Clinical biology and surgical therapy of intramucosal adenocarcinoma of the esophagus

BACKGROUND: Mucosal ablation and endoscopic mucosal resection have been proposed as alternatives to surgical resection as therapy for intramucosal adenocarcinoma (IMC) of the esophagus. Acceptance of these alternative therapies requires an understanding of the clinical biology of IMC and the results of surgical resection modified for treatment of early disease. STUDY DESIGN: Retrospective review of 78 patients (65 men, 13 women; median age 66 years) with IMC who were treated with progressively less-extensive surgical resections (ie, en bloc, transhiatal, and vagal-sparing esophagectomy) from 1987 to 2005. RESULTS: The tumor was located in a visible segment of Barrett's esophagus in 65 (83%) and in cardia intestinal metaplasia in 13 (17%). A visible lesion was present in 53 (68%) and in all but 4 the lesion was cancer. In those patients with visible Barrett's, the tumor was within 3 cm of the gastroesophageal junction in 66% and within 1 cm in 37%. Esophagectomy was en bloc in 23, transhiatal in 31, vagal-sparing in 20, and transthoracic in 4. Operative mortality was 2.6%. Vagal-sparing esophagectomy had less morbidity, a shorter hospital stay, and no mortality. Of the patients who had en bloc resection, a median of 41 nodes were removed. One patient had one lymph node metastasis on hematoxylin and eosin staining and two others, normal on hematoxylin and eosin staining, had micrometastases on immunohistochemistry. Actuarial survival at 5 years was 88% and was similar for all types of resections. Two patients died from systemic metastases and seven from noncancer causes. CONCLUSIONS: IMC occurred in cardia intestinal metaplasia and in Barrett's esophagus. Two-thirds of patients with IMC had a visible lesion. Most tumors occurred near the gastroesophageal junction. Node metastases were uncommon, questioning the need for lymphadenectomy. A vagal-sparing technique had less morbidity than other forms of resection and no mortality. Survival after all types of resection was similar. Outcomes of endoscopic techniques should be compared with this benchmark.     

Columnar-lined esophagus without intestinal metaplasia has no proven risk of adenocarcinoma

Intestinal metaplasia in the columnar-lined esophagus (CLE) has long been recognized as the most significant histologic risk indicator for esophageal adenocarcinoma. Recent concern has been expressed, however, that nonintestinalized metaplastic columnar epithelia (cardiac epithelium in the esophagus) may also indicate risk. Of 2586 consecutive patients undergoing endoscopy and biopsy in the Foregut Surgery Department, we selected (a) 214 patients with a visible CLE who had systemic 4-quadrant biopsies at 1 to 2 cm intervals, with the most proximal biopsy straddling the squamocolumnar junction, and (b) 109 patients without systematic biopsy who had dysplasia or adenocarcinoma. In the first group, 187 (87.4%) patients had intestinal metaplasia, and 27 (12.6%) had cardiac epithelium. Dysplasia or adenocarcinoma was present in 55 patients, all with intestinal metaplasia; its presence was significantly higher than in the cardiac epithelium group, none of whom had dysplasia or adenocarcinoma (P=0.01). In the second group with limited sampling, 49 had only tumor tissue in the biopsy. Of 60 patients with nontumor epithelium, only 34 (56.7%) had residual intestinal metaplasia. We conclude that systematic biopsies of CLE as described in this study separate patients into those with and without intestinal metaplasia in such a manner as to remove the possibility of false-negative diagnosis of intestinal metaplasia. When intestinal metaplasia is absent using this biopsy protocol, the patient is at no or extremely low risk for dysplasia and cancer. When biopsies have a lower level of sampling of the segment of CLE, the absence of intestinal metaplasia cannot be interpreted as a true negative for intestinal metaplasia. Inadequate sampling is a powerful reason why the near absolute association between intestinal metaplasia and adenocarcinoma is not seen in some studies.     

Cytokeratin and DAS-1 immunostaining reveal similarities among cardiac mucosa,CIM, and Barrett's esophagus

OBJECTIVE: The normal histology at the gastroesophageal junction, and in particular the nature of cardiac mucosa, remains in dispute. Likewise, the relationship of intestinal metaplasia at the gastroesophageal junction (CIM) to Barrett's and intestinal metaplasia of the stomach (GIM) is unclear. The aim of this study was to assess the immunostaining characteristics of cardiac mucosa and CIM and compare their staining pattern with that of other foregut mucosal types. We hypothesized that the immunostaining patterns of these foregut tissues would provide insight into the nature and etiology of cardiac mucosa and CIM. METHODS: Paraffin-embedded biopsy specimens from 50 patients with normal antral or fundic mucosa, cardiac mucosa, squamous mucosa, CIM, GIM, or Barrett's were obtained and immunostained with a panel of monoclonal antibodies including those for cytokeratins 7 and 20 (CK7/CK20) and DAS-1. RESULTS: Biopsies from normal gastric antral and fundic mucosa and squamous esophageal mucosa all showed a non-Barrett's type CK7/CK20 immunostaining pattern, whereas in 85% of patients, cardiac mucosa had a Barrett's type CK7/CK20 pattern (p < 0.001). A Barrett's type CK7/ CK20 staining pattern was seen in 100% of Barrett's, 78% of CIM, and 0% of GIM patients. Likewise, DAS-1 staining was similar in patients with CIM and Barrett's and significantly different in patients with GIM. CONCLUSIONS: Cytokeratin immunostaining of cardiac mucosa demonstrates significant differences from recognized normal gastric and esophageal mucosa but a similarity to Barrett's. This suggests that cardiac mucosa, like Barrett's, may be acquired. Likewise, immunostaining similarities between CIM and Barrett's biopsies point to the possibility of a reflux etiology for CIM in some patients.     

Strongyloidiasis Hyperinfection in a Patient with a History of Systemic Lupus Erythematosus

Strongyloidiasis is a parasitic disease caused by Strongyloides stercoralis, a nematode predominately endemic to tropical and subtropical regions, such as Southeast Asia. Autoinfection enables the organism to infect the host for extended periods. Symptoms, when present, are non-specific and may initially lead to misdiagnosis, particularly if the patient has additional co-morbid conditions. Immunosuppressive states place patients at risk for the Strongyloides hyperinfection syndrome (SHS), whereby the organism rapidly proliferates and disseminates within the host. Left untreated, SHS is commonly fatal. Unfortunately, the non-specific presentation of strongyloidiasis and the hyperinfection syndrome may lead to delays in diagnosis and treatment. We describe an unusual case of SHS in a 30-year-old man with a long-standing history of systemic lupus erythematosus who underwent a partial colectomy. The diagnosis was rendered on identification of numerous organisms during histologic examination of the colectomy specimen.Strongyloidiasis is an infection caused predominantly by the helminth Strongyloides stercoralis. This nematode is endemic to tropical and subtropical regions such as Southeast Asia, but is also present in more temperate climates, such as the northern United States and Canada.¹ Infection can rarely occur in areas thought to be non-endemic for the disease. Most chronically infected persons are asymptomatic. Clinical manifestations, when present, are usually mild and non-specific.²Immunosuppression places infected persons at risk for the Strongyloides hyperinfection syndrome (SHS), where the organism proliferates unchecked. This syndrome can cause exacerbation of the patient''s symptoms related to an increased parasite load in the intestine and lungs. Additional symptoms may arise as the organism involves organs not normally associated with the auto-infective life cycle.^2,3 We describe an unusual case of SHS in a patient undergoing chronic corticosteroid treatment for systemic lupus erythematosus (SLE). We review the literature regarding SLS in immunosuppressed patients, with emphasis on those with a history of SLE.A 30 year-old Hispanic man with an eight-year history of poorly controlled SLE came to an emergency department with fever, diffuse generalized pain, and bilateral upper and lower extremity edema. He was treated with antibiotics and methylprednisolone for presumed sepsis and lupus flare. The patient''s symptoms eventually resolved, but he was found to have nephrotic range protein and erythrocyte casts in his urine. He underwent an ultrasound-guided left renal biopsy, which later confirmed class IV G lupus nephritis. The next day, the patient''s systolic blood pressure decreased to 90 mm of Hg, and he began to experience diffuse abdominal pain, rebound tenderness, guarding, rigidity, and emesis. His leukocyte count and lactate dehydrogenase level were increased, and his hemoglobin level decreased significantly.Based on the clinical examination and findings of a computed tomographic (CT) angiography of the abdomen and pelvis (Figure 1), the patient underwent an emergent exploratory celiotomy. Blood clots were visualized in the peritoneal cavity, as well as active slow bleeding from the gastrocolic ligament and the base of the transverse mesocolon. Hematomata were identified in the omental bursa, pelvis, and hepatic flexure. No additional source of peritoneal bleeding was identified. The combined operative and CT findings suggested that the vascular supply to the distal transverse colon was compromised. An extended right hemicolectomy with a colonic mucous fistula and end ileostomy was performed.Open in a separate windowFigure 1.Computed tomographic (CT) image of the patient''s abdomen. Identified are a mesenteric hematoma with fluid density consistent with fresh blood (A), markedly edematous ascending and proximal transverse colon (B), perihepatic fluid consistent with old blood (C), and a defect in the posterior left kidney, consistent with biopsy site (D). There is no perinephric fluid or soft tissue changes to suggest acute hemorrhage of the renal biopsy site. There was no definitive CT evidence of acute vascular injury, pseudoaneurysm, contrast extravasation, perivascular contained hematoma, or dissection.Grossly, the serosa of the colon was covered by dark red-brown blood but was otherwise unremarkable. Several blood clots were seen within the mesentery and the omentum. The colonic mucosa was diffusely edematous with patches of yellow-tan exudate. There was a mild loss of the mucosal folds with focal edema. No lesion, ulceration, or perforation was identified. Microscopically, there were patchy areas of acute inflammatory cells and cellular debris overlying eroded mucosa. The lamina propria was markedly expanded by a lymphoplasmacytic infiltrate with scattered neutrophils and eosinophils.There were numerous filariform larvae and sharply pointed, curved tailed adult worms present within luminal acellular debris overlying the ulcerated mucosa. Similar organisms were seen in the lamina propria infiltrating into and running alongside intact crypts (Figure 2). Numerous organisms were seen in the lymphatics (Figure 3).Open in a separate windowFigure 2.Medium power view of colon, showing filariform larvae consistent with Strongyloides (arrowheads).Open in a separate windowFigure 3.High-power magnification of colon, showing a Strongyloides larva within a lymphatic space (arrowhead).Treatment of the patient''s Strongyloides hyperinfection was started with a 21-day course of ivermectin and albendazole. The patient then showed development of diffuse alveolar hemorrhage causing acute respiratory distress syndrome. A transbronchial lung biopsy was performed, which showed evidence of cytomegalovirus pneumonia, verified by immunohistochemical stainings. The lung biopsy specimen was remarkable for the presence of a giant cell granulomatous inflammatory response surrounding a filariform larva that presumably died secondary to the anti-helminthic agents (Figure 4). His cytomegalovirus pneumonia was treated with intravenous ganciclovir. His previously mentioned class IV lupus nephritis was treated with intravenous immunoglobulin and pulse steroids with steroid taper.Open in a separate windowFigure 4.High-power magnification of a lung biopsy specimen, showing filariform larvae consistent with Strongyloides (arrowhead).The resolution of his infection was confirmed with triplicate negative stool ova and parasites studies. Finally, on hospital day 60, he was discharged to a long-term rehabilitation facility. To date, he has no documented sequelae from his infection with Strongyloides.The interest in this case stems from histopathologic diagnosis of SHS in a patient without any relevant medical history. The patient''s medical history was remarkable only for SLE. The patient indicated a history of professional boxing, which may imply a history of extensive travel; however, this notion is speculative at best. The patient''s condition at admission closely mimicked symptoms described in the patient''s rheumatologic disorder. Accordingly, the index for suspicion for parasitic infections was low to non-existent. Were it not for the series of events that lead to the eventual histopathologic diagnosis, the patient likely would have experienced progression of the hyperinfection syndrome and eventual death.The life cycle of Strongyloides can either be an isolated free-living cycle where the helminth lives independently in soil, as well as a parasitic cycle in which the infective filariform larvae enter the host via intact skin, mature to adults, and proliferate. The rhabtidiform larvae created in the parasitic cycle are either passed in the stool or re-enter the circulation as filariform larvae by penetrating bowel mucosa or perianal skin to perpetuate the parasitic life cycle. This autoinfection cycle differentiates S. stercoralis from many other helminths,^1,4–6 and enables the organism to reside within the host for years, or even decades.Most persons infected with S. stercoralis are asymptomatic. Clinical manifestations, when present, are often mild and involve the intestine (abdominal pain, diarrhea, constipation, nausea, and weight loss), the skin (rash and pruritus, particularly at the site of entry of the larvae), and the lungs (cough, tracheal irritation, wheezing, and asthma).^2,3 The lack of specificity of the clinical syndrome, combined with a lack of sufficiently sensitive diagnostic tests, suggest that the current estimated prevalence of 3–100 million infected persons worldwide^1,4 is likely to be a significant underestimate.Immunosuppressive states place patients at risk for SHS. Although the diagnosis of hyperinfection is not clearly defined, it generally occurs when the immune status of the patient changes, and the organism proliferates unchecked and enters organs not normally involved in the worm''s normal intra-host life cycle. The patient may then show systemic manifestations, or more localized symptoms related to each organ the worm involves (e.g., meningitis or biliary obstruction). Invasion of the larvae through the bowel mucosa may also lead to secondary gram-negative septicemia as gut flora enter the blood stream in tandem with the larvae.^2,4,5 The patient may then undergo multi-organ dysfunction, septic shock, and die.A significant proportion of SHS cases are secondary to immunosuppressive drugs and primary immunodeficiency states, such as genetic disorders and hematologic malignancies. Of these contributing factors, corticosteroids are by far the most common precipitating agent.^4,7 The exact mechanism of this is unclear; hypotheses range from modulation of the T cell–mediated immune response to suppression of eosinophilia that normally occurs in response to parasitic infections.^3,8 Other hypotheses include a possible stimulatory effect of steroids on the adult female''s ability to produce eggs, or on the larval ability to mature.² Underlying infection with human T cell lymphotropic virus 1 may also affect the T helper immune response and predispose to disseminated strongyloidiasis, to the point where infection with human T cell lymphotropic virus 1 may be suspected if a patient exhibits sub-optimal response to anti-helminthic treatment.⁹ Interestingly, an association between acquired imunodeficiency syndrome and an increased risk of SHS has not yet been established. The reason for this finding remains unclear.^3,4,8There is no standard method of diagnosing strongyloidiasis. As in our case, histopathologic diagnosis may be rendered by direct visualization of the larvae or adult worms in biopsy specimens. The filariform larvae can be described histologically as a tubular esophagus measuring 180–380 μm in length with a blunted buccal end and notched tail.^1,10 Adult worms are considerably longer and are identified by one anterior esophagus and two posterior reproductive organs.¹¹ In intestinal biopsy specimens, these organisms are found in the crypt epithelium, the lamina propria, and submucosa.^6,11 Direct detection can also be made in stool specimens. However, some authors recommend analysis of multiple stool samples because a single stool examination may have sensitivity approximating 30%.^12,13 Examination of other specimens, such as sputum, duodenal aspirates, ascitic fluid, pleural fluid, peripheral blood smears, and cerebrospinal fluid, may be performed.^4,10 The blood agar plate method is a unique and sensitive diagnostic method in which presence of the organism is confirmed by visualizing tracts of bacterial colonies left in the organism''s wake as it travels across the agar plate''s surface.³ Newer modalities to detect Strongyloides-specific antigens have been described, such as polymerase chain reaction, which can simultaneously test for presence of other parasitic infections, but can show false-negative results because of potential polymerase chain reaction inhibitors present within patient samples or by inconsistent shedding of the organism in the feces.¹⁴The diagnosis of strongyloidiasis can also be made by using serologic analysis and identification of antibodies against Strongyloides. The enzyme-linked immunosorbent assay has been described as an effective method of testing because of its practicality, ability for automation, and its ability to detect the presence of antibody or antigen, depending on the assay.^14,15 Similar testing methods have been described; these include dipstick assays, gelatin particle agglutination, and immediate hypersensitivity skin tests to Strongyloides antigens.^3,15 Although reasonably effective, these types of tests are prone to cross-reactivity with other helminthic infections and are incapable of differentiating current from past infections.^4,14 Moreover, serologic assays may show false-negative results during acute infections or in immunosuppressed patients.^3,4,14,16 Assays or studies that directly detect the organism or its antigens may prove helpful in these cases. Luciferase immunoprecipitation system assays have recently been developed and showed promise in detection of Strongyloides-specific antibodies because of its high sensitivity and specificity, lack of cross-reactivity with other parasitic infections, and ability to monitor changes in antibody titers over time, resulting in an effective method of assessing treatment response.^14,16,17Treatment of uncomplicated cases requires standard treatment with anti-helminth drugs, such as ivermectin or albendazole. However, treatment protocols for SHS have not been well established because of lack of data. Furthermore, whether strongyloidiasis patients will benefit from concurrent reduction in immunosuppressive therapy remains debatable. Reports have generally advocated daily anti-helminthic treatment until stool ova and parasite samples are repeatedly negative for an extended period, often up to two weeks.^2,4 Response to anti-helminthic therapy is variable in immunosuppressed patients; accordingly, treatment in these patients depends on the etiology of the patient''s immunosuppression.³Thirteen other cases of SHS occurring in a patient with a history of SLE have been identified. For most of these cases, the diagnosis was either made too late in the disease course to prevent death,^18–22 or after the patient succumbed to disease.^8,23–25 In only four of these thirteen cases was the diagnosis made and treatment initiated sufficiently early to provide a favorable clinical outcome for the patient.^8,10,26,27 Compounding the issue is that these diagnoses were also reported in non-endemic areas, where index of suspicion is low,⁷ made possible because of the long periods that S. stercoralis can reside in a host. The high percentage of asymptomatic chronic strongyloidiasis, its non-specific symptoms and similarity in clinical presentation to entities such as the SLE flare (as in our patient), and its appearance in non-endemic areas contribute to the high mortality rate for SHS.⁵To prevent development of SHS and hyperinfection, screening for Strongyloides infection has been advocated for patients with a relevant medical history (such as residence or travel in disease-endemic areas) who are either in a immunosuppressed state or about to undergo immunosuppressive treatment.¹⁶ Serologic assays have been advocated as primary screening tests because of their reliability and the high sensitivity described in some assays.¹⁴ Although some assays are limited in their inability to differentiate current from past infection, some authors state that because of the persistence of strongyloidiasis, a patient with a compatible history and a positive serologic results may benefit from empiric treatment, such as a 1–2 day course of ivermectin if they are immunosuppressed or about to undergo immunosuppressive treatment.^3,16In our patient, the diagnosis was based on identification of an unusual load of worms and filariform larvae detected during the routine histologic examination of the colectomy specimen. A transbronchial pulmonary biopsy obtained soon thereafter isolated larvae in the alveolar septae. In our case, the rapid initiation of anti-helminthic therapy cleared his strongyloidiasis, verified by repeatedly negative stool ova and parasite samples. Our case underscores the importance of maintaining a baseline index of suspicion of stronygloidiasis in immunocompromised patients because this disease is potentially a fatal infection that can be treated successfully with anti-microbial agents.     

Impaired insulin secretion of aging: role of renal failure and hyperparathyroidism.

Available data indicate that insulin secretion is impaired with aging. Almost all the studies that examined insulin secretion by old animals did not take into consideration the state of renal function or the blood levels of parathyroid hormone (PTH). Old animals may have chronic renal failure (CRF) and secondary hyperparathyroidism, and both of these conditions impair insulin secretion. It is possible, therefore, that the impaired insulin secretion of aging is not due to old age per se, but rather to associated CRF and excess PTH. The present study examined this issue in adult (6 month old) and senescent rats (2 year old) with and without CRF and excess PTH. Senescent rats without CRF had normal renal function and normal blood levels of PTH, and the values were not different from those observed in adult rats. Creatinine clearance in senescent rats with CRF was significantly (P less than 0.01) lower and serum levels of PTH were significantly (P less than 0.01) higher than in senescent animals without CRF and than in the adult rats as well. Only the senescent rats with CRF displayed glucose intolerance during intravenous glucose tolerance test. For any given level of blood glucose, plasma insulin levels were lower in senescent rats with CRF than in the adult rat or senescent animals without CRF.(ABSTRACT TRUNCATED AT 250 WORDS)     

Gastrointestinal involvement complicating Stevens-Johnson syndrome

Three cases of Stevens-Johnson syndrome with intestinal involvement are described. Two patients had esophageal involvement, the severity of which paralleled skin lesions and, in 1 case, probably contributed to death. Dysphagia and bleeding were manifestations. The third patient was unique and had gastric, small and large bowel involvement with sparing of other mucosae. Cramps, severe exudative diarrhea, and bleeding were major clinical features. Unusual histologic features included sloughing of cells into the gland lumina of intestinal mucosa.     

Ki67 expression in different epithelial types in columnar lined oesophagus indicates varying levels of expanded and aberrant proliferative patterns

AIMS: To evaluate proliferative patterns in metaplastic columnar epithelia of the oesophagus, classified as oxynto-cardiac (n = 43), cardiac (n = 45) intestinal without dysplasia (n = 41), dysplastic intestinal epithelium (n = 25), and adenocarcinoma (n = 15) by Ki67 immunohistochemistry. METHODS AND RESULTS: Abnormal patterns of Ki67 immunoreactivity were classified into (i) expanded proliferation, characterized by increased levels of Ki67 expression in the deep and mid third of the foveolar pit; and (ii) aberrant proliferation, characterized by positive staining in the surface epithelium and superficial third of the foveolar pit. A significant step-wise increase in the frequency of expanded proliferation was seen in oxynto-cardiac, cardiac, intestinal and dysplastic intestinal epithelium indicative of increasing levels of damage. Aberrant proliferation was absent in oxynto-cardiac mucosa, present at a low and similar level in cardiac, intestinal and low-grade dysplastic epithelia and at a significantly increased frequency in high-grade dysplasia. CONCLUSIONS: These findings suggest that oxynto-cardiac mucosa occurs in a low damage environment and intestinal metaplasia in a high damage environment along the length of the columnar lined oesophageal segment. Aberrant proliferative patterns with Ki67 staining are not useful in differentiating reactive epithelia from low-grade dysplasia, but may prove useful in the diagnosis of high-grade dysplasia.