Primary esophageal lymphoma: a diagnostic challenge in acquired immunodeficiency syndrome--two case reports and review.

Abstract: Although extranodal presentation occurs in the majority of cases of acquired immunodeficiency syndrome-associated non-Hodgkin lymphoma, the esophagus is only rarely affected. We discuss two patients with acquired immunodeficiency syndrome who presented with dysphagia and weight loss, who were found to have human immunodeficiency virus-associated primary esophageal lymphoma. Both patients died within a few weeks of diagnosis, reflecting the poor prognosis associated with this malignancy. Primary esophageal lymphoma should be considered in the differential diagnosis in a human immunodeficiency virus-seropositive patient presenting with dysphagia.

Key Words: acquired immunodeficiency syndrome, esophagus, lymphoma

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Non-Hodgkin lymphomas (NHL) and Kaposi sarcomas constitute more than 90% of the malignancies affecting those infected with human immunodeficiency virus (HIV). (1) Over three fourths of the HIV-associated NHL present extranodally, with most being of the high-grade B-cell type. (2) Of the extranodal sites involved, the gastrointestinal (GI) tract accounts for 17 to 28%. (3) In the HIV-seronegative patient, extranodal presentation occurs less commonly, with approximately one third arising in the GI tract. (4)

In a study of 79 cases of isolated lymphomas of the GI tract in HIV-seronegative patients, sites of involvement were the stomach (55%), small intestine (31%), large intestine (11%), and esophagus (1%). Lymphoma itself accounts for less than 1% of all malignant tumors of the esophagus in this population. (5)

Dawson et al (6) established four criteria necessary for the diagnosis of a primary GI tract lymphoma: no enlargement of peripheral or mediastinal lymph nodes, normal white blood cell count, predominance of alimentary tract lesions with only regional lymph node involvement, and no involvement of the liver and spleen. Although the criteria proposed by Dawson et al have proven useful in the diagnosis of primary esophageal lymphoma in the HIV-seronegative patient, (7-9) the presence of multiple coinfections with opportunistic pathogens in the HIV-seropositive patient makes strict adherence to such criteria difficult. Only 12 cases of HIV-associated primary esophageal lymphoma have been reported thus far. (10-18) In this article, we discuss two patients with HIV-associated primary esophageal lymphoma.

Case Reports

Patient 1

A 27-year-old Hispanic male was diagnosed with acquired immunodeficiency syndrome (AIDS) in August 2000. The patient was noncompliant with antiretroviral therapy. He presented in November 2002 with severe odynophagia, weight loss, and watery diarrhea of 2 to 3 weeks' duration. His most recent viral load and CD4 count, obtained 2 months before admission, were 171,407 copies/mL and 1 cell/[micro]L, respectively. His medical history included Mycobacterium avium complex (MAC) infection, esophageal candidiasis, and Pneumocystis carinii pneumonia diagnosed within 2 months of the most recent admission. Physical examination revealed an afebrile, pale, cachectic man with moderate dehydration and orthostasis. Minimal oral thrush was present. Chest examination was significant for bilateral lower zone dullness to percussion, with minimal crepitations on auscultation. Laboratory tests revealed leukopenia, anemia, thrombocytopenia, hypoalbuminemia, and mild hyponatremia.

The patient was restarted on MAC therapy with clarithromycin and ethambutol. Fluconazole was given for presumed esophageal candidiasis, with no improvement in odynophagia over the next 4 days. The left-sided pleural effusion was aspirated and was found to be an exudate, with negative bacterial, mycobacterial, and fungal stains and cultures. The fluid was negative for malignant cells.

Upper and lower GI tract endoscopy was then performed for further evaluation of persistent odynophagia and diarrhea. Flexible sigmoidoscopy revealed patchy erythematous areas with yellow adherent exudates. A biopsy specimen from the area was consistent with pseudomembranous colitis. Cytomegalovirus (CMV) inclusions and acid-fast bacilli (AFB) were seen at the time of staining. Ganciclovir and metronidazole were started for pseudomembranous colitis.

Esophagogastroduodenoscopy revealed an esophageal ulcer starting at 23 cm and extending over 10 cm in length (Fig. 1), with another deeper ulcer in the distal esophagus. The duodenum was irregular and erythematous. A biopsy specimen from the duodenum was positive for AFB and grew CMV by culture.

A biopsy specimen from the esophageal ulcer base was consistent with high-grade malignant B-cell lymphoma (Fig. 2) with positive B-cell marker CD20 (Fig. 3). T-cell marker CD3 was negative (Fig. 4). The cells were positive for the cell proliferation marker Mib-1 (Fig. 5). CMV inclusions were also seen.

Computed tomographic (CT) scanning of the head revealed no mass lesions. Thoracic and abdominal CT scans showed a solitary anterior diaphragmatic lymph node with a mildly dilated esophagus and bilateral pleural effusions, scattered mesenteric lymph nodes, and an edematous colon. A bone marrow biopsy specimen revealed no evidence of malignancy.

After disclosure of the diagnosis of esophageal lymphoma, the patient decided not to pursue further treatment, and he was subsequently discharged to home hospice. He died 6 weeks later.

Patient 2

A 43-year-old Hispanic man presented with a history of dysphagia, progressive odynophagia, abdominal pain, and weight loss of 1-month duration. His medical history was unremarkable. Physical examination was remarkable only for epigastric tenderness. Laboratory tests revealed anemia and a lactate dehydrogenase of 872 U/L. His liver function tests were within normal limits, and his [alpha]-feto-protein and carcinoembryonic antigen were normal. He was found to be HIV-seropositive, with a CD4 count of 16 cells/[micro]L. Multiple esophageal ulcers were found on esophagogastroduodenoscopy, and the patient was started empirically on ganciclovir. A biopsy specimen from the ulcer revealed large cell immunoblastic lymphoma and CMV esophagitis. A bone marrow biopsy specimen revealed dissemination to the bone marrow. The patient died during his first cycle of chemotherapy 4 weeks later.

Discussion

Patient 1 appeared to have primary lymphoma of the esophagus. No dissemination of malignancy was evident according to head, thoracic, and abdominal CT scanning; thoracentesis; and colonic, duodenal, and bone marrow biopsies. The leukopenia is a reflection of the advanced HIV infection and predated the development of symptoms by several months. The scattered mesenteric lymph nodes seen on abdominal CT scan can be explained by the infection with AFB, consistent with MAC seen on both sigmoid colon and duodenal biopsy specimens.

For Patient 2, an esophageal lymphoma was his initial manifestation of AIDS. Although the bone marrow biopsy specimen was positive for lymphoma, this is felt to be the result of secondary spread from a primary esophageal site. The marked dysphagia for 1 month before presentation and the absence of prominent cytopenias support the esophagus as the primary site. Although some studies suggest a reduction in the incidence of NHL in the era of highly active antiretroviral therapy, (1,19) the challenges of diagnosing extranodal NHL persist.

In decreasing order of frequency, the sites of involvement of extranodal GI tract NHL in HIV-seropositive patients are the stomach, colon, ileum, esophagus, and duodenum, (20) which reflects the pattern seen in the non-HIV population. (5) The frequency of GI tract symptoms are also significantly higher in patients with extranodal GI tract NHL and include abdominal pain, gross blood per rectum, diarrhea, constipation, abdominal distention, early satiety, and dysphagia, which dominate the early clinical course. (20) Review of the 14 cases of primary esophageal lymphoma in HIV-infected patients (Table 1) confirms the predominance of gastrointestinal tract symptoms, including severe dysphagia and odynophagia, leading to significant weight loss at presentation in this group of patients.

[FIGURE 1 OMITTED]

[FIGURE 2 OMITTED]

[FIGURE 3 OMITTED]

[FIGURE 4 OMITTED]

[FIGURE 5 OMITTED]

All patients were severely immunocompromised, with CD4 counts recorded between 0 and 100 cells/[micro]l. (11,12,14-16) Three patients had a history of another AIDS-associated malignancy. (11-13) The predominant histologic types seen in AIDS-related NHL are of the Burkitt's, immunoblastic, and diffuse large cell types. (3) A wide variety of histopathologic types are represented in the cases of primary esophageal lymphoma reviewed here, although both nomenclature and classification have changed over the years.

In this review, the various histopathologic types have been reclassified according to the current World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues (21) for purposes of consistency. Of the patients whose outcomes are known, all but two, one of whom was followed for only 1 month,

died as a result of the complications of the disease.

Conclusion

Suspicion for esophageal malignancy should be heightened by the predominance of dysphagia, odynophagia, and weight loss and when symptoms persist despite appropriate treatment of known coexisting infections of the esophagus such as Candida, CMV, and herpes simplex virus. CT scan of the chest and barium swallow are useful adjunctive tools in the diagnosis of esophageal lymphoma and have demonstrated abnormalities in the majority of patients. (10,13,14,16-18)

Although early endoscopy led to the definitive diagnosis in all reported cases, the mortality of HIV-associated primary esophageal lymphoma remains high. Unlike in the non-HIV population, Dawson's criteria for primary GI tract lymphoma are too restrictive to be applied in HIV-associated primary GI tract lymphoma. HIV itself or opportunistic infection may account for lymphadenopathy, leukopenia, and hepatosplenomegaly. This consideration may facilitate the diagnosis of more primary GI tract lymphomas in patients with AIDS.

Table 1. Profile of reported cases of primary esophageal lymphoma in
human immunodeficiency virus infection (a)

Patient  Reference                Age (yr)/sex  CD4 count

 1       Bernal and del Junco,    40/M          Helper/Suppressor 0.1
           1986 (10)
 2       Bernal and del Junco,    30/M          T-helper cells 3.1%
           1986 (10)
 3       Bernal and del Junco,    40/M          T-helper cells 2.2%
           1986 (10)
 4       Benamouzig et al, 1992   40/M          56 cells/[micro]L
           (11)
 5       Fernandez-Rodreguez et   27/F          37 cells/[micro]L
           al, 1993 (12)
 6       Radin, 1993 (13)         48/M          NR
 7       Moses et al, 1995 (14)   55/M          0 cells/[micro]L
 8       Chow et al, 1996 (15)    41/F          100 cells/[micro]L
 9       Marnejon and Scoccia,    47/M          30 cells/[micro]L
           1997 (16)
10       Sabate et al, 1997 (17)  30/M          NR
11       Sabate et al, 1997 (17)  28/M          NR
12       Seo et al, 1999 (18)     56/F          331 cells/[micro]L: 1 yr
                                                  prior to presentation
13       Weeratunge et al, 2003   27/M          1 cell/[micro]L
           (present study)
14       Weeratunge et al, 2003   43/M          16 cells/[micro]L
           (present study)

Patient  Presentation               Esophageal level    Gross appearance

 1       Dysphagia                  20 and 23 cm        Polypoid mass
 2       Dysphagia, weight loss     36 cm               Ulcerated mass
 3       Dysphagia, weight loss     30-35 cm            Ulcerated mass
 4       Dysphagia, weight loss,    25-40 cm            Ulcer
           chest pain
 5       Dysphagia                  Mid                 Mass
 6       Vomiting, abdominal pain,  Distal half         Uncerated mass
           weight loss                thoracic part
 7       Odynophagia, weight loss   Mid and distal      Ulcer
 8       Dysphagia, weight loss     Mid and distal      Ulcer
 9       Odynophagia, dysphagia,    Mid                 Ulcer
           weight loss
10       Dysphagia, vomiting,       Lower               Mass
           hematemesis
11       Dysphagia                  Mid                 Ulcerated mass
12       Dysphagia, chest pain      Mid                 Ulcerated mass
13       Dysphagia, odynophagia,    23 cm               Ulcer
           weight loss
14       Dysphagia, odynophagia,    Diffuse             Multiple ulcers
           weight loss

Patient  Histology of NHL         Treatment       Outcome

 1       Large cell lymphoma NOS  Radiotherapy    NR
 2       Large cell lymphoma NOS  Radiotherapy    Improvement at 1 mo
                                                    follow-up
 3       Diffuse large B-cell     Radiotherapy    NR
           lymphoma
 4       Diffuse large B-cell     NR              Died within the same
           lymphoma                                 admission
 5       Diffuse large B-cell     CHOP            Died 5 mo after
           lymphoma                 chemotherapy    treatment as a
                                                    result of recurrence
 6       Follicular lymphoma      NR              Died as a result of
                                                    sepsis 6 wk after
                                                    admission
 7       Diffuse large B-cell     CHOP            Died during
           lymphoma                 chemotherapy    chemotherapy:
                                                    esophagus
                                                    perforation
 8       Extranodal T-cell        Chemotherapy    Died 9 mo later as a
           lymphoma                                 result of CMV
                                                    pneumonia
 9       Large cell lymphoma NOS  Refused         Died 3 wk later
                                    treatment
10       Follicular lymphoma      NR              NR
11       Follicular lymphoma      NR              NR
12       Follicular lymphoma      Chemotherapy    Died 3 mo later as a
                                                    result of esophageal
                                                    bleed
13       Diffuse large B-cell     Refused         Died 6 wk later
           lymphoma                 treatment
14       Diffuse large B-cell     CHOP            Died 4 wk later,
           lymphoma                 chemotherapy    during chemotherapy

(a) NHL, non-Hodgkin lymphoma; NR, not recorded; NOS, not otherwise
specified; CHOP, cyclophosphamide, doxorubicin, vincristine, and
prednisone; CMV, cytomegalovirus.

Accepted August 29, 2003.

Copyright [c] 2004 by The Southern Medical Association

0038-4348/04/9704-0383

Please see Keith J. Kaplan's editorial on page 331 of this issue.

References

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10. Bernal A, del Junco GW. Endoscopic and pathologic features of esophageal lymphoma: A report of four cases in patients with acquired immune deficiency syndrome. Gastrointest Endosc 1986;32:96-99.

11. Benamouzig R, Tulliez M, Chaussade S, et al. Primary non-Hodgkin's lymphoma of the esophagus in a patient with acquired immunodeficiency syndrome (AIDS) [in French]. Gastroenterol Clin Biol 1992;16:477-479.

12. Fernandez-Rodriguez R, Monteserin C, Vega M, et al. Primary non-Hodgkin's lymphoma of the esophagus in an AIDS infected female [in French]. Presse Med 1993;22:1106.

13. Radin DR. Primary esophageal lymphoma in AIDS. Abdom Imaging 1993;18:223-224.

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15. Chow DC, Bleikh SH, Eickhoff L, et al. Primary esophageal lymphoma in AIDS presenting as a nonhealing esophageal ulcer. Am J Gastroenterol 1996;91:602-603.

16. Marnejon T, Scoccia V. The coexistence of primary esophageal lymphoma and Candida glabrata esophagitis presenting as dysphagia and odynophagia in a patient with acquired immunodeficiency syndrome. Am J Gastroenterol 1997;92:354-356.

17. Sabate JM, Franquet T, Palmer J, et al. AIDS-related primary esophageal lymphoma. Abdom Imaging 1997;22:11-13.

18. Seo IS, Henley JD, Min KW, et al. True histiocytic lymphoma of the esophagus in an HIV-positive patient: An ultrastructural study. Ultrastruct Pathol 1999;23:333-339.

19. Kirk O, Pedersen C, Cozzi-Lepri A, et al. Non-Hodgkin lymphoma in HIV-infected patients in the era of highly active antiretroviral therapy. Blood 2001;98:3406-3412.

20. Cappell MS, Botros N. Predominantly gastrointestinal symptoms and signs in 11 consecutive AIDS patients with gastrointestinal lymphoma: A multicenter, multiyear study including 763 HIV-seropositive patients. Am J Gastroenterol 1994;89:545-549.

21. Jaffe ES, Harris NL, Stein H, et al (eds). World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France, IARC Press, 2001.

RELATED ARTICLE: Key Points

* Non-Hodgkin lymphoma is one of the most common malignancies affecting those infected with human immunodeficiency virus (HIV), with the majority presenting extranodally.

* The esophagus is a rare site for primary presentation of HIV-associated extranodal non-Hodgkin lymphoma.

* Primary esophageal lymphoma should be considered in the differential diagnosis in an HIV-seropositive patient presenting with dysphagia.

* HIV-associated primary esophageal lymphoma is a highly fatal malignancy.

C. Namal Weeratunge, MBBS, Hector H. Bolivar, MD, Gregory M. Anstead, MD, PHD, and Deedee H. Lu, MD

From the Department of Medicine and the Division of Infectious Diseases, Department of Pathology, University of Texas Health Science Center at San Antonio, and the South Texas Veterans Health Care System, San Antonio, TX.

Reprint requests to C. Namal Weeratunge, MBBS, Division of Infectious Diseases, Department of Medicine, University of Texas Health Science Center at San Antonio, Mail Code 7881, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900. Email: [e-mail]