- Email: [email protected]
Myeloid Metaplasia Masquerading as a Urethral Caruncle
0022-534 7/86/1354-0789$02.00/0 Vol. 135, April
THE JOURNAL OF UROLOGY
Printed in U.S.A.
Copyright © 1986 by The Williams & Wilkins Co.
MYELOID METAPLASIA MASQUERADING AS A URETHRAL CARUNCLE KAROLY BALOGH
AND
CARL J. O'HARA
From the Department of Pathology, New England Deaconess Hospital and Harvard Medical School, Boston, Massachusetts
ABSTRACT
A 64-year-old woman presented with a painless bleeding mass of the urethral meatus that was diagnosed as a caruncle and removed surgically. Histological examination revealed a cellular and vascular polypoid lesion that contained megakaryocytes, as well as groups of hematopoietic stem cells, and maturing cells of the erythroid and granulocytic series. The diagnosis of myeloid metaplasia was confirmed by marker studies with immunoperoxidase techniques. The patient had a long history of bleeding and clotting problems owing to a myeloproliferative disorder with thrombocytosis and gradual development of myelofibrosis. No other foci of extramedullary hematopoiesis were apparent. The patient was free of urinary symptoms 22 months postoperatively. Urethral caruncle is a clinical term designating a small polypoid lesion arising from the posterior wall of the female urethra at or near the meatus. 1 Caruncles are composed of loose vascular connective tissue covered by squamous or transitional cell epithelium. The location predisposes them to inflammation and the resultant vascular granulation tissue may mimic histologically a pyogenic granuloma or an angioma. Rarely, a carcinoma, 2-4 sarcoma4 or malignant lymphoma5 may masquerade as a caruncle. Recently, we observed a diagnostically challenging lesion that presented as a urethral caruncle. CASE REPORT
A 64-year-old woman presented in January 1984 with painless bleeding from the urethral meatus a few days in duration. Topical treatment provided only temporary control and in the next 2 weeks the urethral bleeding episodes became more frequent, with formed clots in the meatus. Cystourethroscopy was completely negative. The source of bleeding was a swollen mass at the urethral meatus. Diagnosis was urethral caruncle and the lesion was amputated by electric cutting current with the patient under local anesthesia. There were no bleeding problems postoperatively. At followup examination 22 months later the patient was free of urinary symptoms. Pathological examination. The removed tissue was irregular, rubbery, pale tan and focally hemorrhagic, and measured 1.2 X 1.2 X 0.4 cm. The specimen was fixed in 4 per cent buffered formaldehyde, dehydrated and embedded in paraffin. Histological sections were cut at 6 µ., and stained with hematoxylin and eosin. Microscopic examination revealed polypoid tissue covered by squamous epithelium. The mucosa was ulcerated focally. The bulk of the lesion consisted of cellular tissue that contained numerous bizarre large cells scattered throughout the vascular stroma. These large cells had hyperchromatic, irregular, lobulated nuclei and abundant eosinophilic cytoplasm. They usually were seen within groups of immature round cells identifiable as stem cells and maturing cells of the erythroid and granulocytic series (fig. 1). Immunoperoxidase studies with the standard Sternberger technique6 on paraffin section revealed positive staining of the large cells with lobulated nuclei for factor VIII-related antigen (anti-factor VIII monoclonal 1:500 DAK0) 7•8 (fig. 2, A), identifying them as megakaryocytes. Clusters of small round cells with dark pyknotic nuclei stained positive for hemoglobin (antihemoglobin 1:500 DAK0) 9 (fig. 2, B). Aggregates of the remaining cells stained positively for lysozyme (anti-lysozyme 1:400 DAK0). 10 The presence of all 3 hematopoietic cell lines confirmed the diagnosis of myeloid metaplasia. Accepted for publication November 18, 1985.
789
DISCUSSION
After the histological diagnosis was established, review of the record revealed a long history of problems attributed to essential (primary) thrombocythemia for which the patient had been given 32phosphorus (32 P) and busulfan in 1970. Subsequently, the symptoms disappeared but recurred gradually and in 1976 the diagnosis of a myeloproliferative disorder with thrombocytosis was made. She responded well to another course ofbusulfan. In 1980 thrombocythemia exacerbated and another course of 32 P and busulfan was administered. Medical treatment, including anticoagulation, did not prevent multiple thrombotic episodes and pulmonary emboli necessitating hospitalization. In April 1981 the patient noticed a lump in the left breast, which proved to be an infiltrating duct carcinoma and a radical mastectomy was performed (stage TlNOMO disease). Following mastectomy the patient noticed easy bruising and episodes of epistaxis occurred with increasing frequency. The physical findings and laboratory data suggested that she had entered a phase of myelofibrosis with subsequent bleeding. At hospitalization for the urethral caruncle in January 1984 splenomegaly was noted on physical examination. No lymphadenopathy, cyanosis or clubbing of digits was found. A computerized tomographic scan of the neck and thorax revealed no metastatic tumor, and the laboratory data were consistent with myelofibrosis.
Fm. 1. Abundant round cells of varying size and large bizarre cells with hyperchromatic nuclei are seen in vascular stroma of caruncle. H & E, reduced from Xl20. Inset, higher magnification of polymorphic cellular infiltrate shows megakaryocytes among immature erythroid and myeloid cells. H & E, reduced from X300.
790
BALOGH AND O'HARA
loid metaplasia occurs most frequently at sites of embryonic hematopoiesis. This recognition has led to the notion that extramedullary hematopoiesis is caused by a stimulus that reawakens the hematopoietic potential of tissues involved in blood formation during embryonic life. However, this attractive theory does not provide a satisfactory explanation for the occurrence of myeloid metaplasia in isolated and unusual sites, such as a urethral caruncle. REFERENCES
~t .,,'
-·
FIG. 2. Immunoperoxidase reactions. A, stain with anti-factor VIIIrelated antigen is positive in cytoplasm of megakaryocytes and endothelial cells. B, anti-hemoglobin identifies normoblasts. Note unstained megakaryocytes and myeloid precursors. Reduced from X300.
Myeloid metaplasia, or extramedullary hematopoiesis, is believed to be caused by encroachment of bone marrow by a pathological process. Long-standing myeloproliferative disorders gradually can lead to myelofibrosis with the development of extramedullary hematopoiesis. 11 - 13 This sequence of events in our case also is supported by the presence of nucleated erythrocytes in the peripheral blood, a characteristic of myelofibrosis with myeloid metaplasia. Although the patient had a history of breast carcinoma, replacement of bone marrow by metastatic carcinoma appears improbable, since there was no clinical evidence of skeletal metastases. Myeloid metaplasia may develop at many sites. It is most prominent in the spleen, liver and lymph nodes but also has been described in numerous other organs, including the skin and central nervous system. 12-15 To the best of our knowledge, its presentation as a urethral mass has not been reported. The question of whether myeloid metaplasia developed in a preexistent caruncle cannot be answered with certainty. Our case also is unusual because, besides splenomegaly, the caruncle was the only clinically manifest mass, whereas tumor-like myeloid metaplasia frequently involves several organs. 12·16 The mechanism of extramedullary hematopoiesis in myelofibrosis is unclear. A commonly held view maintains that an abnormal stimulus acts upon the hematopoietic cells. 12·17 A recent experimental study in which saponin injected into rabbits induced myelofibrosis and myeloid metaplasia indicated that erythroid and myeloid progenitor cells increase in blood and spleen as the stem cells are depleted from the bone marrow.18 These experiments suggest that extramedullary hematopoiesis may be owing to colonization by progenitor cells of bone marrow origin. 12 Alternatively, it is interesting that mye-
1. Hertig, A. T. and Gore, H.: Tumors of the female sex organs. Part 2. Tumors of the vulva, vagina and uterus. In: Atlas of Tumor Pathology. Washington, D. C.: Armed Forces Institute of Pathology, sect. IX, fasc. 33, p. 49, 1960. 2. Ratner, M. and Schneiderman, C.: The relationship of urethral caruncle to carcinoma of urethra. Canad. Med. Ass. J., 58: 373, 1948. 3. Fagan, G. E. and Hertig, A. T.: Carcinoma of the female urethra. Review of the literature; report of eight cases. Obst. Gynec., 6: 1, 1955. 4. Marshall, F. C., Uson, A. C. and Melicow, M. M.: Neoplasms and caruncles of the female urethra. Surg., Gynec. & Obst., 110: 723, 1960. 5. Melicow, M. M., Lattes, R. and Pierre-Louis, C.: Lymphoma of the female urethra masquerading as a caruncle. J. Urol., 108: 748, 1972. 6. Sternberger, L.A.: Immunocytochemistry, 2nd ed. New York: John Wiley & Sons, Inc., 1979. 7. Mukai, K., Rosai, J. and Burgdorf, W. H. C.: Localization of factor VIII-related antigen in vascular endothelial cells using an immunoperoxidase method. Amer. J. Surg. Path., 4: 273, 1980. 8. Sehested, M. and Hou-Jensen, K.: Factor VIII-related antigen as an endothelial cell marker in benign and malignant diseases. Virchows Arch. (A), 391: 217, 1981. 9. Pinkus, G. S. and Said, J. W.: Immunohistochemical localization of hemoglobin. In: Advances in Immunohistochemistry. Edited by R. A. DeLellis. New York: Masson Publishing USA, Inc., chapt. 17,pp. 303-309, 1984. 10. Pinkus, G. S. and Said, J. W.: Profile ofintracytoplasmic lysozyme in normal tissues, myeloproliferative disorders, hairy cell leukemia, and other pathologic processes. An immunoperoxidase study of paraffin sections and smears. Amer. J. Path., 89: 351, 1977. 11. Pitcock, J. A., Reinhard, E. H., Justus, B. W. and Mendelsohn, R. S.: A clinical and pathological study of seventy cases of myelofibrosis. Ann. Intern. Med., 57: 73, 1962. 12. Ward, H.P. and Block, M. H.: The natural history of agnogenic myeloid metaplasia (AMM) and a critical evaluation of its relationship with the myeloproliferative syndrome. Medicine, 50: 357, 1971. 13. Glew, R.H., Haese, W. M. and McIntyre, P.A.: Myeloid metaplasia with myelofibrosis. The clinical spectrum of extramedullary hematopoiesis and tumor formation. Johns Hopkins Med. J., 132: 253, 1973. 14. Lieberman, P. H., Rosvoll, R. V. and Ley, A. B.: Extramedullary myeloid tumors in primary myelofibrosis. Cancer, 18: 727, 1965. 15. Kuo, T., Uhlemann, J. and Reinhard, E. H.: Cutaneous extramedullary hematopoiesis. Arch. Dermatol., 112: 1302, 1976. 16. Bouroncle, B. A. and Doan, C. A.: Myelofibrosis. Clinical, hematologic and pathologic study of 110 patients. Amer. J. Med. Sci., 243: 697, 1962. 17. Dameshek, W.: Some speculations on the myeloproliferative syndromes. Blood, 6: 372, 1951. 18. Wang, J. C. and Tobin, M. S.: Mechanism of extramedullary haematopoiesis in rabbits with saponin-induced myelofibrosis and myeloid metaplasia. Brit. J. Haematol., 51: 277, 1982.
THE JOURNAL OF UROLOGY
Printed in U.S.A.
Copyright © 1986 by The Williams & Wilkins Co.
MYELOID METAPLASIA MASQUERADING AS A URETHRAL CARUNCLE KAROLY BALOGH
AND
CARL J. O'HARA
From the Department of Pathology, New England Deaconess Hospital and Harvard Medical School, Boston, Massachusetts
ABSTRACT
A 64-year-old woman presented with a painless bleeding mass of the urethral meatus that was diagnosed as a caruncle and removed surgically. Histological examination revealed a cellular and vascular polypoid lesion that contained megakaryocytes, as well as groups of hematopoietic stem cells, and maturing cells of the erythroid and granulocytic series. The diagnosis of myeloid metaplasia was confirmed by marker studies with immunoperoxidase techniques. The patient had a long history of bleeding and clotting problems owing to a myeloproliferative disorder with thrombocytosis and gradual development of myelofibrosis. No other foci of extramedullary hematopoiesis were apparent. The patient was free of urinary symptoms 22 months postoperatively. Urethral caruncle is a clinical term designating a small polypoid lesion arising from the posterior wall of the female urethra at or near the meatus. 1 Caruncles are composed of loose vascular connective tissue covered by squamous or transitional cell epithelium. The location predisposes them to inflammation and the resultant vascular granulation tissue may mimic histologically a pyogenic granuloma or an angioma. Rarely, a carcinoma, 2-4 sarcoma4 or malignant lymphoma5 may masquerade as a caruncle. Recently, we observed a diagnostically challenging lesion that presented as a urethral caruncle. CASE REPORT
A 64-year-old woman presented in January 1984 with painless bleeding from the urethral meatus a few days in duration. Topical treatment provided only temporary control and in the next 2 weeks the urethral bleeding episodes became more frequent, with formed clots in the meatus. Cystourethroscopy was completely negative. The source of bleeding was a swollen mass at the urethral meatus. Diagnosis was urethral caruncle and the lesion was amputated by electric cutting current with the patient under local anesthesia. There were no bleeding problems postoperatively. At followup examination 22 months later the patient was free of urinary symptoms. Pathological examination. The removed tissue was irregular, rubbery, pale tan and focally hemorrhagic, and measured 1.2 X 1.2 X 0.4 cm. The specimen was fixed in 4 per cent buffered formaldehyde, dehydrated and embedded in paraffin. Histological sections were cut at 6 µ., and stained with hematoxylin and eosin. Microscopic examination revealed polypoid tissue covered by squamous epithelium. The mucosa was ulcerated focally. The bulk of the lesion consisted of cellular tissue that contained numerous bizarre large cells scattered throughout the vascular stroma. These large cells had hyperchromatic, irregular, lobulated nuclei and abundant eosinophilic cytoplasm. They usually were seen within groups of immature round cells identifiable as stem cells and maturing cells of the erythroid and granulocytic series (fig. 1). Immunoperoxidase studies with the standard Sternberger technique6 on paraffin section revealed positive staining of the large cells with lobulated nuclei for factor VIII-related antigen (anti-factor VIII monoclonal 1:500 DAK0) 7•8 (fig. 2, A), identifying them as megakaryocytes. Clusters of small round cells with dark pyknotic nuclei stained positive for hemoglobin (antihemoglobin 1:500 DAK0) 9 (fig. 2, B). Aggregates of the remaining cells stained positively for lysozyme (anti-lysozyme 1:400 DAK0). 10 The presence of all 3 hematopoietic cell lines confirmed the diagnosis of myeloid metaplasia. Accepted for publication November 18, 1985.
789
DISCUSSION
After the histological diagnosis was established, review of the record revealed a long history of problems attributed to essential (primary) thrombocythemia for which the patient had been given 32phosphorus (32 P) and busulfan in 1970. Subsequently, the symptoms disappeared but recurred gradually and in 1976 the diagnosis of a myeloproliferative disorder with thrombocytosis was made. She responded well to another course ofbusulfan. In 1980 thrombocythemia exacerbated and another course of 32 P and busulfan was administered. Medical treatment, including anticoagulation, did not prevent multiple thrombotic episodes and pulmonary emboli necessitating hospitalization. In April 1981 the patient noticed a lump in the left breast, which proved to be an infiltrating duct carcinoma and a radical mastectomy was performed (stage TlNOMO disease). Following mastectomy the patient noticed easy bruising and episodes of epistaxis occurred with increasing frequency. The physical findings and laboratory data suggested that she had entered a phase of myelofibrosis with subsequent bleeding. At hospitalization for the urethral caruncle in January 1984 splenomegaly was noted on physical examination. No lymphadenopathy, cyanosis or clubbing of digits was found. A computerized tomographic scan of the neck and thorax revealed no metastatic tumor, and the laboratory data were consistent with myelofibrosis.
Fm. 1. Abundant round cells of varying size and large bizarre cells with hyperchromatic nuclei are seen in vascular stroma of caruncle. H & E, reduced from Xl20. Inset, higher magnification of polymorphic cellular infiltrate shows megakaryocytes among immature erythroid and myeloid cells. H & E, reduced from X300.
790
BALOGH AND O'HARA
loid metaplasia occurs most frequently at sites of embryonic hematopoiesis. This recognition has led to the notion that extramedullary hematopoiesis is caused by a stimulus that reawakens the hematopoietic potential of tissues involved in blood formation during embryonic life. However, this attractive theory does not provide a satisfactory explanation for the occurrence of myeloid metaplasia in isolated and unusual sites, such as a urethral caruncle. REFERENCES
~t .,,'
-·
FIG. 2. Immunoperoxidase reactions. A, stain with anti-factor VIIIrelated antigen is positive in cytoplasm of megakaryocytes and endothelial cells. B, anti-hemoglobin identifies normoblasts. Note unstained megakaryocytes and myeloid precursors. Reduced from X300.
Myeloid metaplasia, or extramedullary hematopoiesis, is believed to be caused by encroachment of bone marrow by a pathological process. Long-standing myeloproliferative disorders gradually can lead to myelofibrosis with the development of extramedullary hematopoiesis. 11 - 13 This sequence of events in our case also is supported by the presence of nucleated erythrocytes in the peripheral blood, a characteristic of myelofibrosis with myeloid metaplasia. Although the patient had a history of breast carcinoma, replacement of bone marrow by metastatic carcinoma appears improbable, since there was no clinical evidence of skeletal metastases. Myeloid metaplasia may develop at many sites. It is most prominent in the spleen, liver and lymph nodes but also has been described in numerous other organs, including the skin and central nervous system. 12-15 To the best of our knowledge, its presentation as a urethral mass has not been reported. The question of whether myeloid metaplasia developed in a preexistent caruncle cannot be answered with certainty. Our case also is unusual because, besides splenomegaly, the caruncle was the only clinically manifest mass, whereas tumor-like myeloid metaplasia frequently involves several organs. 12·16 The mechanism of extramedullary hematopoiesis in myelofibrosis is unclear. A commonly held view maintains that an abnormal stimulus acts upon the hematopoietic cells. 12·17 A recent experimental study in which saponin injected into rabbits induced myelofibrosis and myeloid metaplasia indicated that erythroid and myeloid progenitor cells increase in blood and spleen as the stem cells are depleted from the bone marrow.18 These experiments suggest that extramedullary hematopoiesis may be owing to colonization by progenitor cells of bone marrow origin. 12 Alternatively, it is interesting that mye-
1. Hertig, A. T. and Gore, H.: Tumors of the female sex organs. Part 2. Tumors of the vulva, vagina and uterus. In: Atlas of Tumor Pathology. Washington, D. C.: Armed Forces Institute of Pathology, sect. IX, fasc. 33, p. 49, 1960. 2. Ratner, M. and Schneiderman, C.: The relationship of urethral caruncle to carcinoma of urethra. Canad. Med. Ass. J., 58: 373, 1948. 3. Fagan, G. E. and Hertig, A. T.: Carcinoma of the female urethra. Review of the literature; report of eight cases. Obst. Gynec., 6: 1, 1955. 4. Marshall, F. C., Uson, A. C. and Melicow, M. M.: Neoplasms and caruncles of the female urethra. Surg., Gynec. & Obst., 110: 723, 1960. 5. Melicow, M. M., Lattes, R. and Pierre-Louis, C.: Lymphoma of the female urethra masquerading as a caruncle. J. Urol., 108: 748, 1972. 6. Sternberger, L.A.: Immunocytochemistry, 2nd ed. New York: John Wiley & Sons, Inc., 1979. 7. Mukai, K., Rosai, J. and Burgdorf, W. H. C.: Localization of factor VIII-related antigen in vascular endothelial cells using an immunoperoxidase method. Amer. J. Surg. Path., 4: 273, 1980. 8. Sehested, M. and Hou-Jensen, K.: Factor VIII-related antigen as an endothelial cell marker in benign and malignant diseases. Virchows Arch. (A), 391: 217, 1981. 9. Pinkus, G. S. and Said, J. W.: Immunohistochemical localization of hemoglobin. In: Advances in Immunohistochemistry. Edited by R. A. DeLellis. New York: Masson Publishing USA, Inc., chapt. 17,pp. 303-309, 1984. 10. Pinkus, G. S. and Said, J. W.: Profile ofintracytoplasmic lysozyme in normal tissues, myeloproliferative disorders, hairy cell leukemia, and other pathologic processes. An immunoperoxidase study of paraffin sections and smears. Amer. J. Path., 89: 351, 1977. 11. Pitcock, J. A., Reinhard, E. H., Justus, B. W. and Mendelsohn, R. S.: A clinical and pathological study of seventy cases of myelofibrosis. Ann. Intern. Med., 57: 73, 1962. 12. Ward, H.P. and Block, M. H.: The natural history of agnogenic myeloid metaplasia (AMM) and a critical evaluation of its relationship with the myeloproliferative syndrome. Medicine, 50: 357, 1971. 13. Glew, R.H., Haese, W. M. and McIntyre, P.A.: Myeloid metaplasia with myelofibrosis. The clinical spectrum of extramedullary hematopoiesis and tumor formation. Johns Hopkins Med. J., 132: 253, 1973. 14. Lieberman, P. H., Rosvoll, R. V. and Ley, A. B.: Extramedullary myeloid tumors in primary myelofibrosis. Cancer, 18: 727, 1965. 15. Kuo, T., Uhlemann, J. and Reinhard, E. H.: Cutaneous extramedullary hematopoiesis. Arch. Dermatol., 112: 1302, 1976. 16. Bouroncle, B. A. and Doan, C. A.: Myelofibrosis. Clinical, hematologic and pathologic study of 110 patients. Amer. J. Med. Sci., 243: 697, 1962. 17. Dameshek, W.: Some speculations on the myeloproliferative syndromes. Blood, 6: 372, 1951. 18. Wang, J. C. and Tobin, M. S.: Mechanism of extramedullary haematopoiesis in rabbits with saponin-induced myelofibrosis and myeloid metaplasia. Brit. J. Haematol., 51: 277, 1982.