- Email: [email protected]
Angioendotheliomatosis
Illlll
II
Angioendotheliomatosis* Timothy G. Berger, Lieutenant Colonel, MC, USA,** and Nancy A. Dawson, Captain, MC, USA***
Presidio of San Francisco, CA, and Washington, DC "Angioendotheliomatosis" is a diagnostic term used in histopathology to describe the proliferation of dilated vessels filled with mononuclear cells that have varying degrees of atypia. Either benign or malignant angioendotheliomatosis may exhibit this histologic pattern, and depending on the clinical course, cases are classified as either reactive angioendotheliomatosis or neoplastic angioendotheliomatosis. A case of neoplastic angioendotheliomatosis is presented and the literature reviewed with special attention to the pathogenesis of this condition. (J AM ACAD DERMATOL 1988;18:407-12.)
CASE REPORT In February 1983 a healthy 60-year-old white man developed an asymptomatic eruption on the medial aspect of both thighs. Three months later, he complained of blurred vision in both eyes. Examination of the skin revealed a bilateral, barely palpable, violaceous, reticular eruption extending from the mid aspect of the thigh to the knee (Fig. 1). Ophthalmic examination showed cloudy (proteinaceous) vitreous bilaterally. Histologic examination of a biopsy specimen of the involved skin showed dilated vessels, in the dermis and upper subcutaneous fat, filled with large atypical cells that had hyperchromatic nuclei but no nucleoli (Figs. 2 and 3). No transition was seen from the normal endothelial cells to the intravascular cells. All the involved vessels contained fibrin thrombi (Fig. 3). Electron microscopic examination showed marked proliferation of endothelial cells with reduplication of the basement membrane (Fig. 4). Intravaseular cells were too degenerated for evaluation. Human factor VIII was not found in the tumor cells tested by immunoperoxidase
From the Dermatology Service, Department of Medicine, Letterman Army Medical Center, Presidio of San Francisco,** and the Hematology-Oncology Service, Department of Medicine, Walter Reed Army Medical Center, Washington, DC.*** Reprints not available. *The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Army, the Department of Defense, or the U.S. Government,
technic. Results of the following laboratory examinations were within normal limits: complete blood cell count, erythrocyte sedimentation rate, buffy-coat smear, and twenty-channel automated serum chemical analysis. Results of the radiologic examinations were normal, including upper gastrointestinal and barium enema roentgenograms, bone scan, and computerized tomographic scan of the abdomen. Platelet count was 705,000/ram 3, and lactic dehydrogenase was 268 units/ liter (normal, 60-200). A tentative diagnosis of neoplastic angioendotheliomatosis was made, and treatment was instituted with doxorubicin (Adriamycin) at 50 mg/M 2 intravenously every 3 weeks to a total of 500 mg/M 2. The doxorubicin therapy led to a rapid clearing of the skin lesions but no change in the eye findings. One year from the onset of the disease, the patient presented with decreased coordination of the left hand, weakness of the left side, and an unsteady gait. Computed tomographic scan of the head revealed densely enhancing lesions (without mass effect) in the left cerebellar hemisphere, the right posterior frontal lobe, and the deep fight parietal white matter, which was most consistent with multiple infarcts. Whole-brain radiation therapy led to complete resolution of all neurologic findings and normalization of the computed tomographic scan. The patient died suddenly 3 months later. At autopsy, predominantly intravascular, neoplastic cells were found in many organs, including the brain and adrenal glands, but the liver, spleen, and lymph nodes were not microscopically involved. Immuno-
407
408
Journal of the American Academy of Dermatology
Berger and Dawson
~.~i..
,
,
,,
,
~..
,
1. Reticular, palpably cordlike, violaeeous eruption of the medial aspect of the thighs. Fig. 2. Dilated dermal vessels filled with fibrin and cells. (Hematoxylin-eosin stain; x 8.) Fig. 3. Dilated dermal vessels filled with fibrin thrombi and atypical hyperchromatic cells. (Hematoxylin-eosin stain; x 128.) Fig. 4. Involved vessel with reduplication of the basement membrane, hypertrophy and hyperplasia of endothelial cells, intravascular degenerated cells, and fibrin. ( x 5,330.) F i g .
peroxidase staining for common leukocyte antigen was positive in neoplastic ceils infiltrating periadrenal fat. DISCUSSION The diagnostic and distinctive histopathologic feature in all cases of angioendotheliomatosis is the presence of dilated capillaries filled with vail-
ably atypical mononuclear cells.l Since the original description of the disease by Gottron and Nikolowski z in 1958, over sixty-five cases have been described. These cases can be divided into the subsets of reactive (benign) angioendotheliomatosis and neoplastic (malignant) angioendotheliomatosis on the basis of clinical behavior (Table I),
Volume 18 Number 2, Part 2 February 1988
Angioendotheliomatosis
4t)9
Table I. Subsets of angioendotheliomatosis
Sex SBE Skin lesions CNS findings History or findings of lymphoma Prognosis Treatment
Reactive
Neoplastic
Intravascular tumor
Female
Both
Male
All
One third + +
Half
Excellent Antibiotics, corticosteroids
Dismal Systemic chemotherapy ?CNS radiation
Fatal ?
+
CNS: Central nervous system; SBE: subacute bacterial endocarditis.
Reactive angioendotheliomatosis Cases of reactive angioendotheliomatosis are extremely rare, only seven well-documented cases having been reported. 2-s Five cases occurred in women between 31 and 68 years of age, four of whom had an illness resembling subacute bacterial endocarditis characterized by fever and/or a heart murmur. 2-5,8 Blood cultures were positive in only one case. The other two cases occurred in young boys, one 5 years and the other 5 months of age. The older boy had an artificial valve and possible subacute bacterial endocarditis, 6 and the younger boy had a "nevus vasculosus simplex" on the back. 7 All the patients presented with infiltrated, red to blue, 1-cm to palm-sized patches and plaques that often had focal purpura. The lesions were located on the arms, legs, cheeks, ears, and trunks. Histopathologic examination of the skin lesions in these cases of reactive angioendotheliomatosis reveals marked proliferation, throughout the dermis and upper subcutaneous fat, of dilated vessels filled with mononuclear cells and fibrin, to the point of occlusion in some areas. The intravascular cells vary from small, uniformly benign cells to large pleomorphic ceils that have prominent nucleoli and many mitoses. Electron microscopic examination supports endothelial proliferation in one case 6 and an inflammatory destructive process in another. 8 The proliferating cells are not found in the circulation, and no organ other than skin has been involved. Treatments have consisted of antibiotics (three cases), antibiotics plus corticosteroids (two cases), or no treatment (one case). In
all cases the symptoms and lesions have gradually resolved, although there were recurrences in two cases? '7 No deaths were reported.
Neoplastic angioendotheliomatosis Neoplastic angioendotheliomatosis is a multisystem disease with its primary manifestations in the central nervous system and the skin. 9-48Except for two patients 11A and 13 years o f age, all reported patients have been between the ages of 39 and 84 years. Men and women were equally affected. The prognosis is very guarded, with most patients dying in less than 3 years and often in a few months. Skin lesions, seen in about one third of patients, usually appear as erythematous to blue plaques or nodules on the arms, thighs, trunk, or face. T M Telangiectasia may be prominent over lesions, and erosions may occur. The skin lesions of reactive angioendotheliomatosis and neoplastic angioendotheliomatosis cannot be clinically differentiated. Central nervous system involvement (85% of cases) is often the presenting manifestation ~5-24and is characterized by progressive dementia in 55% of cases. 22 Transient episodes of aphasia, numbness, or weakness may (like transient ischemic attacks) herald the onset of the illness. Visual changes as in our patient are reported, zo'z4.39 Seizures, stupor, and coma are preterminal events. 2z Radionucleotide brain imaging, electroencephalography, and computed tomography may show significant brain abnormalities. Cerebral angiograms are usually normal) 2 The only consistently abnormal laboratory stud-
410
Berger and Dawson
ies are an elevated erythrocyte sedimentation rate and an increased level of cerebrospinal fluid protein. In five cases, intravascular hemolysis is suggested by anemia, thrombocytopenia, elevated levels of lactate dehydrogenase, and the presence of occasional circulating fragmented erythrocytes. 2sm,34,38Histopathologic changes in all affected tissues are identical and are similar to those seen in the skin in reactive angioendotheliomatosis, making differentiation difficult: Despite the intravascular cells seen histologically, it is unusual to find the atypical cells in the c i r c u l a t i o n 21'23,36 or the cerebrospinal fluid) 9 At autopsy, intravascular proliferation of cells is found in many organs. Focal extravascul ar extension occurs especially in the adrenal glands. ~2.2~.4~.4zThe frequent lack of involvement of lymph nodes, liver, spleen, and bone marrow is notable: ~,42The central nervous system is often the site of the most severe involvement, correlating with the prominence of central nervous system manifestations. Dilated vessels occluded by cells and fibrin are thrombosed, resulting in multiple areas of ischemic infarction. 24 Originally the intravaseular cells in neoplastic angioendotheliomatosis were considered endothelial. in origin on the basis of electron microscopy and cell-surface staining for human factor VIII. Cell-surface human factor VIII staining is not diagnostic of endothelial origin, however, and may simply represent the adsorption of this substance onto cell surfaces from the serum. ~9:°,42 The ultrastructural findingsz~ (i.e., reduplication of the basement membrane, apparent increased endothelial metabolic activity, and hyperplasia and hypertrophy of endothelial cells) may simply be the result of an intravascular inflammatory event. 8,39 Careful evaluation of low-power electron micrographs usually shows a distinct difference between the intravascular cells and the surrounding endothelium. 39,4°:2 Additionally, in over twenty cases reported recently or studied in retrospect, the intravascular cells are of leukocytic origin. 35.39-43Intravascular cells stain consistently with common leukocyte antigen. 4°'42 In the few cases in which fresh tissue has been available for study, either B cell or T cell markers are f o u n d . 39,41,42 These findings clearly demonstraate that neo-
Journal of the American Academy of Dermatology plastic angioendotheliomatosis is a form of lymphoma, which explains the following features: (1) skin lesions that resemble those seen in non-Hodgkins lymphomas (i.e., red to blue nodules and plaques with occasional erosion), (2) proteinaceous vitreous, as seen in our patient, associated with central nervous system lymphoma, (3) intravascular ceils that are similar in appearance to lymphoid cells when examined by light microscopy, 4° and (4) a diagnosis of lymphoma before or near the onset of neoplastic angioendotheliomatosis in some cases 27,35,44or consideration of a diagnosis lymphoma after examination of histologic material in other cases of neoplastic angioendotheliomatosis. 13,27,34,36,38 Therefore, although endothelial proliferation is present in both reactive angioendotheliomatosis and neoplastic angioendotheliomatosis, it is probably secondary to other intravascular events (i.e., subacute bacterial endocarditis or lymphoma). Both T and B lymphocytes bind to high endothelial venules in mice and humans, 41 an affinity that probably plays a role in normal lymphocyte trafticking and that may be related to the peculiar angiocentricity of the malignant lymphocytes in neoplastic angioendotheliomatosis. Whether malignancies other than lymphoma can cause this pattern is unknown but has been suggested. 29 The treatment of neoplastic angioendotheliomatosis has consisted of local radiation, cortico~ steroids, and chemotherapeutic agents. It has led to temporary remission but no prolonged survival. Recently, aggressive combination chemotherapy, as given for lymphoma, has appeared beneficial, but long-term follow-up is required. 39,41:4 Solid tumors arising from the inner surface of blood vessels may embolize and occlude distal vessels, mimicking neoplastic angioendotheliomatosis. Such cases have been reported in five elderly men who often had skin lesions similar to neoplastic angioendotheliomatosis and had no evidence of central nervous system involvement; all five diedY -48 In summary, angioendotheliomatosis presents a rare histologic picture with two clinical subsets, benign (reactive angioendotheliomatosis) and malignant (neoplastic angioendotheliomatosis). Reactive angioendotheliomatosis occurs primarily in
Volume 18 Number 2, Part 2 February 1988
w o m e n , has prominent skin findings, and is associated with subacute bacterial endocarditis or subacute bacterial endocarditis-like symptoms. N e o p l a s t i c angioendotheliomatosis often has significant central nervous system findings and is a l y m p h o m a . When the histopathologic features of angioendotheliomatosis are found, the patient s h o u l d have a complete workup, including neurologic, cardiovascular, and lymphatic evaluation; b l o o d cultures; and immunohistochemical staining for reticuloendothelial markers. Central nervous s y s t e m involvement excludes a benign diagnosis. I f neoplastic angioendotheliomatosis is considered, a careful search for l y m p h o m a is required, and systemic combination chemotherapy, perhaps with central nervous system radiation, is indicated.
Angioendotheliomatosis
14. 15. 16. 17. 18. 19. 20.
21. REFERENCES
1. Lever WF, Schaumburg-Lever G. Histopathology of the skin. 6th ed. Philadelphia: JB Lippincott Co, 1983: 645-6. 2. Gottron HA, Nikolowski W. Extrarenale L6hlein-Herdnephritis der Haut bei Endocarditis. Arch Klin Exp Dermatol 1958;207:156-76. 3. Plieger L, Tappeiner J. Zur Kenntnis der systemisierten Endotheliomatose der cutanen Blutgefiisse (Retieuloendotheliose?). Hautarzt 1959;10:359-63. 4. Ruiter M, Mandema E. New cutaneous syndrome in subacute bacterial endocarditis. Arch Intern Med 1964;
22. 23. 24. 25. 26.
113:283-90,
5. Eisert J. Skin manifestations of subacute bacterial endocarditis: case report of subacute bacterial endocarditis mimicking Tappeiner's angioendotheliomatosis. Cutis 1980;25:394-400. 6. Martin S, Pitcher D, Tschen dr, Wolf JE Jr. Reactive angioendotheliomatosis. J AM ACADDERMATOL1980;2: 117-23. 7. Pasyk K, Depowski M. Proliferating systematized angioendotheliomatosis of a 5-month-old infant. Arch Dermatol 1978;114:1512-5. 8. Konra K, Brenner W. Ultrastructure of angioendotheliomatosis proliferans systemisata [abstract]. J Cutan Pathol 1983;10:292. 9. Braverman IM, Lemer AB. Diffuse malignant proliferation of vascular endothelium. Arch Dermatol 1961;84: 22-30. 10. Lund HZ. Tumors of the skin. In: Atlas of tumor pathology, fast. 2. Washington, DC: Armed Forces Institute of Pathology, 1957:272-3. 11. Haber H, Harris-Jones drN, Wells AL. Intravascular endothelioma (endothelioma in situ, systemic endotheliomatosis). J Clin Pathol 1964;17:608-11. 12. Strouth JC, Donahue S, Ross A, Aldred A. Neoplastic angioendotheliomatosis. Neurology (Minneap) 1965;15: 644-8. 13. Okagaki T, Richart RM. Systemic proliferating angioen-
27. 28. 29. 30. 31. 32.
33. 34.
411
dotheliomatosis: report of a case. Obstet Gynecol 1971; 37:377-80. Madara J, Shane J, Scarlato M. Systemic endotheliomatosis: a case report. J Clin Pathol 1975;28:476-82. Petito CK, Gotflieb GJ, Dougherty JH, Petito FA. Neoplastic angioendotheliosis: ultrastructural study and review of the literature. Ann Neurol 1978;3:393-9. Bots GT. Angioendotheliomatosis of the central nervous system. Acta Neuropathol (Bed) 1974;28:75-8. Reinglass JL, Muller J, Wissman S, Wellman H. Central nervous system angioendotheliosis: a treatable multiple infarct dementia. Stroke 1977;8:218-21. Keahey TM, Guerry D III, Tuthill RJ, Bondi EE. Malignant angioendotheliomatosis proliferans treated with doxorubiein. Arch Dermatol 1982;118:512-4. Husain MM, Sun CN, White HJ. Neoplastic angioendotheliosis. J Neuropathol Exp Neurol 1979;38:322. Ansbacher L, Low N, Beck D, Boarini D, Jacoby C, Cancilla PA. Neoplastic angioendotheliosis: a clinieopathological entity with multifoeal presentation. J Neurosurg 1981;54:412-5. Wick MR, Banks PM, McDonald TJ. Angioendotheliomatosis of the nose with fatal systemic dissemination. Cancer 1981;48:2510-7. Beal MF, Fisher CM. Neoplastic angioendotheliosis. J Neurol Sei 1982;53:359-75. Shtem RD, Likhachev YP, Endotheliomatosis as a systemic tumour affection. Arch Pathol 1963;25:35-40. Wick MR, Scheithauer BW, Okazaki H, Thomas JE. Cerebral angioendotheliomatosis. Arch Pathol Lab Med 1982;106:342-6. Fulling KH, Gersell DJ. Neoplastic angioendotheliomatosis: histologic, immunohistochernieal, and ultrastructural findings in two cases. Cancer 1983;51:1107-18. LeWitt PA, Forno LS, Brant-Zawadzki M. Neoplastic angioendotheliosis: a case with spontaneous regression and radiographic appearance of cerebral arteritis. Neurology 1983;33:39-44. Scott PWB, Silvers DN, Helwig EB. Proliferating angioendotheliomatosis. Arch Pathol 1975;99:323-6. Arnn ET, Yam LT, Li C-Y. Systemic angioendotheliomatosis presenting with hemolytic anemia. Am J Clin Pathol 1983;80:246-51. Dolman CL, Sweeney VP, Magil A. Neoplastic angioendotheliosis: the case of the missed primary? Arch Neurol 1979;36:5-7. Sunohara N, Mukoyama M, Satoyoshi E, Shibasaki K, Higuchi M. Neoplastic angioendotheliosis of the central nervous system. Rinsho Shinkeigaku 1982;22:49-56. Crosby TW, Chou SM, Gutrecht J. Neoplastic angioendotheliosis [abstract]. J Neuropathol Exp Neurol 1976; 35:36t. Kageyama Y, Kawamura J, Miyazaki T, Iikuni K, Koto A. A case of multiple tumor-cell embolism to the central nervous system simulating neoplastic angioendotheliosis. Rinsho Shinkeigaku 1983;23:110-6, Janda J, Van~kJ. Systematisehe Angioendotheliomatose. Zentralbl Allg Pathol 1978; 122:351-5. Yamamura Y, Akamizu H, Hirata T, Kito S, Hamada T. Malignant lymphoma presenting with neoplastic angioendotheliosis of the central nervous system. Clin Neuropathol 1983;2:62-8.
Journal of the American Academy of Dermatology
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35. Ansell J, Bhawan J, Cohen S, Sullivan J, Sherman D. Histiocytic lymphoma and malignant angioendotheliomatosis: one disease or two? Cancer 1982;50:1506-12. 36. Tanaka M, Yamaguchi H, Uehiyama T, Hirai S, Ishizeki J. An autopsy case of malignant lymphoma mimicking neoplastic angioendotheliosis. Rinsho Shinkeigaku
1982;22:507-13. 37. Midana A, Ormea F. Apropos d' un cas d' "andioendotheliomatosis proliferans systematisata" (de Tappeiner et Pfleger). Ann Derrnatol Syphiligr (Paris) 1965;92: 129-38. 38. Meadors MP, Johnson WW. Diffuse angioendotheliosis. Arch Pathol 1970;90:572-6. 39. Bhawan J, Wolff SM, Ucci AA, Bhan AK, Malignant lymphoma and malignant angioendotheliomatosis; one disease. Cancer 1985;55:570-6. 40. Wrotnowski U, Mills SE, Cooper PH. Malignant angioendotheliomatosis: an angiotropic lymphoma? Am J Clin Pathol 1985;83:244-8. 41. Sheibani K, Battifora H, Winberg CD, et al. Further evidence that "malignant angioendotheliomatosis" is an angiotropic large-cell lymphoma. N Engl J Med 1986; 314:943-8.
42. Wick MR, Mills SE, Scheithauer BW, Cooper PH, Davitz MA, Parkinson K. Reassessment of malignant "angioendotheliomatosis": evidence in favor of its reclassification as "intravascular lymphomatosis." Am J Surg Pathol 1986;10:112-23. 43. Carroll TJ, Schelper RL, Goeken JA, Kemp JD. Neoplastic angioendotheliomatosis: immunopathologic evidence for intravascular malignant lymphoma [abstract]. Lab Invest 1985;52:12-3. 44. Lim HW, Anderson HM. Angioendotheliomatosis associated with histiocytic lymphoma: response to systemic chemotherapy. J AM ACADDERMATOL1985;13:903-8. 45. Sladden RA. Neoplasia of aortic intima. J Clin Pathol 1964;17:602-7. 46. Winkelmann RK, Van Heerden JA, Bernatz PE. Malignant vascular endothelial minor with distal embolization: a new entity. Am J Med 1971;51:692-7. 47. Leu HJ, Sulser J. Maligner endothelialer Tumor der Arteria femoralis mit distaler Embolisation. Virchows Arch [Pathol Anat] 1976;371:153-9. 48. Kurrein F. Systemic angioendotheliomatosis with metastases. J Clin Pathol 1976;29:347-53.
Linear IgM dermatosis of pregnancy J o s e p h Alcalay, M . D . , A r i e h Ingber, M . D . , Bilha Hazaz, B . S c . , M i c h a e l D a v i d , M . D . , and M i r i a m Sandbank, M . D .
Petah Tiqva and Tel Aviv, Israel An intensely pruritic dermatosis that occurred in a woman during the third trimester of pregnancy is described. The clinical manifestations included red follicular papules symmetrically distributed on the skin of the forearms, abdomen, thighs, and legs. The histopathologic findings were not specific. However, immunopathologic examination revealed dense linear deposition of IgM in the dermoepidermal junction. "['he eruption and the immunopathologic findings disappeared at the end of the puerperium. This dermatosis differs from previously described specific dermatoses of pregnancy because of the clinical appearance and the immunopathologic findings. Thus we propose the term linear IgM dermatosis of pregnancy. (J AM ACAD DERMATOL 1988;18:412-15.)
From the Department of Dermatology and the lmmunopathology Unit, Beilinson Medical Center, Petah Tiqva, and the Sackler School of Medicine, Tel Aviv University. Reprint requests to: Dr. J. Alealay, Department of Dermatology, Beilinson Medical Center, Petah Tiqva 49100, Israel.
412
In 1962, Spangler et al 1 described a n e w dermatosis o f p r e g n a n c y termed papular dermatitis of pregnancy. Seventeen years later, another n e w dermatosis of p r e g n a n c y was described under
II
Angioendotheliomatosis* Timothy G. Berger, Lieutenant Colonel, MC, USA,** and Nancy A. Dawson, Captain, MC, USA***
Presidio of San Francisco, CA, and Washington, DC "Angioendotheliomatosis" is a diagnostic term used in histopathology to describe the proliferation of dilated vessels filled with mononuclear cells that have varying degrees of atypia. Either benign or malignant angioendotheliomatosis may exhibit this histologic pattern, and depending on the clinical course, cases are classified as either reactive angioendotheliomatosis or neoplastic angioendotheliomatosis. A case of neoplastic angioendotheliomatosis is presented and the literature reviewed with special attention to the pathogenesis of this condition. (J AM ACAD DERMATOL 1988;18:407-12.)
CASE REPORT In February 1983 a healthy 60-year-old white man developed an asymptomatic eruption on the medial aspect of both thighs. Three months later, he complained of blurred vision in both eyes. Examination of the skin revealed a bilateral, barely palpable, violaceous, reticular eruption extending from the mid aspect of the thigh to the knee (Fig. 1). Ophthalmic examination showed cloudy (proteinaceous) vitreous bilaterally. Histologic examination of a biopsy specimen of the involved skin showed dilated vessels, in the dermis and upper subcutaneous fat, filled with large atypical cells that had hyperchromatic nuclei but no nucleoli (Figs. 2 and 3). No transition was seen from the normal endothelial cells to the intravascular cells. All the involved vessels contained fibrin thrombi (Fig. 3). Electron microscopic examination showed marked proliferation of endothelial cells with reduplication of the basement membrane (Fig. 4). Intravaseular cells were too degenerated for evaluation. Human factor VIII was not found in the tumor cells tested by immunoperoxidase
From the Dermatology Service, Department of Medicine, Letterman Army Medical Center, Presidio of San Francisco,** and the Hematology-Oncology Service, Department of Medicine, Walter Reed Army Medical Center, Washington, DC.*** Reprints not available. *The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Army, the Department of Defense, or the U.S. Government,
technic. Results of the following laboratory examinations were within normal limits: complete blood cell count, erythrocyte sedimentation rate, buffy-coat smear, and twenty-channel automated serum chemical analysis. Results of the radiologic examinations were normal, including upper gastrointestinal and barium enema roentgenograms, bone scan, and computerized tomographic scan of the abdomen. Platelet count was 705,000/ram 3, and lactic dehydrogenase was 268 units/ liter (normal, 60-200). A tentative diagnosis of neoplastic angioendotheliomatosis was made, and treatment was instituted with doxorubicin (Adriamycin) at 50 mg/M 2 intravenously every 3 weeks to a total of 500 mg/M 2. The doxorubicin therapy led to a rapid clearing of the skin lesions but no change in the eye findings. One year from the onset of the disease, the patient presented with decreased coordination of the left hand, weakness of the left side, and an unsteady gait. Computed tomographic scan of the head revealed densely enhancing lesions (without mass effect) in the left cerebellar hemisphere, the right posterior frontal lobe, and the deep fight parietal white matter, which was most consistent with multiple infarcts. Whole-brain radiation therapy led to complete resolution of all neurologic findings and normalization of the computed tomographic scan. The patient died suddenly 3 months later. At autopsy, predominantly intravascular, neoplastic cells were found in many organs, including the brain and adrenal glands, but the liver, spleen, and lymph nodes were not microscopically involved. Immuno-
407
408
Journal of the American Academy of Dermatology
Berger and Dawson
~.~i..
,
,
,,
,
~..
,
1. Reticular, palpably cordlike, violaeeous eruption of the medial aspect of the thighs. Fig. 2. Dilated dermal vessels filled with fibrin and cells. (Hematoxylin-eosin stain; x 8.) Fig. 3. Dilated dermal vessels filled with fibrin thrombi and atypical hyperchromatic cells. (Hematoxylin-eosin stain; x 128.) Fig. 4. Involved vessel with reduplication of the basement membrane, hypertrophy and hyperplasia of endothelial cells, intravascular degenerated cells, and fibrin. ( x 5,330.) F i g .
peroxidase staining for common leukocyte antigen was positive in neoplastic ceils infiltrating periadrenal fat. DISCUSSION The diagnostic and distinctive histopathologic feature in all cases of angioendotheliomatosis is the presence of dilated capillaries filled with vail-
ably atypical mononuclear cells.l Since the original description of the disease by Gottron and Nikolowski z in 1958, over sixty-five cases have been described. These cases can be divided into the subsets of reactive (benign) angioendotheliomatosis and neoplastic (malignant) angioendotheliomatosis on the basis of clinical behavior (Table I),
Volume 18 Number 2, Part 2 February 1988
Angioendotheliomatosis
4t)9
Table I. Subsets of angioendotheliomatosis
Sex SBE Skin lesions CNS findings History or findings of lymphoma Prognosis Treatment
Reactive
Neoplastic
Intravascular tumor
Female
Both
Male
All
One third + +
Half
Excellent Antibiotics, corticosteroids
Dismal Systemic chemotherapy ?CNS radiation
Fatal ?
+
CNS: Central nervous system; SBE: subacute bacterial endocarditis.
Reactive angioendotheliomatosis Cases of reactive angioendotheliomatosis are extremely rare, only seven well-documented cases having been reported. 2-s Five cases occurred in women between 31 and 68 years of age, four of whom had an illness resembling subacute bacterial endocarditis characterized by fever and/or a heart murmur. 2-5,8 Blood cultures were positive in only one case. The other two cases occurred in young boys, one 5 years and the other 5 months of age. The older boy had an artificial valve and possible subacute bacterial endocarditis, 6 and the younger boy had a "nevus vasculosus simplex" on the back. 7 All the patients presented with infiltrated, red to blue, 1-cm to palm-sized patches and plaques that often had focal purpura. The lesions were located on the arms, legs, cheeks, ears, and trunks. Histopathologic examination of the skin lesions in these cases of reactive angioendotheliomatosis reveals marked proliferation, throughout the dermis and upper subcutaneous fat, of dilated vessels filled with mononuclear cells and fibrin, to the point of occlusion in some areas. The intravascular cells vary from small, uniformly benign cells to large pleomorphic ceils that have prominent nucleoli and many mitoses. Electron microscopic examination supports endothelial proliferation in one case 6 and an inflammatory destructive process in another. 8 The proliferating cells are not found in the circulation, and no organ other than skin has been involved. Treatments have consisted of antibiotics (three cases), antibiotics plus corticosteroids (two cases), or no treatment (one case). In
all cases the symptoms and lesions have gradually resolved, although there were recurrences in two cases? '7 No deaths were reported.
Neoplastic angioendotheliomatosis Neoplastic angioendotheliomatosis is a multisystem disease with its primary manifestations in the central nervous system and the skin. 9-48Except for two patients 11A and 13 years o f age, all reported patients have been between the ages of 39 and 84 years. Men and women were equally affected. The prognosis is very guarded, with most patients dying in less than 3 years and often in a few months. Skin lesions, seen in about one third of patients, usually appear as erythematous to blue plaques or nodules on the arms, thighs, trunk, or face. T M Telangiectasia may be prominent over lesions, and erosions may occur. The skin lesions of reactive angioendotheliomatosis and neoplastic angioendotheliomatosis cannot be clinically differentiated. Central nervous system involvement (85% of cases) is often the presenting manifestation ~5-24and is characterized by progressive dementia in 55% of cases. 22 Transient episodes of aphasia, numbness, or weakness may (like transient ischemic attacks) herald the onset of the illness. Visual changes as in our patient are reported, zo'z4.39 Seizures, stupor, and coma are preterminal events. 2z Radionucleotide brain imaging, electroencephalography, and computed tomography may show significant brain abnormalities. Cerebral angiograms are usually normal) 2 The only consistently abnormal laboratory stud-
410
Berger and Dawson
ies are an elevated erythrocyte sedimentation rate and an increased level of cerebrospinal fluid protein. In five cases, intravascular hemolysis is suggested by anemia, thrombocytopenia, elevated levels of lactate dehydrogenase, and the presence of occasional circulating fragmented erythrocytes. 2sm,34,38Histopathologic changes in all affected tissues are identical and are similar to those seen in the skin in reactive angioendotheliomatosis, making differentiation difficult: Despite the intravascular cells seen histologically, it is unusual to find the atypical cells in the c i r c u l a t i o n 21'23,36 or the cerebrospinal fluid) 9 At autopsy, intravascular proliferation of cells is found in many organs. Focal extravascul ar extension occurs especially in the adrenal glands. ~2.2~.4~.4zThe frequent lack of involvement of lymph nodes, liver, spleen, and bone marrow is notable: ~,42The central nervous system is often the site of the most severe involvement, correlating with the prominence of central nervous system manifestations. Dilated vessels occluded by cells and fibrin are thrombosed, resulting in multiple areas of ischemic infarction. 24 Originally the intravaseular cells in neoplastic angioendotheliomatosis were considered endothelial. in origin on the basis of electron microscopy and cell-surface staining for human factor VIII. Cell-surface human factor VIII staining is not diagnostic of endothelial origin, however, and may simply represent the adsorption of this substance onto cell surfaces from the serum. ~9:°,42 The ultrastructural findingsz~ (i.e., reduplication of the basement membrane, apparent increased endothelial metabolic activity, and hyperplasia and hypertrophy of endothelial cells) may simply be the result of an intravascular inflammatory event. 8,39 Careful evaluation of low-power electron micrographs usually shows a distinct difference between the intravascular cells and the surrounding endothelium. 39,4°:2 Additionally, in over twenty cases reported recently or studied in retrospect, the intravascular cells are of leukocytic origin. 35.39-43Intravascular cells stain consistently with common leukocyte antigen. 4°'42 In the few cases in which fresh tissue has been available for study, either B cell or T cell markers are f o u n d . 39,41,42 These findings clearly demonstraate that neo-
Journal of the American Academy of Dermatology plastic angioendotheliomatosis is a form of lymphoma, which explains the following features: (1) skin lesions that resemble those seen in non-Hodgkins lymphomas (i.e., red to blue nodules and plaques with occasional erosion), (2) proteinaceous vitreous, as seen in our patient, associated with central nervous system lymphoma, (3) intravascular ceils that are similar in appearance to lymphoid cells when examined by light microscopy, 4° and (4) a diagnosis of lymphoma before or near the onset of neoplastic angioendotheliomatosis in some cases 27,35,44or consideration of a diagnosis lymphoma after examination of histologic material in other cases of neoplastic angioendotheliomatosis. 13,27,34,36,38 Therefore, although endothelial proliferation is present in both reactive angioendotheliomatosis and neoplastic angioendotheliomatosis, it is probably secondary to other intravascular events (i.e., subacute bacterial endocarditis or lymphoma). Both T and B lymphocytes bind to high endothelial venules in mice and humans, 41 an affinity that probably plays a role in normal lymphocyte trafticking and that may be related to the peculiar angiocentricity of the malignant lymphocytes in neoplastic angioendotheliomatosis. Whether malignancies other than lymphoma can cause this pattern is unknown but has been suggested. 29 The treatment of neoplastic angioendotheliomatosis has consisted of local radiation, cortico~ steroids, and chemotherapeutic agents. It has led to temporary remission but no prolonged survival. Recently, aggressive combination chemotherapy, as given for lymphoma, has appeared beneficial, but long-term follow-up is required. 39,41:4 Solid tumors arising from the inner surface of blood vessels may embolize and occlude distal vessels, mimicking neoplastic angioendotheliomatosis. Such cases have been reported in five elderly men who often had skin lesions similar to neoplastic angioendotheliomatosis and had no evidence of central nervous system involvement; all five diedY -48 In summary, angioendotheliomatosis presents a rare histologic picture with two clinical subsets, benign (reactive angioendotheliomatosis) and malignant (neoplastic angioendotheliomatosis). Reactive angioendotheliomatosis occurs primarily in
Volume 18 Number 2, Part 2 February 1988
w o m e n , has prominent skin findings, and is associated with subacute bacterial endocarditis or subacute bacterial endocarditis-like symptoms. N e o p l a s t i c angioendotheliomatosis often has significant central nervous system findings and is a l y m p h o m a . When the histopathologic features of angioendotheliomatosis are found, the patient s h o u l d have a complete workup, including neurologic, cardiovascular, and lymphatic evaluation; b l o o d cultures; and immunohistochemical staining for reticuloendothelial markers. Central nervous s y s t e m involvement excludes a benign diagnosis. I f neoplastic angioendotheliomatosis is considered, a careful search for l y m p h o m a is required, and systemic combination chemotherapy, perhaps with central nervous system radiation, is indicated.
Angioendotheliomatosis
14. 15. 16. 17. 18. 19. 20.
21. REFERENCES
1. Lever WF, Schaumburg-Lever G. Histopathology of the skin. 6th ed. Philadelphia: JB Lippincott Co, 1983: 645-6. 2. Gottron HA, Nikolowski W. Extrarenale L6hlein-Herdnephritis der Haut bei Endocarditis. Arch Klin Exp Dermatol 1958;207:156-76. 3. Plieger L, Tappeiner J. Zur Kenntnis der systemisierten Endotheliomatose der cutanen Blutgefiisse (Retieuloendotheliose?). Hautarzt 1959;10:359-63. 4. Ruiter M, Mandema E. New cutaneous syndrome in subacute bacterial endocarditis. Arch Intern Med 1964;
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5. Eisert J. Skin manifestations of subacute bacterial endocarditis: case report of subacute bacterial endocarditis mimicking Tappeiner's angioendotheliomatosis. Cutis 1980;25:394-400. 6. Martin S, Pitcher D, Tschen dr, Wolf JE Jr. Reactive angioendotheliomatosis. J AM ACADDERMATOL1980;2: 117-23. 7. Pasyk K, Depowski M. Proliferating systematized angioendotheliomatosis of a 5-month-old infant. Arch Dermatol 1978;114:1512-5. 8. Konra K, Brenner W. Ultrastructure of angioendotheliomatosis proliferans systemisata [abstract]. J Cutan Pathol 1983;10:292. 9. Braverman IM, Lemer AB. Diffuse malignant proliferation of vascular endothelium. Arch Dermatol 1961;84: 22-30. 10. Lund HZ. Tumors of the skin. In: Atlas of tumor pathology, fast. 2. Washington, DC: Armed Forces Institute of Pathology, 1957:272-3. 11. Haber H, Harris-Jones drN, Wells AL. Intravascular endothelioma (endothelioma in situ, systemic endotheliomatosis). J Clin Pathol 1964;17:608-11. 12. Strouth JC, Donahue S, Ross A, Aldred A. Neoplastic angioendotheliomatosis. Neurology (Minneap) 1965;15: 644-8. 13. Okagaki T, Richart RM. Systemic proliferating angioen-
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35. Ansell J, Bhawan J, Cohen S, Sullivan J, Sherman D. Histiocytic lymphoma and malignant angioendotheliomatosis: one disease or two? Cancer 1982;50:1506-12. 36. Tanaka M, Yamaguchi H, Uehiyama T, Hirai S, Ishizeki J. An autopsy case of malignant lymphoma mimicking neoplastic angioendotheliosis. Rinsho Shinkeigaku
1982;22:507-13. 37. Midana A, Ormea F. Apropos d' un cas d' "andioendotheliomatosis proliferans systematisata" (de Tappeiner et Pfleger). Ann Derrnatol Syphiligr (Paris) 1965;92: 129-38. 38. Meadors MP, Johnson WW. Diffuse angioendotheliosis. Arch Pathol 1970;90:572-6. 39. Bhawan J, Wolff SM, Ucci AA, Bhan AK, Malignant lymphoma and malignant angioendotheliomatosis; one disease. Cancer 1985;55:570-6. 40. Wrotnowski U, Mills SE, Cooper PH. Malignant angioendotheliomatosis: an angiotropic lymphoma? Am J Clin Pathol 1985;83:244-8. 41. Sheibani K, Battifora H, Winberg CD, et al. Further evidence that "malignant angioendotheliomatosis" is an angiotropic large-cell lymphoma. N Engl J Med 1986; 314:943-8.
42. Wick MR, Mills SE, Scheithauer BW, Cooper PH, Davitz MA, Parkinson K. Reassessment of malignant "angioendotheliomatosis": evidence in favor of its reclassification as "intravascular lymphomatosis." Am J Surg Pathol 1986;10:112-23. 43. Carroll TJ, Schelper RL, Goeken JA, Kemp JD. Neoplastic angioendotheliomatosis: immunopathologic evidence for intravascular malignant lymphoma [abstract]. Lab Invest 1985;52:12-3. 44. Lim HW, Anderson HM. Angioendotheliomatosis associated with histiocytic lymphoma: response to systemic chemotherapy. J AM ACADDERMATOL1985;13:903-8. 45. Sladden RA. Neoplasia of aortic intima. J Clin Pathol 1964;17:602-7. 46. Winkelmann RK, Van Heerden JA, Bernatz PE. Malignant vascular endothelial minor with distal embolization: a new entity. Am J Med 1971;51:692-7. 47. Leu HJ, Sulser J. Maligner endothelialer Tumor der Arteria femoralis mit distaler Embolisation. Virchows Arch [Pathol Anat] 1976;371:153-9. 48. Kurrein F. Systemic angioendotheliomatosis with metastases. J Clin Pathol 1976;29:347-53.
Linear IgM dermatosis of pregnancy J o s e p h Alcalay, M . D . , A r i e h Ingber, M . D . , Bilha Hazaz, B . S c . , M i c h a e l D a v i d , M . D . , and M i r i a m Sandbank, M . D .
Petah Tiqva and Tel Aviv, Israel An intensely pruritic dermatosis that occurred in a woman during the third trimester of pregnancy is described. The clinical manifestations included red follicular papules symmetrically distributed on the skin of the forearms, abdomen, thighs, and legs. The histopathologic findings were not specific. However, immunopathologic examination revealed dense linear deposition of IgM in the dermoepidermal junction. "['he eruption and the immunopathologic findings disappeared at the end of the puerperium. This dermatosis differs from previously described specific dermatoses of pregnancy because of the clinical appearance and the immunopathologic findings. Thus we propose the term linear IgM dermatosis of pregnancy. (J AM ACAD DERMATOL 1988;18:412-15.)
From the Department of Dermatology and the lmmunopathology Unit, Beilinson Medical Center, Petah Tiqva, and the Sackler School of Medicine, Tel Aviv University. Reprint requests to: Dr. J. Alealay, Department of Dermatology, Beilinson Medical Center, Petah Tiqva 49100, Israel.
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In 1962, Spangler et al 1 described a n e w dermatosis o f p r e g n a n c y termed papular dermatitis of pregnancy. Seventeen years later, another n e w dermatosis of p r e g n a n c y was described under