Marrow Granulomas in Coal Workers' Pneumoconiosis
A Histologic Study with Elemental Analysis
RICHARD J. PELSTRING, M.D., C. KURTIS KIM, M.D., ELYSE E. LOWER, M.D.,
AND STEVEN H. SWERDLOW, M.D.
The differential diagnosis of bone marrow granulomas is
lengthy but has not previously included coal workers' pneumoconiosis. This report describes the first case in which noncaseating epithelioid granulomas containing anthracotic pigment
and birefringent silica containing crystals were discovered in
the marrow of a patient with progressive massive fibrosis of
coal workers' pneumoconiosis. The silicotic nature of the crystals was confirmed using energy dispersive x-ray microanalysis. There was no evidence of a mycobacterial, fungal, or
other etiology for the granulomas. This case demonstrates that
coal workers' pneumoconiosis should be added to the differential diagnosis of bone marrow granulomas and that marrow
examination may be a source of tissue for documentation of
specific occupational exposures. (Key words: Coal worker's
pneumoconiosis; Bone marrow; Granulomas; Elemental analysis) Am J Clin Pathol 1988; 89: 553-556
EXTRAPULMONARY anthracotic and anthracosilicotic material associated with coal workers' pneumoconiosis has been described only rarely with the reported
sites of involvement limited to the liver, spleen and regional lymph nodes.7'9 The anthracotic or anthracosilicotic material has been described as being present in
macrophages but not as being associated with epithelioid granulomas.79 We report a case of a retired coal
miner with characteristic radiographic evidence of coal
workers' pneumoconiosis in whom marrow examination, as part of an anemia evaluation, revealed well
formed, noncaseating epithelioid granulomas containing anthracotic pigment as well as birefringent silica
containing crystals.
Report of a Case
An 82-year-old, nonsmoking black male miner initially presented in
1958 with dyspnea and was diagnosed as having coal workers' pneumoconiosis. He had been a shaft miner of soft coal in Glen Rodgers,
West Virginia, from 1920 to 1945. Evaluation in 1958 also revealed
Mycobacterium tuberculosis pericarditis for which he received 14
months of isoniazid, streptomycin, and para-aminobenzoic acid. With
Received April 22, 1987; received revised manuscript and accepted
for publication June 4, 1987.
Address reprint requests to Dr. Swerdlow: Department of Pathology,
U.C. College of Medicine, 231 Bethesda Avenue, Cincinnati, Ohio
45267-0529.
Department of Pathology and Laboratory Medicine and
Department of Internal Medicine, University of Cincinnati
College of Medicine, Cincinnati, Ohio
the exception of slowly progressive dyspnea and the appearance of an
iron deficiency anemia in 1978, he did relatively well until August
1981, at which time he presented with a right pleural effusion. Although pleuralfluid,sputum, gastric lavage, and urine cultures were all
negative for acid fast organisms, he was empirically treated with isoniazid and rifampin for 12 months with resolution of the effusion. Later
that year he suffered a myocardial infarction and was briefly maintained on procainamide until side effects necessitated discontinuation
of the drug. His dyspnea continued to progress, and a diagnosis of
progressive massivefibrosiswas made radiographically.
The etiology of his microcytic anemia was thought to be iron deficiency based on red blood cell indices and serum iron studies. Persistent heme positive stools made a gastrointestinal source suspect; however, he repeatedly refused endoscopic evaluation. By February 1986,
he was requiring home oxygen therapy, and his hemoglobin had
dropped to 3.72 mmol/L (6.0 g/dL). He underwent posterior iliac crest
marrow biopsy and aspiration to further evaluate the anemia. He was
given iron and discharged. He currently remains dyspneic but is otherwise asymptomatic.
Materials and Methods
Marrow examination was performed with the aspirate
used for Wright-stained smears and bacterial, mycobacterial, and fungal cultures. In addition, some of the aspirated marrow particles were filtered andfixedin B5. The
particle preparation and a B5 fixed biopsy were processed routinely and stained with hematoxylin and eosin
(H & E), periodic acid-Schiff, Prussian blue, Grocott
methenamine silver, and an acid-fast stain. The sections
were examined using routine and polarized light microscopy.
The energy dispersive x-ray microanalysis (EDXMA)
was performed using a 6-n H & E stained tissue section
as described by Johnson.6 Routinely prepared H & E
stained tissue sections were placed in xylene for six to
eight hours after the coverslips had been removed by
heating the slides over a gas burner. The sections were
then coated with U.S. P. flexible colloidon (Fisher Scientific, Fair Lawn, NJ) to make a thin film and dried
553
554
PELSTRING ET AL.
A.J.C.P.-April 19
•1 VaT « * ; '
.«*'
"^to>/
*^n* ^^
At
^
*.
FIG. 1 (left). Marrow particle preparation: Notice the well formed granuloma composed
predominantly of epithelioid histiocytes. Hematoxylin and eosin (X66).
FlG. 2 (right). Marrow particle preparation: A (upper). Notice the anthracotic pigment within the epithelioid histiocytes. Hematoxylin and eosin
(X330). B (lower). With polarized microscopy note the strongly birefringent needle-shaped particles characteristic of silicates (arrow) and the
smaller more weakly birefringent particles characteristic of free silica. Hematoxylin and eosin (X200).
overnight. Areas containing granulomas and birefringent particles were selected and cut from the glass slides
using a razor blade. The colloidon films were mounted
on a carbon disc, and the colloidon then removed using
acetone. The tissue left on the carbon disc was coated
with carbon for EDXMA (Model 7000, Kevex Corp.,
Foster City, CA), combined with scanning electron microscopy (Model ETEC Autoscan, Perkin-Elmer Corp.,
Hayward, CA).
Results
Histopathologic Findings
Multiple noncaseating granulomas were identified in
the marrow particle preparation (Fig. 1). The granulomas were composed predominantly of epithelioid histiocytes, many of which contained anthracotic pigment.
Numerous birefringent particles were also present, including brightly birefringent needle-shaped particles
characteristic of combined silica (silicates), and small,
weakly birefringent particles consistent with quartz (free
silica) (Fig. 2). Some granulomas contained admixed
lymphocytes and plasma cells. Neither multinucleated
giant cells nor necrosis were observed. Special stains for
fungal and acid fast organisms were negative.
Scanning Electron Microscopy and EDXMA
Scanning electron microscopy revealed rare elongated
particles having smooth and laminated surfaces.
EDXMA performed on a representative particle displayed a prominent silica peak with minor calcium and
potassium peaks reflecting the combined chemical
composition characteristic of silicates (Fig. 3).
Microbiologic Findings
Cultures of the marrow and sputum for mycobacteria
and fungi were all negative.
SINGLE CASE REPORTS
Vol. 89 • No. 4
555
Discussion
Coal workers' pneumoconiosis is a chronic respiratory disorder affecting approximately 10% of coal
miners.18 The disease is characterized by accumulation
of dust filled macrophages in the walls of respiratory
bronchioles and adjacent alveoli. The coal dust containing macrophage aggregates ("coal dust macules") eventually become fibrotic and can lead to focal emphysema.
Nodular lesions and progressive massive fibrosis may
also develop.5'810-12-15
Rare reports in the literature describe extrapulmonary
anthracotic and anthracosilicotic deposition in patients
with coal workers' pneumoconiosis. In an autopsy study
of 99 former coal workers, LeFevre and associates9 reported approximately 40% of spleens and 30% of livers
to have "more than trace amounts of pigment" with
19.5% of spleens and 10.4% of livers classified as having
moderate to heavy pigmentation.9 They describe black
to yellow-brown pigmented material and rare birefringent needle shaped crystals primarily confined to the
cytoplasm of macrophages within the portal tracts of the
liver and the marginal zones of the spleen. Although
such a distribution is within cells of the mononuclear
phagocyte system, they did not present any data or discuss whether pigment was present in the bone marrow.
Their proposed mechanisms of pigment transport included migration of dust laden macrophages through
pulmonary blood vessels into the systemic circulation
and the possible direct entry of ingested particles from
the gastrointestinal tract into the blood stream. Kadas
and co-workers7 analyzed the autopsy liver material in
15 coal miners with anthracosilicosis. Of these 15, only
one had demonstrable anthracosilicotic material in the
Kupfer cells of the liver. X-ray microanalysis documented the presence of silica and aluminum in addition
to the anthracotic pigment. No known series have included coal workers' pneumoconiosis in the differential
diagnosis of bone marrow granulomas.21317
Silicosis, a distinct but epidemiological^ related disorder caused by deposition of quartz crystals (free silica),
has also been shown to exhibit extrapulmonary manifestations.1-3-4"16 In most cases the extrapulmonary silicotic lesions are reported to be in the liver, spleen or
lymph nodes,1'3" although very rare cases of postmortem marrow lesions are also reported.416 These lesions
are described as inconspicuous dust-laden macrophages
containing birefringent crystals as well as fully developed fibrotic silicotic nodules.416 True epithelioid granulomas have not been described. In a review of 58 patients with marrow granulomas, Bodem and colleagues
did include one patient with a classic radiographic picture for pulmonary silicosis and no known granulomatous disease. Although they suggest the possibility of
FlG. 3. EDXMA demonstrates a prominent silica peak with minor
potassium and calcium peaks. Inset: Scanning electron micrograph of
the crystal used for analysis (X3.000).
silica as the etiology for the granulomas, they did not
demonstrate the presence of silica in the marrow.2
Marrow histologic sections from the patient reported
here demonstrated well formed noncaseating epithelioid
granulomas containing anthracotic pigment (coal dust)
and silicates. The silica component was recognized as
birefringent needle-shaped particles and then documented using EDXMA. The coexistence of coal dust
and silica is not unexpected, as silica containing particles, present as either quartz or silicates, are often contaminants of coal. Due to the limited sampling of the
crystals, the concurrent presence of quartz (free silica)
could not be excluded. Although only an association
between the coal dust and silicates and the granulomas
is demonstrated here, there was no evidence of any other
etiology for the granulomas. The patient did have a prior
history of tuberculosis, but had received two prior
courses of combined antituberculous therapy and had
negative marrow and sputum cultures during the current admission. There has been no clinical evidence of
tuberculosis during the one year since his marrow examination. The possibility of a drug related etiology might
also be considered given the history of procainamide
therapy, which has been associated with marrow granulomas'417; however, this seems extremely unlikely since
the drug had been discontinued five years prior to the
biopsy.
In summary, this case illustrates that coal workers'
pneumoconiosis should be added to the differential
diagnosis of bone marrow granulomas. In addition, it
demonstrates that marrow may be a valuable, easily accessible source of tissue for documenting certain occupational exposures. Further studies are required to determine the incidence of marrow granulomas in patients
with coal workers' pneumoconiosis and the frequency
PELSTRING ET AL.
556
with which marrow examination can provide proof of
exposure to free silica, silicates, or other injurious environmental agents.
Acknowledgments. The authors thank Ms. Naomi Hayes for secretarial assistance, Ms. Felisa Thompson for technical assistance, and
Mr. Jay Card for photographic assistance.
References
1. Belt TH: Silicosis of the spleen: A study of the silicotic nodule. J
Pathol Bacteriol 1939;49:39-45.
2. Bodem CR, Hamory BH, Taylor HM, KJeopfer L: Granulomatous bone marrow disease: A review of the literature and clinicopathologic analysis of 58 cases. Medicine 1983;62:372-383.
3. Carmichael GP, Jr., Targoff C, Pintar K, et al: Hepatic silicosis.
Am J Clin Pathol 1980;73:720-722.
4. Eide J, Gylseth B, Skaug V: Silicotic lesions of the bone marrow:
Histopathology and microanalysis. Histopathology
1984;8:693-703.
5. Heppleston AG: The essential lesion of pneumoconiosis in Welsh
coal workers. J Pathol Bacteriol 1947;59:453-460.
6. Johnson FB: Foreign substances in tissue: Histochemistry in
pathologic diagnosis. Edited by SS Spicer. New York, Marcel
Dekker, Inc., 1986, pp 103-114.
7. Kadas 1, Szende B, Csikos A, Szendroi M: Extrapulmonary localization of carbon and silica particles in anthracosilicosis. Med
Lav 1984;75:404-406.
A.J.C.P. • April 1988
8. KJeinerman J, Green F, Lapp L, et al: Pathology standards for coal
workers' pneumoconiosis. Arch Pathol Lab Med
1979;103:375-385.
9. LeFevre ME, Green FH, Joel DD, Laqueur W: Frequency of black
pigment in livers and spleens of coal workers: Correlation with
pulmonary pathology and occupational information. Hum
Pathol 1982;13:1121-1126.
10. Liebow AA: Pathology of coal workers' pneumoconiosis. Industr
Med Surg 1970;39:118-119.
11. Lynch KM: Silicosis of systemic distribution. Am J Pathol
1942;18:313-319.
12. Naeye RL, Dellinger WS: Lung disease in Appalachian soft-coal
miners. Am J Pathol 1970;58:557-564.
13. Pease GL: Granulomatous lesions in bone marrow. Blood
1956;11:720-734.
14. Riker J, Baker J, Swanson M: Bone marrow granulomas and neutropenia associated with procainamide: Report of a case. Arch
IntMed 1978;138:1731-1732.
15. Robbins SL, Cotran RS, Kumar V (eds): Environmental pathology. Pathologic basis of disease, third edition. Philadelphia, WB
Saunders Co, 1984, pp 431-437.
16. Slavin RE, Swedo JL, Brandes D, et al: Extrapulmonary silicosis:
A clinical, morphologic and ultrastructural study. Hum Pathol
1985;16:393-412.
17. Swerdlow SH, Collins RD: Marrow granulomas. Pathology of
granulomas. Edited by HL Ioachim. New York, Raven Press,
1983, pp 125-150.
18. Wyatt JP: Occupational lung diseases and inferential relationships
to general population hazards. Am J Pathol 1971;64:197-216.
Familial Hypercholesterolemia with Unusual Foamy Histiocytes
Report of a Case with Myelophthisic Anemia and Xanthoma of the Maxillary Sinus
MYONG HO NAM, M.D., JOSEPH P. GRANDE, PH.D., M.D., CHIN-YANG LI, M.D., BRUCE A. KOTTKE, M.D., PH.D.,
ALVARO A. PINEDA, M.D., AND LOUIS H. WEILAND, M.D.
Accumulation of phagocytic histiocytes with a foam cell morphology has been described in a number of diseases. Familial
hypercholesterolemia, one such disease, is characterized by
foamy histiocytic accumulation in cutaneous or tendinous xanthomas and within atheromatous lesions. This report describes
a patient with familial hypercholesterolemia who had two unusual manifestations of foamy histiocytic accumulation: a
maxillary sinus xanthoma, which presented as an expansile
mass, and diffuse bone marrow replacement with foamy histiocytes, which was associated with myelophthisic anemia. The
accumulation of foamy cells in both locations resembled that
seen in many of the storage diseases. The possibility of foamy
histiocytic accumulation should be considered in the differential diagnosis of patients with these disease entities who
present with space-occupying lesions. (Key words: Familial
hypercholesterolemia; Xanthoma; Myelophthisic anemia;
Foamy histiocyte) Am J Clin Pathol 1988; 89: 556-561
Received April 14, 1987; received revised manuscript and accepted
for publication July 17, 1987.
Dr. Nam's present address: Department of Pathology, Washington
Hospital Center, Washington, D.C.
Address reprint requests to Dr. Li: Department of Laboratory Medicine, 200 First Street, SW, Rochester, Minnesota 55905.
Department of Laboratory Medicine, Department of
Pathology, and Division of Cardiovascular Diseases and
Internal Medicine, Mayo Clinic and Mayo Foundation,
Rochester, Minnesota
PHAGOCYTIC HISTIOCYTES are derived from the
monocyte-macrophage system and are widely distributed throughout the body. Their functions include the
removal of organisms, effete cells, particles, and complex molecules. Ingested materials are then digested and
disassembled and, if necessary, processed for antibody
formation. In normal tissues, histiocytes may be difficult to find and foamy histiocytes are seldom present.
However, whenever there are excessive complex molecules, whether the basic defect is an enzyme deficiency
(as in storage diseases) or a receptor defect (as in familial
hypercholesterolemia), histiocytes actively phagocytize