Download PDF

Vol. 78 • No. 5
CASE REPORTS
neck areas. The light microscopic characterization is that
of small cell carcinoma that involves primarily the dermis. The tumor cells have scanty cytoplasm, round to
oval nuclei, and indistinct nucleoli. Ultrastructurally,
the tumor cells are characterized by having short cytoplasmic processes that contain small, round, dense-core,
membrane-bound granules. The alleged histogenetic
origin of this neoplasm is from the epidermal Merkel
cell.6 The tumor is locally aggressive and often metastasizes to regional lymph nodes from where it can disseminate, eventually causing death. The youngest patient reported so far is a 49-year-old woman.4 We are
aware of a still younger patient, unreported, that at the
time of diagnosis was thirty-five years of age. The patient
we report here is twenty-four years of age, the youngest
patient known so far to have a neuroendocrine carcinoma of the skin. The lesion was associated with a concurrent basal cell carcinoma at another site. The association of neuroendocrine carcinomas with squamous
carcinoma of the skin has been reported recently.1 In
most of these cases, squamous carcinoma was located
at the same site of the neuroendocrine carcinoma. The
simultaneous occurrence of neuroendocrine carcinoma
and basal cell carcinoma of the skin in a 24-year-old
patient is highly unusual. Whether these two tumors are
related to a common carcinogenic stimulus or are just
coincidental is not known. The relationship of these
neoplasms to the underlying congenital ectodermal dysplasia, if any, appears more obscure; no other instance
of this association is known to us. In recent review ar-
785
ticles on congenital ectodermal dysplasia, no relationship or predisposition to develop skin neoplasms is mentioned, 7 " although a previously reported patient with
ectodermal dysplasia had diffuse eccrine poromatosis.10
References
1. Gomez LG, DiMaio SM, Silva EG, Mackay B: The association
between neuroendocrine (Merkel cell) carcinoma and squamous carcinoma of the skin. Lab Invest 1981; 44:24
2. Gu J, Polak J, Tapia FJ, et al: Neuron-specific enolase in the
Merkel cells of mammalian skin. Am J Pathol 1981; 104:6368
3. Hartschuh W, Weihe E, Biicher M, et al: Met-enkephalin-like
immunoreactivity in Merkel cells. Cell Tissue Res 1979;
20:343-348
4. Sibley RK, Rosai J, Foucar E, et al: Neuroendocrine (Merkel cell)
carcinoma of the skin. Am J Surg Pathol 1980; 4:211-221
5. Sidhu GS, Feiner H, Flotte TJ, et al: Merkel cell neoplasms. Histology, electron microscopy, biology, and histogenesis. Am J
Dermatopathol 1980; 2:101-119
6. Silva EG, Mackay B: Neuroendocrine (Merkel cell) carcinoma of
the skin. An ultrastructural study of nine cases. Ultrastructural
Pathology 1981;2:1-10
7. Soloman LM, Kener EJ: The ectodermal dysplasias. Problems of
classification and some newer syndromes. Dermatol 1980;
116:1295-1299
8. Tang C, Toker C: Trabecular carcinoma of the skin. Cancer 1978;
42:2311-2321
9. Toker C: Trabecular carcinoma of the skin. Arch Dermatol 1972;
105:107-110
10. Wilkinson RD, Schopflocher P, Rozenfeld M: Hidrotic ectodermal dysplasia with diffuse eccrine poromatosis. Arch Dermatol
1977; 113:472-476
11. Witkop CG, Brearley LJ, Gentry WC: Hypoplastic enamel, onycholysis, and hypohidrosis inherited as an autosomal dominant trait: A review of ectodermal dysplasia syndromes. Oral
Surg 1975;39:71-86
Systemic Visceral Talc Granulomatosis Associated with
Miliary Tuberculosis in a Drug Addict
RENATO MARIANI-COSTANTINI, M.D., FRANK S. JANNOTTA, M.D., AND FRANK B. JOHNSON, M.D.
Light and scanning electron microscopic study of tissues obtained at biopsy and at autopsy from a 64-year-old male drug
addict revealed the presence of foreign body granulomas associated with birefringent crystals in the lungs, liver, bone
marrow, spleen, and lymph nodes. Caseating granulomas associated with Myeobacteriaceoe tuberculosis were also present.
Energy dispersive X-ray analysis identified the crystals as talc.
Received August 19, 1981; received revised manuscript and accepted for publication May 10, 1982.
Address reprint requests to Dr. Johnson: Department of Chemical
Pathology, Armed Forces Institute of Pathology, Washington, D.C.
20306.
Department of Pathology, George Washington University
Medical Center and Department of Chemical Pathology,
Armed Forces Institute of Pathology, Washington, D.C.
Minute talc crystals were also visualized in urine sediment, by
scanning electron microscopy and identified by energy dispersive X-ray analysis. (Key words: Granuloma; Drug addiction;
Talc; Energy dispersive X-ray analysis; Urinary crystals) Am
J Clin Pathol 1982; 78: 785-789
PULMONARY and more rarely hepatic granulomas
due to microcrystalline emboli in drug addicts have been
0002-9173/82/1100/0785 $01.05 © American Society of Clinical Pathologists
MARIANI-COSTANTINI ET AL.
786
documented by previous reports in the English literature. 4 ' 5 ' 7,810131417 They are caused by the particulate
filler material present in pharmacologic preparations intended for oral use but illicitly administered intravenously. The principal filler able to produce granulomatous lesions is talc (hydrous magnesium silicate:
Mg3Si4Oio(OH)2.13 Talc-containing pharmaceuticals
that have been used intravenously by drug offenders include methadone, morphine, methylphenidate, tripelennamine, and propoxyphene.1314
This paper presents an unusual case of widespread
visceral talc granulomatosis studied in biopsy and autopsy tissue by both light and scanning electron microscopy. We also report here the elimination of talc
crystals in the urine. The mineralogic identity of the
crystalline particles has been confirmed by energy dispersive X-ray analysis.3
Report of a Case
The patient was a 64-year-old male, retired, black, construction
worker with a past medical history of intravenous drug abuse and of
severe chronic obstructive pulmonary disease. He was hospitalized for
evaluation and treatment of fever and dyspnea. The chest X-ray revealed interstitial and alveolar infiltrates in the upper lobes of both
lungs, chronic fibrotic changes, and increased pulmonary radiolucency. The arterial blood gases were: Poj 52 mmHg, Pco, 30 mmHg,
and pH 7.53. Multiple blood, urine, sputum, and bronchial washing
cultures for bacteria, mycobacteria, and fungi were negative. The PPD
was also negative. The clinical question became one of excluding
anergic miliary tuberculosis. For this reason, liver and bone marrow
biopsies were performed, both of which revealed crystal-containing
granulomas. The patient died two days later because of massive gastric
hemorrhage due to a penetrating ulcer.
Pathologic Findings
At autopsy, the lungs had a combined weight of 1,800
g, and revealed marked interstitial fibrosis, and panacinar and centrilobular emphysema. Multiple white
nodules measuring from 0.1 to 0.3 cm were present on
the pleural and cut surfaces. The heart weighed 310 g.
The right ventricle was dilated and hypertrophic. The
liver weighed 2,000 g. and was moderately firm. The
spleen was also firm and weighed 350 g. The abdominal,
retroperitoneal, thoracic, axillary, and inguinal lymph
nodes were enlarged, white, and rubbery. Samples of
bone marrow (vertebral column, ribs, sterum, iliac
crests) were grossly not remarkable. The antecubital
veins of both arms were grossly obliterated and fibrotic.
By light microscopy, the lungs revealed disruption of
the alveolar septa with formation of large air spaces,
striking septal, perivascular, and peribronchial fibrosis,
and randomly located areas of nodular fibrosis. In addition, a prominent feature was the presence of foci of
caseous necrosis. Multiple foreign body (noncaseating)
granulomas were present within the fibrotic areas and
in the alveolar septa. Colorless, clear, needle-shaped or
flat, birefringent crystals, single or in clusters, measuring
A.J.C.P. • November 1982
from 2 to 17 fi in length, were visualized within the granulomas. The pulmonary arteries (small and medium
sized) and the arterioles were tortuous and showed organized thrombosis, intimal proliferation, eccentric fibrosis, and medial hypertrophy. Granulomas containing
birefringent crystals were present in intraluminal, intramural, and perivascular positions (Fig. 1). The foci of
caseous necrosis were often demarcated by histiocytes
and Langhans giant cells and contained acid-fast bacilli,
identified on culture as Mycobacteriaceae tuberculosis.
The liver revealed advanced portal fibrosis. The connective tissue of the portal areas contained innumerable
needle-shaped, birefringent crystals, foreign body giant
cells, foamy histiocytes, and a few lymphocytes, at times
forming granulomas. Noncaseating granulomas, most
bearing birefringent crystals, and caseating granulomas
containing acid-fast bacilli and rare or no crystals, were
scattered in the parenchyma (Fig. 2). The spleen revealed
innumerable birefringent crystals within histiocytic cells
and multiple granulomas, some containing crystals and
some with caseous necrosis. The abdominal, retroperitoneal, thoracic, axillary, and inguinal lymph nodes
showed densefibrosiswith rare birefringent crystals and
granulomas, some with caseation. The bone marrow
showed scattered granulomas, containing foamy histiocytes, few giant cells and crystals. Some granulomas
showed early caseation, but no acid-fast bacilli were visualized. The crystals found in the liver, spleen, and
bone marrow measured from 2 to 10 n in length.
The kidneys revealed scattered caseating granulomas
with acid-fast bacilli and no birefringent crystals. A few
isolated crystals were noted within glomerular capillaries
and in the interstitium. The myocardium showed a few
isolated, birefringent crystals in the interstitium, free or
within histiocytes. The thyroid showed caseating granulomas with no crystals. Microscopic examination of
the eyes revealed a few birefringent crystals in capillaries
in the retina and optic nerve. The antecubital veins
showed large perivenous and intravenous foreign body
granulomas containing innumerable, needle-shaped or
flat, birefringent crystals. Parathyroids, adrenals, hypophysis and central nervous system were normal microscopically.
Scanning Electron Microscopy and Mineralogic
Analysis
Scanning electron microscopy was performed on a
portion of bone marrow aspirate obtained from the right
iliac crest three days prior to death and on a digested
sediment of liver parenchyma obtained at autopsy. Energy dispensive X-ray analysis (EDXA) was also carried
out on the bone marrow sample. Sediment from the
digestion of hepatic tissue in 1.0 N NaOH and deparaffinized sections of bone marrow aspirate were mounted
on spectrographically pure carbon. These were coated
Vol. 78 • No. 5
CASE REPORTS
FIG. 1 (upper, left). Lung, periarterial foreign body granulomas. Note birefringent crystals, single or clustered.
Hematoxylin and eosin (partially polarized light X300).
FIG. 2 (upper, right). Liver, portal fibrosis with foreign body granulomas, birefringent crystals, and adjacent intralobular,
caseating granulomas. Hematoxylin and eosin (partially polarized light X300).
FIG. 3 (lower, left). Liver, collection of flat crystals morphologically consistent with talc (scanning electron microscopy X5,000).
FIG. 4 (lower, right). Energy dispersive X-ray analysis spectrum of crystals in carbon coated liver section. Note peaks
for magnesium and silicon (from left to right).
787
MARIANI-COSTANTINI ET AL.
788
A.J.C.P. • November 1982
with carbon (liver sediment) or gold (bone marrow sections), and examined using a Philips 401 scanning electron microscope. Aggregates of crystals with the typical
foliate morphologic features of talc were visualized (Fig.
3) and subjected to EDXA. Only magnesium and silicon
were detected in significant quantity (Fig. 4). The relative heights of the peaks were typical of talc. The association of the crystalline morphologic features with
the EDXA findings was characteristic of talc.
Urine was collected in sterile containers during the
last few days of life. Five hundred milliliters of urine
were centrifuged at 3,000 rpm for 15 minutes. The sediment, washed twice with distilled water, was preserved
in 95° alcohol and smeared on slides for light microscopic examination, as well as mounted on spectrographically pure carbon and coated with carbon for
scanning electron microscopy. Scanning electron microscopy of this sediment demonstrated foliate, laminated crystals consistent with talc. EDXA on these crystals revealed only magnesium and silicon. Light microscopic examination of the urine sediment revealed a few
minute crystals consistent with talc.
spleen, bone marrow, and systemic lymph nodes. The
frequency of the crystals present in the lungs and in the
visceral organs of this individual suggests a long and
heavy exposure, which was probably achieved through
frequent intravenous injections of oral pharmaceuticals.14
The systemic talc embolization may be related to the
largely obliterated and disrupted pulmonary septal capillary bed leading to the formation of arteriovenous
shunts. It appears that only the smaller crystals (2-10
fi in length) were able to spread systemically. The larger
crystals (10—17 ^t) remained localized in the lungs.
Whether the active tuberculous lesions contributed to
the mobilization of the talc is a possibility that cannot
be proven. However, most of the extrapulmonary granulomas were of recent origin, being formed by macrophages and giant cells with absent or scarcefibrosis.This
suggests a causal relationship between the necrotizing
pulmonary tuberculosis and the systemic dissemination
of talc. The massive involvement of the systemic macrophages in the uptake of crystals may have also been
a factor facilitating the spread of Mycobacterium tuberculosis.
Discussion
Assuming random dispersion of the crystals in the
vascular system, granulomas would be expected in every
organ. However, no talc-related lesions were documented in this case in numerous sections of central nervous system, including the choroid plexuses and the
hypophysis. Only a few crystals were present in the
myocardium, in the retina and optic nerve, and in the
kidneys. In contrast, the lungs, spleen, liver, bone marrow, and lymph nodes demonstrated abundant crystals
and granulomas.
The presence of phagocytic histiocytes was a common
denominator of the organs in which there was a heavy
concentration of talc particles and related pathologic
characteristics. In addition, the lungs acted as the primary filter following intravenous administration.
The presence of talc particles in the .urine demonstrates that talc crystals may pass through the glomerular
capillary bed. This finding is consistent with the observations of Cook and Olson2 relating to the finding of
amphibole asbestos fibers and other mineral particles in
the urine in cases where these were ingested with drinking water.
•In conclusion, talc crystals should be regarded as a
possible cause of systemic granulomatosis and should
be considered in the differential diagnosis of granulomatous lesions. In addition, this case suggests the possibility of detecting talc crystals in the urine of cases of
systemic talc embolization.
The . intravenous administration of pharmacologic
preparations containing talc crystals is known to produce pulmonary angiothrombosis, foreign body granulomas, and pulmonaryfibrosisin durg addicts.4'5'8'10'1314,17
These changes lead to pulmonary hypertension11015 and
may progress12" to cardiorespiratory insufficiency'and
death.10 The pulmonary vascular bed acts as a filter,
retaining the crystalline particles, so that in the majority
of cases the pathologic lesions due to talc are limited to
the lungs. However, the presence of extrapulmonary,
visceral lesions proves that the crystals are able to escape
the pulmonary filter, either because advanced pulmonaryfibrosisand angiothrombosis lead to the formation
of arteriovenous shunts or because preexisting cardiac
defects allow right to left vascular shunting.1416 Reported cases of extrapulmonary, visceral talcosis demonstrated minute crystals found sparsely in the spleen
and in the interstitial tissue of the myocardium and kidneys.14"17 These crystals have been thought to be unable
to produce significant damage.14 In contrast, hepatic
granulomas attributed to talc have been reported in drug
offenders.6'916 In one case,6 the crystalline particles have
been identified as talc by X-ray diffraction, and the
pathologic changes described consisted of portal fibrosis
and chronic triaditis with collections of crystal-bearing
macrophages.
Our case demonstrates that intravenously administered talc is capable of producing granulomatous lesions
not only in the lungs and in the liver, but also in the
Acknowledgments. The authors wish to thank Ms. Sophie Turner
for excellent technical assistance.
CASE REPORTS
Vol. 78 • No. 5
References
1. Bainborough AR, Jericho KWF: Cor pulmonale secondary to talc
granulomata in the lungs of a drug addict. Can Med Assoc J
1970; 103:1297-1298
2. Cook PM, Olson GF: Ingested mineral fibers: elimination in human urine. Science 1979; 204:195-198
3. Fumahashi A, Siegesmund KA, Dragan RF, et al: Energy dispersive analysis in the study of pneumoconioses. Br J Ind Med
1977;34:95-101
4. Hopkins GB: Pulmonary angiothrombotic granulomatosis in drug
offenders. JAMA 1972; 221:909-911
5. Hopkins GB, Taylor DG: Pulmonary talc granulomatosis: a complication of drug abuse. Am Rev Respir Dis 1970; 101:101 —
104
6. Ishak BW, Ishak KG: Foreign-body reaction in the liver of a drug
addict. J Forensic Sci 1969; 14:515-520
7. Johnston WH, Waiman J: Pulmonary corn starch granulomas in
a drug user. Arch Pathol 1971; 92:196-202
8. Kramer L: Parenteral talcum granulomatosis: a complication of
narcotic addiction. Lab Invest 1962; i 1:671
789
9. Lancet editorial: Granulomas of the liver. Lancet 1975; 2:10791080
10. Lewman LV: Fatal pulmonary hypertension from intravenous
injection of methylphenidate (Ritalin) tablets. Hum Pathol
1972; 3:67-70
11. Miller A, Teirstein AS, Bader ME, Bader RA, SelikofT IJ: Talc
Pneumoconiosis. Am J Med 1971; 50:395-402
12. Napoli LD, Citgay SO, Twigg HL, et al: The lungs and drug abuse.
Am Fam Physician 1974; 9:90-98
13. Siegel H: Human pulmonary pathology associated with narcotics
and other addictive drugs. Hum Pathol 1972; 3:55-66
14. Tomashefski JF, Hirsch CS: The pulmonary vascular lesions of
intravenous drug abuse. Hum Pathol 1980; 11:133-145
15. Wendt VE, Puro HE, Shapiro J, Mathews W, Wolf PL: Angiothrombotic pulmonary hypertension in addicts. "Blue velvet"
addiction. JAMA 1964; 188:755-757
16. Whan Min K, Gyorkey F, Cain GD: Talc granulomata in liver
disease in narcotic addicts. Arch Pathol 1974; 98:331-335
17. Zientara M, Moore S: Fatal talc embolism in a drug addict. Hum
Pathol 1970; 1:324-327.
Postpartum Hemophilia
BARRY S. SHITAMOTO, M.D., KEVIN O. LESLIE, M.D., AND WILLIAM B. GALLOWAY, M.D.
An acquired circulating inhibitor to Factor VIII:C was found
in a 27-year-old postpartum woman who presented with ecchymoses and hematomas. Postpartum Factor VIII:C inhibitors can clinically manifest with signs and symptoms not unlike
those in a classic hemophiliac. The natural history of this inhibitor is typically one of spontaneous disappearance with the
return of the patient's previous hemostatic capacity. The authors describe a patient with the postpartum Factor VIII:C
inhibitor, and discuss this unusual disease entity along with
the therapeutic considerations. (Key words: Circulating inhibitor; Factor VIII) Am J Clin Pathol 1982; 78: 789-791
ACQUIRED CIRCULATING INHIBITORS to antihemophiliac globulin (Factor VIII:C) in the postpartum
patient are very rare. Approximately 30 cases have been
reported to date. Accurate diagnosis of this condition
is important to the institution of appropriate therapy,
as well as to the prediction of the natural course of the
disease in affected patients. In this report, we present a
patient with a postpartum Factor VIII:C inhibitor, along
with a brief review of the cjinical and laboratory characteristics of this disorder.
Received April 7, 1981; received revised manuscript and accepted
for publication May 28, 1982.
Supported in part by a gift from the R. J. Reynolds Industries, Inc.
Address reprint requests to Dr. Shitamoto: Dept. of Laboratory
Medicine and Pathology, 4540 Garfield Avenue South, University of
Minnesota, Minneapolis, Minnesota 55455.
Division of Blood Bank and Hematology, Denver General
Hospital Department of Pathology, University of Colorado
Health Sciences Center, Denver, Colorado
Report of a Case
A 27-year-old white woman, was admitted to Denver General Hospital five months postpartum with fever, chills, hematuria, and sharp
pains in her right side which radiated to the pelvis. During the threeweek period prior to admission, she had developed a swollen, painful
left calf, followed by the development of several painful bruises on the
left hand, elbow, axilla, and right wrist. The patient had never manifested these symptoms previously. The patient had recently been on
birth control pills, however, and stopped taking these four days prior
to admission. The past medical history is pertinent for an uncomplicated delivery of a term 2,280-g, female infant. The family history is
unremarkable.
Physical examination on admission was pertinent for multiple swollen, tender ecchymoses present over the hands, upper arms, axillae,
and right buttock. A test for occult stool blood was positive. The
remainder of the physical examination was unremarkable.
Laboratory assessment revealed normal electrolytes, the hematocrit,
37.1%; the hemoglobin, 11.5 g/dL; the erythrocyte sedimentation rate,
43 mm/hr; the platelet count, 295,000/mm3; the bleeding time, 7
minutes. Other coagulation data are shown in Table 1. The antinuclear
antibody and rheumatoid factor were negative. Liver function tests
were normal. A chest x-ray was unremarkable, and an intravenous
pyelogram was normal.
The patient's first day of hospitalization included acute lower extremity intramuscular bleeding and a drop in the hematocrit to 26%.
0002-9173/82/1100/0789 $00.95 © American Society of Clinical Pathologists