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10. Scott JK: Surgical emphysema, bilateral pneumothorax, pneumomediastinum, and pneumoperitoneum complicating intubation for anesthesia. Postarad Med J 51:654. 1975 11. Advers J: Spontaneous pneumomediastinum. J Trauma 14:414, 1974 12. Minton G, ‘RI HK: Pneumomediastinum, pneumothorax, and cervical emphysema following mandibular fractures. Oral Surg 57:490, 1984

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13. Sicher H, Du Brul EL: Oral Anatomy, 6th ed. St. Louis, CV Mosby, 1975, p 490 14. Habal MB, Beart R, Murray JE: Mediastinal emphysema secondary to fracture of orbital floor. Am J Surg 123606, 1972 15. Hamman L: Mediastinal emphysema. J Am Med Assoc 128:1, 1945 16. Munsell WP: Pneumomediastinum. J Am Med Assoc 202:689, 1%7

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Oral Kaposi’s Sarcoma in Acquired Immune Deficiency Syndrome KANYON KEENEY, DDS, NABIL A. ABAZA, DMD, MS, PhD, OTTO TIDWEL, AND PETER QUINN, DMD, MD

Acquired immune deficiency syndrome (AIDS) has become one of the most widely publicized epidemics of modern times. In 1981, the Centers for Disease Control (CDC) informed the medical community of an apparent syndrome affecting previously healthy, male homosexuals with Pneumocystis carinii pneumonia (PCP), Kaposi’s sarcoma (KS), and other severe opportunistic infections.lF2 Soon afterwards, the populations at risk were expanded to include male and female IV drug abusers and recipients of blood products.2 Currently the disease is no longer confined to these risk groups, as male and females, adults and children, including infants, are contracting AIDS. Present data suggest that AIDS is a communicable disease caused by a retrovirus that belongs to the human T-cell lymphotropic virus group. This virus has undergone name changes from HTLV-III to HTLV-IWLAV (lymphadenopathy associated virus) to HIV (human immune deficiency virus).3,4 Awareness and understanding of the scope of this extraordinarily deadly disease are vital. AIDS is characterized by a defect in cell mediated immunity that leaves the host vulnerable to a variety of opportunistic infections and neoplasms.5 Diseases most frequently associated with this synReceived from The Medical College of Pennsylvania and Hospital and School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Address correspondence and reprint requests to Dr. Abaza: Medical College of Pennsylvania, 3300 Henry Avenue, Philadelphia, PA 19129. 0278-2391/87 $0.00 + .25

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drome are PCP and KS, although other opportunistic infections are seen with great frequency. These include encephalitis, meningitis, or pneumonia caused by cryptococci, cytomegalovirus, atypical mycobacteria, Aspergillus, Candida, Nocardia, Strongyloides, and Toxoplasma organisms, as well as esophagitis caused by candida or herpes.5 There is an incredibly wide variety of events associated with the early presentation of AIDS. Beginning as an asymptomatic immune disturbance, the initial signs and symptoms are not necessarily dramatic. The latent period or prodromal manifestation of the infection may include fever of unknown origin, lymphadenopathy, diarrhea, weight loss, anorexia, respiratory difficulty, and candidiasis.5 These symptoms can continue for months to years before a more serious disease is evident. Associated immunologic abnormalities are complex and sometimes confusing yet, clearly, AIDS is a most devastating disease of the adult immune system.’ A profound defect in T-cell immunity is responsible for its clinical effects.’ The principal immunological feature is the reversal of the helper/ suppressor T-lymphocyte ratio which is often used as a marker indicating HIV exposure. It is the generalized depletion in helper/inducer T-lymphocytes that results in the lowering of this T,/T, ratio, which in normal subjects is approximately 2: 1.I Moreover, the natural killer cell activity is diminished, as is the lymphocyte proliferative response.’ Autoimmune phenomena, including lupus erythematosus and thrombocytopenic purpura, may be observed.6-8 Overall, this severe disruption of cell

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mediated immunity results in leukopenia, lymphocytopenia, anergy (such as to mumps and candida antigens), and defective lymphocyte transformation. This results in an increase in opportunistic infections, more severe than those of patients on immunosuppressive therapy, as well as an increase in tumors, diffuse non-Hodgkin’s lymphoma, and Kaposi’ s sarcoma (KS) .8 Therefore, among communicable diseases, AIDS seems to occupy a unique position because it is manifested by two different processes-opportunistic infections and cancer.9 Kaposi’s sarcoma, a type of angiosarcoma, is the major neoplastic lesion associated with AIDS. Its incidence in AIDS patients previously was thought to range between 30-50%. Recently, however, a study by Moskowitz et al.9 suggested that KS is much more common and has a wider morphologic spectrum than has been previously realized and may, in fact, be present in all AIDS patients. First described by Moritz Kaposi in 1872 as idiopathic multiple pigmented sarcoma of skin, KS has variations in its clinical manifestation, occurring within one of four distinct population groups.iO*** The four subsets described are classic, African, renal, transplant-associated, and epidemic Kaposi’s sarcomas. I1 In the classic form, KS is a rare neoplasm in the United States, North America, and Europe, occurring predominantly in patients of Mediterranean, Jewish, and Italian origin in their seventh decade of life. In the United States, its incidence was reported to be 0.02% to 0.06% of all malignant lesions.10 In the latter situations, the lesions could be multifocal, but are usually localized and frequently involve the lower extremities.2,10p11 They are classically radiosensitive and often respond to single agent chemotherapy, with a mean survival rate beyond 10 years.* In less than 10% of these patients their disease had spread to lymph nodes or viscera.2 In Africa, KS is seen either as an indolent neoplasm reminiscent of the classic disease seen in Europe and North America or as a uniquely florid, aggressive disease.” The more aggressive form of KS affects young black men of the equatorial region. In Uganda, it approaches 10% of all malignant tumors.*,” This form not only affects cutaneous and mucosal surfaces but also visceral organs and lymph nodes.* Progressing rapidly, this form of disease often results in death within one or two years from gastrointestinal tract hemorrhage. Patients with iatrogenic, pre-existing immunosuppressionthose on corticosteroids, chemotherapy, radiotherapy, or organ transplant recipients-have had an increased incidence of KS.* This variant was first noted in renal transplant patients.“*‘* It has been estimated that the incidence

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of KS in these patients has been between 150 and 200 times the expected incidence in the general population.” The course of the neoplasm ranges from localized skin lesions to a more progressive and widespread form.” Epidemic KS of AIDS also commonly follows an aggressive course involving skin and lymph nodes. Multiple organ involvement is not infrequent and mucosal involvement may be extensive.*s9 AIDS victims have thus far presented with KS lesions on the face, neck, chest and extremities, and in the abdomen, gastrointestinal mucosa, liver, lungs, diaphragm, heart, gallbladder, testes, and the oral cavity.*$13 KS is seen in nearly every mucosal, cutaneous, and lymphatic region of the head and neck.9T13,14Approximately 93% of all head and neck cases of epidemic KS in the United States have been diagnosed in homosexuals or bisexuals. ** Therapy for KS of AIDS has not been as effective as that of the classic form of KS. Treatment has included systemic chemotherapy, radiation, and immunologic reconstitution.* More frequently, however, AIDS patients die of other systemic processes associated with the syndrome before succumbing to KS.” Classic KS usually appears as asymptomatic brownish-red to purple or blue-colored patches, plaques, or nodular skin lesions, frequently located on the lower extremities, especially the ankles and soles.” However, the morphology of the lesions of epidemic KS is, much more varied than what is seen in the classic type of the disease.” The earliest faint, flat, macular lesions may rapidly become elevated, developing into papules or plaques which, when numerous, tend to occur in a bilateral symmetrical distribution along Langer’s lines. l1 Unlike classic KS lesions, the lesions of the epidemic form of the disease are often elongated, fusiform, or oval in shape.” The characteristic histopathology of all types of KS is similar regardless of the different clinical behavior seen in the various subsets.” An early and a late lesion have been described.‘1T15 In the early lesion, focal proliferation of bizarre-shaped, dilated, vascular spaces lined with endothelial cells are present in the upper portion of the dermis or the lamina propria of the mucosa. The lesions also exhibit superficial and deep perivascular mononuclear cell infiltrate composed of lymphocytes and plasma cells. Among the collagen fibers a few grouped spindle-shaped cells are seen, with characteristically few extravasated erythrocytes interspersed between them.‘O The late nodular or tumor-stage reveals a very few, thin, endothelium-lined, vascular slits that are surrounded by interweaving bundles of spindle-shaped cells. lo Extravasated

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erythrocytes and hemosiderin-laden macrophages are seen throughout the lesion.‘OJ5 In contrast to early lesions, the nodular stage has fewer inflammatory cells. *OJs Oral manifestations of KS appear commonly in over 50% of AIDS patients.15 Generally, the palate is the most common site of oral KS, although other areas of the oral cavity cannot be excluded.15 Some authors have previously commented on the similarity of oral KS and other common oral lesions. Histologically and clinically, there are cases of KS that have similarity with pyogenic granulomas and other vascular lesions such as hemangiomas.15 Previous literature also indicates that KS, including that of the oral cavity, may present as the first symptom of AIDS.*O The case presented here not only demonstrates that fact but also emphasizes the early precautions that should be undertaken with patients exposed to the known high risk factors for AIDS. Report of a Case

x 3.5 cm in size. The anterior dent&ion appeared to have been directly involved with the expansive nature of the lesion, and flaring of the dentition was noted (Fig. 1). The lesion was totally compressible and quickly resumed its expansive contour upon the removal of the pressure. There was palpable thrill to the mass and aspiration biopsy yielded what was considered to be arterial blood. Upon removal of the biopsy needle, a pulsating, bleeding vessel was noted; bleeding was controlled by the application of pressure to the biopsy site. The differential diagnoses considered focused on vascular malformations, with an arterial hemangioma as the principal diagnosis. The patient was immediately scheduled for admission and concurrent completion of a diagnostic laboratory workup to rule out any systemic diseases, to have a computed tomographic (CT) scan, and a bilateral carotid angiogram to verify the working diagnosis of a vascular malformation and to identify the feeder vessel(s) to the suspected lesion. The laboratory workup included: a CBC with differential, count serum chemistry, PT/PTT, UA, and speciality screens for hepatitis A, B, non-A, non-B, and RPRJFTA. All of the results of the routine clinical laboratory tests were well within normal limits except for positive findings for hepatitis A and B. The CT scan (Fig. 2) re-

FIGURE 1. The tumor at time of presentation of the patient. Notice the hemorrhagic nature and the purplish-brown color of the lesion.

vealed the irregular limits of the lesion, denoting invasion of the palatal space, maxillary sinus and nasal cavity, and presenting findings suggestive of an odontogenic tumor, but also clearly indicating that the mass demonstrated enhancement with a contrast medium. The bilateral carotid angiogram (Fig. 3) confirmed the highly vascular nature of the lesion within the hard palate and nasal cavity, with 80% of the vascularity being supplied mainly by the greater palatine arteries, bilaterally. Following completion of the routine laboratory and special radiographic studies, the lesion was assumed to be an arterial hemangioma. However, the clinical diagnosis of Kaposi’s sarcoma as a manifestation of AIDS was also seriously considered. The special T-cell inversion study was ordered and when received five days later it indicated an inversion. The total T-cell lymphocyte was 78%, suppressor cells was 52%, and the helper cells was 23%, with a helper/ suppressor ratio of 0.4 (normal range, 0.8-4.0). The patient was referred to a hematologist/oncologist for evaluation and workup. This workup was inconclusive, and a biopsy of the lesion was requested. A conservative incisional biopsy was completed on 15 July, 1985. A conclusive diagnosis of Kaposi’s sarcoma was unable to be made by the pathologist. The pathologist stated that the biopsy findings are insufficient for a diagnosis of Kaposi’s sarcoma or hemangioma, as in the early stages, Kaposi’s sarcoma may appear like granulation tissue. Joint consultation with attending doctors from the departments of neuroradiology, radiation therapy, hematology/oncology, and oral and maxillofacial surgery resulted in a decision to proceed with a major resection of the lesion. On August 7th, 1985, under general nasotracheal anesthesia, the lesion was approached by initially ligating the palatal arteries bilaterally. An anterior partial maxillectomy was then performed to remove the lesion in toto. Hemorrhage was brisk, with an estimated blood loss of 900 ml. Intraoral closure was attained after a separate repair of the nasal mucosa. The patient tolerated the procedure well and his postoperative course was uncomplicated. The specimen was divided in half and submitted in toto. The gross specimen consisted of a badly distorted irregular-shaped mass measuring 5.4 x 2.8 x 2 cm, which was accompanied by five noncarious incisors, several tags of necrotic tissue, and a few splinters of alveolar bone. The tumor mass was greatly distorted and showed on the surface two pale-grey, smooth mucosal areas measuring up to 2.4 x 1.8 cm in size. On dissection, the part

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FIGURE 2 (tap). Preoperative CT scans of the mass revealing (Iefr) its expansile and osteolytic nature and its encroachment into the nasal cavity (right). FIGURE 3 (borrom right). Carotid angiogram revealing the vascular&y of the tumor that is mainly provided by the greater palatine arteries.

with the necrotic dark surface was not hemorrhagic showed deep areas of bright yellow tissue.

and

Microscopically, the sections from the surgical specimen revealed a large mass of tissue with an overlying squamous mucosal epithelium that showed some areas of parakeratosis and acanthosis. In the underlying submucosal tissue, extending to the base of the rete pegs, was a large nodule composed of spindle-shaped cells and large areas of necrosis. The spindle-shaped cells appeared to form vascular slits in many areas with large numbers of red cells present (Fig. 4). There was some whirling pattern to the lesion. There appeared to be no stromal tissue and in some foci there were large collections of polymorphonuclear leukocytes and plasma cells. In one instance, giant cells were present and an asteroid body was seen. This was noted at the edge of the tissue, and the scattered plasma cells were seen more peripheryly. The spindle-shaped cells forming the neoplasm showed minimal to moderate hyperchromatism and atypicality (Fig. 5). In the depth of the lesion, the vascular components consisted of vascular slits and the plasma cells and lymphocytes were scanty (Figs. 5,6). A diagnosis of a tumor consistent with Kaposi’s sarcoma was rendered, pending special stain for the presumed cell of origin. Sutures were removed as appropriate and the patient was referred back to the radiologist for continued evalua-

tion and radiation therapy. The radiologist requested the removal of the remaining maxillary and the mandibular dentition that was felt to be nonrestorable. Surgical removal of the nonrestorable dentition was completed under local anesthesia without event. The area appeared to heal well (Fig. 7) and radiation therapy was initiated shortly thereafter. The patient received a total of 40 Gy by September 16th, 1985. The patient is alive and has been followed closely. When examined in March 1987, the patient appeared to be enjoying total remission of his primary lesion, with no evidence of recurrence of KS lesions in the mouth or elsewhere on his body. In addition, the patient has not experienced notable relapse of his immune system, and has not presented with PCP or other associated immune deficiency symptoms.

Several studies9J6J7 have shown that Kaposi’s sarcoma occurs in a large percentage of patients with AIDS. Whereas the initial prevalence was thought to range between 30-50%, studies by Moskowitz et al.,9 Whimbey et al.,” and others have

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Photomicrograph showing the FIGURE 4 (top lefr). whirling pattern of the lesion and its numerous vascular channels or slits with large numbers of red cells present. (Hematoxylin and eosin. Original magnification, X 140.) FIGURE 5 (top right). High power photomicrograph revealing whirling pattern and minimal to moderate hyperchromatism and atypicality of the cells (Hematoxylin and eosin. Original magnification, x 560.) FIGURE 6 (bottom right). High power photomicrograph from the depth of the neoplasm revealing vascular slits with red blood cells and the paucity of mononuclear cells. (Hematoxylin and eosin. Original magnification, x 560.)

shown the incidence to range in excess of 80% of those patients they studied. The timing of presentations of KS in the groups varied from early in the course of AIDS to first being discovered at postmortem examination.9J0J4 At the time of our patient’s presentation, oral KS as an initial presentation of AIDS was rarely reported. In this patient, the T-cell inversion studies were used in the initial evaluation for diagnosis of AIDS. Two tests now commonly used for HIV detection,

FIGURE 7. Postoperative photograph showing excellent healing. Note the residual oro-nasal fistula.

the ELISA (enzyme-linked immunosorbent assay) and the Western Blot test, were not used. The ELISA test is used frequently to screen for the presence of HIV antibodies in blood and blood products; the Western Blot technique is used as a confirmatory test. Both these tests manifest the typical weaknesses associated with many antibody tests. A positive ELISA test may indicate clinical or subclinical HIV infection, immunity, an active carrier state, or may represent a biologically false positive reaction as cross-reactivity to other antigens or viruses.r1J8 The Western Blot, although less sensitive than the ELISA, is more specific if positive. Together, these two tests serve only to assist in the diagnosis of AIDS as fewer than 10% of the patients who are HIV positive have developed AIDS.i9 The T-cell inversion study does not confirm the presence of HIV but does indicate an immunologic alteration that is present in AIDS. The initial clinical presentation of this patient’s lesion was that of an inflammatory and/or a vascular type lesion. Its pulsatile nature as well as the aspiration of blood from the lesion led to an initial hesitation in performing an incisional or excisional biopsy. After the subsequent CT scan and angiography were completed, a working diagnosis of ar-

820 terial hemangioma was made. The subsequent Tcell inversion studies ordered because of the sexual history led to the strong suspicion of KS despite the lesion’s deviation from the usual intraoral manifestations. Although the initial biopsy was inconclusive, examination of the subsequent surgical specimen confirmed the diagnosis. The histologic criteria for diagnosis of Kaposi’s sarcoma are under thorough investigation. Several studies1iJ5 have indicated the presence of a flat, early state and a late, tumorous stage. The early stage is generally characterized by bizarre-shaped vascular channels with intercellular infiltration by lymphocytes and plasma cells.” The late tumorous stage is predominantly characterized by thin vascular slits within interweaving bundles of spindleshaped cells with extravasation of erythrocytes and hemosiderin and few or rare inflammatory cells. l u5 It is to be stressed that the final diagnosis should take in serious consideration the associated clinical and other available laboratory data. With the prevalence of AIDS rapidly escalating and victims outside the standard risk groups increasing, the health care provider should remain increasingly aware of the early signs and symptoms of the disease and approach all patients with these signs with a high index of suspicion. These symptoms are frequently manifested in the head and neck region, especially intraorally. Thus, it is of grave importance to recognize them when they are present. In a recent study by Silverman et al.,i6 80% of those patients with AIDS had KS, of which half were intraoral. Seventy percent had oral candidiasis, and 23% had hairy leukoplakia as well as an increased incidence of other oral pathology. Our responsibility for recognition of the early signs and symptoms of AIDS is for the welfare of our patients, our protection, and the protection of our staff and colleagues. I6 Clearly as practitioners, there is a risk of exposure, but by following recent Public Health Service Guidelines, the risk is minimal.i9~20 Several studiesi9~*‘*** on health care workers have shown this to be true. Among 1500 health care workers who had sustained needlestick injuries or direct exposure to potentially infectious secretions from patients with AIDS, only three became HTLV-III positive. The risk of infection with the virus is thus very low, in marked contrast to the risk of hepatitis B virus infection (6-30%) after similar kinds of exposure.19 Yet, the recognition of early symptoms is also important for the patients, including those receiving surgery or dental work. These patients can seek supportive care, possibly improving prognosis. Patients with KS whose immune function is minimally compromised, or who are in the early stage of

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AIDS, respond more favorably to interferon treatment and also show a significantly lower rate of opportunistic infection and a longer survival.23 Since patients with AIDS and ARC (AIDS related complex) are increased surgical risks, early recognition could prevent intraoperative and postoperative complications. Idiopathic thrombocytopenic purpura, circulating coagulation inhibitors, and lupustype anticoagulants associated with these patients threaten their hemostasis (oral-palatal petechiae may be present early). 6*7Also important are precautions against the increased risk of postoperative infection, fever of unknown origin, pneumonia, urinary tract infection, and septicemia that are likely in the immunosuppressed AIDS patient.

References 1. Fauci AS, Macher AM, Longo DL, et al: Acquired immunodeficiency syndrome: epidemiologic, clinical, immunologic and therapeutic considerations. Ann Intern Med 100:92, 1984 2. Patow CA, Steis R, Longo DL, et al: Kaposi’s sarcoma of the head and neck in the acquired immune deficiency syndrome. Otolaryngol Head Neck Surg 92:255, 1984 3. Centers for Disease Control: Classification system for human T-lymphotropic virus type IIUlymphadenopathyassociated virus infections. Ann Intern Med 105:234, 1986 4. Coffin J. Haase A, Levy JA, et al: Human immunodeficiency viruses. Science 232:697, 1986 5. Garber KA, Weathers DR: Three cases of acquired immune deficiency syndrome (AIDS) with oral manifestations. Compendium Contin Educ 6:97, 1985 6. Abrams DI. Kiorov DD. Goedert JJ. et al: Antibodies to human T:lymphotropic virus type III and development of the acquired immunodeficiency syndrome in homosexual men presenting with immune thrombocytopenia. Ann Intern Med: 104:47, 1986 7. Cohen AJ, Philips TM, Kessler, CM: Circulating coagulation inhibitors in the acquired immunodeficiency syndrome. Ann Intern Med 104:175, 1986 8. Napier BL, McTighe AH, Snow JF, et al: Acquired immune deficiency syndrome presenting as oral pharyngeal and cutaneous Kaposi’s sarcoma. Laryngoscope 93: 1466, 1983 9. Moskowitz LB, Hensky GT, Gould EW: Frequency and anatomic distribution of lymphadenopathic Kaposi’s sarcoma in the acquired immunodeficiency syndrome. Human Path01 16447, 1985 10. Mostoli RS, Lagroteria LB, Harris JE, et al: Oral Kaposi’s sarcoma: an early manifestation of AIDS. Oral Health 75~59, 1985 11. DeVita Jr VT, Hellman S, Rosenberg SA: AIDS: Etiology, Diagnosis, Treatment and Prevention, 1st ed. Philadelphia, JB Lippincott, 1985, pp 58-65, 185-211 12. Penn I: Kaposi’s sarcoma in organ transplant recipients. Transplantation 27:8, 1979 13. Mitsuyasu RT, Taylor’JMG, Glaspy J: Heterogeneity of epidemic Kaposi’s sarcoma: implications for therapy. Cancer 57: 1657, 1986 14. Gnepp DR, Chandler W, Hyams V: Primary Kaposi’s sarcoma of the head and neck. Ann Intern Med 100:107, 1984 15. Green TL, Beckstead JH, Lozada-Nus F, et al: Histopathologic spectrum of oral Kaposi’s sarcoma. Oral Surg 58:306. 1984

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16. Silverman S Jr, Migliorati CA, Lozada-Nur F, et al: Oral findings in people with or at high risk for AIDS: a study of 375 homosexual males. J Am Dent Assoc 112:187, 1986 17. Whimbey E, Gold JWM, Polsky B, et al: Bacteremia and fungemia with the acquired immunodeficiency syndrome. Ann Intern Med 104:511, 1986 18. Centers for Disease Control: Provisional public health service inter-agency recommendations for screening donated blood and plasma for antibody to the virus causing acquired immunodeticiency syndrome. MMWR 34: 1, 1985. 19. Health and Public Committee, American College of Physicians and the Infectious Diseases Society of America: Acquired immunodeticiency syndrome. Ann Intern Med 104:575, 1986

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20. Center for Disease Control: Recommendations for preventing transmission of infection with human T-lymphotropic Virus type IIIilymphadenopathy-associated virus in the workplace. MMWR 34:681, 1985 21. Henderson DK, Saah AJ, Zak BJ, et al: Risk of nosocomial infection with human T-cell lymphotropic virus type III lymphadenopathy-associated virus in a large cohort of intensively exposed health care workers. Ann Intern Med 104644, 1986 22. Weiss SH, Saxinger WC, Rechtman D, et al: HTLV-III infection among health care workers. JAMA 254:2089, 1985 23. Known SE, Real FX, Vadhan-Raj S, et al: Kaposi’s sarcoma and the acquired immune deficiency syndrome. Cancer 57: 1662, 1986