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Macroglossia in myelomatosis
MACROGLOSSIA
IN M Y E L O M A T O S I S
By JAMESBUCHANAN,M.D., M.R.C.P.(Ed.), M.R.C.P.(Glasg.) Consultant Physician, Law Hosital, Carluke IAIN D. O. FREW, M.D.
Consultant Pathologist, Good Hope Hospital, Sutton Coldfield IRIS I. J. M. GIBSON, M.A., M.B., M.R.C.P.(Glasg.), D.Obst.R.C.O.G.
Consultant Physician in Geriatric Medicine, Southern General Hospital, Glasgow THOMAS GIBSON, M.B., F.R.C.S.(Ed.), F.R.C.S.(Glasg.)
Consultant Plastic Surgeon, Western Regional Hospital Board AGNES R. RUSSELL,B.Sc., M.B., F.R.C.S.(Ed.), D.M.R.T., F.F.R.
Assistant Radiotherapist, Glasgow Institute for Radiotherapy (Royal and Western Infirmaries) THE relationship between " p r i m a r y amyloidosis " and paramyloid deposits associated with multiple myeloma is known to be close, and the conditions may be identical (Osserman, I959). The common sites of deposition are similar and staining properties are similar. Tissue infiltrates developing in multiple myeloma may precede skeletal manifestations by months or years (Magnus-Levy I933, I952). Macroglossia is a classic sign o f " primary amyloid" and obvious in one-third of cases (Dahlin, I949). I f macroglossia is equally classic in paramyloid the importance of diagnosis is obvious, in view of the possibility of treating myeloma. Patients with myeloma with paramyloid have a diagnostic pattern which differs from that of isolated myeloma. Until late in the course of the disorder bone lesions are relatively rare. Hyperglobulinaemia is rare and the Westergren erythrocyte sedimentation rate therefore does not reach typical myeloma levels. Bence-Jones protein is usually found in the urine. Serum cholesterol may be unduly high and calcium high. An abnormal bleeding tendency is frequent, possibly due to deposition ofparamyloid in blood vessels (Snapper et al., I953 ; Chambers et al., I958). Simple biopsy is possible by sternal marrow aspiration, and this should always be done in cases of macroglossia. Three patients are described : Case I.--A man aged 60 years was admitted to hospital in December I963. He had noted a large, firm swelling at the base of his tongue which was considerably enlarged and protruded from his mouth. The submandibular glands were palpably enlarged. Biopsy of tongue showed irregular areas of pale hyaline material which gave a positive reaction for amyloid with congo red. There was normochromic, normocytic anaemia with h~emoglobin 9"9 g./IOO ml. Westergren E.S.R. was 54 mm. in the first hour. Thrombotest activity was 62 per cent. Serum proteins totalled 6.4 g./Ioo ml. and electrophoresis gave a normal pattern. Cryoglobulin serum test was negative. Urine was normal. On X-ray an oval translucent area was seen in the cortex of the left femur and two small translucent areas were observed in the skull. Sternal marrow aspiration was unsuccessful but it was considered that the patient had amyloidosis probably related to myelomatosis. In April I964 he required treatment for congestive cardiac failure. There was a small quantity of albumin in the urine. Serum protein electrophoresis now revealed increased alpha2 and beta globulins in a total protein of 5"6 g./ml. E.S.R. remained 55 mm. Sternal marrow showed reduced cellularity with a relative increase in plasma cells. The abnormal area in the left femur was unchanged on X-ray. I57
158
BRITISH JOURNAL OF PLASTIC SURGERY
In June 1964 the patient developed increasing difficulty in swallowing because of progressive enlargement of his tongue. Before any further steps could be taken he died suddenly at home from cardiac failure. Case 2.--A woman aged 59 years attended hospital because of a painless swelling of her lower lip. This was excised early in I961. Microscopic examination showed numerous small ectopic loci of salivary gland tissue with markedly hyalinised muscle bundles. By October I961 slight enlargement of her submandibular glands and numerous small submucous nodules on her lips were present. Similar nodules were noted on the floor of the mouth and at the edge of the tongue within a few months. Those on the tongue gradually enlarged but remained painless and caused difficulty with speech and mastication. Further biopsy specimens were secured from upper lip and tongue. Hyalinised and partly necrotic muscle tissue similar to that found in the earlier specimen from the lip, suggested the diagnosis of amyloid disease. There was normocytic, normochromic anaemia with hmmoglobin II.1 g./ml. E.S.R. was 40 mm. Hess's test was positive. Serum proteins totalled 6"9 g./xoo ml. Electrophoresis showed a normal albumin band but globulins were generally decreased with a dense, compact protein band between beta and gamma globulins, presumably myeloma protein. Bence-Jones protein was found in the urine. Sternal marrow showed an increase in plasma cells consistent with myelomatosis. The diagnosis was considered to be myelomatosis with secondary amyloid disease. The patient had generalised joint pain, muscular weakness with winging of the scapulae and carpal tunnel syndrome. In March 1963 treatment was begun with Prednisolone 6o mg. daily. There was almost immediate subjective improvement but within a month Patient 3 attempting to close her mouth, severe ha~morrhage occurred from the alimentary tract. A recent barium meal had suggested rigidity of the oesophageal wall (possibly due to amyloid involvement) but there was no evidence of any gastroduodenal abnormality. Corticotrophin 40 units daily was substituted for Prednisolone and no further complication arose. Within a few months E.S.R. had fallen to xo ram. and Hess's test was negative. Serum protein electrophoresis, however, still showed a dense myeloma band. The patient felt much improved but required treatment for congestive cardiac failure. By February I964 she was bedfast and died in August. Case 3.--A woman aged 61 years was admitted to hospital in January 1962 with left-sided chest pain and a rigor. No definite diagnosis was reached and chest X-ray and two electrocardiograms were normal. During convalescence in another hospital she had a third cardiogram which showed clear abnormalities in the posterior leads. The possibility that she had sustained a myocardial infarction was again considered but no satisfactory conclusion was reached. She returned in September I962 with non-tender enlargement of the submandibular glands and tongue. Her skin and hair were dry and she was sluggish in movement and thought. Myxoedema was excluded by radio-iodine studies of thyroid function and by repeatedly normal protein bound iodine I27 levels. Biopsies of skin, fascia and muscle showed no abnormality. About this time purpura and ecchymoses developed and became a prominent feature of her condition. This bleeding tendency seemed to be due to vascular abnormality, since hmmostatic function was normal. It was particularly severe in April I963 when excision of part of her tongue was attempted, partly for cosmetic reasons as she was unable to close her lips over her hugely swollen tongue (illus.), and partly to obtain a good biopsy specimen. On the day before operation she developed severe purpura and spontaneous mouth bleeding. A stitch inserted in her tongue in theatre led to such marked interstitial h~emorrhage that tracheostomy became
MACROGLOSSIA IN MYELOMATOSIS
159
necessary; the operation was abandoned. Prednisolone was given in high dosage without marked effect. From April 1963 a number of positive tests were found. X-ray films showed fractured ribs with areas of erosion, one small osteolytic area in the skull and another in the upper end of the right femur. Serum proteins were below normal levels and the albumin-globulin ratio TABLE
Results of Detailed Histological Studies
Tissue
Staining method on ctyostat sections Fernardo
Heart Lungs Liver Spleen . Pancreas Duodenum Ileum Mesentery Kidney . Skin Submandibular gland Tongue Hip joint capsule and adjacent tissue Femoral deposit Skull deposit .
++++ ++
Thioflavine T . +-/-++
Staining method of paraffin sections Fernando +++
Thioflavine T. ++++
+ +
+q-q+
Congo Red ++++
+ + + +
++ + ++
+++ +
++÷
+ + +
+ ++
++÷ + +++
+++
++++
+++
++++
+ +++
++
++++
+
,
+ Minimal amounts present. ++ Small amounts present. -+-+ + Moderate amounts present. ++++ Very large amounts present, resulting in the virtual replacement of the tissue by amyloid. In general, where minimal or small amounts of amyloid were seen, amyloid was present only around small blood vessels. Where larger amounts were seen amyloid appeared between the normal tissue constituents.
was reversed but no myeloma protein was found and at no time was there Bence-Jones proteinuria. E.S.R. varied between 47 and 86 mm. The serum cholesterol, previously normal, was 581 rag. per cent. and remained high. Serum calcium was above normal. In July sternal marrow was found to be crowded with plasma cells. The diagnosis of myelomatosis with secondary amyloid disease was made. The patient spent her last three months in hospital. She was lethargic and bedfast but relatively content, although her tongue was grossly enlarged and constantly lolled from her mouth. Widespread ecchymosis developed. She died in January 1964 from pneumonia. At post-mortem examination amyloid tissue was found widely distributed throughout the body. The affected organs and the stains used in demonstration are summarised in the Table• The tongue itself was very large, being 9o mm. in length, 95 ram. across and 15 ram. in depth• The osteolytic lesions in skull and femur contained numerous plasma cells and the marrow was again overrun with plasma cells. SUMMARY Three patients with macroglossia are described. T w o had confirmed myelomatosis with secondary amyloid or paramyloid. T h e special pattern of this disorder is emphasised
I60
BRITISH JOURNAL OF PLASTIC SURGERY
a n d the n e e d to i n v e s t i g a t e every p a t i e n t w i t h macroglossia a c c o r d i n g to this p a t t e r n is also e m p h a s i s e d .
We should like to thank the staff in various hospitals who investigated and cared for these patients, but in particular Dr A. A. Charteris, Mr Robert Cochran, Dr John Colvin, Professor Bernard Lennox, Dr Ian Murray, Dr E. R. Watson and Dr T. M. Young. REFERENCES
CHAMBERS,R. A., MEDD, W. E. and SPENCER,H. (1958). Q. Jl Med. 27, 207. DAHLIN, D. C. (I949). Ann. intern. Med. 31, lO5. MAGNus-LEVY,A. (1933). Ztsehr. klin. Med. 126, 62. -(I952). J. Mr. Sinai Hosp. 19, 8. OSSERMAN,E. F. (1959). New Engl. ft. Med. 26I, lOO6. SNAPPER, I., TURNER, L. B. and MoscovITZ, H. L. (1953). " Multiple Myeloma ". New York : Grune and Stratton.
IN M Y E L O M A T O S I S
By JAMESBUCHANAN,M.D., M.R.C.P.(Ed.), M.R.C.P.(Glasg.) Consultant Physician, Law Hosital, Carluke IAIN D. O. FREW, M.D.
Consultant Pathologist, Good Hope Hospital, Sutton Coldfield IRIS I. J. M. GIBSON, M.A., M.B., M.R.C.P.(Glasg.), D.Obst.R.C.O.G.
Consultant Physician in Geriatric Medicine, Southern General Hospital, Glasgow THOMAS GIBSON, M.B., F.R.C.S.(Ed.), F.R.C.S.(Glasg.)
Consultant Plastic Surgeon, Western Regional Hospital Board AGNES R. RUSSELL,B.Sc., M.B., F.R.C.S.(Ed.), D.M.R.T., F.F.R.
Assistant Radiotherapist, Glasgow Institute for Radiotherapy (Royal and Western Infirmaries) THE relationship between " p r i m a r y amyloidosis " and paramyloid deposits associated with multiple myeloma is known to be close, and the conditions may be identical (Osserman, I959). The common sites of deposition are similar and staining properties are similar. Tissue infiltrates developing in multiple myeloma may precede skeletal manifestations by months or years (Magnus-Levy I933, I952). Macroglossia is a classic sign o f " primary amyloid" and obvious in one-third of cases (Dahlin, I949). I f macroglossia is equally classic in paramyloid the importance of diagnosis is obvious, in view of the possibility of treating myeloma. Patients with myeloma with paramyloid have a diagnostic pattern which differs from that of isolated myeloma. Until late in the course of the disorder bone lesions are relatively rare. Hyperglobulinaemia is rare and the Westergren erythrocyte sedimentation rate therefore does not reach typical myeloma levels. Bence-Jones protein is usually found in the urine. Serum cholesterol may be unduly high and calcium high. An abnormal bleeding tendency is frequent, possibly due to deposition ofparamyloid in blood vessels (Snapper et al., I953 ; Chambers et al., I958). Simple biopsy is possible by sternal marrow aspiration, and this should always be done in cases of macroglossia. Three patients are described : Case I.--A man aged 60 years was admitted to hospital in December I963. He had noted a large, firm swelling at the base of his tongue which was considerably enlarged and protruded from his mouth. The submandibular glands were palpably enlarged. Biopsy of tongue showed irregular areas of pale hyaline material which gave a positive reaction for amyloid with congo red. There was normochromic, normocytic anaemia with h~emoglobin 9"9 g./IOO ml. Westergren E.S.R. was 54 mm. in the first hour. Thrombotest activity was 62 per cent. Serum proteins totalled 6.4 g./Ioo ml. and electrophoresis gave a normal pattern. Cryoglobulin serum test was negative. Urine was normal. On X-ray an oval translucent area was seen in the cortex of the left femur and two small translucent areas were observed in the skull. Sternal marrow aspiration was unsuccessful but it was considered that the patient had amyloidosis probably related to myelomatosis. In April I964 he required treatment for congestive cardiac failure. There was a small quantity of albumin in the urine. Serum protein electrophoresis now revealed increased alpha2 and beta globulins in a total protein of 5"6 g./ml. E.S.R. remained 55 mm. Sternal marrow showed reduced cellularity with a relative increase in plasma cells. The abnormal area in the left femur was unchanged on X-ray. I57
158
BRITISH JOURNAL OF PLASTIC SURGERY
In June 1964 the patient developed increasing difficulty in swallowing because of progressive enlargement of his tongue. Before any further steps could be taken he died suddenly at home from cardiac failure. Case 2.--A woman aged 59 years attended hospital because of a painless swelling of her lower lip. This was excised early in I961. Microscopic examination showed numerous small ectopic loci of salivary gland tissue with markedly hyalinised muscle bundles. By October I961 slight enlargement of her submandibular glands and numerous small submucous nodules on her lips were present. Similar nodules were noted on the floor of the mouth and at the edge of the tongue within a few months. Those on the tongue gradually enlarged but remained painless and caused difficulty with speech and mastication. Further biopsy specimens were secured from upper lip and tongue. Hyalinised and partly necrotic muscle tissue similar to that found in the earlier specimen from the lip, suggested the diagnosis of amyloid disease. There was normocytic, normochromic anaemia with hmmoglobin II.1 g./ml. E.S.R. was 40 mm. Hess's test was positive. Serum proteins totalled 6"9 g./xoo ml. Electrophoresis showed a normal albumin band but globulins were generally decreased with a dense, compact protein band between beta and gamma globulins, presumably myeloma protein. Bence-Jones protein was found in the urine. Sternal marrow showed an increase in plasma cells consistent with myelomatosis. The diagnosis was considered to be myelomatosis with secondary amyloid disease. The patient had generalised joint pain, muscular weakness with winging of the scapulae and carpal tunnel syndrome. In March 1963 treatment was begun with Prednisolone 6o mg. daily. There was almost immediate subjective improvement but within a month Patient 3 attempting to close her mouth, severe ha~morrhage occurred from the alimentary tract. A recent barium meal had suggested rigidity of the oesophageal wall (possibly due to amyloid involvement) but there was no evidence of any gastroduodenal abnormality. Corticotrophin 40 units daily was substituted for Prednisolone and no further complication arose. Within a few months E.S.R. had fallen to xo ram. and Hess's test was negative. Serum protein electrophoresis, however, still showed a dense myeloma band. The patient felt much improved but required treatment for congestive cardiac failure. By February I964 she was bedfast and died in August. Case 3.--A woman aged 61 years was admitted to hospital in January 1962 with left-sided chest pain and a rigor. No definite diagnosis was reached and chest X-ray and two electrocardiograms were normal. During convalescence in another hospital she had a third cardiogram which showed clear abnormalities in the posterior leads. The possibility that she had sustained a myocardial infarction was again considered but no satisfactory conclusion was reached. She returned in September I962 with non-tender enlargement of the submandibular glands and tongue. Her skin and hair were dry and she was sluggish in movement and thought. Myxoedema was excluded by radio-iodine studies of thyroid function and by repeatedly normal protein bound iodine I27 levels. Biopsies of skin, fascia and muscle showed no abnormality. About this time purpura and ecchymoses developed and became a prominent feature of her condition. This bleeding tendency seemed to be due to vascular abnormality, since hmmostatic function was normal. It was particularly severe in April I963 when excision of part of her tongue was attempted, partly for cosmetic reasons as she was unable to close her lips over her hugely swollen tongue (illus.), and partly to obtain a good biopsy specimen. On the day before operation she developed severe purpura and spontaneous mouth bleeding. A stitch inserted in her tongue in theatre led to such marked interstitial h~emorrhage that tracheostomy became
MACROGLOSSIA IN MYELOMATOSIS
159
necessary; the operation was abandoned. Prednisolone was given in high dosage without marked effect. From April 1963 a number of positive tests were found. X-ray films showed fractured ribs with areas of erosion, one small osteolytic area in the skull and another in the upper end of the right femur. Serum proteins were below normal levels and the albumin-globulin ratio TABLE
Results of Detailed Histological Studies
Tissue
Staining method on ctyostat sections Fernardo
Heart Lungs Liver Spleen . Pancreas Duodenum Ileum Mesentery Kidney . Skin Submandibular gland Tongue Hip joint capsule and adjacent tissue Femoral deposit Skull deposit .
++++ ++
Thioflavine T . +-/-++
Staining method of paraffin sections Fernando +++
Thioflavine T. ++++
+ +
+q-q+
Congo Red ++++
+ + + +
++ + ++
+++ +
++÷
+ + +
+ ++
++÷ + +++
+++
++++
+++
++++
+ +++
++
++++
+
,
+ Minimal amounts present. ++ Small amounts present. -+-+ + Moderate amounts present. ++++ Very large amounts present, resulting in the virtual replacement of the tissue by amyloid. In general, where minimal or small amounts of amyloid were seen, amyloid was present only around small blood vessels. Where larger amounts were seen amyloid appeared between the normal tissue constituents.
was reversed but no myeloma protein was found and at no time was there Bence-Jones proteinuria. E.S.R. varied between 47 and 86 mm. The serum cholesterol, previously normal, was 581 rag. per cent. and remained high. Serum calcium was above normal. In July sternal marrow was found to be crowded with plasma cells. The diagnosis of myelomatosis with secondary amyloid disease was made. The patient spent her last three months in hospital. She was lethargic and bedfast but relatively content, although her tongue was grossly enlarged and constantly lolled from her mouth. Widespread ecchymosis developed. She died in January 1964 from pneumonia. At post-mortem examination amyloid tissue was found widely distributed throughout the body. The affected organs and the stains used in demonstration are summarised in the Table• The tongue itself was very large, being 9o mm. in length, 95 ram. across and 15 ram. in depth• The osteolytic lesions in skull and femur contained numerous plasma cells and the marrow was again overrun with plasma cells. SUMMARY Three patients with macroglossia are described. T w o had confirmed myelomatosis with secondary amyloid or paramyloid. T h e special pattern of this disorder is emphasised
I60
BRITISH JOURNAL OF PLASTIC SURGERY
a n d the n e e d to i n v e s t i g a t e every p a t i e n t w i t h macroglossia a c c o r d i n g to this p a t t e r n is also e m p h a s i s e d .
We should like to thank the staff in various hospitals who investigated and cared for these patients, but in particular Dr A. A. Charteris, Mr Robert Cochran, Dr John Colvin, Professor Bernard Lennox, Dr Ian Murray, Dr E. R. Watson and Dr T. M. Young. REFERENCES
CHAMBERS,R. A., MEDD, W. E. and SPENCER,H. (1958). Q. Jl Med. 27, 207. DAHLIN, D. C. (I949). Ann. intern. Med. 31, lO5. MAGNus-LEVY,A. (1933). Ztsehr. klin. Med. 126, 62. -(I952). J. Mr. Sinai Hosp. 19, 8. OSSERMAN,E. F. (1959). New Engl. ft. Med. 26I, lOO6. SNAPPER, I., TURNER, L. B. and MoscovITZ, H. L. (1953). " Multiple Myeloma ". New York : Grune and Stratton.