A proposed N-category which involved dividing the nodal status into N0 (no nodal involvement), N1 (< or =4 nodes or < or =20% nodal involvement), and N2 (>4 nodes, or >20%, or non-regional nodal involvement) subgroups was used for survival analysis.

RESULTS: The overall 5-year cumulative survival rate was 27%. Lymph node metastases were identified in 101 (54.3%) patients. Cumulative survival rates were 46% at 4 years in the N0 group and 21% at 4 years in the N1 group, whereas no patients in N2 group survived longer than 3 years (P<0.01). A multivariable analysis revealed that independent prognostic factors included the depth of tumor invasion (P<0.01), nodal involvement (P<0.01), and organ metastasis (P<0.01).

CONCLUSION: In addition to the location of nodes, the extent of nodal involvement in SCC of the thoracic esophagus also plays an important role in prognosis prediction.

TREATMENT  

A clinical study of surgical treatment of patients with carcinoma of the cervical esophagus extending to the thoracic esophagus.

Saito R, Suzuki H, Motoyama S, Sasaki S, Okuyama M, Ogawa J, Kitamura M.

Second Department of Surgery, Akita University School of Medicine, Japan.

Jpn J Thorac Cardiovasc Surg 2000 Jul;48(7):417-23 Abstract quote

OBJECTIVE: We studied optimum surgery for carcinoma of the cervical esophagus extending to the thoracic esophagus (Ce-Ut carcinoma).

METHODS: Subjects were 13 patients diagnosed with Ce-Ut carcinoma treated at our institute from January 1989 to December 1998. Clinicopathologic information such as surgical procedures, pathologic findings, and postoperative complications were analyzed.

RESULTS: In 10, laryngoesophagectomy was conducted due to tracheal invasion by the tumor. In 7, mediastinal tracheostomy was done because of the extended resection of the proximal trachea. In 3, the larynx was preserved and, in 2, cricopharyngeal myotomy was added. Lymph node metastasis was found only in the neck and the upper mediastinum at surgery and recurrences were all lung metastasis. The incidence of postoperative complications was very high (76.9%), and 1 patient died due to widespread tracheal necrosis. The cumulative 5-year survival rate for the group was 33.3% and that for the 9 curative cases was 50%, but most of the cases who underwent noncurative resection and/or who received preoperative therapy for widespread invasion to surrounding organs died within a year.

CONCLUSION: The prognosis of patients who undergoing curative extended resection of the proximal trachea and suitable lymph node dissection in the neck and upper mediastinum may improve, and larynx-preserving surgery is recommended for patients without tracheal invasion. Despite preoperative chemoradiotherapy, the prognosis of patients with widespread invasion to surrounding organs was very poor, and clinical studies on new therapeutic strategies for these advanced cases are needed to improve the prognosis of Ce-Ut carcinoma patients.

Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction.

Macdonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC, Stemmermann GN, Haller DG, Ajani JA, Gunderson LL, Jessup JM, Martenson JA.

St Vincent's Comprehensive Cancer Center, New York, USA.

N Engl J Med 2001 Sep 6;345(10):725-30 Abstract quote

BACKGROUND: Surgical resection of adenocarcinoma of the stomach is curative in less than 40 percent of cases. We investigated the effect of surgery plus postoperative (adjuvant) chemoradiotherapy on the survival of patients with resectable adenocarcinoma of the stomach or gastroesophageal junction.

METHODS: A total of 556 patients with resected adenocarcinoma of the stomach or gastroesophageal junction were randomly assigned to surgery plus postoperative chemoradiotherapy or surgery alone. The adjuvant treatment consisted of 425 mg of fluorouracil per square meter of body-surface area per day, plus 20 mg of leucovorin per square meter per day, for five days, followed by 4500 cGy of radiation at 180 cGy per day, given five days per week for five weeks, with modified doses of fluorouracil and leucovorin on the first four and the last three days of radiotherapy. One month after the completion of radiotherapy, two five-day cycles of fluorouracil (425 mg per square meter per day) plus leucovorin (20 mg per square meter per day) were given one month apart.

RESULTS: The median overall survival in the surgery-only group was 27 months, as compared with 36 months in the chemoradiotherapy group; the hazard ratio for death was 1.35 (95 percent confidence interval, 1.09 to 1.66; P=0.005). The hazard ratio for relapse was 1.52 (95 percent confidence interval, 1.23 to 1.86; P<0.001). Three patients (1 percent) died from toxic effects of the chemoradiotherapy; grade 3 toxic effects occurred in 41 percent of the patients in the chemoradiotherapy group, and grade 4 toxic effects occurred in 32 percent.

CONCLUSIONS: Postoperative chemoradiotherapy should be considered for all patients at high risk for recurrence of adenocarcinoma of the stomach or gastroesophageal junction who have undergone curative resection.

Long-term survival following induction chemoradiotherapy and esophagectomy for esophageal carcinoma.

Lew JI, Gooding WE, Ribeiro U Jr, Safatle-Ribeiro AV, Posner MC.

Department of Surgery, The University of Chicago Hospitals, and the Pritzker School of Medicine, 5841 S Maryland Ave, MC 5031, Chicago, IL 60637, USA.

Arch Surg 2001 Jul;136(7):737-42; Abstract quote

HYPOTHESIS: Long-term survival is rare in patients treated for esophageal carcinoma. Several clinical trials suggest the possibility of prolonged survival in patients who undergo induction chemoradiotherapy plus esophagectomy.

DESIGN: Prospective uncontrolled study.

SETTING: University hospital.

PATIENTS AND METHODS: Forty-four patients with carcinoma of the esophagus or gastroesophageal junction were prospectively entered into a phase II trial of preoperative 5-fluorouracil, cisplatin, and interferon alfa with concurrent external beam radiotherapy before esophagectomy. Curative resection was performed on 36 of 41 patients who completed the induction chemoradiotherapy.

RESULTS: Of the 44 patients, 17 are alive at a median follow-up of 50 months. Of these 17 patients, 15 show no evidence of recurrent disease. Of the 14 patients with long-term survival (> or =3 years), 1 patient died of disease, and another patient is alive with disease. The remaining 12 patients are alive and disease-free (median follow-up, 54 months). Six patients have survived longer than 4 years and 3 patients longer than 5 years. Subsequent primary tumors have developed in 2 patients. One patient had a recurrence at 11 months following initiation of treatment and remains disease-free 43 months postresection of a single brain metastasis. Standard clinicopathologic parameters (age, sex, histologic findings, chemoradiotherapy regimen, and clinical and pathologic stages) were not significantly associated with a survival time of 3 years or longer (Fisher exact test, 2-tailed). Although not significant, p 53 mutational status suggested long-term survival. In 11 of 14 patients who are alive with no history of recurrence, p53 genotyping demonstrated no point mutations in 10 patients. Median survival time for the long-term survivors has not been reached.

CONCLUSIONS: Long-term survival can be achieved in patients with esophageal carcinoma who undergo induction chemoradiotherapy and esophagectomy. Recurrence is unlikely in patients who survive for 3 years or longer after undergoing this multimodality treatment.

A three-step strategy of induction chemotherapy then chemoradiation followed by surgery in patients with potentially resectable carcinoma of the esophagus or gastroesophageal junction.

Ajani JA, Komaki R, Putnam JB, Walsh G, Nesbitt J, Pisters PW, Lynch PM, Vaporciyan A, Smythe R, Lahoti S, Raijman I, Swisher S, Martin FD, Roth JA.

Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.

Cancer 2001 Jul 15;92(2):279-86 Abstract quote

BACKGROUND: Patients with locoregional carcinoma of the esophagus or gastroesophageal junction have a poor survival rate after surgery. Preoperative chemotherapy or chemoradiotherapy has not improved the outcome for these patients. Our study was designed to assess the feasibility of preoperative induction combination chemotherapy in addition to chemoradiotherapy to improve the curative resection rate, local control, and survival.

PATIENTS AND METHODS Patients having histologic proof of localized carcinoma (either squamous cell carcinoma or adenocarcinoma) of the esophagus or gastroesophageal junction underwent full classification including endoscopic ultrasonography (EUS). Patients first received up to two courses of induction chemotherapy consisting of 5-fluorouracil at 750 mg/m(2)/day as continuous infusion on Days 1--5, cisplatin at 15 mg/m(2)/day as an intravenous bolus on Days 1--5, and paclitaxel at 200 mg/m(2) as a 24-hour intravenous infusion on Day 1. The second course was repeated on Day 29. This was followed by radiotherapy (45 grays in 25 fractions) and concurrent admission of 5-fluorouracil (300 mg/m(2)/day as a continuous infusion 5 days/week) and cisplatin (20 mg/m(2) on Days 1--5 of radiotherapy). After chemoradiotherapy, patients underwent surgery. The feasibility of this approach, curative resection rates, patient survival, and patterns of failure were assessed.

RESULTS: Thirty-seven of 38 patients enrolled were evaluable for toxicity and survival. Adenocarcinoma and distal esophageal location of carcinoma were observed frequently. Thirty-five (95%) of the 37 patients underwent surgery, all of whom had an R0 (curative) resection. A pathologic complete response was noted in 11 (30%) of the 37 total patients. In addition, 5 patients (14%) had only microscopic carcinoma. According to EUS classification, 31 (89%) of the 35 patients who underwent surgery had a T3 carcinoma whereas according to pathologic classification only 3 (9%) had a T3 carcinoma (P

CONCLUSIONS: These data show that the three-step strategy of preoperative paclitaxel-based induction chemotherapy then chemoradiotherapy followed by surgery is feasible and appears quite active in patients having locoregional carcinoma of the esophagus or gastroesophageal junction. Future investigations should focus on substituting cisplatin with less toxic agents and including more systemic therapy with newer classes of agents.

ENDOSCOPIC MUCOSAL RESECTION  
Histopathological criteria for additional treatment after endoscopic mucosal resection for esophageal cancer: analysis of 464 surgically resected cases.

Eguchi T, Nakanishi Y, Shimoda T, Iwasaki M, Igaki H, Tachimori Y, Kato H, Yamaguchi H, Saito D, Umemura S.

[1] 1Clinical Laboratory Division, National Cancer Center Hospital, Tokyo, Japan [2] 2Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan [3] 3Second Department of Internal Medicine, Yokohama City University, Kanagawa, Japan.

Mod Pathol. 2006 Mar;19(3):475-80. Abstract quote  

No previous reports on lymph-node metastasis (LNM) from superficial squamous cell carcinoma of the esophagus have proposed definite criteria for additional treatment after endoscopic mucosal resection (EMR).

We investigated the association between histopathological factors and LNM in 464 consecutive patients with superficial squamous cell carcinoma of the esophagus who had undergone a radical esophagectomy with lymph-node dissection (14 'M1' lesions: intraepithelial tumors, 36 'M2' lesions: tumors invading the lamina propria, 50 'M3' lesions: tumors in contact with or invading the muscularis mucosa, 32 'SM1' lesions: tumors invading the most superficial 1/3 of the submucosa and 332 'SM2/3' lesions: tumors invading deeper than SM1 level).

Histopathological factors including invasion depth, size, lymphatic invasion (LY), venous invasion, tumor differentiation, growth pattern, degree of nuclear atypia and histological grade were assessed for their association with LNM in 82 M3 or SM1 lesions to determine which patients need additional treatment after EMR. LNM was found in 0.0, 5.6, 18.0, 53.1 and 53.9% of the M1, M2, M3, SM1 and SM2/3 lesions, respectively.

A univariate analysis showed that each of the following histopathological factors had a significant influence on LNM: invasion depth (M3 vs SM1), LY, venous invasion and histological grade. Invasion depth and LY were significantly associated with LNM in a multivariate analysis. Four out of 38 patients (10.3%) with M3 lesions without LY had LNM, whereas five out of 12 patients (41.7%) with M3 lesions and LY had LNM.

Only patients with M1/2 lesions are good candidates for EMR. Invading the muscularis mucosa (M3) is a high-risk condition for LNM the same as submucosal invasion, but M3 lesions without LY can be followed up after EMR without any additional treatment.

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