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Cutaneous mercury granuloma
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Cutaneous mercury granuloma* A clinicopathologic study and review of the literature G. P. Lupton, Lieutenant Colonel, MC, USA,** G. F. Kao, M.D., F. B. Johnson, M.D., J. H. Graham, M.D., and E. B. Helwig, M.D.
Washington, DC Cutaneous mercury granulomas are rarely encountered. Clinically they pose difficulty in diagnosis when there is no clear history of penetrating injury by objects containing metallic mercury. Histologic, chemical, and scanning electron microscopic studies of such cutaneous lesions were performed on four cases from the Armed Forces Institute of Pathology files. Reported cases from the literature were reviewed. Metallic mercury in tissue sections appears as dark, opaque globules, usually spherical in shape and of varying sizes and numbers. A zone of collagen necrosis often surrounds the mercury globules. A granulomatous foreign body-giant cell reaction and a mixed inflammatory cellular infiltrate composed of neutrophils, lymphocytes, histiocytes, plasma cells, and occasional eosinophils are usually present. Epidermal and dermal necrosis, with or without ulceration or pseudoepitheliomatous hyperplasia, is also a common finding. The gold lysis test and energy-dispersive x-ray analysis confirmed the presence of metallic mercury in the tissue. Following cutaneous injury from mercury, systemic toxicity may develop and death may even occur. An approach to clinical management is discussed. (J AM ACAD DERMATOL12:296-303, 1985.)
The deposition of metallic mercury into the skin is an uncommon occurrence. It is usually caused by an accidental penetration of an object containing mercury, 1.5 but it may be deliberate. 6" A local granulomatous tissue reaction typically ensues.H! In the absence of an obvious history, however, the From the Department of Dermatopathology and the Veterans Administration Special Reference Laboratory for Pathology at the Armed Forces Institute of Pathology. Accepted for publication Sept. 19, 1984. Reprint requests to: Dr. Grace F. Kao, Department of Dermatopathology, Armed Forces Institute of Pathology, Washington, DC 20306. *The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense, **Present address: Dermatology Service, Walter Reed Army Medical Center, Washington, DC.
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diagnosis of cutaneous mercury granuloma may be difficult. Moreover, it is not widely recognized that local deposits of metallic mercury in the skin and subcutaneous tissue can produce signs and symptoms of mercury poisoning~,3,6,7 and may even cause death. 2.7 Histologic and chemical studies and scanning electron microscopy (SEM) of cutaneous mercury granuloma were performed on four cases on file at the Armed Forces Institute of Pathology (AFIP). The purpose of this study is to present the clinical features, characteristic histopathologic findings, and confirmatory laboratory results of these four cases. Cases from the literature were reviewed so that we could clearly define the spectrum of reactions to metallic mercury deposition in the skin and subcutaneous tissue. An approach to clinical management will also be discussed.
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Table I. Data on patients with cutaneous mercury granuloma (AFIP cases) Case I Age No. (yr)
Site
Sex
1
35
M
Not specified
2
28
M
3
22
M
Multiple lesions, upper and lower extremities Right wrist
4
16
M
Chest; right knee
Method of introduction
Elevated serum and urine mercury levels
Toxicity
Accidental, broken thermometer Self-injection suspected
Unknown
No
Unknown
Yes
Accidental, from fall on metal pipe Self-injection
Unknown
No
Urine, 2,300 p,g/liter*
No
*Normal, 0 to 20 i.~g/liter. MATERIALS AND METHODS From 1930 to 1983, sixty-one cases of mercury intoxication were recorded in the AFIP files. Of these, four cases with cutaneous deposition of metallic mercury were identified. The clinical history and data were obtained from the patient records and, for case 4, also by verbal communication with the contributing pathologist. The clinical summaries, surgical pathology reports, and routine hematoxylin-eosin-stained sections were reviewed. Also available for study were paraffin blocks (Cases 2, 3, and 4), formalin-fixed wet tissues (Cases 2 and 4), and x-ray films of the lesions on the skin of the anterior chest and fight knee (Case 4). Additional microscopic sections were prepared from paraffin blocks and stained with hematoxylin and eosin, periodic acid-Schiff, and Movat's pentachrome methods. The gold lysis test and SEM were performed on paraffin sections for Cases 2, 3, and 4. For the gold lysis test we covered deparaffinized sections with coverslips coated with 50% reflecting gold, with the coated surface facing the section. Lysis of the gold coating the coverslip, resulting in a dark zone around the spherical droplets in the sections, constituted a positive reaction for mercury (Fig. 1). For SEM and energy-dispersive x-ray analysis, we mounted paraffin sections on spectrographic-grade carbon discs, removed the paraffin with several changes of xylenes, evaporated the xylenes, coated the sections with carbon in vacuo, and examined them in a Philips Scanning Electron Microscope 501 equipped with an energy-dispersive x-ray analysis (EDXA) system (KEVEX Corp., Foster City, CA). CASE REPORTS The clinical histories and pathologic findings are described separately and are presented in Table I. The
histologie, chemical, and SEM findings are discussed as a group because of their similarities. Case 1 A 3S-year-old man presented in 1967 with a history of cutaneous injury from a broken thermometer. The size, site, and duration of the lesion were not specified. Representative microscopic sections were available for study. The contributing pathologist's diagnosis was "mercury foreign body granuloma with abscess formation." Case 2 A 28-year-old man presented in 1982 with a history of recurrent nodular lesions on the upper arm (Fig. 2) and lower extremities. His symptoms were associated with malaise and fever. The clinical differential diagnosis included panniculitis, sarcoidosis, acute febrile neutrophilic dermatosis (Sweet's syndrome), lymphomatoid granulomatosis, deep fungal infection, and nodular vasculitis. The contributing pathologist's diagnosis was "nodular and diffuse dermatitis." Histopathologic examination revealed foreign body granulomas surrounding dark, spherical globules suggestive of metallic mercury. The gold lysis test and energy-dispersive xray analysis were performed on paraffin-embedded tissue and confirmed the presence of metallic mercury in the lesions. Although unproved, the belief was that deliberate self-injection was the most likely cause of this patient's lesions. Case 3 A 22-year-old male prisoner in the Philippines presented in 1949 with a mass on the flexor surface of the fight wrist. He complained of progressive weakness of his right hand. One year previously he had fallen in the
298
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Lupton et al
Fig. 1. Demonstration of positive results with gold lysis test. Note dark zones surrounding metallic mercury globules. (AFIP negative No. 83-9250-2.) prison laundry where he worked and had lacerated his hand on a metal pipe. The wound healed within 1 month. During the next 8 to 10 months, a gradually enlarging, asymptomatic nodule developed at this site. On physical examination, the mass measured 3 • 5 • 2 cm and was fixed to the underlying tissue. The overlying skin, however, was mobile. There were no signs of acute inflammation around the lesion. Findings on neurologic examination were normal. Radiographic examination revealed a radiopaque shadow composed of hundreds of tiny round dots resembling the appearance of a paintbrush stipple. The mass was excised, and foreign material could be visualized in the tissue at the time of surgery. When the tissue was sectioned, a gritty sensation was noted by the pathologist. Spectrographic examination performed by the Federal Bureau of Investigation in Washington, DC, confirmed that the foreign material was metallic mercury. Why the pipe contained metallic mercury was unclear. A follow-up letter from the contributing pathologist reported that several other cases of cutaneous mercury granuloma had been seen at a hospital in the Philippines after mercury had been injected into the skin by local natives as "protection" against bullets.
Case 4 A 16-year-old boy who worked on a farm during the summer months presented in August, 1983, with a firm, erythematous, subcutaneous mass on the prestemal region. A biopsy was performed. The contributing pathologist's diagnosis was "foreign body granulomas and microabscesses." Additional histologic sections were prepared from the submitted paraffin blocks; the gold lysis test, energy-dispersive x-ray analysis, and
Fig. 2. Recurrent cutaneous mercury granulomas on upper arm of 28-year-old man (Case 2). Lesions are suspected to be secondary to self-injection. (AFIP negative No. 83-9250.) SEM were performed on the tissue retrieved from the paraffin blocks. The chemical studies and SEM confirmed the presence of metallic mercury in the tissue. After repeated questioning by the clinician, the patient eventually admitted deliberate injection of mercury into the skin. Radiographic examination disclosed multiple radiopaque shadows in the presternal region (Fig. 3, A), as well as in the subcutaneous tissue of the right knee at the site of an eczematous patch (Fig. 3, B). The mercury level of the urine was 2,300 I~g/liter (normal, 0-20 ~g/liter).
Pathologic findings Gross pathology. A portion of formalin-fixed tissue was retrieved from the AFIP file on Case 3, some 34 years after being submitted to the Institute. A fresh-cut surface of this tissue showed patchy areas of aggregates of shining metallic mercury globules embedded in the dermis and subcutaneous tissue (Fig. 4). The mercury globules correlated well with those seen on the radiographs of Case 4 (Fig. 3). Microscopic features. Representative microscopic sections from the lesions showed pseudoepitheliomatous hyperplasia. Metallic mercury in tissue was readily recognized, appearing as dark-gray to black opaque globules, usually spherical and of varying sizes and numbers. A zone of collagen necrosis often surrounded the mercury globules (Fig. 5). A granulomatous foreign body-giant cell reaction accompanied by granulation tissue and a mixed inflammatory infiltrate composed of polymorphonuclear leukocytes, eosinophils, lymphocytes, plasma cells, and histiocytes was usually present
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Fig. 3. A, Radiograph of the presternal region of a 16-year-old boy (Case 4) shows multiple radiopaque shadows composed of hundreds of tiny round dots resembling a paintbrush stipple. (AFIP negative No. 83-3413-1 .) B, Radiograph of right knee at site of eczematous patch of same patient shows similar findings as in A. (AFIP negative No. 83-3413-2.)
in the vicinity of the metallic mercury globules. Epidermal and dermal necrosis with or without ulceration was also a common finding. Gold lysis test. Positive results with the gold lysis test, as demonstrated by lysis of the gold coating the coverslip, resulting in a dark zone around the spherical droplets in the sections (Fig. 1), is diagnostic of metallic mercury. Energy-dispersive x-ray analysis. Characteristic emissions at 2.24, 9.98, and 11.82 electron volts (Fig. 6) were obtained on specimens from Cases 2, 3, and 4 and confirmed the presence of metallic mercury. S E M findings. Spherical to egg-shaped globules characteristic of metallic mercury (Fig. 7) and surrounded by a clear zone of collagen necrosis were identified in specimens from Cases 2, 3, and 4. DISCUSSION M e r c u r y poisoning usually occurs following oral ingestion of inorganic salts of the metal but m a y also result from inhalation of vapor of metallic m e r c u r y and from organic mercurials. Central nervous system, renal, and gastrointestinal toxicity appears to be most significant.12 Mercury poisoning m a y also occur as a result of metallic mercury in body tissues. Metallic mercury undergoes a
Fig. 4. Cut surface of cutaneous mercury granuloma in Case 3 shows numerous areas of shining metallic mercury aggregates embedded in dermis and subcutaneous tissue. (AFIP negative No. 83-10253-1.) slow ionization through biologic oxidation. T h e mercuric salts that are formed interfere with the sulfhydryl radical in many enzyme systems. T h e colon, kidneys, and salivary glands excrete a large proportion of the mercuric salt. ~3Ingested metallic mercury undergoes no appreciable degree of o•
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Fig. 5. Metallic mercury in tissue section appearing as spherical dark-gray to black opaque globules with zone of collagen necrosis. Granulation tissue, mixed inflammatory infiltrate, and multinucleated giant cells can be seen in vicinity. (AFIP negative No. 84-6185-4.) (Hematoxylin-eosin stain; original magnification, • 160.) dation in the gastrointestinal tract and is only negligibly absorbed. It thus poses no health hazard as a rule.t4 However, Birnbaum ~5 reported a patient with appendicitis secondary to metallic mercury from a ruptured intestinal tube, and Lindemuth ~6 described a patient who developed a persistent fecal fistula following leakage of metallic mercury from a Miller-Abbott intestinal tube. A review of the published cases involving penetration of the skin by metallic mercury revealed features similar to those of our cases. Of accidental causes, injury by a broken mercury thermometer and following anaerobic blood sampling procedures where mercury was used as a sealant in syringes 5 accounted for half of the cases of cutaneous mercury granuloma. The remaining half were a result of deliberate injection of metallic mercury into the skin and subcutaneous tissue. In all cases there was a local tissue reaction to the metallic mercury. The period during which mercury was in tissue varied from 23 days 4 to over 6 years? Acute inflammation and necrosis were more commonly seen in the shorter time periods (weeks to months), whereas granulomatous foreign body-giant cell reactions and fibrosis were
associated with prolonged deposition of mercury (months to years). Systemic absorption eventuating in embolization is fairly common following local cutaneous penetration by metallic mercury 2"3'58'1~ and may result in elevated serum 7.~,~t a n d u r i n e 3,7"9,t I mercury levels, as well as signs and symptoms of mercury poisoning. 2,3.6,7 The reaction to metallic mercury in the skin and subcutaneous tissue may remain localized, with no signs or symptoms of systemic involvement. Our Cases 1 and 3 appear to be in this category. Lathem et al 5 reported two patients who experienced peripheral embolism of metallic mercury in the digits and elbow during arterial blood sampling with syringes containing mercury as a sealant. X-rays revealed particulate metallic material in the soft tissues. Fine particles of mercury were continuously extruded through the skin of the fingertips for 3~,4 years in one patient. No evidence of systemic toxicity was noted. Rachman ~ and Theodorou et al 4 described patients injured by a broken mercury thermometer who developed only local tissue reactions without evidence of systemic involvement. Systemic absorption of metallic mercury from cutaneous sites may result in elevated levels of
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mercury in the blood and urine, with or without signs of toxicity. In our Case 4 the marked elevations of mercury in the urine, without evidence o f functional impairment, were demonstrative. Kern et al 9 described an aspiring boxer who injected "quicksilver" (a popular layman's term for metallic mercury) into both forearms in the hope o f making his punches "quicker." X-rays showed multiple radiopaque globules in the soft tissue. The urine mercury level was elevated, but no other signs o f mercury poisoning were noted. Krohn et al t' studied a disturbed 13-year-old boy who had swallowed a tablespoonful of metallic mercury. One week later, after no apparent ill effects, he injected metallic mercury subcutaneously into six different sites with his mother's insulin syringes. A n estimated 0.1 ml was injected into each site, where tender, nonfluctuant masses developed within 2 days. Serum and urine mercury levels were elevated. Surgical excision of the mercury granulomas significantly lowered serum and urine mercury levels despite some residual mercury evident on postoperative x-rays. Hill 8 described a 21year-old diabetic woman who injected metallic mercury into both thighs with subsequently elevated mercury levels in both serum and urine. En bloc excision of the involved areas was performed, after which mercury levels returned to normal. No clinical signs of mercury poisoning were noted. Systemic absorption and embolization of metallic mercury from a cutaneous focus can have more serious, and even fatal, consequences. In our Case 2 the patient presented with malaise and fever that were probably due to systemic effects of mercury. Conrad et al 6 reported a 26-year-old man who presented with chest pain, cough, fever, dyspnea, and transient urinary and hepatic abnormalities. X-rays o f the lung fields, as well as of the pelvic and paravertebral vessels, showed multiple metallic globules. Five weeks later he developed, at the antecubital fossa, a nodule that contained metallic mercury. Deliberate intravenous injection of metallic mercury by the patient was suspected. Arcadio et al 3 reported a patient who injured her right palm with a broken mercury thermometer. Within a few weeks there followed oliguria, a metallic taste in the mouth, and diarrhea. The urinary
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Fig. 6. Energy-dispersive x-ray analysis on specimens obtained from Cases 2, 3, and 4 shows characteristic emission spikes at 2.24, 9.98, and 11.82 electron volts. (AFLP negative No. 83-10060-2.)
Fig. 7. SEM photograph shows spherical to egg-shaped metallic mercury globules surrounded by clear zone of collagen necrosis. (AFIP negative No. 83-9537.) assay for mercury revealed a daily excretion of 200 Ixg. Surgical excision of the wound was performed 6 weeks after the accident, but the mercury-containing tissue was incompletely excised to avoid functional impairment of the muscles and tendons of the palm. Ten months later, acrodynial changes occurred, and the patient was treated with penicillamine, resulting in the urinary excretion of as much as 960 Izg of mercury per day. Popper 2 reported a 19-year-old student nurse w h o ultimately died as a result of accidental injury to her left hand with a mercury thermometer. T h e wound
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healed uneventfully, but 2 years later she developed bronchitis, pneumonia, and bronchiectasis. A left lower lobectomy 4 years after the accident showed disseminated mercury emobli in the pulmonary arteries. Six years after the accident she developed a pulmonary abscess and empyema, and died. At autopsy, vascular occlusion of the pulmonary arteries by metallic mercury was evident. Johnson and Koumides 7 described a 23-year-old laboratory technician who deliberately injected between 1 and 2 ml of metallic mercury into her left forearm. Three weeks later, cutaneous tenderness and swelling developed with symptoms of median nerve damage. At surgery, betwen 0.5 and 0.75 ml of mercury were removed. Postoperatively, she developed fever and muscular spasms and became comatose. X-rays showed mercury emboli present throughout both lungs and scattered elsewhere in the body. She developed renal failure and died 31 days after the injection of the mercury. Although the majority of cutaneous mercury granulomas present as erythematous subcutaneous masses or cutaneous ulcerated nodules, one instance of cutaneous mercury granuloma mimicking nodular malignant melanoma was reported by Grenga and Pietrocola. z~ A 24-year-old man presented with a black, ulcerated nodule at the left antecubital fossa. The mass was diagnosed clinically as nodular melanoma. There were also several small subcutaneous nodules palpable in the epitrochlear area of the left forearm. A series of chest x-rays prior to surgery revealed multiple punctate metallic densities in both lung fields. At surgery, metallic mercury was found in the lesion and nearby nodules. Later x-rays also showed mercury globules in the pelvis and left arm. Although self-injection was suspected, the patient denied it. The spectrum of reactions to cutaneous injury by metallic mercury, as evident from the examples presented here, is variable. The diagnosis of cutaneous mercury granuloma may be evident if the history is revealing. When the history is vague or the patient denies accidental or deliberate injury by a mercury-containing object, diagnosis must depend on histopathologic examination. The features described earlier will usually permit a correct diagnosis if the pathologist is familiar with the
constellation of findings, particularly with the appearance of metallic mercury globules in the tissue. The gold lysis test is very specific for the presence of mercury, as is the SEM appearance of mercury globules and emission spikes on energydispersive x-ray analysis. These findings should be used for confirmation of the presence of metallic mercury, especially when the history does not support the histopathologic diagnosis. The following steps outlined by Krohn et aP 1 seem appropriate in the management of the patient with cutaneous injury by metallic mercury. First, prompt excision o f all accessible cutaneous and subcutaneous tissue containing mercury is recommended. Radiographic guidance before and during surgery is helpful. Second, there should be appropriate monitoring of central nervous system and renal functions for evidence of mercury poisoning. Third, if poisoning is evident, chelation therapy is recommended. The agents used, listed in the order of effectiveness, ~2 are N-Acetyl-D,Lpenicillamine (NAP), calcium ethylenediaminetetraacetate (Ca EDTA), and 2,3-dimercapto-lpropanol (British anti-lewisite, or BAL). Fourth, psychiatric consultation and treatment in those cases of deliberate self-injection, either proved or suspected, are usually indicated. REFERENCES
1. RachmanR: Soft tissue injury by mercury from a broken thermometer. Am J Clin Pathol 61:296-300, 1974. 2. Popper L: Tod nach thermometerverletzung.Wien Med Wochenschr 116:779-780, 1960. 3. ArcadioF, Thivolet J, Perrot H: Acrodynia following the accidental subcutaneousinfiltrationof mercury. Bull Soc Fr Dermatol Syphiligr75:509-510, 1968. 4. Theodorou SD, Vlachos P, Vamvasakis E: Knee joint injury by mercury from a broken thermometer. Clin Orthop 160:159-162, 1981. 5. Lathem W, Lesser GT, Messinger WJ, Galdston M: Peripheral embolism by metallic mercury during arterial blood sampling. Arch Intern Meal 93:550-555, 1954. 6. Conrad ME, Sanford JP, Preston JA: Metallic mercury embolization: Clinical and experimental. Arch Intern Med 100:59-65, 1957. 7. Johnson HRM, Koumides 0: Unusual case of mercury poisoning. Br Med J 1:340-341, 1967. 8. Hill DM: Self-administrationof mercury by subcutaneous injection. Br Med J 1:342-343, 1967. 9. KernFB, Condo F, Michel SL: Mercury granuloma with absorption. JAMA 222:88-89, 1972. 10. Grenga TE, Pietrocola DM: Subcutaneous injection of
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mercury mimicking nodular melanoma. NY State J Med 82:1231-1233, 1982. 11. Krohn IT, SolofA, Mobini J, Wagner DK: Subcutaneous injection of metallic mercury. JAMA 243:548-549, 1980. 12. Gilman AG, Goodman LS, Gilman A, editors: Goodman and Gilman's The pharmacological basis of therapeutics. New York, 1980, Macmillan Publishing Co., Inc., pp. 1622-1628.
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13. Buston JT Jr, Hewitt JC, Gadsden RH, Bradham GB: Metallic mercury embolism. JAMA 193:103-105, 1965. 14. Gerstner HB, Huff JE: Clinical toxicology of mercury. J Toxicol Environ Health 2:491-526, 1977. 15. Birnbaum W: Inflammation of vermiform appendix by metallic mercury. Am J Surg 74:494, 1947. 16. Lindemuth WW: Fecal fistula due to metallic mercury from Miller-Abbott tube. JAMA 141:986, 1949.
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Cutaneous mercury granuloma* A clinicopathologic study and review of the literature G. P. Lupton, Lieutenant Colonel, MC, USA,** G. F. Kao, M.D., F. B. Johnson, M.D., J. H. Graham, M.D., and E. B. Helwig, M.D.
Washington, DC Cutaneous mercury granulomas are rarely encountered. Clinically they pose difficulty in diagnosis when there is no clear history of penetrating injury by objects containing metallic mercury. Histologic, chemical, and scanning electron microscopic studies of such cutaneous lesions were performed on four cases from the Armed Forces Institute of Pathology files. Reported cases from the literature were reviewed. Metallic mercury in tissue sections appears as dark, opaque globules, usually spherical in shape and of varying sizes and numbers. A zone of collagen necrosis often surrounds the mercury globules. A granulomatous foreign body-giant cell reaction and a mixed inflammatory cellular infiltrate composed of neutrophils, lymphocytes, histiocytes, plasma cells, and occasional eosinophils are usually present. Epidermal and dermal necrosis, with or without ulceration or pseudoepitheliomatous hyperplasia, is also a common finding. The gold lysis test and energy-dispersive x-ray analysis confirmed the presence of metallic mercury in the tissue. Following cutaneous injury from mercury, systemic toxicity may develop and death may even occur. An approach to clinical management is discussed. (J AM ACAD DERMATOL12:296-303, 1985.)
The deposition of metallic mercury into the skin is an uncommon occurrence. It is usually caused by an accidental penetration of an object containing mercury, 1.5 but it may be deliberate. 6" A local granulomatous tissue reaction typically ensues.H! In the absence of an obvious history, however, the From the Department of Dermatopathology and the Veterans Administration Special Reference Laboratory for Pathology at the Armed Forces Institute of Pathology. Accepted for publication Sept. 19, 1984. Reprint requests to: Dr. Grace F. Kao, Department of Dermatopathology, Armed Forces Institute of Pathology, Washington, DC 20306. *The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense, **Present address: Dermatology Service, Walter Reed Army Medical Center, Washington, DC.
296
diagnosis of cutaneous mercury granuloma may be difficult. Moreover, it is not widely recognized that local deposits of metallic mercury in the skin and subcutaneous tissue can produce signs and symptoms of mercury poisoning~,3,6,7 and may even cause death. 2.7 Histologic and chemical studies and scanning electron microscopy (SEM) of cutaneous mercury granuloma were performed on four cases on file at the Armed Forces Institute of Pathology (AFIP). The purpose of this study is to present the clinical features, characteristic histopathologic findings, and confirmatory laboratory results of these four cases. Cases from the literature were reviewed so that we could clearly define the spectrum of reactions to metallic mercury deposition in the skin and subcutaneous tissue. An approach to clinical management will also be discussed.
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Table I. Data on patients with cutaneous mercury granuloma (AFIP cases) Case I Age No. (yr)
Site
Sex
1
35
M
Not specified
2
28
M
3
22
M
Multiple lesions, upper and lower extremities Right wrist
4
16
M
Chest; right knee
Method of introduction
Elevated serum and urine mercury levels
Toxicity
Accidental, broken thermometer Self-injection suspected
Unknown
No
Unknown
Yes
Accidental, from fall on metal pipe Self-injection
Unknown
No
Urine, 2,300 p,g/liter*
No
*Normal, 0 to 20 i.~g/liter. MATERIALS AND METHODS From 1930 to 1983, sixty-one cases of mercury intoxication were recorded in the AFIP files. Of these, four cases with cutaneous deposition of metallic mercury were identified. The clinical history and data were obtained from the patient records and, for case 4, also by verbal communication with the contributing pathologist. The clinical summaries, surgical pathology reports, and routine hematoxylin-eosin-stained sections were reviewed. Also available for study were paraffin blocks (Cases 2, 3, and 4), formalin-fixed wet tissues (Cases 2 and 4), and x-ray films of the lesions on the skin of the anterior chest and fight knee (Case 4). Additional microscopic sections were prepared from paraffin blocks and stained with hematoxylin and eosin, periodic acid-Schiff, and Movat's pentachrome methods. The gold lysis test and SEM were performed on paraffin sections for Cases 2, 3, and 4. For the gold lysis test we covered deparaffinized sections with coverslips coated with 50% reflecting gold, with the coated surface facing the section. Lysis of the gold coating the coverslip, resulting in a dark zone around the spherical droplets in the sections, constituted a positive reaction for mercury (Fig. 1). For SEM and energy-dispersive x-ray analysis, we mounted paraffin sections on spectrographic-grade carbon discs, removed the paraffin with several changes of xylenes, evaporated the xylenes, coated the sections with carbon in vacuo, and examined them in a Philips Scanning Electron Microscope 501 equipped with an energy-dispersive x-ray analysis (EDXA) system (KEVEX Corp., Foster City, CA). CASE REPORTS The clinical histories and pathologic findings are described separately and are presented in Table I. The
histologie, chemical, and SEM findings are discussed as a group because of their similarities. Case 1 A 3S-year-old man presented in 1967 with a history of cutaneous injury from a broken thermometer. The size, site, and duration of the lesion were not specified. Representative microscopic sections were available for study. The contributing pathologist's diagnosis was "mercury foreign body granuloma with abscess formation." Case 2 A 28-year-old man presented in 1982 with a history of recurrent nodular lesions on the upper arm (Fig. 2) and lower extremities. His symptoms were associated with malaise and fever. The clinical differential diagnosis included panniculitis, sarcoidosis, acute febrile neutrophilic dermatosis (Sweet's syndrome), lymphomatoid granulomatosis, deep fungal infection, and nodular vasculitis. The contributing pathologist's diagnosis was "nodular and diffuse dermatitis." Histopathologic examination revealed foreign body granulomas surrounding dark, spherical globules suggestive of metallic mercury. The gold lysis test and energy-dispersive xray analysis were performed on paraffin-embedded tissue and confirmed the presence of metallic mercury in the lesions. Although unproved, the belief was that deliberate self-injection was the most likely cause of this patient's lesions. Case 3 A 22-year-old male prisoner in the Philippines presented in 1949 with a mass on the flexor surface of the fight wrist. He complained of progressive weakness of his right hand. One year previously he had fallen in the
298
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Fig. 1. Demonstration of positive results with gold lysis test. Note dark zones surrounding metallic mercury globules. (AFIP negative No. 83-9250-2.) prison laundry where he worked and had lacerated his hand on a metal pipe. The wound healed within 1 month. During the next 8 to 10 months, a gradually enlarging, asymptomatic nodule developed at this site. On physical examination, the mass measured 3 • 5 • 2 cm and was fixed to the underlying tissue. The overlying skin, however, was mobile. There were no signs of acute inflammation around the lesion. Findings on neurologic examination were normal. Radiographic examination revealed a radiopaque shadow composed of hundreds of tiny round dots resembling the appearance of a paintbrush stipple. The mass was excised, and foreign material could be visualized in the tissue at the time of surgery. When the tissue was sectioned, a gritty sensation was noted by the pathologist. Spectrographic examination performed by the Federal Bureau of Investigation in Washington, DC, confirmed that the foreign material was metallic mercury. Why the pipe contained metallic mercury was unclear. A follow-up letter from the contributing pathologist reported that several other cases of cutaneous mercury granuloma had been seen at a hospital in the Philippines after mercury had been injected into the skin by local natives as "protection" against bullets.
Case 4 A 16-year-old boy who worked on a farm during the summer months presented in August, 1983, with a firm, erythematous, subcutaneous mass on the prestemal region. A biopsy was performed. The contributing pathologist's diagnosis was "foreign body granulomas and microabscesses." Additional histologic sections were prepared from the submitted paraffin blocks; the gold lysis test, energy-dispersive x-ray analysis, and
Fig. 2. Recurrent cutaneous mercury granulomas on upper arm of 28-year-old man (Case 2). Lesions are suspected to be secondary to self-injection. (AFIP negative No. 83-9250.) SEM were performed on the tissue retrieved from the paraffin blocks. The chemical studies and SEM confirmed the presence of metallic mercury in the tissue. After repeated questioning by the clinician, the patient eventually admitted deliberate injection of mercury into the skin. Radiographic examination disclosed multiple radiopaque shadows in the presternal region (Fig. 3, A), as well as in the subcutaneous tissue of the right knee at the site of an eczematous patch (Fig. 3, B). The mercury level of the urine was 2,300 I~g/liter (normal, 0-20 ~g/liter).
Pathologic findings Gross pathology. A portion of formalin-fixed tissue was retrieved from the AFIP file on Case 3, some 34 years after being submitted to the Institute. A fresh-cut surface of this tissue showed patchy areas of aggregates of shining metallic mercury globules embedded in the dermis and subcutaneous tissue (Fig. 4). The mercury globules correlated well with those seen on the radiographs of Case 4 (Fig. 3). Microscopic features. Representative microscopic sections from the lesions showed pseudoepitheliomatous hyperplasia. Metallic mercury in tissue was readily recognized, appearing as dark-gray to black opaque globules, usually spherical and of varying sizes and numbers. A zone of collagen necrosis often surrounded the mercury globules (Fig. 5). A granulomatous foreign body-giant cell reaction accompanied by granulation tissue and a mixed inflammatory infiltrate composed of polymorphonuclear leukocytes, eosinophils, lymphocytes, plasma cells, and histiocytes was usually present
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Fig. 3. A, Radiograph of the presternal region of a 16-year-old boy (Case 4) shows multiple radiopaque shadows composed of hundreds of tiny round dots resembling a paintbrush stipple. (AFIP negative No. 83-3413-1 .) B, Radiograph of right knee at site of eczematous patch of same patient shows similar findings as in A. (AFIP negative No. 83-3413-2.)
in the vicinity of the metallic mercury globules. Epidermal and dermal necrosis with or without ulceration was also a common finding. Gold lysis test. Positive results with the gold lysis test, as demonstrated by lysis of the gold coating the coverslip, resulting in a dark zone around the spherical droplets in the sections (Fig. 1), is diagnostic of metallic mercury. Energy-dispersive x-ray analysis. Characteristic emissions at 2.24, 9.98, and 11.82 electron volts (Fig. 6) were obtained on specimens from Cases 2, 3, and 4 and confirmed the presence of metallic mercury. S E M findings. Spherical to egg-shaped globules characteristic of metallic mercury (Fig. 7) and surrounded by a clear zone of collagen necrosis were identified in specimens from Cases 2, 3, and 4. DISCUSSION M e r c u r y poisoning usually occurs following oral ingestion of inorganic salts of the metal but m a y also result from inhalation of vapor of metallic m e r c u r y and from organic mercurials. Central nervous system, renal, and gastrointestinal toxicity appears to be most significant.12 Mercury poisoning m a y also occur as a result of metallic mercury in body tissues. Metallic mercury undergoes a
Fig. 4. Cut surface of cutaneous mercury granuloma in Case 3 shows numerous areas of shining metallic mercury aggregates embedded in dermis and subcutaneous tissue. (AFIP negative No. 83-10253-1.) slow ionization through biologic oxidation. T h e mercuric salts that are formed interfere with the sulfhydryl radical in many enzyme systems. T h e colon, kidneys, and salivary glands excrete a large proportion of the mercuric salt. ~3Ingested metallic mercury undergoes no appreciable degree of o•
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Fig. 5. Metallic mercury in tissue section appearing as spherical dark-gray to black opaque globules with zone of collagen necrosis. Granulation tissue, mixed inflammatory infiltrate, and multinucleated giant cells can be seen in vicinity. (AFIP negative No. 84-6185-4.) (Hematoxylin-eosin stain; original magnification, • 160.) dation in the gastrointestinal tract and is only negligibly absorbed. It thus poses no health hazard as a rule.t4 However, Birnbaum ~5 reported a patient with appendicitis secondary to metallic mercury from a ruptured intestinal tube, and Lindemuth ~6 described a patient who developed a persistent fecal fistula following leakage of metallic mercury from a Miller-Abbott intestinal tube. A review of the published cases involving penetration of the skin by metallic mercury revealed features similar to those of our cases. Of accidental causes, injury by a broken mercury thermometer and following anaerobic blood sampling procedures where mercury was used as a sealant in syringes 5 accounted for half of the cases of cutaneous mercury granuloma. The remaining half were a result of deliberate injection of metallic mercury into the skin and subcutaneous tissue. In all cases there was a local tissue reaction to the metallic mercury. The period during which mercury was in tissue varied from 23 days 4 to over 6 years? Acute inflammation and necrosis were more commonly seen in the shorter time periods (weeks to months), whereas granulomatous foreign body-giant cell reactions and fibrosis were
associated with prolonged deposition of mercury (months to years). Systemic absorption eventuating in embolization is fairly common following local cutaneous penetration by metallic mercury 2"3'58'1~ and may result in elevated serum 7.~,~t a n d u r i n e 3,7"9,t I mercury levels, as well as signs and symptoms of mercury poisoning. 2,3.6,7 The reaction to metallic mercury in the skin and subcutaneous tissue may remain localized, with no signs or symptoms of systemic involvement. Our Cases 1 and 3 appear to be in this category. Lathem et al 5 reported two patients who experienced peripheral embolism of metallic mercury in the digits and elbow during arterial blood sampling with syringes containing mercury as a sealant. X-rays revealed particulate metallic material in the soft tissues. Fine particles of mercury were continuously extruded through the skin of the fingertips for 3~,4 years in one patient. No evidence of systemic toxicity was noted. Rachman ~ and Theodorou et al 4 described patients injured by a broken mercury thermometer who developed only local tissue reactions without evidence of systemic involvement. Systemic absorption of metallic mercury from cutaneous sites may result in elevated levels of
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mercury in the blood and urine, with or without signs of toxicity. In our Case 4 the marked elevations of mercury in the urine, without evidence o f functional impairment, were demonstrative. Kern et al 9 described an aspiring boxer who injected "quicksilver" (a popular layman's term for metallic mercury) into both forearms in the hope o f making his punches "quicker." X-rays showed multiple radiopaque globules in the soft tissue. The urine mercury level was elevated, but no other signs o f mercury poisoning were noted. Krohn et al t' studied a disturbed 13-year-old boy who had swallowed a tablespoonful of metallic mercury. One week later, after no apparent ill effects, he injected metallic mercury subcutaneously into six different sites with his mother's insulin syringes. A n estimated 0.1 ml was injected into each site, where tender, nonfluctuant masses developed within 2 days. Serum and urine mercury levels were elevated. Surgical excision of the mercury granulomas significantly lowered serum and urine mercury levels despite some residual mercury evident on postoperative x-rays. Hill 8 described a 21year-old diabetic woman who injected metallic mercury into both thighs with subsequently elevated mercury levels in both serum and urine. En bloc excision of the involved areas was performed, after which mercury levels returned to normal. No clinical signs of mercury poisoning were noted. Systemic absorption and embolization of metallic mercury from a cutaneous focus can have more serious, and even fatal, consequences. In our Case 2 the patient presented with malaise and fever that were probably due to systemic effects of mercury. Conrad et al 6 reported a 26-year-old man who presented with chest pain, cough, fever, dyspnea, and transient urinary and hepatic abnormalities. X-rays o f the lung fields, as well as of the pelvic and paravertebral vessels, showed multiple metallic globules. Five weeks later he developed, at the antecubital fossa, a nodule that contained metallic mercury. Deliberate intravenous injection of metallic mercury by the patient was suspected. Arcadio et al 3 reported a patient who injured her right palm with a broken mercury thermometer. Within a few weeks there followed oliguria, a metallic taste in the mouth, and diarrhea. The urinary
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Fig. 6. Energy-dispersive x-ray analysis on specimens obtained from Cases 2, 3, and 4 shows characteristic emission spikes at 2.24, 9.98, and 11.82 electron volts. (AFLP negative No. 83-10060-2.)
Fig. 7. SEM photograph shows spherical to egg-shaped metallic mercury globules surrounded by clear zone of collagen necrosis. (AFIP negative No. 83-9537.) assay for mercury revealed a daily excretion of 200 Ixg. Surgical excision of the wound was performed 6 weeks after the accident, but the mercury-containing tissue was incompletely excised to avoid functional impairment of the muscles and tendons of the palm. Ten months later, acrodynial changes occurred, and the patient was treated with penicillamine, resulting in the urinary excretion of as much as 960 Izg of mercury per day. Popper 2 reported a 19-year-old student nurse w h o ultimately died as a result of accidental injury to her left hand with a mercury thermometer. T h e wound
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healed uneventfully, but 2 years later she developed bronchitis, pneumonia, and bronchiectasis. A left lower lobectomy 4 years after the accident showed disseminated mercury emobli in the pulmonary arteries. Six years after the accident she developed a pulmonary abscess and empyema, and died. At autopsy, vascular occlusion of the pulmonary arteries by metallic mercury was evident. Johnson and Koumides 7 described a 23-year-old laboratory technician who deliberately injected between 1 and 2 ml of metallic mercury into her left forearm. Three weeks later, cutaneous tenderness and swelling developed with symptoms of median nerve damage. At surgery, betwen 0.5 and 0.75 ml of mercury were removed. Postoperatively, she developed fever and muscular spasms and became comatose. X-rays showed mercury emboli present throughout both lungs and scattered elsewhere in the body. She developed renal failure and died 31 days after the injection of the mercury. Although the majority of cutaneous mercury granulomas present as erythematous subcutaneous masses or cutaneous ulcerated nodules, one instance of cutaneous mercury granuloma mimicking nodular malignant melanoma was reported by Grenga and Pietrocola. z~ A 24-year-old man presented with a black, ulcerated nodule at the left antecubital fossa. The mass was diagnosed clinically as nodular melanoma. There were also several small subcutaneous nodules palpable in the epitrochlear area of the left forearm. A series of chest x-rays prior to surgery revealed multiple punctate metallic densities in both lung fields. At surgery, metallic mercury was found in the lesion and nearby nodules. Later x-rays also showed mercury globules in the pelvis and left arm. Although self-injection was suspected, the patient denied it. The spectrum of reactions to cutaneous injury by metallic mercury, as evident from the examples presented here, is variable. The diagnosis of cutaneous mercury granuloma may be evident if the history is revealing. When the history is vague or the patient denies accidental or deliberate injury by a mercury-containing object, diagnosis must depend on histopathologic examination. The features described earlier will usually permit a correct diagnosis if the pathologist is familiar with the
constellation of findings, particularly with the appearance of metallic mercury globules in the tissue. The gold lysis test is very specific for the presence of mercury, as is the SEM appearance of mercury globules and emission spikes on energydispersive x-ray analysis. These findings should be used for confirmation of the presence of metallic mercury, especially when the history does not support the histopathologic diagnosis. The following steps outlined by Krohn et aP 1 seem appropriate in the management of the patient with cutaneous injury by metallic mercury. First, prompt excision o f all accessible cutaneous and subcutaneous tissue containing mercury is recommended. Radiographic guidance before and during surgery is helpful. Second, there should be appropriate monitoring of central nervous system and renal functions for evidence of mercury poisoning. Third, if poisoning is evident, chelation therapy is recommended. The agents used, listed in the order of effectiveness, ~2 are N-Acetyl-D,Lpenicillamine (NAP), calcium ethylenediaminetetraacetate (Ca EDTA), and 2,3-dimercapto-lpropanol (British anti-lewisite, or BAL). Fourth, psychiatric consultation and treatment in those cases of deliberate self-injection, either proved or suspected, are usually indicated. REFERENCES
1. RachmanR: Soft tissue injury by mercury from a broken thermometer. Am J Clin Pathol 61:296-300, 1974. 2. Popper L: Tod nach thermometerverletzung.Wien Med Wochenschr 116:779-780, 1960. 3. ArcadioF, Thivolet J, Perrot H: Acrodynia following the accidental subcutaneousinfiltrationof mercury. Bull Soc Fr Dermatol Syphiligr75:509-510, 1968. 4. Theodorou SD, Vlachos P, Vamvasakis E: Knee joint injury by mercury from a broken thermometer. Clin Orthop 160:159-162, 1981. 5. Lathem W, Lesser GT, Messinger WJ, Galdston M: Peripheral embolism by metallic mercury during arterial blood sampling. Arch Intern Meal 93:550-555, 1954. 6. Conrad ME, Sanford JP, Preston JA: Metallic mercury embolization: Clinical and experimental. Arch Intern Med 100:59-65, 1957. 7. Johnson HRM, Koumides 0: Unusual case of mercury poisoning. Br Med J 1:340-341, 1967. 8. Hill DM: Self-administrationof mercury by subcutaneous injection. Br Med J 1:342-343, 1967. 9. KernFB, Condo F, Michel SL: Mercury granuloma with absorption. JAMA 222:88-89, 1972. 10. Grenga TE, Pietrocola DM: Subcutaneous injection of
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mercury mimicking nodular melanoma. NY State J Med 82:1231-1233, 1982. 11. Krohn IT, SolofA, Mobini J, Wagner DK: Subcutaneous injection of metallic mercury. JAMA 243:548-549, 1980. 12. Gilman AG, Goodman LS, Gilman A, editors: Goodman and Gilman's The pharmacological basis of therapeutics. New York, 1980, Macmillan Publishing Co., Inc., pp. 1622-1628.
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13. Buston JT Jr, Hewitt JC, Gadsden RH, Bradham GB: Metallic mercury embolism. JAMA 193:103-105, 1965. 14. Gerstner HB, Huff JE: Clinical toxicology of mercury. J Toxicol Environ Health 2:491-526, 1977. 15. Birnbaum W: Inflammation of vermiform appendix by metallic mercury. Am J Surg 74:494, 1947. 16. Lindemuth WW: Fecal fistula due to metallic mercury from Miller-Abbott tube. JAMA 141:986, 1949.
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