CAMEO
PRIMARY THYMIC CARCINOMA AND ITS ASSOCIATION WITH DERMATOMYOSITIS AND PURE RED CELL APLASIA POH HAURT FONG, M.R.C.P., AILEEN WEE, F.R.C.P.A.,
.
H.L. CHAN, F.R.C.P., E.R.A.C.P., AND Y . O . TAN, F.R.C.P. (GLAS), E.R.C.P.E., E.R.C.P.C.
A 60-year-old Chinese retired clerk presented at the National University Hospital, in January 1989, with a pruritic eruption affecting the face and the upper limbs. He had also noticed weight loss of about 10 kg and progressive weakness of the arms and legs. He had no significant medical history except for an episode of gout 10 years before. On clinical examination, a scaly erythematous rash was evident on the eyelids, forehead, arms, and "V" of the neck. Erythematous plaques were seen over the knuckles of the fingers (Gottron's sign) (Fig. 1). The neurologic examination confirmed muscle weakness of grade 4/5 power involving both shoulder and hip girdles. The rest of the physical examination was unremarkable. Laboratory tests revealed hemoglobin to be 15.4 g/dL, white blood cell count 6.1 x 10 g/L, ESR was 26 mm/h, serum aldolase varying from 7.9 u/L to 20 u/L (NR 0-7.6), ALT was 94 u/L (NR 5-40), GGT 103 u/L (NR 5-40)+, LDH 1530 u/L (300-530). ANA and anti-DNA were negative. The electromyogram was within normal limits. The patient refused a muscle biopsy. The initial chest x-ray was reported as normal. Gastroduodenoscopy revealed a benign shallow duodenal ulcer, while abdominal CT scan and an ENT examination did not reveal any evidence of malignancy. The serum alpha-fetoprotein and carcinoembryonic antigen were normal. He was treated with hydroxyzine 25 mg t.i.d., prednisolone 15 mg om, and 0.01% betamethasone cream, which provided initial symptomatic response. Four months later, he was readmitted with problems of intense pruritus and the appearance of a fiery erythema on the trunk. The laboratory tests now revealed a hemoglobulin of 5.2 g/dL with normochromic RBCS, total white count of 31.0 X 109/L, and an ESR or 112 mm/h. Protein electrophoresis showed a positive acute phase response and polyclonal gammopathy with no M component detected. The gastrocolonoscopy showed no evidence of an active bleed from the stomach or colon. The ANA, anti-DNA, and direct Coomb's Test were negative, but cold agglutinin was positive, reticulocyte count varied from 0.2% to 1.0%, serum haptoglobulin 40.3 mg/dL (NR 27-139), serum bilirubln 11 |imol/L (NR 5-30). Bone marrow biopsy revealed a hypercellular marrow with an increase in hematopoiesis in all three cell lines. The peripheral blood smear was Interpreted as consistent with a leukemoid reaction. At this stage it was felt that he
From the Departments of Medicine and Pathology, National University Hospital, Singapore. Address for correspondence: Dr. Poh Haurt Fong, Department of Medicine, National University Hospital, Lower Kent Ridge Road, Singapore 0511.
• , .-:- ...-••^. ••-.-'
. ;
Figure 1. Gottron papules: erythematous plaques are seen on the dorsum of the fingers.
probably had an acute hemolysis that had resolved. Although he was given blood transfusions and the dose of prednisolone increased to 30 mg daily, there was no improvement. A repeat chest x-ray in July 1989 revealed a large anterior mediastlnal mass (Fig. 2), which was subsequently confirmed on CT scan of the thorax. An open thoracotomy in August 1989 revealed a large vascular and necrotic ovoid thymic mass adjacent to and adherent to the arch of aorta. Histologically, the tumor was composed of sheets of large cells with round to ovoid vesicular nuclei, prominent nucleoli, ample pale eosinophilic cytoplasm, and cellular pleomorphism. Mitoses were present. There was a vague suggestion of packeting of the tumor cells with a lymphoid admixture in areas (Fig. 3). No evidence of mucin or melanin was identified. Immunohistochemically, the tumor cells stained positively for wide-spectrum keratin, cytokeratin (CAM 5.2), and vimentin. There was focal staining for a-1 antitrypsin. The stain for afetoprotein was negative. The histologic appearances were those of a carcinoma, type unclassified. By exclusion the tumor was considered to be consistent with a thymic carcinoma with an atypical histologic appearance. The patient continued to have problems of severe anemia with a hemoglobin ranging from 6.7 to 8.7 g/dL and absent reticulocytosls. The repeat bone marrow was reported as normocellular with marked erythroid hypoplasia and a myeloidierythroid ratio of 45:1. The myeloid series was increased with normal maturation features. These hematologic features were, therefore, consistent with a pure red cell aplasia. An MDP Tc99m bone scan and CT scan of the abdomen were normal.
Dermatomyositis Fong et al.
^'J'S
Figure 3. The tumor was characterized by sheets of large undifferentiated epithelial cells with vesicular nucleus and prominent nucleoli (hemotoxylin and eosin, original magnification X 300).
Figure 2.
in general. In a study from the Mayo clinic by Lewis et al. of 283 patients with thymomas, 52% of them had some form of paraneoplastic syndrome such as myasthenia gravis, systemic lupus erythematosus, pure red cell aplasia, pemphigus vulgaris, and alopecia areata.* In a search of the literature we have not come across any reported cases of thymic carcinoma presenting with both dermatomyositis and pure red cell aplasia. The diagnosis of dermatomyositis is based on the criteria proposed by Bohan and Peter.^ Of the five major criteria for the diagnosis of dermatomyositis, viz (1) symmetrical weakness of limb girdle muscles, (2) evidence of necrosis of type I and II muscle fibers and inflammatory exudate on muscle biopsy specimen, (3) elevation of skeletal derived muscle enzyme in serum, (4) characteristic electromyographic findings, and (5) dermatologic signs of heliotrope rash, Gottron's papules, and a scaly erythema; three of these criteria were fulfilled in our patient. Acquired pure red cell aplasia (PRCA) is a hematologic disorder of heterogenous origin characterized by a profound normocytic normochromic anemia with absent reticulocytosis, erythroid hypoplasia but normal granuIocytic and megakaryotic series.** It can be congenital (hypoplastic anemia of Blackfan and Diamond), primary in origin due to an immunoglobulin inhibitor, or secondary to various other conditions such as thymomas, systemic lupus erythematosus, or leukemias and lymphomas. As many as 50% of patients with PRCA have an underlying thymoma although only 5% of thymoma patients have PRCA. Secondary PRCA is usually self limiting, while the primary acquired PRCA often responds to immunosuppressive therapy. The precise association of PRCA with thymoma is uncertain although an IgG inhibitor directed against nucleated red blood cells, or against erythropoetin is suspected.' While the coexistence of both these autoimmune paraneoplastic phenomenoma is unusual, it is not unexpected.
Chest x-ray reveals a right hilar mass.
Even with frequent blood transfusions, localized radiotherapy, and chemotherapy with cisplatinum, epirubicin, and vincristin, he continued to deteriorate. He succumbed 19 months later, in July, 1990 from respiratory failure, local tumor invasion, and superior vena caval obstruction. There was no clinical evidence of distant metastases. No autopsy was performed.
DISCUSSION
There have been several classifications of thymic tumors. Thymic neoplasms are classified according to their morphologic features and presumed histogenesis. According to Rosai, Levine and others,^'^'^ the term thymoma is reserved for tumors originating from thymic epithelium. Benign thymomas are well-encapsulated tumors that may rarely recur locally. Malignant thymomas are locally invasive, tend to recur, and can occasionally metastasize widely. In addition to the invasive thymoma variety of malignant thymomas, there are certain thymic neoplasms that exhibit unequivocal cytologic and histologic features of malignancy but cannot be differentiated histologically from carcinomas arising in extrathymic sites (e.g., squamous cell, basaloid, mucoepidermoid, undifferentiated carcinomas, and others). This group can be identified as true thymic carcinomas.^ The thymic carcinoma in our patient was described as having an atypical histologic appearance as it failed to bear the other features mentioned. Thymic carcinomas although rare are seen in patients aged 40 to 60 years old and have been reported in both Caucasian and Chinese patients.-' A high incidence of paraneoplastic phenomena has been noted in thymomas 427
International Journal of Dermatology Vol. 31, No. 6, June 1992
This case demonstrates the strength of association between dermatomyositis and an underlying malignancy especially in the older age group, which varies from 15 to 34% and rises with age above 50 years.'" Thymic carcinoma generally has a poor prognosis" with an average survival of 18 months after diagnosis. Myasthenia gravis'^ and other paraneoplastic hematologic abnormalities have been associated with a poorer survival in some series,'^ but since the numbers are small this data should be interpreted with care.
5.
Chua ET, Tan BC, Chia KB, et al. Malignant thymoma - a study of 30 cases. Singapore Med J 1988; 29: 565569.
6.
Lewis JE, Wick MR, Scheithauer BW, et al. Thymoma —a clinicopathologic review. Cancer 1987; 60: 27272743.
7.
Bohan A, Peter J. Polymyositis and dermatomyositis. Part 1. N EngI J Med 1975; 292:344-347.
8.
Ammus SS, Yunis SS. Acquired pure red cell aplasia. Am J Hematol 1987; 24:311-326.
9.
Taniguchi S, Shihuya T, Morioka E, et al. Demonstration of three distinct immunological disorders on erythropoiesis in a patient with pure red cell aplasia and • - autoimmune haemolytic anaemia associated with thymoma. Br J Haemotol 1988; 68:473-477.
REEERENCES
1. 2.
3.
4.
Legolvan DP, Abell MR. Thymomas. Cancer 1977; 39:2142-2157. Ricci C, Rendina EA, Pescarmona FO, et al. Correlations between histological type, clinical behaviour, and prognosis in thymoma. Thorax 1989; 44:455-460. Levine GD, Rosai J. Thymic hyperplasia and neoplasia: a review of current concepts. Hem Pathol 1978; 9: 495-515. Snover DC, Levine GD, Rosai J. Thymic carcinoma. Five distinctive histological variants. Am J Surg Pathol 1982; 6:451-470.
10.
Bohan A, Peter J. Polymyositis and dermatomyositis. Part 2. N Eng J Med 1975; 292:403-407.
11.
Wick MR, Scheithauer BW, Weiland LH, Bernatz PE. Primary thymic carcinomas. Am J Surg Pathol 1982; 6:613-630.
12.
Monden Y, Uyama T, Taniki T, et al. The characteristics of thymoma with myasthenia gravis: a 28-year experience. J Surg Oncol 1988; 38:151-154.
13.
Salyer RW, Eggleston JC. Thymoma — a clinical and pathological study of 65 cases. Cancer 1976; 37: 299-249.
A popular pair of tattoos (see p.425). From the World of Tattoos collection, Honolulu, HI. Suhmitted by Norman Goldstein, M.D., Honolulu, HI. 428
PRIMARY THYMIC CARCINOMA AND ITS ASSOCIATION WITH DERMATOMYOSITIS AND PURE RED CELL APLASIA POH HAURT FONG, M.R.C.P., AILEEN WEE, F.R.C.P.A.,
.
H.L. CHAN, F.R.C.P., E.R.A.C.P., AND Y . O . TAN, F.R.C.P. (GLAS), E.R.C.P.E., E.R.C.P.C.
A 60-year-old Chinese retired clerk presented at the National University Hospital, in January 1989, with a pruritic eruption affecting the face and the upper limbs. He had also noticed weight loss of about 10 kg and progressive weakness of the arms and legs. He had no significant medical history except for an episode of gout 10 years before. On clinical examination, a scaly erythematous rash was evident on the eyelids, forehead, arms, and "V" of the neck. Erythematous plaques were seen over the knuckles of the fingers (Gottron's sign) (Fig. 1). The neurologic examination confirmed muscle weakness of grade 4/5 power involving both shoulder and hip girdles. The rest of the physical examination was unremarkable. Laboratory tests revealed hemoglobin to be 15.4 g/dL, white blood cell count 6.1 x 10 g/L, ESR was 26 mm/h, serum aldolase varying from 7.9 u/L to 20 u/L (NR 0-7.6), ALT was 94 u/L (NR 5-40), GGT 103 u/L (NR 5-40)+, LDH 1530 u/L (300-530). ANA and anti-DNA were negative. The electromyogram was within normal limits. The patient refused a muscle biopsy. The initial chest x-ray was reported as normal. Gastroduodenoscopy revealed a benign shallow duodenal ulcer, while abdominal CT scan and an ENT examination did not reveal any evidence of malignancy. The serum alpha-fetoprotein and carcinoembryonic antigen were normal. He was treated with hydroxyzine 25 mg t.i.d., prednisolone 15 mg om, and 0.01% betamethasone cream, which provided initial symptomatic response. Four months later, he was readmitted with problems of intense pruritus and the appearance of a fiery erythema on the trunk. The laboratory tests now revealed a hemoglobulin of 5.2 g/dL with normochromic RBCS, total white count of 31.0 X 109/L, and an ESR or 112 mm/h. Protein electrophoresis showed a positive acute phase response and polyclonal gammopathy with no M component detected. The gastrocolonoscopy showed no evidence of an active bleed from the stomach or colon. The ANA, anti-DNA, and direct Coomb's Test were negative, but cold agglutinin was positive, reticulocyte count varied from 0.2% to 1.0%, serum haptoglobulin 40.3 mg/dL (NR 27-139), serum bilirubln 11 |imol/L (NR 5-30). Bone marrow biopsy revealed a hypercellular marrow with an increase in hematopoiesis in all three cell lines. The peripheral blood smear was Interpreted as consistent with a leukemoid reaction. At this stage it was felt that he
From the Departments of Medicine and Pathology, National University Hospital, Singapore. Address for correspondence: Dr. Poh Haurt Fong, Department of Medicine, National University Hospital, Lower Kent Ridge Road, Singapore 0511.
• , .-:- ...-••^. ••-.-'
. ;
Figure 1. Gottron papules: erythematous plaques are seen on the dorsum of the fingers.
probably had an acute hemolysis that had resolved. Although he was given blood transfusions and the dose of prednisolone increased to 30 mg daily, there was no improvement. A repeat chest x-ray in July 1989 revealed a large anterior mediastlnal mass (Fig. 2), which was subsequently confirmed on CT scan of the thorax. An open thoracotomy in August 1989 revealed a large vascular and necrotic ovoid thymic mass adjacent to and adherent to the arch of aorta. Histologically, the tumor was composed of sheets of large cells with round to ovoid vesicular nuclei, prominent nucleoli, ample pale eosinophilic cytoplasm, and cellular pleomorphism. Mitoses were present. There was a vague suggestion of packeting of the tumor cells with a lymphoid admixture in areas (Fig. 3). No evidence of mucin or melanin was identified. Immunohistochemically, the tumor cells stained positively for wide-spectrum keratin, cytokeratin (CAM 5.2), and vimentin. There was focal staining for a-1 antitrypsin. The stain for afetoprotein was negative. The histologic appearances were those of a carcinoma, type unclassified. By exclusion the tumor was considered to be consistent with a thymic carcinoma with an atypical histologic appearance. The patient continued to have problems of severe anemia with a hemoglobin ranging from 6.7 to 8.7 g/dL and absent reticulocytosls. The repeat bone marrow was reported as normocellular with marked erythroid hypoplasia and a myeloidierythroid ratio of 45:1. The myeloid series was increased with normal maturation features. These hematologic features were, therefore, consistent with a pure red cell aplasia. An MDP Tc99m bone scan and CT scan of the abdomen were normal.
Dermatomyositis Fong et al.
^'J'S
Figure 3. The tumor was characterized by sheets of large undifferentiated epithelial cells with vesicular nucleus and prominent nucleoli (hemotoxylin and eosin, original magnification X 300).
Figure 2.
in general. In a study from the Mayo clinic by Lewis et al. of 283 patients with thymomas, 52% of them had some form of paraneoplastic syndrome such as myasthenia gravis, systemic lupus erythematosus, pure red cell aplasia, pemphigus vulgaris, and alopecia areata.* In a search of the literature we have not come across any reported cases of thymic carcinoma presenting with both dermatomyositis and pure red cell aplasia. The diagnosis of dermatomyositis is based on the criteria proposed by Bohan and Peter.^ Of the five major criteria for the diagnosis of dermatomyositis, viz (1) symmetrical weakness of limb girdle muscles, (2) evidence of necrosis of type I and II muscle fibers and inflammatory exudate on muscle biopsy specimen, (3) elevation of skeletal derived muscle enzyme in serum, (4) characteristic electromyographic findings, and (5) dermatologic signs of heliotrope rash, Gottron's papules, and a scaly erythema; three of these criteria were fulfilled in our patient. Acquired pure red cell aplasia (PRCA) is a hematologic disorder of heterogenous origin characterized by a profound normocytic normochromic anemia with absent reticulocytosis, erythroid hypoplasia but normal granuIocytic and megakaryotic series.** It can be congenital (hypoplastic anemia of Blackfan and Diamond), primary in origin due to an immunoglobulin inhibitor, or secondary to various other conditions such as thymomas, systemic lupus erythematosus, or leukemias and lymphomas. As many as 50% of patients with PRCA have an underlying thymoma although only 5% of thymoma patients have PRCA. Secondary PRCA is usually self limiting, while the primary acquired PRCA often responds to immunosuppressive therapy. The precise association of PRCA with thymoma is uncertain although an IgG inhibitor directed against nucleated red blood cells, or against erythropoetin is suspected.' While the coexistence of both these autoimmune paraneoplastic phenomenoma is unusual, it is not unexpected.
Chest x-ray reveals a right hilar mass.
Even with frequent blood transfusions, localized radiotherapy, and chemotherapy with cisplatinum, epirubicin, and vincristin, he continued to deteriorate. He succumbed 19 months later, in July, 1990 from respiratory failure, local tumor invasion, and superior vena caval obstruction. There was no clinical evidence of distant metastases. No autopsy was performed.
DISCUSSION
There have been several classifications of thymic tumors. Thymic neoplasms are classified according to their morphologic features and presumed histogenesis. According to Rosai, Levine and others,^'^'^ the term thymoma is reserved for tumors originating from thymic epithelium. Benign thymomas are well-encapsulated tumors that may rarely recur locally. Malignant thymomas are locally invasive, tend to recur, and can occasionally metastasize widely. In addition to the invasive thymoma variety of malignant thymomas, there are certain thymic neoplasms that exhibit unequivocal cytologic and histologic features of malignancy but cannot be differentiated histologically from carcinomas arising in extrathymic sites (e.g., squamous cell, basaloid, mucoepidermoid, undifferentiated carcinomas, and others). This group can be identified as true thymic carcinomas.^ The thymic carcinoma in our patient was described as having an atypical histologic appearance as it failed to bear the other features mentioned. Thymic carcinomas although rare are seen in patients aged 40 to 60 years old and have been reported in both Caucasian and Chinese patients.-' A high incidence of paraneoplastic phenomena has been noted in thymomas 427
International Journal of Dermatology Vol. 31, No. 6, June 1992
This case demonstrates the strength of association between dermatomyositis and an underlying malignancy especially in the older age group, which varies from 15 to 34% and rises with age above 50 years.'" Thymic carcinoma generally has a poor prognosis" with an average survival of 18 months after diagnosis. Myasthenia gravis'^ and other paraneoplastic hematologic abnormalities have been associated with a poorer survival in some series,'^ but since the numbers are small this data should be interpreted with care.
5.
Chua ET, Tan BC, Chia KB, et al. Malignant thymoma - a study of 30 cases. Singapore Med J 1988; 29: 565569.
6.
Lewis JE, Wick MR, Scheithauer BW, et al. Thymoma —a clinicopathologic review. Cancer 1987; 60: 27272743.
7.
Bohan A, Peter J. Polymyositis and dermatomyositis. Part 1. N EngI J Med 1975; 292:344-347.
8.
Ammus SS, Yunis SS. Acquired pure red cell aplasia. Am J Hematol 1987; 24:311-326.
9.
Taniguchi S, Shihuya T, Morioka E, et al. Demonstration of three distinct immunological disorders on erythropoiesis in a patient with pure red cell aplasia and • - autoimmune haemolytic anaemia associated with thymoma. Br J Haemotol 1988; 68:473-477.
REEERENCES
1. 2.
3.
4.
Legolvan DP, Abell MR. Thymomas. Cancer 1977; 39:2142-2157. Ricci C, Rendina EA, Pescarmona FO, et al. Correlations between histological type, clinical behaviour, and prognosis in thymoma. Thorax 1989; 44:455-460. Levine GD, Rosai J. Thymic hyperplasia and neoplasia: a review of current concepts. Hem Pathol 1978; 9: 495-515. Snover DC, Levine GD, Rosai J. Thymic carcinoma. Five distinctive histological variants. Am J Surg Pathol 1982; 6:451-470.
10.
Bohan A, Peter J. Polymyositis and dermatomyositis. Part 2. N Eng J Med 1975; 292:403-407.
11.
Wick MR, Scheithauer BW, Weiland LH, Bernatz PE. Primary thymic carcinomas. Am J Surg Pathol 1982; 6:613-630.
12.
Monden Y, Uyama T, Taniki T, et al. The characteristics of thymoma with myasthenia gravis: a 28-year experience. J Surg Oncol 1988; 38:151-154.
13.
Salyer RW, Eggleston JC. Thymoma — a clinical and pathological study of 65 cases. Cancer 1976; 37: 299-249.
A popular pair of tattoos (see p.425). From the World of Tattoos collection, Honolulu, HI. Suhmitted by Norman Goldstein, M.D., Honolulu, HI. 428
