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Oral manifestations of disseminated Cryptococcus neoformans in a patient with acquired immunodeficiency syndrome
Oral manifestations of disseminated Cryptococcus neoformans in a patient with acquired immunodeficiency svndrome J
Michael Glick, D.M.D.,* S. Gary Cohen, D.M.D.,** Richard T. Cheney, M.D.,*** Gary Walter Crooks, M.D.,**** and Martin S. Greenberg, D.D.S.,***** Philadelphia, HOSPITAL
OF THE
UNIVERSITY
Pa.
OF PENNSYLVANIA
A palatal lesion was the initial manifestation of disseminated cryptococcosis in a patient with acquired immunodeficiency syndrome (AIDS). The diagnosis was initially verified with cytologic smears in situ and later confirmed with pathologic findings from an excisional biopsy specimen. As cryptococcosis is one of the major opportunistic infections in persons with AIDS, an increased incidence of oral manifestations of cryptococcosis can be expected. (ORAL
SIJRG ORAL
MED
OIUL
PATHOL
1987;64:454-9)
T
he first case of cryptococcosis in a human being was reported by Buscke in 1895.’ Cases of cryptococcal meningitis were documented in the literature by 19 14,2 and since then an increased number of cases
has been recorded. Most cases of Cryptococcus neoformans infections are limited to the lungs. They occur through aspiration of airborne
spores that lodge in the lungs and
colonize in susceptible persons. A variety of symptoms may be present, including sputum production, cough, chest pain, dyspnea, fever, night sweats, and malaise. Whenever the fungus is limited to the lungs, a good prognosis can be expected. If the organism is evident on the skin or on the mucosa, dissemination via the bloodstream must be suspected since mucocutaneous lesions are rarely primary in nature.
*Oral Medicine Resident, Hospital of the University of Pennsylvania. **Director, General Practice Residency, Hospital of the University of Pennsylvania; Associate Professor of Oral Medicine, School of Dental Medicine, University of Pennsylvania. ***Fellow in Cytopathology, Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania. ****Attending Physician, Hospital of the University of Pennsylvania; Assistant Professor of Medicine, School of Medicine, University of Pennsylvania. *****Professor of Oral Medicine, University of Pennsylvania School of Dental Medicine; Chairman, Department of Dental Medicine, Hospital of the University of Pennsylvania.
454
Disseminated cryptococcosis is now being recognized with increased frequency as a result of better diagnostic procedures, wider use of immunosuppressive drugs, and the increased incidence-of acquired immunodeficiency syndrome (AIDS). As part of an ongoing interest in oral infections among immunoincompetent patients, this article discusses a case of disseminated cryptococcosis in which the initial lesion occurred intraorally. CASE
REPORT
The patient, a 25year-old black man, was admitted to the Hospital of the University of Pennsylvaniaon Oct. 2, 1986.At that time, he had increasing shortness of breath, diarrhea,
dehydration,
loss of appetite, fevers, and sweats.
He had a productive cough, no hemoptysis,and some vomiting of green, bilious material once a day for 1 week. His medical history was significant in that it included a recent diagnosis of AIDS. He had been treated for candidal pharyngitis and odynophagia in May 1986 and for Pneumocystiscarinii pneumonia in June 1986. An
allergy to penicillin wasshownby the patient. On examination, the patient had a fever of 101°F as measured rectally, a blood pressure of 140/80 mm Hg, a pulse of 100, and a respiratory rate of 24. He had a
nontender,slightly erythematouspharynx with a 1 X 1.5 cm ulceratedlesionon the hard palate that wastender to palpation.
He had two skin lesions on his lower extremities
that wereraisedand purplish,theselesionswereclinically consistent with cutaneousKaposi’ssarcoma.
Volume 64 Number 4
Oral manifestations
of disseminated
Cryptococcus neoformans in AIDS
455
Fig. 1. Ulcer located on middle-posteriorpart of hard palate wasinitial clinical feature. It wassituatedon top of an elevated,smooth,erythematous,indurated lesion3 cm in diameter. The ulcer is centrally depressedand reddish with a thick, elevatedwhite border and a diameterof 1.1 cm. The anterior palatal ulcer is one of the secondary lesions.It is mildly depressedand erythematouswith white, elevatedbordersand hasa diameterof 0.4 cm.
The remainderof his physical examinationwaswithin normallimits. His white bloodcell count was2.0 x 106/D1 with a differential of 42 polymorphonuclearleukocytes,24 bands,and 2 monocytes,and the LDH level waselevated at 780 U/L. The remainderof his laboratory valueswere normal. While hospitalized, the patient was leukopenic and neutropenic.He continuedto havefeversof up to 100°F to 103°F daily with repeatednegativebloodcultures.He was empirically treated with vancomycin, 1 gm IV every 12 hours. A dental consultation was requestedin order to evaluate his palatal lesion as a potential sourceof his fevers. The ulcer waslocatedon the middleposteriorpart of the hard palate.It wassituatedon top of an elevated,smooth, erythematous,induratedlesion3.0 cm in diameter,which waspainful to palpation. The ulcer was mildly depressed and reddishwith thick, elevated,white borders,and it had a diameterof 1.1 cm (Fig. 1). The initial differential diagnosisof the ulcer included (a) trauma, (b) aggressiveherpessimplex,and (c) chronic fungal infection. A cytologic evaluationshowednumerous cryptococci together with nonspecificinflammation. A subsequentblood culture isolateda Cryptococcusspecies, which was later identified as Cryptococcusneoformans. India ink preparation of cerebrospinal fluid (CSF) obtained via a lumbar puncture revealed Cryptococcus with a titer of 1512 for cryptococcal antigenasmeasured through a latex agglutination assay.His serumtiter was 1:16,000.The patient was started on amphotericinB, 30 mg in 250cc DSW with 50 mghydrocortisoneIV, that was infused over 4 hours every day for an initial 6-week course. Rigors developedin the patient during the first two infusions,and he was,thereafter, premeditatedwith Ben-
Fig. 2. Facial lesionsconsistentwith clinical diagnosisof disseminatedcutaneouscryptococcosis.
adryl, 50mgIV, togetherwith Tylenol, 650mgP.O., before subsequentinfusions.Viscouslidocainewasusedto alleviate the pain causedby the ulcer. Facial lesionsdevelopedin the patient and he was seenin the departmentof dermatology, wherea clinical diagnosisconsistentwith disseminated cutaneouscryptococcdsiswasmade(Fig. 2). The palatal indurationand pain resolvedwithin 12days. The initial ulcerative lesionwasstill present11 days after treatment with amphotericin B was initiated; its size remainedunchanged.The lesion was suspectedto be a sourceof dissemination.Computerizedtomography scans did not reveal any definite bone resorptionof the cribriform plate or other adjacentbonestructures(Fig. 3). An excisionalbiopsyof a 1.5 cm X 1.Ocm X 1.5 cm specimen demonstrateda continuation of the lesion into the soft palateanda certain amountof boneerosion.The resection specimendiscloseda central cavity within the soft palate extending from the mucosalsurface deep to the minor salivary glands.This cavity containedamorphous,myxoid material in which numerouscryptococci wereidentified. A sparseinflammatory infiltrate with neutrophils, lymphocytes, and histiocyteswas presentat the periphery of the lesion.Two more painlessulcers were noticed anterior to the initial palatal lesion(Fig. 1). Both of theseulcerswere 0.4 cm in diameter, mildly depressed,and erythematous
456
Oral Surg. October 1987
Glick et al.
Fig. 3. CT scan showing hard palate. It was not possible to have a diagnosis of definite resorption of the cribriform plate.
with white, elevated borders. A second cytologic evaluation again showed the presence of degenerating Cryptococcus neoformans and inflammation. The amphotericin B was eventually tolerated very well. After 7 days, the patient then began to have spiking fever curves. His serum cryptococcal antigen titer at this time was 1:16,000. A repeat CSF evaluation showed budding yeasts and a cryptococcal antigen titer of 1:256. A second facial lesion that was diagnosed as herpes simplex developed in the patient, and he was given a full course of acyclovir, 300mg IV infused over 1 hour every 8 hrs for 7 days. Ten days after the biopsy was performed, the patient remained afebrile and showed marked improvement of symptoms. The remaining palatal lesions did not diminish in size but were asymptomatic. The patient was discharged from the hospital but continued his amphoteritin B therapy, 30 mg IV twice a week, as an outpatient. Pathology
The smears of the palatal ulcer were fixed immediately in 95% ethanol and stained in a routine fashion with Papanicolaou’s stain (PAP). Initial examination revealed squamous cells, necrotic debris, and a mixed inflammatory infiltrate that included neutrophils, lymphocytes, macrophages, and numerous encapsulated yeastlike organisms. Definitive identification of these organisms was not possible with the PAP-stained preparation. The slides were destained with xylene and graded alcohols and then restained with the mucicarmine and Gomori’s methenamine silver (Grocott) techniques. The mucicarmine stain showed numerous budding, yeastlike organisms with prominent thick carminophilic capsules (Fig. 4). This morphology (narrow-based budding) and staining characteristic (carminophilic capsule) are virtually pathognomonic for Cryptococcus species. The capsule-staining quality sepa-
Fig. 4. Numerous encapsulated, budding yeastlike organisms admixed with inflammatory cells are seen. Note that the budding is narrow based and that the capsule is uniformly thick and strongly carminophilic (arrows). This morphology is consistent with C~yprococc~s species. (Mucicarmine stain. Magnification, X1000.)
rates cryptococci from other pathogenic fungi, notably Histopfasma. Final identification and species separation require isolation and biochemical verification. The excisional biopsy specimen was fixed in Bouin’s solution, processed in a routine fashion, and stained with hematoxylin and eosin, Gomori’s methanamine silver (Grocott), or mucicarmine. The specimen showed a section of palate in which there was erosion of the squamous mucosa by an expansile submucosal cavity that extended deep into minor salivary glands (Fig. 5). The cavity was filled with necrotic debris and numerous cryptococcal organisms. There was a minimal mixed acute and chronic inflammatory response at the periphery of the lesion (Fig 6). DISCUSSION
Cryptococcus neoformans is a nonmycelial budding yeast that produces a unique mutinous capsule inert. The capsule can be that is immunologically stained with periodic acid-Schiff or mucicarmine, or the organism can be stained with methanamine silver
Volume 64 Number4
Oral manifestations
of disseminated
Cryptococcus neoformans in AIDS
457
Fig. 5. Expansilecavity filled with necrotic debris and organisms,which extends from mucosalsurface deep in submucosaand minor salivary glands, is identified. An area of mucosal ulceration was present (not shown). (Hematoxylin and Eosinstain. Magnification, x200.)
Fig. 6. Peripheryof cavity demonstrates numerouscryptococcal organismsboth within cavity and infiltrating adjacent tissue.The cavity is focally lined with residual mucosawith a mild mixed inflammatory infiltrate including neutrophils, lymphocytes,and histiocytes. (Mucicarminestain. Magnification, x400.)
(Grocott).3 The yeast cell is round or elliptic, usually 4 to 6 grn in diameter. The capsule can be 1 to 30 grn or even thicker. The organism is prevalent in soil and animals. The Cryptococcus not existing in human beings is usually much smaller because it lacks the surrounding capsule. This facilitates aspiration of the yeast into the alveoli. Cryptococci have been isolated from pigeon stools, and although there exists a high natural resistance in human beings against the yeast, it is estimated that one-fourth of all pigeon breeders have had a subclinical course of a cryptococcal infection.4 An increased incidence of cryptococcal infections has been reported among immunosuppressed persons, and it constitutes one of the major opportunistic infections associated with AIDS. Of 2,995 patients in New York City in whom AIDS was diagnosed through Jan. 30, 1985, 191 (6%) had cryptococcal infection.5 Another study showed cryptococcosis in
7.5% of patients with AIDS.6 In the same study, 7 of 27 (26%) patients with cryptococcal infection exhibited cryptococcosis as the first manifestation of the syndrome. Of all AIDS patients between June 1, 1981, and Jan. 31, 1986, 7% had cryptococcosis while 63% had Pneumocystis carinii pneumonia. Twenty-four percent had Kaposi’s sarcoma, 14% had esophagitis resulting from Candida albicans, and 7% were positive for cytomegalovirus.’ These values tend to reflect initially diagnosed infections rather than subsequent infections. Thus, cryptococcal infection might be more common than reflected in the literature. The virulence of the organism probably plays a relatively small part in determining the outcome of infection. The crucial factor appears to be the immune status of the host8 Before the introduction of amphotericin B, cryptococcal meningitis was a uniformly fatal disease.9 Even with amphotericin B treatment, patients with
&a
Glick et al.
high titers of cryptoccal antigens in CSF and serum show a tendency to relapse.‘O In one study,5 a concentration of antigens in spinal fluid over l:lO,OOO showed a 100% mortality. Amphotericin B is also used with flucytosine.” The mechanism for the syngergistic interaction is not fully understood, but it may involve increased intracellular penetration of flucytosine because of damage to the cell membrane by amphotericin B. Thus, a decreased dosage of amphotericin B can be used. In this case, flucytosine was not used as decreased dosage of amphotericin B is warranted in only cases with definite short (6 to 8 week) courses, not in patients with AIDS who require indefinite therapy. In addition, this patient’s anemia, leukopenia, thrombocytopenia, or diarrhea could all have been exacerbated by flucytosine. Studies of patients with AIDS have indicated that the synergistic effect of flucytosine with amphotericin B does not always show improved therapeutic results.5*6 The organism is most frequently found in the central nervous system and in the lungs, but other involved organs include the kidney, the heart, the spleen, the pancreas, the adrenal glands, the ovaries, the lymph nodes, the skeletal muscles, the liver, and the gastrointestinal tract. Cutaneous lesions also have been described.12-I5 Oral manifestations are frequent in persons with AIDS and AIDS-related complex in whom oral candidiasis, Kaposi’s sarcoma, and hairy leukoplakia have been reported as the first clinical signs of the disease.*6-19 Other common oral manifestations are oral squamous carcinoma, xerostomia, herpes simplex virus, and venereal warts.“, 20,21 In this case, a palatal lesion was the initial manifestation of disseminated cryptococcosis. A previous case of oral cryptococcosis was reported 25 years ago22 in a person with chronic lymphocytic leukemia, but to our knowledge, this is the first case in which an oral lesion with Cryptococcus neoformans has been documented in a patient with AIDS. Littman and Zimmerman13 stated that 3% of all cases of cryptococcal infection manifestations in the mucous membrane. This can be argued today since so few cases with mucosal involvement have been documented. Clinical differential diagnosis of oral mucosal cryptococcosis may be difficult. This is because similar clinical appearances can be produced by Mycobacterium avium intracellulare,2’ herpes simplex virus, trauma, gummatous syphilis, or other fungal infections. Toxoplasmosis has been reported with the initial manifestation of intraoral lymphadenitis, while the oral manifestation of disseminated
Oral Surg. October 1987
histoplasmosis has been well documented.2”27 Distinguishing cryptococcosis from other granulomatous mycoses, in particular histoplasmosis, may be especially problematic.28 Precise data for the sensitivity and specificity of the cytology preparation are difficult to obtain. The specificity of the special stains employed (Grocott and mucicarmine) is quite high (>95%) if performed on well-prepared material and if proper controls are included. Cryptococcus is the only fungi in man that demonstrates narrow-based budding with a carminophilic capsule. The sensitivity of the cytologic preparation is, however, dependent on the quality and, perhaps, on the quantity of the material examined. A smear should be taken from the advancing edge of a suspicious lesion. Smears taken from the central portion of a lesion may reveal only necrotic debris, inflammatory cells, and degenerating organisms that may not be definitely identifiable. The smears should be fixed immediately since air-drying artifact can render a diagnosis difficult. Acid mucopolysaccharide capsules are quite sensitive to air drying and lose their characteristic morphology and staining pattern easily. The taking of several smears of a lesion may be necessary before a definitive diagnosis can be rendered. Cryptococcosis is one of the major opportunistic infections in persons with AIDS; thus, an increased incidence of oral manifestations of cryptococcosis can be expected. The dentist may be the only health professional with regular ongoing contact with these persons. His or her ability to correctly diagnose and treat oral lesions can be crucial. REFERENCES
1 Buscke A. Ueber eine durch Cocciden hervorgerufene Krankheit des Menschen. Dtsch Med Wochenschr 1895;21, 3v:14. 2. Verse M. Ueber einen Fall von generalisierter Blastomykose beim Menschen. Verh Dtsch Path01 Ges 1914;17:275-8. 3. Bennet JE. The deep mycoses. Petersdorf RG, Adams RD, Braunwald E, et al. eds. Harrison’s principles of internal medicine. 10th ed. New York: McGraw-Hill, 1983: 1056-7. 4. Holmberg K, Schonheyder H, Stenderup A. Kryptokockinfektioner-klinik. diaanostik och behandlinn. Lakartidninaen 1984;81:1831-5. 5. Zuger A, Louie E, Holzman RS, Simberkoff MS, Rahal JJ. Cryptococcal disease in patients with the acquired immunodeficiency syndrome. Diagnostic features and outcome of treatment. Ann Intern Med 1986;104:234-40. 6. Kovacs AM, Kovacs AA, Polis M, et al. Cryptococcosis in the acquired immunodeficiencv_ syndrome. Ann Intern Med _ 1985;103:533-8. 7. CDC update: acquired immunodeficiency syndrome. United States MMWR 1986;35:17-21. 8. Perfect JR, Durack DT, Gallis HA. Cryptococcemia. Medicine 1983;62:98-109. 9. Campbell GD, Currier RD, A Busey JF. Survival in untreated cryptococcal meningitis. Neurology 1981;31:1154-7.
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of disseminated
10. Diamond RD, Bennett DE. Prognostic factors in cryptococcal meningitis. A study in 111 cases. Ann Intern Med 1974; 80:176-81. 11. Bennett JE, Dismukes WE, Duma RJ, et al. A comparison of amphotericin B alone and combined with flucytosine in the treatment of cryptococcal meningitis. N Engl J Med 1979; 301:126-31. 12. Schupbach CW, Wheeler Jr CE, Briggaman RA, Warner NA, Kanof EP. Cutaneous manifestations of disseminated cryptococcosis. Arch Dermatol 1976;112: 1734-40. 13. Littman ML, Zimmerman LE. Cryptococcosis. New York: Grune & Stratton, 1956:24-30. 14. Lewis JL, Rabinovich S. The wide spectrum of cryptococcal infections. Am J Med 1972,53:315-22. 15. Baes H Van Cutsem J. Primary cutaneous cryptococcosis. Dermatologica 1985;171:357-61. 16. Lozada F, Silverman S, Migliorati CA, Conant MA, Volberding PA. Oral manifestations of tumor and opportunistic infections in the acquired immunodeficiency syndrome (AIDS): findings in 53 homosexual men with Kaposi’s sarcoma. ORAL SURG ORAL MED ORAL PATHOL 1983;56:491-4. 17. Silverman Jr S, Migliorati CA, Lozada-Nur F, Greenspan D, Conant MA. Oral findings in people with or at high risk for AIDS: a study of 375 homosexual males. J Am Dent Assoc 1986;112:187-92. 18. Klein RS, Harris CA, Butkus R, et al. Oral candidiasis in high risk patients as the initial manifestation of the acquired immunodeficiency syndrome. N Engl J Med 1984;311:3548.
19. Greenspan D, Greenspan J, Goldman H. Oral viral lesion (hairy leukoplakia) associated with acquired immunodeficiencv svndrome. MMWR 1985:341361:549-50 20. Andholo Jr M, Wolf JW, Rosenberg JS. AIDS and AIDS-
Cryptococcus neoformans in AIDS
459
related complex: oral manifestations and treatment. J Am Dent Assoc 1986;113:586-9. 21. Volpe F, Schwimmer A, Barr C. Oral manifestation of disseminated Mycobacterium avium intracellulare in a patient with AIDS. ORAL SURG ORAL MED ORAL PATHOL 1985;60:567-70.
Newman CW, Rosenbaum D. Oral cryptococcosis. J Periodontol 1962;33:266-9. 23. Appel BN, Mendelow HD, Pasqual HN. Acquired Toxoplasma lymphadenitis ORAL SURG ORAL MED ORAL PATHOL 22.
1979;47:429-32. 24.
Toth BB, Frame RR. Oral histoplasmosis: diagnostic complication and treatment. ORAL SURG ORAL MED ORAL PATHOL 1983;55:597.
Hupp JR, Layne JM, Glickman RS. Solitary palatal ulcers. J Oral Maxillofac Surg 1985;43:365-71. 26. Miller RL, Gould AR, Skolnick JL, Epstein WM. Localized oral histoplasmosis. ORAL SURG ORAL MED ORAL PATHOL 25.
1982;53:367-74.
Bennett DE. Histoplasmosis of the oral cavity and larynx. Arch Intern Med 1967;120:417. 28. Gorlin RJ, Goldman HM. Thoma’s oral pathology. Vol III. St. Louis: The CV Mosby Co, 1970:738-9. 27.
Reprint
requests
to:
Dr. Michael Glick Hospital of the University of Pennsylvania Department of Oral Medicine 3400 Spruce St. lG1 Philadelphia, PA 19 104
Michael Glick, D.M.D.,* S. Gary Cohen, D.M.D.,** Richard T. Cheney, M.D.,*** Gary Walter Crooks, M.D.,**** and Martin S. Greenberg, D.D.S.,***** Philadelphia, HOSPITAL
OF THE
UNIVERSITY
Pa.
OF PENNSYLVANIA
A palatal lesion was the initial manifestation of disseminated cryptococcosis in a patient with acquired immunodeficiency syndrome (AIDS). The diagnosis was initially verified with cytologic smears in situ and later confirmed with pathologic findings from an excisional biopsy specimen. As cryptococcosis is one of the major opportunistic infections in persons with AIDS, an increased incidence of oral manifestations of cryptococcosis can be expected. (ORAL
SIJRG ORAL
MED
OIUL
PATHOL
1987;64:454-9)
T
he first case of cryptococcosis in a human being was reported by Buscke in 1895.’ Cases of cryptococcal meningitis were documented in the literature by 19 14,2 and since then an increased number of cases
has been recorded. Most cases of Cryptococcus neoformans infections are limited to the lungs. They occur through aspiration of airborne
spores that lodge in the lungs and
colonize in susceptible persons. A variety of symptoms may be present, including sputum production, cough, chest pain, dyspnea, fever, night sweats, and malaise. Whenever the fungus is limited to the lungs, a good prognosis can be expected. If the organism is evident on the skin or on the mucosa, dissemination via the bloodstream must be suspected since mucocutaneous lesions are rarely primary in nature.
*Oral Medicine Resident, Hospital of the University of Pennsylvania. **Director, General Practice Residency, Hospital of the University of Pennsylvania; Associate Professor of Oral Medicine, School of Dental Medicine, University of Pennsylvania. ***Fellow in Cytopathology, Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania. ****Attending Physician, Hospital of the University of Pennsylvania; Assistant Professor of Medicine, School of Medicine, University of Pennsylvania. *****Professor of Oral Medicine, University of Pennsylvania School of Dental Medicine; Chairman, Department of Dental Medicine, Hospital of the University of Pennsylvania.
454
Disseminated cryptococcosis is now being recognized with increased frequency as a result of better diagnostic procedures, wider use of immunosuppressive drugs, and the increased incidence-of acquired immunodeficiency syndrome (AIDS). As part of an ongoing interest in oral infections among immunoincompetent patients, this article discusses a case of disseminated cryptococcosis in which the initial lesion occurred intraorally. CASE
REPORT
The patient, a 25year-old black man, was admitted to the Hospital of the University of Pennsylvaniaon Oct. 2, 1986.At that time, he had increasing shortness of breath, diarrhea,
dehydration,
loss of appetite, fevers, and sweats.
He had a productive cough, no hemoptysis,and some vomiting of green, bilious material once a day for 1 week. His medical history was significant in that it included a recent diagnosis of AIDS. He had been treated for candidal pharyngitis and odynophagia in May 1986 and for Pneumocystiscarinii pneumonia in June 1986. An
allergy to penicillin wasshownby the patient. On examination, the patient had a fever of 101°F as measured rectally, a blood pressure of 140/80 mm Hg, a pulse of 100, and a respiratory rate of 24. He had a
nontender,slightly erythematouspharynx with a 1 X 1.5 cm ulceratedlesionon the hard palate that wastender to palpation.
He had two skin lesions on his lower extremities
that wereraisedand purplish,theselesionswereclinically consistent with cutaneousKaposi’ssarcoma.
Volume 64 Number 4
Oral manifestations
of disseminated
Cryptococcus neoformans in AIDS
455
Fig. 1. Ulcer located on middle-posteriorpart of hard palate wasinitial clinical feature. It wassituatedon top of an elevated,smooth,erythematous,indurated lesion3 cm in diameter. The ulcer is centrally depressedand reddish with a thick, elevatedwhite border and a diameterof 1.1 cm. The anterior palatal ulcer is one of the secondary lesions.It is mildly depressedand erythematouswith white, elevatedbordersand hasa diameterof 0.4 cm.
The remainderof his physical examinationwaswithin normallimits. His white bloodcell count was2.0 x 106/D1 with a differential of 42 polymorphonuclearleukocytes,24 bands,and 2 monocytes,and the LDH level waselevated at 780 U/L. The remainderof his laboratory valueswere normal. While hospitalized, the patient was leukopenic and neutropenic.He continuedto havefeversof up to 100°F to 103°F daily with repeatednegativebloodcultures.He was empirically treated with vancomycin, 1 gm IV every 12 hours. A dental consultation was requestedin order to evaluate his palatal lesion as a potential sourceof his fevers. The ulcer waslocatedon the middleposteriorpart of the hard palate.It wassituatedon top of an elevated,smooth, erythematous,induratedlesion3.0 cm in diameter,which waspainful to palpation. The ulcer was mildly depressed and reddishwith thick, elevated,white borders,and it had a diameterof 1.1 cm (Fig. 1). The initial differential diagnosisof the ulcer included (a) trauma, (b) aggressiveherpessimplex,and (c) chronic fungal infection. A cytologic evaluationshowednumerous cryptococci together with nonspecificinflammation. A subsequentblood culture isolateda Cryptococcusspecies, which was later identified as Cryptococcusneoformans. India ink preparation of cerebrospinal fluid (CSF) obtained via a lumbar puncture revealed Cryptococcus with a titer of 1512 for cryptococcal antigenasmeasured through a latex agglutination assay.His serumtiter was 1:16,000.The patient was started on amphotericinB, 30 mg in 250cc DSW with 50 mghydrocortisoneIV, that was infused over 4 hours every day for an initial 6-week course. Rigors developedin the patient during the first two infusions,and he was,thereafter, premeditatedwith Ben-
Fig. 2. Facial lesionsconsistentwith clinical diagnosisof disseminatedcutaneouscryptococcosis.
adryl, 50mgIV, togetherwith Tylenol, 650mgP.O., before subsequentinfusions.Viscouslidocainewasusedto alleviate the pain causedby the ulcer. Facial lesionsdevelopedin the patient and he was seenin the departmentof dermatology, wherea clinical diagnosisconsistentwith disseminated cutaneouscryptococcdsiswasmade(Fig. 2). The palatal indurationand pain resolvedwithin 12days. The initial ulcerative lesionwasstill present11 days after treatment with amphotericin B was initiated; its size remainedunchanged.The lesion was suspectedto be a sourceof dissemination.Computerizedtomography scans did not reveal any definite bone resorptionof the cribriform plate or other adjacentbonestructures(Fig. 3). An excisionalbiopsyof a 1.5 cm X 1.Ocm X 1.5 cm specimen demonstrateda continuation of the lesion into the soft palateanda certain amountof boneerosion.The resection specimendiscloseda central cavity within the soft palate extending from the mucosalsurface deep to the minor salivary glands.This cavity containedamorphous,myxoid material in which numerouscryptococci wereidentified. A sparseinflammatory infiltrate with neutrophils, lymphocytes, and histiocyteswas presentat the periphery of the lesion.Two more painlessulcers were noticed anterior to the initial palatal lesion(Fig. 1). Both of theseulcerswere 0.4 cm in diameter, mildly depressed,and erythematous
456
Oral Surg. October 1987
Glick et al.
Fig. 3. CT scan showing hard palate. It was not possible to have a diagnosis of definite resorption of the cribriform plate.
with white, elevated borders. A second cytologic evaluation again showed the presence of degenerating Cryptococcus neoformans and inflammation. The amphotericin B was eventually tolerated very well. After 7 days, the patient then began to have spiking fever curves. His serum cryptococcal antigen titer at this time was 1:16,000. A repeat CSF evaluation showed budding yeasts and a cryptococcal antigen titer of 1:256. A second facial lesion that was diagnosed as herpes simplex developed in the patient, and he was given a full course of acyclovir, 300mg IV infused over 1 hour every 8 hrs for 7 days. Ten days after the biopsy was performed, the patient remained afebrile and showed marked improvement of symptoms. The remaining palatal lesions did not diminish in size but were asymptomatic. The patient was discharged from the hospital but continued his amphoteritin B therapy, 30 mg IV twice a week, as an outpatient. Pathology
The smears of the palatal ulcer were fixed immediately in 95% ethanol and stained in a routine fashion with Papanicolaou’s stain (PAP). Initial examination revealed squamous cells, necrotic debris, and a mixed inflammatory infiltrate that included neutrophils, lymphocytes, macrophages, and numerous encapsulated yeastlike organisms. Definitive identification of these organisms was not possible with the PAP-stained preparation. The slides were destained with xylene and graded alcohols and then restained with the mucicarmine and Gomori’s methenamine silver (Grocott) techniques. The mucicarmine stain showed numerous budding, yeastlike organisms with prominent thick carminophilic capsules (Fig. 4). This morphology (narrow-based budding) and staining characteristic (carminophilic capsule) are virtually pathognomonic for Cryptococcus species. The capsule-staining quality sepa-
Fig. 4. Numerous encapsulated, budding yeastlike organisms admixed with inflammatory cells are seen. Note that the budding is narrow based and that the capsule is uniformly thick and strongly carminophilic (arrows). This morphology is consistent with C~yprococc~s species. (Mucicarmine stain. Magnification, X1000.)
rates cryptococci from other pathogenic fungi, notably Histopfasma. Final identification and species separation require isolation and biochemical verification. The excisional biopsy specimen was fixed in Bouin’s solution, processed in a routine fashion, and stained with hematoxylin and eosin, Gomori’s methanamine silver (Grocott), or mucicarmine. The specimen showed a section of palate in which there was erosion of the squamous mucosa by an expansile submucosal cavity that extended deep into minor salivary glands (Fig. 5). The cavity was filled with necrotic debris and numerous cryptococcal organisms. There was a minimal mixed acute and chronic inflammatory response at the periphery of the lesion (Fig 6). DISCUSSION
Cryptococcus neoformans is a nonmycelial budding yeast that produces a unique mutinous capsule inert. The capsule can be that is immunologically stained with periodic acid-Schiff or mucicarmine, or the organism can be stained with methanamine silver
Volume 64 Number4
Oral manifestations
of disseminated
Cryptococcus neoformans in AIDS
457
Fig. 5. Expansilecavity filled with necrotic debris and organisms,which extends from mucosalsurface deep in submucosaand minor salivary glands, is identified. An area of mucosal ulceration was present (not shown). (Hematoxylin and Eosinstain. Magnification, x200.)
Fig. 6. Peripheryof cavity demonstrates numerouscryptococcal organismsboth within cavity and infiltrating adjacent tissue.The cavity is focally lined with residual mucosawith a mild mixed inflammatory infiltrate including neutrophils, lymphocytes,and histiocytes. (Mucicarminestain. Magnification, x400.)
(Grocott).3 The yeast cell is round or elliptic, usually 4 to 6 grn in diameter. The capsule can be 1 to 30 grn or even thicker. The organism is prevalent in soil and animals. The Cryptococcus not existing in human beings is usually much smaller because it lacks the surrounding capsule. This facilitates aspiration of the yeast into the alveoli. Cryptococci have been isolated from pigeon stools, and although there exists a high natural resistance in human beings against the yeast, it is estimated that one-fourth of all pigeon breeders have had a subclinical course of a cryptococcal infection.4 An increased incidence of cryptococcal infections has been reported among immunosuppressed persons, and it constitutes one of the major opportunistic infections associated with AIDS. Of 2,995 patients in New York City in whom AIDS was diagnosed through Jan. 30, 1985, 191 (6%) had cryptococcal infection.5 Another study showed cryptococcosis in
7.5% of patients with AIDS.6 In the same study, 7 of 27 (26%) patients with cryptococcal infection exhibited cryptococcosis as the first manifestation of the syndrome. Of all AIDS patients between June 1, 1981, and Jan. 31, 1986, 7% had cryptococcosis while 63% had Pneumocystis carinii pneumonia. Twenty-four percent had Kaposi’s sarcoma, 14% had esophagitis resulting from Candida albicans, and 7% were positive for cytomegalovirus.’ These values tend to reflect initially diagnosed infections rather than subsequent infections. Thus, cryptococcal infection might be more common than reflected in the literature. The virulence of the organism probably plays a relatively small part in determining the outcome of infection. The crucial factor appears to be the immune status of the host8 Before the introduction of amphotericin B, cryptococcal meningitis was a uniformly fatal disease.9 Even with amphotericin B treatment, patients with
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high titers of cryptoccal antigens in CSF and serum show a tendency to relapse.‘O In one study,5 a concentration of antigens in spinal fluid over l:lO,OOO showed a 100% mortality. Amphotericin B is also used with flucytosine.” The mechanism for the syngergistic interaction is not fully understood, but it may involve increased intracellular penetration of flucytosine because of damage to the cell membrane by amphotericin B. Thus, a decreased dosage of amphotericin B can be used. In this case, flucytosine was not used as decreased dosage of amphotericin B is warranted in only cases with definite short (6 to 8 week) courses, not in patients with AIDS who require indefinite therapy. In addition, this patient’s anemia, leukopenia, thrombocytopenia, or diarrhea could all have been exacerbated by flucytosine. Studies of patients with AIDS have indicated that the synergistic effect of flucytosine with amphotericin B does not always show improved therapeutic results.5*6 The organism is most frequently found in the central nervous system and in the lungs, but other involved organs include the kidney, the heart, the spleen, the pancreas, the adrenal glands, the ovaries, the lymph nodes, the skeletal muscles, the liver, and the gastrointestinal tract. Cutaneous lesions also have been described.12-I5 Oral manifestations are frequent in persons with AIDS and AIDS-related complex in whom oral candidiasis, Kaposi’s sarcoma, and hairy leukoplakia have been reported as the first clinical signs of the disease.*6-19 Other common oral manifestations are oral squamous carcinoma, xerostomia, herpes simplex virus, and venereal warts.“, 20,21 In this case, a palatal lesion was the initial manifestation of disseminated cryptococcosis. A previous case of oral cryptococcosis was reported 25 years ago22 in a person with chronic lymphocytic leukemia, but to our knowledge, this is the first case in which an oral lesion with Cryptococcus neoformans has been documented in a patient with AIDS. Littman and Zimmerman13 stated that 3% of all cases of cryptococcal infection manifestations in the mucous membrane. This can be argued today since so few cases with mucosal involvement have been documented. Clinical differential diagnosis of oral mucosal cryptococcosis may be difficult. This is because similar clinical appearances can be produced by Mycobacterium avium intracellulare,2’ herpes simplex virus, trauma, gummatous syphilis, or other fungal infections. Toxoplasmosis has been reported with the initial manifestation of intraoral lymphadenitis, while the oral manifestation of disseminated
Oral Surg. October 1987
histoplasmosis has been well documented.2”27 Distinguishing cryptococcosis from other granulomatous mycoses, in particular histoplasmosis, may be especially problematic.28 Precise data for the sensitivity and specificity of the cytology preparation are difficult to obtain. The specificity of the special stains employed (Grocott and mucicarmine) is quite high (>95%) if performed on well-prepared material and if proper controls are included. Cryptococcus is the only fungi in man that demonstrates narrow-based budding with a carminophilic capsule. The sensitivity of the cytologic preparation is, however, dependent on the quality and, perhaps, on the quantity of the material examined. A smear should be taken from the advancing edge of a suspicious lesion. Smears taken from the central portion of a lesion may reveal only necrotic debris, inflammatory cells, and degenerating organisms that may not be definitely identifiable. The smears should be fixed immediately since air-drying artifact can render a diagnosis difficult. Acid mucopolysaccharide capsules are quite sensitive to air drying and lose their characteristic morphology and staining pattern easily. The taking of several smears of a lesion may be necessary before a definitive diagnosis can be rendered. Cryptococcosis is one of the major opportunistic infections in persons with AIDS; thus, an increased incidence of oral manifestations of cryptococcosis can be expected. The dentist may be the only health professional with regular ongoing contact with these persons. His or her ability to correctly diagnose and treat oral lesions can be crucial. REFERENCES
1 Buscke A. Ueber eine durch Cocciden hervorgerufene Krankheit des Menschen. Dtsch Med Wochenschr 1895;21, 3v:14. 2. Verse M. Ueber einen Fall von generalisierter Blastomykose beim Menschen. Verh Dtsch Path01 Ges 1914;17:275-8. 3. Bennet JE. The deep mycoses. Petersdorf RG, Adams RD, Braunwald E, et al. eds. Harrison’s principles of internal medicine. 10th ed. New York: McGraw-Hill, 1983: 1056-7. 4. Holmberg K, Schonheyder H, Stenderup A. Kryptokockinfektioner-klinik. diaanostik och behandlinn. Lakartidninaen 1984;81:1831-5. 5. Zuger A, Louie E, Holzman RS, Simberkoff MS, Rahal JJ. Cryptococcal disease in patients with the acquired immunodeficiency syndrome. Diagnostic features and outcome of treatment. Ann Intern Med 1986;104:234-40. 6. Kovacs AM, Kovacs AA, Polis M, et al. Cryptococcosis in the acquired immunodeficiencv_ syndrome. Ann Intern Med _ 1985;103:533-8. 7. CDC update: acquired immunodeficiency syndrome. United States MMWR 1986;35:17-21. 8. Perfect JR, Durack DT, Gallis HA. Cryptococcemia. Medicine 1983;62:98-109. 9. Campbell GD, Currier RD, A Busey JF. Survival in untreated cryptococcal meningitis. Neurology 1981;31:1154-7.
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10. Diamond RD, Bennett DE. Prognostic factors in cryptococcal meningitis. A study in 111 cases. Ann Intern Med 1974; 80:176-81. 11. Bennett JE, Dismukes WE, Duma RJ, et al. A comparison of amphotericin B alone and combined with flucytosine in the treatment of cryptococcal meningitis. N Engl J Med 1979; 301:126-31. 12. Schupbach CW, Wheeler Jr CE, Briggaman RA, Warner NA, Kanof EP. Cutaneous manifestations of disseminated cryptococcosis. Arch Dermatol 1976;112: 1734-40. 13. Littman ML, Zimmerman LE. Cryptococcosis. New York: Grune & Stratton, 1956:24-30. 14. Lewis JL, Rabinovich S. The wide spectrum of cryptococcal infections. Am J Med 1972,53:315-22. 15. Baes H Van Cutsem J. Primary cutaneous cryptococcosis. Dermatologica 1985;171:357-61. 16. Lozada F, Silverman S, Migliorati CA, Conant MA, Volberding PA. Oral manifestations of tumor and opportunistic infections in the acquired immunodeficiency syndrome (AIDS): findings in 53 homosexual men with Kaposi’s sarcoma. ORAL SURG ORAL MED ORAL PATHOL 1983;56:491-4. 17. Silverman Jr S, Migliorati CA, Lozada-Nur F, Greenspan D, Conant MA. Oral findings in people with or at high risk for AIDS: a study of 375 homosexual males. J Am Dent Assoc 1986;112:187-92. 18. Klein RS, Harris CA, Butkus R, et al. Oral candidiasis in high risk patients as the initial manifestation of the acquired immunodeficiency syndrome. N Engl J Med 1984;311:3548.
19. Greenspan D, Greenspan J, Goldman H. Oral viral lesion (hairy leukoplakia) associated with acquired immunodeficiencv svndrome. MMWR 1985:341361:549-50 20. Andholo Jr M, Wolf JW, Rosenberg JS. AIDS and AIDS-
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related complex: oral manifestations and treatment. J Am Dent Assoc 1986;113:586-9. 21. Volpe F, Schwimmer A, Barr C. Oral manifestation of disseminated Mycobacterium avium intracellulare in a patient with AIDS. ORAL SURG ORAL MED ORAL PATHOL 1985;60:567-70.
Newman CW, Rosenbaum D. Oral cryptococcosis. J Periodontol 1962;33:266-9. 23. Appel BN, Mendelow HD, Pasqual HN. Acquired Toxoplasma lymphadenitis ORAL SURG ORAL MED ORAL PATHOL 22.
1979;47:429-32. 24.
Toth BB, Frame RR. Oral histoplasmosis: diagnostic complication and treatment. ORAL SURG ORAL MED ORAL PATHOL 1983;55:597.
Hupp JR, Layne JM, Glickman RS. Solitary palatal ulcers. J Oral Maxillofac Surg 1985;43:365-71. 26. Miller RL, Gould AR, Skolnick JL, Epstein WM. Localized oral histoplasmosis. ORAL SURG ORAL MED ORAL PATHOL 25.
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Bennett DE. Histoplasmosis of the oral cavity and larynx. Arch Intern Med 1967;120:417. 28. Gorlin RJ, Goldman HM. Thoma’s oral pathology. Vol III. St. Louis: The CV Mosby Co, 1970:738-9. 27.
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