—  SPECIALTY CONFERENCE  —

Pulmonary Pathology

Case 3 - Pulmonary Foreign Body Embolism and Granulomatosis Associated with Injection of Pharmaceutical Tablets

Joseph F. Tomashefski, Jr.
MetroHealth Medical Center and
Case Western Reserve University
Cleveland, Ohio, U.S.A.


Click on each slide thumbnail image for an enlarged view
Clinical History
A 40-year old African-American woman with sickle cell disease and frequent sickle cell crises died 2 weeks after hospitalization for Enterococcus cloacae sepsis. Her hospital course included respiratory failure requiring supplemental oxygen and mechanical ventilation. Echocardiogram revealed an elevated pulmonary artery pressure of 69 mm Hg. The patient was taking hydromorphone and methadone, as well as multiple other medications for pain control, and was on a patient-controlled anesthesia pump.


Case 3 - Figure 1 - H&E, low magnification
Case 3 - Figure 2 - H&E, intermediate magnification
Case 3 - Figure 3 - H&E, polarized light



Case 3 - Figure 4 - Mucicarmine stain (left panel), Movat stain (right panel)(40X magnification, both panels)
Case 3 - Figure 5 - Congo red stain, intermediate magnification
Case 3 - Figure 6 - Gomorri methenamine silver stain (left panel), Movat stain (right panel) 40X magnification, both panels)


Diagnosis
Pulmonary Foreign Body Embolism and Granulomatosis Associated with Injection of Pharmaceutical Tablets

Discussion
Foreign body embolism and granulomatosis is an important pulmonary vascular complication of intravenous drug abuse [1, 2, 3, 4] . Although a small amount of insoluble material such as talc or cotton fibers may embolize to the lung following the intravenous injection of processed narcotics, the most important cause of foreign body emboli is the intravenous injection of aqueous suspensions of pharmaceutical tablets intended for oral consumption [1, 2, 3] . Patients with indwelling venous access devices are particularly susceptible to this practice. Drugs frequently used in this manner include methadone, methylphenidate, pentazocine and hydromorphone [5, 6, 7] . Antihistamine tablets, including tripelennamine and diphenhydramine, may be injected concurrently to decrease nausea induced by the narcotic [2].

Pharmaceutical tablets contain abundant inert, insoluble, filler substances which impart bulk and physical properties to the tablet [4, 8] . These filler materials act as lubricants, binders and disintegrants which, respectively, facilitate the smooth production of tablets, promote tablet cohesiveness, and allow for rapid dispersal of the tablets when ingested. The most important materials likely to be encountered in the lung are talc, cornstarch, microcrystalline cellulose, and crospovidone [3, 4, 6, 9, 10, 11, 12, 13] (Table 1).

Table 1. Tablet Filler Substances*

Filler Shape Size Polarization Histochemistry
Cornstarch Round
Polyhedral 		8-12цm Maltese Cross PAS/D, GMS
Talc Needle-like
Platy 		5-15цm Needle-like
Stacked plates 		Unstained (H&E)
Movat (weakly blue)
Microcrystalline
Cellulose 		Rod-like
Needle-like 		25-200цm Rods
Matchstick-like 		GMS, PAS, Congo Red
Movat (yellow)
Crospovidone Globular
Coral-like 		100цm Non-polarized H&E, Mucicarmine
Congo-red
Movat (orange or green-blue)
Magnesium stearate Irregular rounded 5-10цm Positive Negative
Siliciumoxid (silica)Elongate 10-20цm Positive Negative

* Reference 9

Tablet excipients may have distinctive histochemical staining properties and/or a characteristic birefringence when viewed under polarized light, which facilitates their recognition in tissue sections (Table 1). Talc particles appear as brightly birefringent crystals having a needle-like or "stacked plate" appearance [3, 11] . Talc consistently appears light blue-green with Movat pentachrome stain. Microcrystalline cellulose particles are large, brightly birefringent, rod-like ("matchstick-like"), and often have a stacked appearance. Microcrystalline cellulose stains well with GMS (gray to black), Congo-red (orange}, and Movat (yellow}, but stains variably with PAS [6, 12, 14] . Starch granules are polyhedral and brightly birefringent with a central "Maltese-cross" pattern. Starch particles stain brilliantly with PAS and are jet black with GMS (resembling large fungal yeast forms). While most inert particles persist within the lung, starch may be metabolized and disappear over time, and has therefore been considered to be a marker of recent drug injection [11]. Crospovidone, a polymer of vinyl pyrrolidone, is non-birefringent, deeply basophilic when stained with hematoxylin and eosin, and has a convoluted, coral-like structure [13]. Crospovidone is also well demonstrated by mucicarmine and Congo-red stains [4, 13] (Table 1).

Vascular Remodeling
Inert particles induce thrombosis, intravascular inflammation, foreign body reaction, and granuloma formation [3]. Migration of foreign material and granulomas through the vascular wall occurs over time [3, 15] . Angiocentric foreign body granulomasimpart a macroscopically granular texture and appearance to the parenchyma [3, 6] . Histologically, vascular remodeling includes recanalized arteries, eccentric intimalfibrosis, and web lesions admixed with foreign material [3]. Plexiform-like and angiomatoid lesions may be seen with severe pulmonary hypertension [3, 7, 10, 12] . Infrequently, plexiform lesions occur in the absence of, or with only minimal, embolized foreign material [3]. In such instances, other causes of pulmonary hypertension like primary pulmonary hypertension, hepatic cirrhosis, HIV infection, or collagen vascular disease should be carefully excluded. Small particles which escape the lung's filtration and pass through its capillary bed may be incidentally detected at autopsy in solid viscera or observed clinically as pinpoint bright reflections on funduscopic examination [2, 3, 16] .

Parenchymal lesions
A unique form of panacinar emphysema afflicts intravenous drug users who chronically inject talc-containing pharmaceutical tablets [17, 18] . Histologically, numerous brightly birefringent interstitial talc particles are associated with perivascular fibrosis and panacinar emphysema [17, 18] . Individuals with talc-induced emphysema progress from predominantly restrictive to severe obstructive lung disease. The mechanism by which foreign-body microemboli induce emphysema may relate to repeated episodes of intracapillary neutrophil sequestration and release of inflammatory mediators and proteases [19].

Another uncommon parenchymal response to embolized foreign material is progressive massive fibrosis, resembling that seen in mineral dust pneumoconiosis [20, 21] .

Differential Diagnosis
The differential diagnosis of injectional foreign body granulomatosis includes incidental foreign body emboli associated with indwelling lines or intravascular prosthetic devices, inhalation exposures, crystallized hyperalimentation fluid, endogenous crystals and aspiration. Injectional talcosis is histologically distinguished from inhalational talcosis by the intravascular and perivascular location of talc particles as well as their size distribution. Compared to inhaled talc, pulmonary talc particles in injectional talcosis tend to be larger ( > 5ųm vs < 5ųm) [22]. Rarely, inhaled mineral additives such as silica may contribute to interstitial fibrosis in alkaloidal cocaine smokers [23, 24] .

Intravascular birefringent calcium phosphate crystals have been reported in patients on hyperalimentation [25, 26] . These crystals can be distinguished from tablet additives by histochemical stains or elemental analysis. Endogenous birefringent calcium particles in sarcoidal granulomas tend to be more amorphous than talc or cellulose and can be removed from the histologic section by acid digestion [27]. When tablet preparations are aspirated, filler materials reside within distal airspaces and are associated with acute and organizing pneumonia. Aspirated crospovidone may be confused with foci of dystrophic calcification or with the potassium binding polystyrene resin, Kayexalate [28]. Compared to crospovidone, Kayexalate has a smooth surface and is sharply angulated [28].

When necessary, the elemental composition of mineral particles can be determined by electron microscopy and energy dispersive x-ray analysis, in conjunction with characteristic ultrastructural features [29]. Raman laser and infrared spectroscopy have also been used to identify crospovidone and/or microcrystalline cellulose in tissue sections [13, 30] .

References

  1. Glassroth J, Adams GD, Schnoll S. The impact of substance abuse on the respiratory system. Chest 1987; 91:596-602.

  2. Radow SK, Nachamkin I, Morrow C, et al. Foreign body granulomatosis: Clinical and immunologic findings. Am Rev Respir Dis 1983; 127:575-80.

  3. Tomashefski JF Jr, and Hirsch CS. The pulmonary vascular lesions of intravenous drug abuse. Hum Pathol 1980; 11:133-45.

  4. Tomashefski JF Jr, Felo JA. The pulmonary pathology of illicit drug and substance abuse. Current Diagnostic Pathology 2004; 10:413-426.

  5. Pare JAP, Fraser RG, Hogg JC, Howlett JG, Murphy SB. Pulmonary 'Mainline' Granulomatosis: talcosis of intravenous methadone abuse. Medicine 1979; 58:229-39.

  6. Tomashefski JF Jr, Hirsch CS, Jolly PN. Microcrystalline cellulose pulmonary embolism and granulomatosis. A complication of illicit intravenous injections of pentazocine tablets. Arch Pathol Lab Med 1981;105:89-93.

  7. Waller BF, Brownlee WJ, Roberts WC. Self-induced pulmonary granulomatosis. A consequence of intravenous injections of drugs intended for oral use. Chest; 1980; 78:90-94.

  8. Rowe RC, Sheskey PJ, Weller PJ (ed). Handbook of pharmaceutical excipients 4th ed. Pharmaceutical Press, London, 2003.

  9. Kringsholm B, Christoffersen P. The nature and the occurrence of birefringent material in different organs in fatal drug addiction. Forensic Sci Intern 1987; 34:53-62

  10. Arnett EN, Battle WE, Russo JV, Roberts WC. Intravenous injection of talc-containing drugs intended for oral use. A cause of pulmonary granulomatosis and pulmonary hypertension. Am J Med 1976; 60:711-718.

  11. Lamb D, Roberts G. Starch and talc emboli in drug addicts' lungs. J Clin Path 1972;25: 876-881.

  12. Zeltner TB, Nussbaumer U, Rudin O, Zimmermann A. Unusual pulmonary vascular lesions after intravenous injections of microcrystalline cellulose. Virch Arch (Pathol Anat) 1982; 395:207-216.

  13. Ganesan S, Felo J, Saldana M, Kalasinsky VF, Lewin-Smith MR, Tomashefski JF Jr. Embolized crospovidone (poly[N-vinyl-2-pyrrolidone]) in the lungs of intravenous drug users. Mod Pathol 2003; 16(4):286-292.

  14. Houck RJ, Bailey GL, Daroca PJ Jr, Brazda F, Johnson FB and Klein RC. Pentazocine abuse – report of a case with pulmonary arterial cellulose granulomas and pulmonary hypertension. Chest 1980; 77:2:227-230.

  15. Puro HE, Wolf PL, Skirgaudas J and Vazquez J. Experimental production of human "blue velvet" and "red devil" lesions. JAMA, 1966; 197(13):152-154.

  16. Liu YC, Tomashefski J Jr, McMahon JT, Petrelli, M. Mineral-associated hepatic injury: A report of seven cases with x-ray microanalysis. Hum Pathol 1991; 22:1120-1127.

  17. Pare JP, Cote G, Fraser RS. Long-term follow-up of drug abusers with intravenous talcosis. Am Rev Respir Dis 1989; 139:233-241.

  18. Schmidt RA, Glenny RW, Godwin JD, Hampson NB, Cantino ME, Reichenbach D. Panlobular emphysema in young intravenous Ritalin abusers. Am Rev Respir Dis 1991; 143:649-656.

  19. Farber HW, Fairman RP, Millan JE, Rounds S, Glauser FL. Pulmonary response to foreign body microemboli in dogs: Release of neutrophil chemoattractant activity by vascular endothelial cells. Am J Respir Cell Molec Biol 1989; 1:27 -35.

  20. Crouch E, Churg A. Progressive massive fibrosis of lung secondary to intravenous injection of talc. A pathologic and mineralogic analysis. Am J Clin Pathol 1983; 80:520-526.

  21. Sienkiewicz DJ, Nidecker AC. Conglomerate pulmonary disease: a form of talcosis in intravenous methadone abusers. AJR 1980; 135:697-702.

  22. Abraham JL, Brambilla C. Particle size for differentiation between inhalation and injection pulmonary talcosis. Environ Res 1980; 21:94-96.

  23. O'Donnell AE, Mappin FG, Sebo TJ, Tazelaar H. Interstitial pneumonitis associated with crack cocaine abuse. Chest 1991; 100:1155-7.

  24. Dicpinigaitis PV, Jones JG, Frymus MM, Folkert VW. "Crack" cocaine-induced syndrome mimicking sarcoidosis. Am J Med Sci 1999; 317:416-8.

  25. Pomerance HH, Rader RE. Crystal formation: a new complication of total parenteral nutrition. Pediatr 1973; 52:864-866.

  26. Knowles JB, Cussons G, Smith M, et al. Pulmonary deposition of calcium phosphate crystals as a complication of home total parenteral nutrition. J Parent Enteral Nutr 1989;13:209-213.

  27. Reid JD, Andersen MS. Calcium oxalate in sarcoid granulomas. Am J Clin Pathol 1988; 90:545-558.

  28. Fenton JJ, Johnson FB, Przygodzki RM, Kalasinsky VF, Al-Dayel F, Travis WD. Sodium polystyrene sulfonate (Kayexalate) aspiration. Histological appearance and infrared microspectrophotometric analysis of two cases. Arch Pathol Lab Med 1996; 120:967-9.

  29. Hammar S, Williams MG, Dodson RF. Pulmonary granulomatous vasculitis induced by insolule particulates: a case report. Ultrastructural Pathology 2003; 27:439-449.

  30. Abraham J, Tomashefski JF Jr, Andersen M. Diagnosis of Munchausen syndrome using microanalytical techniques. Lab Invest 1982; 46:082