1CLINICOPATHOLOGIC CONFERENCE
Dysphagia and an Abdominal Mass in a 43-Year-Old Man with Acquired Immunodeficiency Syndrome
A
43-year-old homosexual attorney was admitmass was also noted in the tail of the pancreas, and ted to Barnes Hospital on November 4, 1988, there was a mild increase in the size of the pancreatfor evaluation of dysphagia, vomiting, dehydration, ic body and tail. Biopsy of the patient’s skin lesions and an abdominal mass. revealed only chronic inflammatory changes. The patient was generally healthy until April During the next several weeks the patient’s oral 1988, when he developed cough, fever, and fatigue. intake decreased, his weight loss continued, and Physical examination revealed only pharyngeal er- oral candidiasis developed. He was admitted to ythema with white mucosal patches and posterocerBarnes Hospital on November 4, 1988, for further vital adenopathy. A diagnosis of tracheobronchitis evaluation. was made and treatment with amoxicillin resulted Physical examination revealed a thin, middlein minimal improvement. A chest radiograph dem- aged man in no acute distress. The blood pressure was 140/70 mm Hg supine and 110/65 mm Hg onstrated a diffuse pulmonary infiltrate. Human standing; the pulse rate was go/minute supine and immunodeficiency virus (HIV) serology was found to be positive. He was hospitalized and underwent 120/minute standing. The respiratory rate was 201 bronchoscopy. All specimens were negative for minute, and the temperature was normal. Scaling Pneumocystis carinii as well as for acid-fast organ- dry lesions were present bilaterally on the external isms; the bronchial washings did demonstrate can- ear. Results of funduscopic examination were normal, as were the extraocular movements. The phardida and probably aspergillus. Klebsiella pneumoniae was also cultured, and the patient was ynx was erythematous with white mucosal patches; treated with a 2-week course of cefazolin. Treatthe neck was supple and without adenopathy. Difment with zidovudine was started but was discon- fuse expiratory wheezes were present. Results of tinued approximately 1 month later due to anemia. cardiovascular examination were normal. Bowel The patient did well until October 1988, when he sounds were present and the abdomen was nondispresented with complaints of anorexia, early satie- tended; however, a 5-cm pulsatile, nontender epity, and a 5 kg weight loss over the preceding 4 gastric mass was palpated. A bruit was heard over the mass. No hepatosplenomegaly or inguinal adweeks. He also noted epigastric fullness, abdominal pain, dysphagia with solid foods, and vomiting of enopathy was detected, and there was no cyanosis. bilious material. There was no history of cough, A scaling, violaceous, 3-cm plaque was present in region; a similar lesion was also lymphadenopathy, diaphoresis, or change in bowel the midabdominal habits. Further complaints included scaling red present on the anterior aspect of the right lower leg. demonstrated normal tone patches on his abdomen and extremities, which had Rectal examination with no mass, tenderness, or Hemoccult@ positivity. been present for several weeks. An upper gastroinLaboratory values were remarkable for a sodium testinal series demonstrated a 6- X 3.5cm mass at of 130 mEq/L, a normal creatinine, and a glucose of the gastroesophageal junction posteriorly. Upper 141 mg/dL. The serum calcium was 8.5 mg/dL, the endoscopy failed to show mucosal abnormalities, although the previously identified mass was local- albumin 3.4 g/dL, and the uric acid and blood urea nitrogen normal. The hemoglobin level was 11 g/dL, ized. Biopsy demonstrated only atrophic gastritis. the mean corpuscular volume 190 fL, the reticuloTherapy with Hz antagonists resulted in symptomatic improvement. A computed tomographic (CT) cyte count 0.9%, the white blood cell count 10,500/ mm3 (11% lymphocytes; 7% monocytes; and 82% scan of the abdomen revealed a soft-tissue density at the gastroesophageal junction and nodular densi- granulocytes), the platelet count 496,000/mm3, and the coagulation studies normal. The T4-to-T8 ratio ties in the gastrocolic ligament. A small soft-tissue was very low. The serum amylase was 45 IU/mL. Chest radiography demonstrated small bilateral Stenographic reports of weekly clinicopathologic conferences held in pleural effusions; the cardiac silhouette and pulmoBarnes and Wohl Hospitals are published in each issue of the Journal. nary vasculature were normal. The electrocardioMembers of the Departments of Internal Medicine, Radiology, and Pagram revealed normal sinus rhythm with a leftward thology of the Washington University School of Medicine participate jointly in these conferences. Kenneth M. Ludmerer. M.D., and John M. KisP-wave axis and a nonspecific intraventricular consane, M.D., are the editors of this feature. duction delay. September
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of Medicine
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ABDOMINAL
Figure 1. Upper gastrointestinal sue mass (arrows) impressing tion.
MASS, AND AIDS
radiograph shows on the gastroesophageal
a soft-tisjunc-
Following admission to the hospital, the patient developed low-grade fevers; on the second hospital day his temperature spiked to 39.5“C. A second CT scan of the abdomen demonstrated an increase in the size of the previously noted mass in the gastroesophageal junction to approximately 8 X 10 cm. Intrahepatic biliary ducts were dilated as was the common bile duct. Also noted was periportal and left para-aortic adenopathy. Following fluid replacement, a diagnostic procedure was performed.
CLINICALDISCUSSION Dr. Charles Parker: I would like to begin by asking Dr. Glazer to review the radiographs. 366
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Dr. Harvey Glazer: A radiograph from the upper gastrointestinal examination demonstrates a mass impressing on the gastroesophageal junction (Figure 1). The underlying mucosal surface appears normal. The mass is confirmed on a subsequent CT scan. In addition, several smaller soft-tissue nodules are seen in the fat adjacent to the colon and stomach. Enlarged lymph nodes are seen around the pancreas, in the porta hepatis, and in the aortocaval region (Figure 2). CT examination approximately 3 weeks later shows interval increase in the lymphadenopathy. Bile duct dilatation is also present, probably secondary to obstruction of the common bile duct by portal and peripancreatic lymphadenopathy. Dr. Parker: In summary, this is a 43-year-old homosexual man with immunologically verified acquired immunodeficiency syndrome (AIDS) since April 1988. He subsequently developed multiple upper abdominal masses. These masses have apparently progressed considerably over a less than 2-month period. Dr. Powderly will initiate the discussion. I have asked him to describe how he approaches a patient with AIDS and what his impressions are in terms of this patient’s recent clinical manifestations. Dr. William G. Powderly: Using this patient as an example of a typical patient with HIV infection, I would like to review how such patients might be approached. Note that I said an HIV-infected patient and not a patient with AIDS, because there is a spectrum of disease seen before patients present with AIDS. We see asymptomatic patients who are HIV-positive as well as patients with severe immunodepletion who present with opportunistic infection and malignancies. We therefore need to develop a consistent clinical approach to HIV infection. The first point that must be emphasized is that the primary problem in HIV disease is the profound immunodepletion that occurs. The virus has a tropism for cells bearing the CD4 surface marker, and from an immunologic viewpoint the major targets include T4 helper T lymphocytes and macrophages. Consequently, progressive destruction and loss of such cells are seen. Most if not all patients infected with HIV infection have progressive loss of T4 helper cells. When their level of T4 cells reaches a certain threshold, they lose the critical function of those cells, which is to orchestrate the host defenses by controlling macrophage, B-cell, and cytotoxic Tcell function. At this point patients are at risk for both opportunistic infection and, if we can use the term, opportunistic malignancy. For this reason the T4 count is often used as a marker for disease progression. When a patient presents with HIV infection (di89
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Figure 2. CT scan through the upper abdomen demonstrates enlarged lymph nodes (arrows) around the porta hepatis and aorta (A).
agnosed by a positive antibody and confirmed by Western blot), several questions need to be answered. (1) Is the patient asymptomatic or symptomatic? (2) What is the extent of immunologic compromise? (3) Can a diagnosis of AIDS be made? (4) If not, what is the risk of progression to AIDS in the next year, 4 years, and so on? (5) Is therapyeither licensed or experimental-now available for the patient? Let us look now at this particular case and answer those questions. The first issue is whether this patient was symptomatic. He clearly was symptomatic when he presented. He had a history of fatigue and some weight loss, which, although obviously nonspecific, can be HIV-related. He also had oral candidiasis, which in patients who are not receiving steroids or antibiotics may be a manifestation of HIV disease. The next issue is assessing the level of his immunodeficiency. Oral candidiasis does not occur in HIV-infected patients until they have some immunologic dysfunction. The best single marker available is the level of circulating T4 lymphocytes. This patient had a T4 count of 116 cells/mm3, which is profoundly depressed. The normal T4 count in a healthy population ranges from 800 to 1,200 cells/ mm3. Most asymptomatic HIV-infected individuals have T4 counts in the range of 200 to 800 cells/mm3, and the clinical syndrome of AIDS rarely develops until the T4 count drops below 300 cells/mm3. Did this patient have AIDS when he first presented? It must first be remembered that AIDS is a “catch-all” diagnostic label designed primarily as a case-finding tool to identify patients for epidemiologic purposes. AIDS is defined by the presence of certain opportunistic infections such as Pneumo(PCP) or cryptococcal cystis carinii pneumonia
meningitis, and certain malignancies such as Kaposi’s sarcoma or non-Hodgkin’s lymphoma. This patient presented with diffuse pulmonary infiltrates. If they were due to PCP or cytomegalovirus, then he could be diagnosed as having AIDS. But, by the strict criteria, he did not have AIDS when he presented in April. Of interest, a syndrome of nonspecific interstitial pneumonitis has recently been described in HIV-infected individuals [l]. Although this syndrome is a possibility in the present case, it, too, is not an AIDS-defining illness. What was the patient’s risk of progressing to AIDS? Obviously, his risk was high. With his level of T4 cells, 25% of patients will contract PCP in the next year, and the overall risk of developing an AIDS-defining illness within 12 months is about 40%. Certain prognostic factors exist [2]. The presence of AIDS-related complex (ARC), i.e., oral candidiasis, unexplained weight loss, multidermatomal herpes zoster, and persistent diarrhea, can be used prognostically. Other prognostic factors for development of AIDS include anemia on presentation, a high sedimentation rate, and, most specifically, a low T4 count or a rapidly decreasing T4 count. For this patient the final question is treatment. This case falls into the category of a group of cases for which zidovudine is clearly indicated. Zidovudine should be administered to all patients with AIDS and patients with ARC and T4 counts less than 200 cells/mm3 because its use has been shown to reduce the incidence of opportunistic infections and mortality [3]. However, zidovudine is not the answer to AIDS. Most patients do not tolerate zidovudine at its full dosage. Nausea occurs in the majority of patients in whom zidovudine treatment is begun and may be dose-limiting. More important,
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zidovudine has bone marrow toxicity: both anemia and granulocytopenia may occur [4]. Two types of anemia are associated with the drug. Many patients develop a macrocytic anemia, with megaloblastic marrow changes, which usually causes a mildly decreased hematocrit. This condition generally stabilizes and patients can continue to receive the full dosage. However, a severe aplastic or hypoplastic condition with normochromic, normocytic anemia also occurs. Its onset is often sudden, not predicted by other laboratory markers, and usually requires transfusion and dosage reduction or cessation. The development of granulocytopenia may also lead to changes in dosage. Consequently, by the end of a year, as many as 55% of patients who have initially been treated with zidovudine will no longer be able to tolerate a full dosage, and the drug will be discontinued in many [5]. This case exemplifies this major negative aspect of zidovudine. The patient did not tolerate zidovudine, and since no other antiretroviral therapy is yet available, the development of an AIDS-defining illness was likely. His final presentation probably represents this AIDS-defining illness. Although Dr. MacDermott will discuss the gastrointestinal manifestations of AIDS and HIV disease, let me give you my impressions. Although certain infections may present with lymphadenopathy, particularly mycobacterial and fungal infections, I think his adenopathy and gastric mass were more likely the result of tumor. The two tumors most likely to occur are lymphoma and Kaposi’s sarcoma. The violaceous skin lesions described in the protocol are highly suggestive of Kaposi’s sarcoma. In the presence of Kaposi’s sarcoma involving the skin, a high percentage of patients also have visceral involvement, and the gastrointestinal tract is the organ most commonly affected by visceral Kaposi’s sarcoma. Thus, I think the odds make it more likely that he had Kaposi’s sarcoma than a lymphoma, but there is no way of determining this with certainty unless a biopsy is performed. Dr. Parker: Thank you. Dr. MacDermott will now discuss the gastrointestinal manifestations. Dr. Richard MacDermott: Patients with AIDS commonly present to gastroenterologists. We most often see patients with presenting manifestations of diarrhea, malabsorption, or weight loss, or any combination of the three. A wide variety of now wellrecognized infectious agents cause the diarrhea, which may be either profuse or bloody. In some patients, weight loss and malabsorption will be the presenting manifestations of atypical mycobacteria or neoplasia. If no etiology is found, the diagnosis of AIDS enteropathy is made. The second most common gastrointestinal manifestation of AIDS is dysphagia. Dysphagia is very
often due to candidiasis, and the patient under discussion indeed had oral candidiasis. However, in this particular patient, because of the mass at the gastroesophageal junction, the dysphagia during his last admission was most likely due to the obstructing lesion. In addition to candid&is, esophagitis due to either herpes or cytomegalovirus can be seen. Dysphagia can be caused by the HIV virus itself. Usually this is at the initial onset of HIV infection and resolves as HIV is managed by the normal immune response of the individual. This patient had hepatobiliary manifestations of AIDS, a less commonly seen but nevertheless very important problem. With regard to infectious disease considerations, the most common causes of abnormalities on liver function tests are mycobacteria, fungal organisms, or viruses. It is important to be aware of the fact that most patients with AIDS have also been infected with hepatitis B virus, and thus chronic active hepatitis and/or cirrhosis unrelated to HIV often occurs in AIDS patients. In AIDS patients, the most common neoplasm involving the liver is Kaposi’s sarcoma. The second most common hepatic neoplasm in AIDS is lymphoma. This patient was noted to have dilated ducts on his last CT scan. Recent clinical studies have demonstrated that an entity similar to sclerosing cholangitis can occur in AIDS patients. Dr. John Cello and co-workers at San Francisco General Hospital have described a series of patients who have dilated intrahepatic and extrahepatic ducts. Pathologically the hepatic changes resemble sclerosing cholangitis. In a number of instances these investigators noted papillary stenosis, which was treated by sphincterotomy. The etiology of the papillary stenosis appears to have been immune-mediated, in that a chronic inflammatory infiltrate was present in the papilla. The dilated ducts in the patient under discussion could alternatively be due to obstruction with tumor. Cholangiocarcinoma, lymphoma, and Kaposi’s sarcoma would be the primary possibilities. In evaluating the AIDS patient with hepatobiliary manifestations, CT scan is used to rule out obstruction, and endoscopic retrograde cholangiopancreatography is undertaken in patients who may have obstruction. Liver biopsy is not usually of additional help if the patient already has a disseminated disease such as Kaposi’s sarcoma or lymphoma. If the patient does not have documented disseminated disease, then a liver biopsy would be of value in a patient with extensive hepatic abnormalities. With regard to the gastric mass in this patient, Kaposi’s sarcoma is the most common gastrointestinal tumor in the AIDS population. AIDS patients who have skin involvement with Kaposi’s sarcoma
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often have gastrointestinal involvement that is asymptomatic. Patients frequently present with multifocal Kaposi’s sarcoma of the gastrointestinal tract, with the stomach being the most commonly involved organ and the small intestine being the second most commonly involved organ. Endoscopy can reveal Kaposi’s sarcoma lesions in the gastrointestinal tract that appear very similar to the skin lesions. In the AIDS patient, gastrointestinal Kaposi’s sarcoma is a very aggressive tumor. Lymphoma often presents with gastric outlet obstruction. Similar to cases of Kaposi’s sarcoma in the AIDS population, the presentation is commonly multifocal with an aggressive course. Kaposi’s sarcoma of the gastrointestinal tract is often difficult to diagnose at endoscopy because it usually presents as a submucosal lesion, and therefore most of these patients require laparotomy for a definitive diagnosis. A laparotomy would be indicated in the patient we are discussing, because it is impossible to know from the information given whether the patient had Kaposi’s sarcoma, lymphoma, or both. Even if the skin biopsy were repeated and demonstrated Kaposi’s sarcoma, a laparotomy would still be needed to rule out lymphoma, which has a high incidence in patients with Kaposi’s sarcoma. Cases have been described in which both Kaposi’s sarcoma and lymphoma have been seen in the same lymph node or gastrointestinal lesion. Finally, we also need to be mindful of the fact that AIDS patients can still develop common, non-AIDS-related gastrointestinal disorders, such as metastatic adenocarcinoma. Dr. Parker: Obviously, if he did not have AIDS, diagnoses such as carcinoma of the lung, stomach, or pancreas would deserve serious consideration. He is a known smoker and certainly these are common tumors in smokers. If we make the reasonable assumption that his abdominal condition is indeed associated with AIDS, we still have to consider at least four diagnoses: lymphoma, Kaposi’s sarcoma, AIDS-related nonspecific lymphadenopathy, and lymphadenopathy or abscess formation associated with an infectious agent known to affect AIDS patients, such as Mycobacterium avium. All these disease processes are common in AIDS. Nonspecific lymphoid hyperplasia is often a presenting manifestation in AIDS patients. Not infrequently, a diagnosis of hyperplasia is made on the initial biopsy, but later biopsies show clear-cut evidence of lymphoma. However, the large size of the local lesions and the absence of generalized adenopathy make this diagnosis unlikely. Non-Hodgkin’s lymphoma is the most common form of lymphoma in AIDS patients. Lymphomas associated with AIDS may affect many organs, in-
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cluding the liver and bowel, although their most outstanding characteristic is the exceptionally high frequency of involvement of the brain. Kaposi’s sarcoma is also a common complication of AIDS. A number of features of Kaposi’s sarcoma in AIDS patients differ from the usual forms of this tumor, including its high frequency, younger average age at onset, lack of strong predilection for certain ethnic groups, much more frequent involvement of the upper part of the body, and the aggressive character of the tumor. A high predominance in males is observed in both forms of Kaposi’s sarcoma. In the patient under discussion, the character of the skin lesions strongly suggests this diagnosis. Although an earlier skin biopsy showed only chronic inflammation, negative initial biopsy results are common in this disease and by no means exclude the diagnosis. The upper abdominal findings are consistent with Kaposi’s sarcoma, although he does not have the most characteristic intestinal manifestation, which is a diffuse infiltrative lesion of the intestines. Lymph node involvement does occur in Kaposi’s sarcoma with combined histologic features of lymphoid hyperplasia and vascular proliferation similar to that found in the skin. There may also be an associated lymphoma. A variety of infections producing chronic inflammation and granulomata occur in AIDS patients as a manifestation of their decreased cellular immunity. According to two recent publications, cat scratch disease can be confused with Kaposi’s sarcoma in patients with AIDS because of the presence of violaceous skin lesions. This is an interesting but unlikely possibility. Other granulomatous infections might also be considered, but I think Kaposi’s sarcoma is the most likely diagnosis here. Since I believe this individual does indeed have Kaposi’s sarcoma, I will take this opportunity to review briefly some fascinating studies recently published in Nature on the mechanism of Kaposi’s sarcoma associated with HIV infection [6]. The viruses known to infect T cells are more or less typical retroviruses with long terminal repeats, group specific antigen genes, polymerase, and envelope protein sequences. They differ with respect to the other genes that are present. The human T-cell leukemia (type 1) virus has a gene coding for 40-, 27-, and 21kd proteins (P40, P27, and P21). These proteins appear to activate transcription and greatly stimulate replication of the virus. The P40 protein may also activate transcription of the receptor for interleukin-2 (IL-2) and perhaps of IL-2 itself. Increases in these products may result in autocrine stimulation of T-cell growth. The HIV virus produces a protein known as TAT-3, which seems to act at the post-transcriptional level to increase gene expres-
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b
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1 / / / /
sion. Transgenic experiments have been done injecting the TAT-3 gene into the pronucleus of fertilized mouse eggs, retransplanting these eggs into pseudopregnant females, and determining if the TAT gene is expressed in the progeny. Northern blot analyses in male and female transgenic animals indicate that the TAT gene is expressed in the skin but not elsewhere in both sexes. Hyperplasia is observed in the skin of male but not female mice expressing the TAT gene, beginning at about 4 months of age. By 12 to 18 months of age, about 15% of male mice have developed tumors. These tumors show a good deal of similarity histopathologically to Kaposi’s sarcoma lesions in humans, which are also largely limited to males. It is of further interest that the tumor cells apparently do not express the TAT3 gene. This suggests an indirect mechanism of tumor induction perhaps involving a known or unknown growth factor. Obviously these observations have important implications for the pathogenesis of tumors in patients with AIDS and eventually might have therapeutic implications as well. In conclusion, there is very little doubt that this individual has AIDS that has become complicated by an additional disease process. There is good reason to believe that the complicating disease is Kaposi’s sarcoma. Lymphoma and chronic granulomatous infection are considerably less likely. There are several diagnostic procedures that might have been performed. Despite the original negative skin biopsy result, I would have been tempted to perform another skin biopsy in an effort to avoid subjecting him to abdominal surgery. But that decision would have depended on the appearance of the skin lesions and his general condition at that time. A laparotomy with multiple biopsies would have had the 370
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Figure 3. Lower-power hematoxylin and eosin-stained section shows abnormal lymph node architecture disrupted by numerous irregular blood-filled channels. There are no normal-appearing vascular structures and the cells lining these channels appear to be proliferative (original magnification X150, reduced by 30%).
best chance of producing a definitive diagnosis, although obviously surgical procedures should be kept to a minimum in these patients. Because of the vascularity of Kaposi’s sarcoma lesions and the question of the large mass being pulsatile, I would have been reluctant to perform a blind needle biopsy of the mass.
PATHOLOGICDISCUSSION Dr. Kenneth Murphy: Several small hemorrhagic fragments of tissue were processed for routine histology. These showed a proliferation of vascular spaces and anastomosing channels in a background of large round and spindle cells (Figure 3). The extravasation of red blood cells into the surrounding stroma that is typical of Kaposi’s sarcoma was evident. At higher power, the epithelioid nature of the cells lining these vascular channels was more evident (Figure 4). Abundant hemosiderin was present. This was clearly an example of Kaposi’s sarcoma involving a mesenteric lymph node. On epidemiologic grounds, Kaposi’s sarcoma has been divided into four groups: classic, African, renal transplant-associated, and epidemic. Differing in the population, clinical characteristics, and course, the lesions appear similar at the microscopic level. Kaposi’s sarcoma was a rare tumor of soft tissues, only infrequently encountered by the average clinician or pathologist until the AIDS epidemic. Usually involving the skin, Kaposi’s sarcoma can occur in almost any site, frequently involving lymph nodes and parenchymal organs. The histogenesis of Kaposi’s sarcoma is unclear. However, ultrastructural and immunohistochemical studies point to a vascular endothelial derivation of the lesion. 89
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figure 4. High-power photomicrograph shows the epithelioid nature of cells lining the proliferative vascular spaces, the extravasation of red blood cells into adjacent tissue, and the characteristic deposits of hemosiderin (hematoxylin and eosin: original magnification X400, reduced by 30%).
Recent investigations have questioned whether Kaposi’s sarcoma is a true neoplasm [7,8]. Some evidence would suggest that the proliferation of vascular endothelium is a response to local production of a new fibroblast growth factor-like growth factor produced by HIV-infected CD4+ cells. Kaposi’s sarcoma-like lesions were produced in the skin of transgenic mice harboring the TAT gene from the HIV genome, suggesting that the transcriptional regulatory functions of the TAT gene may be involved in Kaposi’s sarcoma of the epidemic type. Final Pathologic Diagnosis: Kaposi’s sarcoma.
REFERENCES 1. Ognibene
without
FP, Masur H, Rogers P, et al. Nonspecific interstitial pneumonitis evidence of Pneumocystis carinii in asymptomatic patients infected
with human immunodeficiency virus (HIV). Ann Intern Med 1988; 109: 874 9. 2. Moss AR. Predicting who will progress to AIDS. Br Med J 1988; 297: 10678. 3. Fischl MA, Richman DD. Grieco MH, et al. The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex: a double-blind, placebo-controlled trial. N Engl J Med 1987; 318: 185-91. 4. Richman DD. Fischl MA, Grieco MH, eta/. The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. N Engl J Med 1987; 318: 192-7. 5. Dournon E, Matheron S, Rozenbaum W, et al. Effects of zidovudine in 365 consecutive patients with AIDS or AIDS-related complex. Lancet 1988; 2: 12971302. 6. Vogel J, Hinrichs SH, Reynolds RK, Luciw PA, Jay G. The HIV tat gene induces dermal lesions resembling Kaposi’s sarcoma in transgenic mice. Nature 1988; 335: 606-11. 7. Salahuddin SZ, Nakamura S, Biberfeld P, eta/. Angiogenic properties of Kaposi’s sarcoma-derived cells after long term culture in-vitro. Science 1988; 242: 430-3. 6. Nakamura S, Salahuddin SZ. Biberfeld P. et al. Kaposi’s sarcoma cells: longterm culture with growth factor from retrovirus-infected CD4+ T cells. Science 1988; 242: 426-30.
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1990
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Dysphagia and an Abdominal Mass in a 43-Year-Old Man with Acquired Immunodeficiency Syndrome
A
43-year-old homosexual attorney was admitmass was also noted in the tail of the pancreas, and ted to Barnes Hospital on November 4, 1988, there was a mild increase in the size of the pancreatfor evaluation of dysphagia, vomiting, dehydration, ic body and tail. Biopsy of the patient’s skin lesions and an abdominal mass. revealed only chronic inflammatory changes. The patient was generally healthy until April During the next several weeks the patient’s oral 1988, when he developed cough, fever, and fatigue. intake decreased, his weight loss continued, and Physical examination revealed only pharyngeal er- oral candidiasis developed. He was admitted to ythema with white mucosal patches and posterocerBarnes Hospital on November 4, 1988, for further vital adenopathy. A diagnosis of tracheobronchitis evaluation. was made and treatment with amoxicillin resulted Physical examination revealed a thin, middlein minimal improvement. A chest radiograph dem- aged man in no acute distress. The blood pressure was 140/70 mm Hg supine and 110/65 mm Hg onstrated a diffuse pulmonary infiltrate. Human standing; the pulse rate was go/minute supine and immunodeficiency virus (HIV) serology was found to be positive. He was hospitalized and underwent 120/minute standing. The respiratory rate was 201 bronchoscopy. All specimens were negative for minute, and the temperature was normal. Scaling Pneumocystis carinii as well as for acid-fast organ- dry lesions were present bilaterally on the external isms; the bronchial washings did demonstrate can- ear. Results of funduscopic examination were normal, as were the extraocular movements. The phardida and probably aspergillus. Klebsiella pneumoniae was also cultured, and the patient was ynx was erythematous with white mucosal patches; treated with a 2-week course of cefazolin. Treatthe neck was supple and without adenopathy. Difment with zidovudine was started but was discon- fuse expiratory wheezes were present. Results of tinued approximately 1 month later due to anemia. cardiovascular examination were normal. Bowel The patient did well until October 1988, when he sounds were present and the abdomen was nondispresented with complaints of anorexia, early satie- tended; however, a 5-cm pulsatile, nontender epity, and a 5 kg weight loss over the preceding 4 gastric mass was palpated. A bruit was heard over the mass. No hepatosplenomegaly or inguinal adweeks. He also noted epigastric fullness, abdominal pain, dysphagia with solid foods, and vomiting of enopathy was detected, and there was no cyanosis. bilious material. There was no history of cough, A scaling, violaceous, 3-cm plaque was present in region; a similar lesion was also lymphadenopathy, diaphoresis, or change in bowel the midabdominal habits. Further complaints included scaling red present on the anterior aspect of the right lower leg. demonstrated normal tone patches on his abdomen and extremities, which had Rectal examination with no mass, tenderness, or Hemoccult@ positivity. been present for several weeks. An upper gastroinLaboratory values were remarkable for a sodium testinal series demonstrated a 6- X 3.5cm mass at of 130 mEq/L, a normal creatinine, and a glucose of the gastroesophageal junction posteriorly. Upper 141 mg/dL. The serum calcium was 8.5 mg/dL, the endoscopy failed to show mucosal abnormalities, although the previously identified mass was local- albumin 3.4 g/dL, and the uric acid and blood urea nitrogen normal. The hemoglobin level was 11 g/dL, ized. Biopsy demonstrated only atrophic gastritis. the mean corpuscular volume 190 fL, the reticuloTherapy with Hz antagonists resulted in symptomatic improvement. A computed tomographic (CT) cyte count 0.9%, the white blood cell count 10,500/ mm3 (11% lymphocytes; 7% monocytes; and 82% scan of the abdomen revealed a soft-tissue density at the gastroesophageal junction and nodular densi- granulocytes), the platelet count 496,000/mm3, and the coagulation studies normal. The T4-to-T8 ratio ties in the gastrocolic ligament. A small soft-tissue was very low. The serum amylase was 45 IU/mL. Chest radiography demonstrated small bilateral Stenographic reports of weekly clinicopathologic conferences held in pleural effusions; the cardiac silhouette and pulmoBarnes and Wohl Hospitals are published in each issue of the Journal. nary vasculature were normal. The electrocardioMembers of the Departments of Internal Medicine, Radiology, and Pagram revealed normal sinus rhythm with a leftward thology of the Washington University School of Medicine participate jointly in these conferences. Kenneth M. Ludmerer. M.D., and John M. KisP-wave axis and a nonspecific intraventricular consane, M.D., are the editors of this feature. duction delay. September
1990
The American
Journal
of Medicine
Volume
89
365
CPC / DYSPHAGIA,
ABDOMINAL
Figure 1. Upper gastrointestinal sue mass (arrows) impressing tion.
MASS, AND AIDS
radiograph shows on the gastroesophageal
a soft-tisjunc-
Following admission to the hospital, the patient developed low-grade fevers; on the second hospital day his temperature spiked to 39.5“C. A second CT scan of the abdomen demonstrated an increase in the size of the previously noted mass in the gastroesophageal junction to approximately 8 X 10 cm. Intrahepatic biliary ducts were dilated as was the common bile duct. Also noted was periportal and left para-aortic adenopathy. Following fluid replacement, a diagnostic procedure was performed.
CLINICALDISCUSSION Dr. Charles Parker: I would like to begin by asking Dr. Glazer to review the radiographs. 366
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Dr. Harvey Glazer: A radiograph from the upper gastrointestinal examination demonstrates a mass impressing on the gastroesophageal junction (Figure 1). The underlying mucosal surface appears normal. The mass is confirmed on a subsequent CT scan. In addition, several smaller soft-tissue nodules are seen in the fat adjacent to the colon and stomach. Enlarged lymph nodes are seen around the pancreas, in the porta hepatis, and in the aortocaval region (Figure 2). CT examination approximately 3 weeks later shows interval increase in the lymphadenopathy. Bile duct dilatation is also present, probably secondary to obstruction of the common bile duct by portal and peripancreatic lymphadenopathy. Dr. Parker: In summary, this is a 43-year-old homosexual man with immunologically verified acquired immunodeficiency syndrome (AIDS) since April 1988. He subsequently developed multiple upper abdominal masses. These masses have apparently progressed considerably over a less than 2-month period. Dr. Powderly will initiate the discussion. I have asked him to describe how he approaches a patient with AIDS and what his impressions are in terms of this patient’s recent clinical manifestations. Dr. William G. Powderly: Using this patient as an example of a typical patient with HIV infection, I would like to review how such patients might be approached. Note that I said an HIV-infected patient and not a patient with AIDS, because there is a spectrum of disease seen before patients present with AIDS. We see asymptomatic patients who are HIV-positive as well as patients with severe immunodepletion who present with opportunistic infection and malignancies. We therefore need to develop a consistent clinical approach to HIV infection. The first point that must be emphasized is that the primary problem in HIV disease is the profound immunodepletion that occurs. The virus has a tropism for cells bearing the CD4 surface marker, and from an immunologic viewpoint the major targets include T4 helper T lymphocytes and macrophages. Consequently, progressive destruction and loss of such cells are seen. Most if not all patients infected with HIV infection have progressive loss of T4 helper cells. When their level of T4 cells reaches a certain threshold, they lose the critical function of those cells, which is to orchestrate the host defenses by controlling macrophage, B-cell, and cytotoxic Tcell function. At this point patients are at risk for both opportunistic infection and, if we can use the term, opportunistic malignancy. For this reason the T4 count is often used as a marker for disease progression. When a patient presents with HIV infection (di89
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Figure 2. CT scan through the upper abdomen demonstrates enlarged lymph nodes (arrows) around the porta hepatis and aorta (A).
agnosed by a positive antibody and confirmed by Western blot), several questions need to be answered. (1) Is the patient asymptomatic or symptomatic? (2) What is the extent of immunologic compromise? (3) Can a diagnosis of AIDS be made? (4) If not, what is the risk of progression to AIDS in the next year, 4 years, and so on? (5) Is therapyeither licensed or experimental-now available for the patient? Let us look now at this particular case and answer those questions. The first issue is whether this patient was symptomatic. He clearly was symptomatic when he presented. He had a history of fatigue and some weight loss, which, although obviously nonspecific, can be HIV-related. He also had oral candidiasis, which in patients who are not receiving steroids or antibiotics may be a manifestation of HIV disease. The next issue is assessing the level of his immunodeficiency. Oral candidiasis does not occur in HIV-infected patients until they have some immunologic dysfunction. The best single marker available is the level of circulating T4 lymphocytes. This patient had a T4 count of 116 cells/mm3, which is profoundly depressed. The normal T4 count in a healthy population ranges from 800 to 1,200 cells/ mm3. Most asymptomatic HIV-infected individuals have T4 counts in the range of 200 to 800 cells/mm3, and the clinical syndrome of AIDS rarely develops until the T4 count drops below 300 cells/mm3. Did this patient have AIDS when he first presented? It must first be remembered that AIDS is a “catch-all” diagnostic label designed primarily as a case-finding tool to identify patients for epidemiologic purposes. AIDS is defined by the presence of certain opportunistic infections such as Pneumo(PCP) or cryptococcal cystis carinii pneumonia
meningitis, and certain malignancies such as Kaposi’s sarcoma or non-Hodgkin’s lymphoma. This patient presented with diffuse pulmonary infiltrates. If they were due to PCP or cytomegalovirus, then he could be diagnosed as having AIDS. But, by the strict criteria, he did not have AIDS when he presented in April. Of interest, a syndrome of nonspecific interstitial pneumonitis has recently been described in HIV-infected individuals [l]. Although this syndrome is a possibility in the present case, it, too, is not an AIDS-defining illness. What was the patient’s risk of progressing to AIDS? Obviously, his risk was high. With his level of T4 cells, 25% of patients will contract PCP in the next year, and the overall risk of developing an AIDS-defining illness within 12 months is about 40%. Certain prognostic factors exist [2]. The presence of AIDS-related complex (ARC), i.e., oral candidiasis, unexplained weight loss, multidermatomal herpes zoster, and persistent diarrhea, can be used prognostically. Other prognostic factors for development of AIDS include anemia on presentation, a high sedimentation rate, and, most specifically, a low T4 count or a rapidly decreasing T4 count. For this patient the final question is treatment. This case falls into the category of a group of cases for which zidovudine is clearly indicated. Zidovudine should be administered to all patients with AIDS and patients with ARC and T4 counts less than 200 cells/mm3 because its use has been shown to reduce the incidence of opportunistic infections and mortality [3]. However, zidovudine is not the answer to AIDS. Most patients do not tolerate zidovudine at its full dosage. Nausea occurs in the majority of patients in whom zidovudine treatment is begun and may be dose-limiting. More important,
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zidovudine has bone marrow toxicity: both anemia and granulocytopenia may occur [4]. Two types of anemia are associated with the drug. Many patients develop a macrocytic anemia, with megaloblastic marrow changes, which usually causes a mildly decreased hematocrit. This condition generally stabilizes and patients can continue to receive the full dosage. However, a severe aplastic or hypoplastic condition with normochromic, normocytic anemia also occurs. Its onset is often sudden, not predicted by other laboratory markers, and usually requires transfusion and dosage reduction or cessation. The development of granulocytopenia may also lead to changes in dosage. Consequently, by the end of a year, as many as 55% of patients who have initially been treated with zidovudine will no longer be able to tolerate a full dosage, and the drug will be discontinued in many [5]. This case exemplifies this major negative aspect of zidovudine. The patient did not tolerate zidovudine, and since no other antiretroviral therapy is yet available, the development of an AIDS-defining illness was likely. His final presentation probably represents this AIDS-defining illness. Although Dr. MacDermott will discuss the gastrointestinal manifestations of AIDS and HIV disease, let me give you my impressions. Although certain infections may present with lymphadenopathy, particularly mycobacterial and fungal infections, I think his adenopathy and gastric mass were more likely the result of tumor. The two tumors most likely to occur are lymphoma and Kaposi’s sarcoma. The violaceous skin lesions described in the protocol are highly suggestive of Kaposi’s sarcoma. In the presence of Kaposi’s sarcoma involving the skin, a high percentage of patients also have visceral involvement, and the gastrointestinal tract is the organ most commonly affected by visceral Kaposi’s sarcoma. Thus, I think the odds make it more likely that he had Kaposi’s sarcoma than a lymphoma, but there is no way of determining this with certainty unless a biopsy is performed. Dr. Parker: Thank you. Dr. MacDermott will now discuss the gastrointestinal manifestations. Dr. Richard MacDermott: Patients with AIDS commonly present to gastroenterologists. We most often see patients with presenting manifestations of diarrhea, malabsorption, or weight loss, or any combination of the three. A wide variety of now wellrecognized infectious agents cause the diarrhea, which may be either profuse or bloody. In some patients, weight loss and malabsorption will be the presenting manifestations of atypical mycobacteria or neoplasia. If no etiology is found, the diagnosis of AIDS enteropathy is made. The second most common gastrointestinal manifestation of AIDS is dysphagia. Dysphagia is very
often due to candidiasis, and the patient under discussion indeed had oral candidiasis. However, in this particular patient, because of the mass at the gastroesophageal junction, the dysphagia during his last admission was most likely due to the obstructing lesion. In addition to candid&is, esophagitis due to either herpes or cytomegalovirus can be seen. Dysphagia can be caused by the HIV virus itself. Usually this is at the initial onset of HIV infection and resolves as HIV is managed by the normal immune response of the individual. This patient had hepatobiliary manifestations of AIDS, a less commonly seen but nevertheless very important problem. With regard to infectious disease considerations, the most common causes of abnormalities on liver function tests are mycobacteria, fungal organisms, or viruses. It is important to be aware of the fact that most patients with AIDS have also been infected with hepatitis B virus, and thus chronic active hepatitis and/or cirrhosis unrelated to HIV often occurs in AIDS patients. In AIDS patients, the most common neoplasm involving the liver is Kaposi’s sarcoma. The second most common hepatic neoplasm in AIDS is lymphoma. This patient was noted to have dilated ducts on his last CT scan. Recent clinical studies have demonstrated that an entity similar to sclerosing cholangitis can occur in AIDS patients. Dr. John Cello and co-workers at San Francisco General Hospital have described a series of patients who have dilated intrahepatic and extrahepatic ducts. Pathologically the hepatic changes resemble sclerosing cholangitis. In a number of instances these investigators noted papillary stenosis, which was treated by sphincterotomy. The etiology of the papillary stenosis appears to have been immune-mediated, in that a chronic inflammatory infiltrate was present in the papilla. The dilated ducts in the patient under discussion could alternatively be due to obstruction with tumor. Cholangiocarcinoma, lymphoma, and Kaposi’s sarcoma would be the primary possibilities. In evaluating the AIDS patient with hepatobiliary manifestations, CT scan is used to rule out obstruction, and endoscopic retrograde cholangiopancreatography is undertaken in patients who may have obstruction. Liver biopsy is not usually of additional help if the patient already has a disseminated disease such as Kaposi’s sarcoma or lymphoma. If the patient does not have documented disseminated disease, then a liver biopsy would be of value in a patient with extensive hepatic abnormalities. With regard to the gastric mass in this patient, Kaposi’s sarcoma is the most common gastrointestinal tumor in the AIDS population. AIDS patients who have skin involvement with Kaposi’s sarcoma
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often have gastrointestinal involvement that is asymptomatic. Patients frequently present with multifocal Kaposi’s sarcoma of the gastrointestinal tract, with the stomach being the most commonly involved organ and the small intestine being the second most commonly involved organ. Endoscopy can reveal Kaposi’s sarcoma lesions in the gastrointestinal tract that appear very similar to the skin lesions. In the AIDS patient, gastrointestinal Kaposi’s sarcoma is a very aggressive tumor. Lymphoma often presents with gastric outlet obstruction. Similar to cases of Kaposi’s sarcoma in the AIDS population, the presentation is commonly multifocal with an aggressive course. Kaposi’s sarcoma of the gastrointestinal tract is often difficult to diagnose at endoscopy because it usually presents as a submucosal lesion, and therefore most of these patients require laparotomy for a definitive diagnosis. A laparotomy would be indicated in the patient we are discussing, because it is impossible to know from the information given whether the patient had Kaposi’s sarcoma, lymphoma, or both. Even if the skin biopsy were repeated and demonstrated Kaposi’s sarcoma, a laparotomy would still be needed to rule out lymphoma, which has a high incidence in patients with Kaposi’s sarcoma. Cases have been described in which both Kaposi’s sarcoma and lymphoma have been seen in the same lymph node or gastrointestinal lesion. Finally, we also need to be mindful of the fact that AIDS patients can still develop common, non-AIDS-related gastrointestinal disorders, such as metastatic adenocarcinoma. Dr. Parker: Obviously, if he did not have AIDS, diagnoses such as carcinoma of the lung, stomach, or pancreas would deserve serious consideration. He is a known smoker and certainly these are common tumors in smokers. If we make the reasonable assumption that his abdominal condition is indeed associated with AIDS, we still have to consider at least four diagnoses: lymphoma, Kaposi’s sarcoma, AIDS-related nonspecific lymphadenopathy, and lymphadenopathy or abscess formation associated with an infectious agent known to affect AIDS patients, such as Mycobacterium avium. All these disease processes are common in AIDS. Nonspecific lymphoid hyperplasia is often a presenting manifestation in AIDS patients. Not infrequently, a diagnosis of hyperplasia is made on the initial biopsy, but later biopsies show clear-cut evidence of lymphoma. However, the large size of the local lesions and the absence of generalized adenopathy make this diagnosis unlikely. Non-Hodgkin’s lymphoma is the most common form of lymphoma in AIDS patients. Lymphomas associated with AIDS may affect many organs, in-
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cluding the liver and bowel, although their most outstanding characteristic is the exceptionally high frequency of involvement of the brain. Kaposi’s sarcoma is also a common complication of AIDS. A number of features of Kaposi’s sarcoma in AIDS patients differ from the usual forms of this tumor, including its high frequency, younger average age at onset, lack of strong predilection for certain ethnic groups, much more frequent involvement of the upper part of the body, and the aggressive character of the tumor. A high predominance in males is observed in both forms of Kaposi’s sarcoma. In the patient under discussion, the character of the skin lesions strongly suggests this diagnosis. Although an earlier skin biopsy showed only chronic inflammation, negative initial biopsy results are common in this disease and by no means exclude the diagnosis. The upper abdominal findings are consistent with Kaposi’s sarcoma, although he does not have the most characteristic intestinal manifestation, which is a diffuse infiltrative lesion of the intestines. Lymph node involvement does occur in Kaposi’s sarcoma with combined histologic features of lymphoid hyperplasia and vascular proliferation similar to that found in the skin. There may also be an associated lymphoma. A variety of infections producing chronic inflammation and granulomata occur in AIDS patients as a manifestation of their decreased cellular immunity. According to two recent publications, cat scratch disease can be confused with Kaposi’s sarcoma in patients with AIDS because of the presence of violaceous skin lesions. This is an interesting but unlikely possibility. Other granulomatous infections might also be considered, but I think Kaposi’s sarcoma is the most likely diagnosis here. Since I believe this individual does indeed have Kaposi’s sarcoma, I will take this opportunity to review briefly some fascinating studies recently published in Nature on the mechanism of Kaposi’s sarcoma associated with HIV infection [6]. The viruses known to infect T cells are more or less typical retroviruses with long terminal repeats, group specific antigen genes, polymerase, and envelope protein sequences. They differ with respect to the other genes that are present. The human T-cell leukemia (type 1) virus has a gene coding for 40-, 27-, and 21kd proteins (P40, P27, and P21). These proteins appear to activate transcription and greatly stimulate replication of the virus. The P40 protein may also activate transcription of the receptor for interleukin-2 (IL-2) and perhaps of IL-2 itself. Increases in these products may result in autocrine stimulation of T-cell growth. The HIV virus produces a protein known as TAT-3, which seems to act at the post-transcriptional level to increase gene expres-
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sion. Transgenic experiments have been done injecting the TAT-3 gene into the pronucleus of fertilized mouse eggs, retransplanting these eggs into pseudopregnant females, and determining if the TAT gene is expressed in the progeny. Northern blot analyses in male and female transgenic animals indicate that the TAT gene is expressed in the skin but not elsewhere in both sexes. Hyperplasia is observed in the skin of male but not female mice expressing the TAT gene, beginning at about 4 months of age. By 12 to 18 months of age, about 15% of male mice have developed tumors. These tumors show a good deal of similarity histopathologically to Kaposi’s sarcoma lesions in humans, which are also largely limited to males. It is of further interest that the tumor cells apparently do not express the TAT3 gene. This suggests an indirect mechanism of tumor induction perhaps involving a known or unknown growth factor. Obviously these observations have important implications for the pathogenesis of tumors in patients with AIDS and eventually might have therapeutic implications as well. In conclusion, there is very little doubt that this individual has AIDS that has become complicated by an additional disease process. There is good reason to believe that the complicating disease is Kaposi’s sarcoma. Lymphoma and chronic granulomatous infection are considerably less likely. There are several diagnostic procedures that might have been performed. Despite the original negative skin biopsy result, I would have been tempted to perform another skin biopsy in an effort to avoid subjecting him to abdominal surgery. But that decision would have depended on the appearance of the skin lesions and his general condition at that time. A laparotomy with multiple biopsies would have had the 370
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Figure 3. Lower-power hematoxylin and eosin-stained section shows abnormal lymph node architecture disrupted by numerous irregular blood-filled channels. There are no normal-appearing vascular structures and the cells lining these channels appear to be proliferative (original magnification X150, reduced by 30%).
best chance of producing a definitive diagnosis, although obviously surgical procedures should be kept to a minimum in these patients. Because of the vascularity of Kaposi’s sarcoma lesions and the question of the large mass being pulsatile, I would have been reluctant to perform a blind needle biopsy of the mass.
PATHOLOGICDISCUSSION Dr. Kenneth Murphy: Several small hemorrhagic fragments of tissue were processed for routine histology. These showed a proliferation of vascular spaces and anastomosing channels in a background of large round and spindle cells (Figure 3). The extravasation of red blood cells into the surrounding stroma that is typical of Kaposi’s sarcoma was evident. At higher power, the epithelioid nature of the cells lining these vascular channels was more evident (Figure 4). Abundant hemosiderin was present. This was clearly an example of Kaposi’s sarcoma involving a mesenteric lymph node. On epidemiologic grounds, Kaposi’s sarcoma has been divided into four groups: classic, African, renal transplant-associated, and epidemic. Differing in the population, clinical characteristics, and course, the lesions appear similar at the microscopic level. Kaposi’s sarcoma was a rare tumor of soft tissues, only infrequently encountered by the average clinician or pathologist until the AIDS epidemic. Usually involving the skin, Kaposi’s sarcoma can occur in almost any site, frequently involving lymph nodes and parenchymal organs. The histogenesis of Kaposi’s sarcoma is unclear. However, ultrastructural and immunohistochemical studies point to a vascular endothelial derivation of the lesion. 89
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figure 4. High-power photomicrograph shows the epithelioid nature of cells lining the proliferative vascular spaces, the extravasation of red blood cells into adjacent tissue, and the characteristic deposits of hemosiderin (hematoxylin and eosin: original magnification X400, reduced by 30%).
Recent investigations have questioned whether Kaposi’s sarcoma is a true neoplasm [7,8]. Some evidence would suggest that the proliferation of vascular endothelium is a response to local production of a new fibroblast growth factor-like growth factor produced by HIV-infected CD4+ cells. Kaposi’s sarcoma-like lesions were produced in the skin of transgenic mice harboring the TAT gene from the HIV genome, suggesting that the transcriptional regulatory functions of the TAT gene may be involved in Kaposi’s sarcoma of the epidemic type. Final Pathologic Diagnosis: Kaposi’s sarcoma.
REFERENCES 1. Ognibene
without
FP, Masur H, Rogers P, et al. Nonspecific interstitial pneumonitis evidence of Pneumocystis carinii in asymptomatic patients infected
with human immunodeficiency virus (HIV). Ann Intern Med 1988; 109: 874 9. 2. Moss AR. Predicting who will progress to AIDS. Br Med J 1988; 297: 10678. 3. Fischl MA, Richman DD. Grieco MH, et al. The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex: a double-blind, placebo-controlled trial. N Engl J Med 1987; 318: 185-91. 4. Richman DD. Fischl MA, Grieco MH, eta/. The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. N Engl J Med 1987; 318: 192-7. 5. Dournon E, Matheron S, Rozenbaum W, et al. Effects of zidovudine in 365 consecutive patients with AIDS or AIDS-related complex. Lancet 1988; 2: 12971302. 6. Vogel J, Hinrichs SH, Reynolds RK, Luciw PA, Jay G. The HIV tat gene induces dermal lesions resembling Kaposi’s sarcoma in transgenic mice. Nature 1988; 335: 606-11. 7. Salahuddin SZ, Nakamura S, Biberfeld P, eta/. Angiogenic properties of Kaposi’s sarcoma-derived cells after long term culture in-vitro. Science 1988; 242: 430-3. 6. Nakamura S, Salahuddin SZ. Biberfeld P. et al. Kaposi’s sarcoma cells: longterm culture with growth factor from retrovirus-infected CD4+ T cells. Science 1988; 242: 426-30.
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