- Email: [email protected]
Angioendotheliomatosis associated with histiocytic lymphoma
Angioendotheliomatosis associated with histiocytic lymphoma Response to systemic chemotherapy Henry W. Lim, M.D.,* and Helen M. Anderson, M.D.** San Diego, CA A patient with cutaneous lesions consistent histologically, ultrastructurally, and immunohistochemically with angioendotheliomatosis is described. The cutaneous lesions appeared 14 months prior to the diagnosis of histiocytic lymphoma of the retroperitoneum. Both the cutaneous lesions and the lymphoma responded well to systemic chemotherapy consisting of cyclophosphamide, hydroxydoxorubicin, vincristine, and prednisone. (J AM ACAD DERMATOL 13:903-908, 1985.)
Angioendotheliomatosis is a rare disease process characterized by multifocal intravascular proliferation of endothelial cells. The term was first used by Pfleger and Tappeiner 1 in 1959; however, a patient with similar histopathologic changes was described a year earlier, t To date, over forty cases have been reported? There is no sexual predilection, and the majority of the patients are over 50 years old; however, onset as early as 5 months of age has been reported. 3.4 On the basis of the clinical features, angioendotheliomatosis has been divided into two categories: a more common malignant, aggressive form and a benign type2 '6 We report a patient with cutaneous lesions consistent histologically, ultrastructurally, and immunohistochemically with angioendotheliomatosis, which appeared 14 months prior to the diagnosis of histiocytic lymphoma of the retroperitoneum. Both the cutaneous lesions and the lymphoma responded well to systemic chemotherapy consisting of cy-
Fig.1. Indurated, yellow patch with poorly defined border on medial aspect of thigh. Multiple firm, movable, nontender subcutaneous nodules were palpated in indurated area. clophosphamide, hydroxydoxorubicin, vincristine, and prednisone. CASE REPORT
From the Divisions of Dermatology* and Hematology-Oneology,** Department of Medicine, University of California. Reprint requests to: Dr. Henry W. Lira, Division of Dermatology, H-81 l-J, University of California Medical Center, 225 Dickinson St., San Diego, CA 92103/61%294-5580. tGottron HA, Nikolowski W: Extrarenale L6hlein-Herdnephritis der haut bei endocarditis. Arch Klin Exp Dermato1207:156-176, 1958.
The patient, a 66-year-old white woman, was referred to the University of California, San Diego (UCSD), Dermatology Service in April, 1983, for the evaluation of asymptomatic skin lesions on the medial aspects of her thighs of 13 months' duration. The only significant past medical history is the resection of adenocarcinoma of the sigmoid colon in 1976, which was 903
904
Lim and Anderson
Journal of the American Academy of Dermatology
Fig. 2. Marked proliferation of endothelial cells of dermal capillaries, resulting in obliteration of capillary lumina. (Original magnification, x 100.) classified as Dukes' type C2 (positive regional lymph nodes). This was followed by a 1-year course of intermittent 5-fluorouracil as an adjuvant therapy. Since then she had been followed up by her private physician with annual colonoscopic or proctoscopic examinations, without any evidence of recurrence. Repeated determinations of serum carcinoembryonic antigen, a tumor marker, were also negative. Skin examination revealed that the patient had asymptomatie, indurated patches with poorly defined borders on the medial aspect of her thighs. Each patch measured 12 × 8 cm and had an intact epidermis and yellow discoloration; many dilated capillaries were observed on the surface (Fig. 1). In addition, multiple firm, movable, nontender subcutaneous nodules, each measuring 1 to 1.5 cm in diameter, were palpated in the indurated areas. On both legs there were also three reddish yellow indurated patches, each measuring 5 × 4 cm. The rest of the skin examination was unremarkable. Biopsies of the skin lesion were performed on April 15, 1983. On her return visit on April 22, 1983, the patient was noted to have puffiness of the face and eyelids and marked edema of the feet and legs in association with a 20-pound weight gain, anorexia, and nausea. She was referred to the medical service for further evaluation. Complete physical examination performed on April 25, 1983, showed a well-developed, well-nourished white woman with a blood pressure of 110/80 mm Hg, a pulse of 110 beats/min, and a temperature of 36 ° C. Abnormal physical findings were skin lesions and edema, as noted previously, and a finn, right-sided pelvic mass. The rest of her physical examination, in-
cluding neurologic evaluation, was within normal limits. Five days later the patient had a syncopal episode and developed severe, persistent lower abdominal pain radiating to the back, as well as nausea, vomiting, and urinary hesitancy. She was admitted to the UCSD Medical Center. On admission, the physical findings were unchanged from those of April 25, 1983. Pertinent abnormal laboratory data were as follows: hematocrit, 28%: hemoglobin, 9.5 gm/dl; white blood count, 2,800/mm 3 with segmented neutrophils 44%, bands 12%, lymphocytes 29%, mononuclear cells 11%, and eosinophils 4%; erythrocyte sedimentation rate (Westergren), 66 mm/hr; serum sodium, 126 mEq/L; serum potassium, 3.9 mEq/L; lactic dehydrogenase, 472 IU/L; and serum albumin, 2.2 gm/dl. Results of the remainder of the laboratory studies, including the coagulation profile and determinations of the other liver enzymes, were within normal limits. Chest roentgenogram was unremarkable. Abdominal and pelvic ultrasound studies disclosed moderate right hydronephrosis and a soR tissue mass posterior to the urinary bladder. Barium enema, flexible sigmoidoscopic examination of the colon to 33 cm, and biopsy of the anastomotic site of the sigmoid colon revealed no evidence of recurrence of the colonic cancer. At laparotomy the pelvic mass arising from behind the bladder extended upward along the course of the right ureter. The liver, spleen, mesentery, and intestine were normal in appearance; no other abdominal mass was observed. Biopsy of the retroperitoneal mass showed cells with large, vesicular, folded nuclei, prominent eosinophilic nucleoli, and pale, eosinophilic cy-
Volume 13 Number 5, Part 2 November, 1985
Angioendotheliomatosis with histiocytic lymphoma 90S
Fig. 3. Electron micrograph showing capillary in which endothelial proliferation has almost obliterated lumen. (Original magnification, x 32,000.) toplasm. The cell borders were indistinct, and there was a high mitotic index. These findings were diagnosed as those of diffuse, large-cell histiocytic lymphoma. Faintly positive staining of the tumor cells with antibodies to lamda and mu chains of the immunoglobulin were noted by immunoperoxidase method, consistent with changes observed in poorly differentiated large-cell lymphoma. Systemic chemotherapy every 21 days was begun, with cyclophosphamide, 750 mg/m 2 given intravenously, hydroxydoxorubicin, 50 mg/m 2 given intravenously, vincristine, 2 mg/m2 given intravenously on day 1 of each cycle, and prednisone, 50 mg/m 2 given orally on days 1 to 5 of each cycle. On day 5 of the first course of chemotherapy, the patient experienced the sudden onset of dysarthria, decreased recent memory, right-sided facial weakness, left-sided hypoglossal weakness, and hyperreflexia of the right arm. Her hematologic profile was as follows: hematocrit, 39.4%; hemoglobin, 13.3 gm/dl; white blood cell count, 5,100 cells/mm3 with segmented neutrophils of 92% and lymphocytes of 8%; platelet count, 71,000 cells/mm3; normal prothrombin time; and normal partial thromboplastin time. Computed tomographic scan of the head, which was normal on admission, showed hemorrhage into the left internal capsule. No lymphomatous cells were observed on examination of the cerebrospinal fluid. It was believed that the patient's symptoms were due to the involvement of the microvasculature of the central nervous system with either angioendotheliomatosis or lymphoma. The
neurologic impairment resolved gradually in a few weeks, while the patient continued her chemotherapy. The patient completed six courses of systemic chemotherapy. Her generalized edema resolved after the first course. In March, 1984, a computed tomographic scan of the head showed nearly complete resolution of the previously described abnormality in the region of the left internal capsule, and her retroperitoneal mass was no longer detectable by computed tomography. In July, 1984, the results of complete physical examination, complete blood count, and blood chemistry studies were normal. Only a slight yellow discoloration was observed at the sites of skin lesions on her thighs; the subcutaneous nodules on the thighs and the skin lesions on the legs had resolved completely. Skin biopsies. Studies were performed on the skin biopsy specimens obtained from the indurated lesion on the thigh. Examination of tissue sections stained with hematoxylin and eosin showed superficial and deep perivascular lymphohistiocytic infiltrate with many plasma cells. The blood vessels were dilated, and many were engorged with erythrocytes. Some of the vessels had marked proliferation of endothelial cells, which obliterated the lumina (Fig. 2). Some fibrin thrombi were observed, and rare mitotic figures were seen. These changes were interpreted to represent those of angioma, possibly angioendotheliomatosis. With the use of the immunoperoxidase technic, the cells lining the vessel walls stained positively with anti-factor VIII antibody, confirming the endothelial origin of these
906
Lira and Anderson
Journal of the American Academy of Dermatology
Fig. 4. High-power electron micrograph showing detail from endothelial cell. Membrane-
associated pinocytotic vesicles (arrow) and intracytoplasmic filaments are present. (Original magnification, x 44,000.) cells. Furthermore, they also stained positively with B271 antibody, which was relatively specific for endothelial cells. Examination of a section 1 ~m in thickness showed proliferation of endothelial cells of dermal capillaries, with prominent vascular walls and narrow lumina; this was confirmed by electron microscopic examination (Fig. 3). The proliferating cells at the capillary wails had many pinocytotic vesicles, intracytoplasmic filaments, and, in some of them, Weibel-Palade bodies, which are intracytoplasmic inclusions diagnostic of endothelium (Fig. 4). The changes were consistent with those of proliferating angioendotheliomatosis. DISCUSSION
Since angioendotheliomatosis was first recognized in 1959, ~ this entity has been described under various terms, including "proliferating," ' 'reactive, . . . . malignant," ' 'neoplastic," or ' 'systematized . . . . angioendotheliomatosis," "endotheliomatosis," "angioendotheliosis," or "endotheliosis."216 In addition, because of variations in clinical manifestations and biologic behavior, cases were reported not only in the dermatology literature but also in neurology and pathology journals. Both of these factors may account for the discrepancy of the total number of reported cases, which varies from eighteen to over forty cases in articles published just 6 months apart. 2'9 Two of the most common clinical manifestations of angioendotheliomatosis are cutaneous lesions and neurologic impairments, either or both of
which occurred in over 50% of the cases reported? '6 However, involvement of heart, lungs, liver, spleen, pancreas, gastrointestinal tract, adrenals, kidneys, genitourinary tract, lymph nodes, blood vessels, and bone has also been reported. Most of the cutaneous lesions are plum-colored, red, or purple firm patches, nodules, or plaques. The lesions may be ecchymotic, and some are tender. Dilated, tortuous blood vessels are noted on the surface of some of the lesions. The cutaneous lesions sometimes are associated with edema of the legs. Lesions are predominantly located on the extremities and trunk. The most common neurologic manifestation of angioendotheliomatosis is dementia, which occurred in 25% of the patients. 3 Other signs and symptoms of neurologic involvement include syncope, seizure, visual and auditory impairments, sensory loss, hyperreflexia, paraparesis, and hemiparesis. In addition, many of the patients also had fever, malaise, weight loss, myalgia, and arthralgia. The varied clinical manifestations of angioendotheliomatosis share similar histologic changes. 6"~° There is dilatation of small vessels in the dermis, occluded by round-to-ovoid cells with large nuclei, prominent nucleoli, and basophilic cytoplasm. Fibrin thrombi and occasional mitotic figures are seen. On electron microscopy, these cells have an ovoid nucleus, and the cytoplasm contains dilated mitochondria, prominent rough endoplasmic retic-
Volume 13 Number 5, Part 2 November, 1985
Angioendotheliomatosis with histiocytic lymphoma 907
ulum, and pinocytotic vesicles. 6'~° Rodlike cytoplasmic inclusions, consistent in appearance with Weibel-Palade bodies, which are characteristic of endothelial cells, have also been observed.~t The results of immunohistochemical staining for factor VIII-related antigen, an endothelial cell marker, have been variable, probably reflecting the degree of differentiation of the neoplastic cells. ~H3 On the basis of the clinical features, it has been proposed that angioendotheliomatosis can be divided into two groups, a malignant, progressive form, which usually is rapidly fatal, and a benign form, often associated with subacute bacterial endocarditis. 5'6 Histologic and ultrastructural changes in both groups are indistinguishable. The majority of the reported cases is the malignant form. The overall mortality rate for both groups is over 80%, and many of the patients died within 1 year2 The clinical manifestations of the disease and the histologic, ultrastructural, and immunohistochemical findings of the skin lesions in our patient are consistent with those of angioendotheliomatosis. However, this patient also had histiocytic lymphoma, and the appearance of her cutaneous lesions preceded the diagnosis of lymphoma by 14 months. There have been two other reported patients with angioendotheliomatosis associated with lymphoma. ~4.. Both were female, and one had histiocytic lymphoma of the abdominal nodes, whereas the other had lymphoma of the gastrointestinal tract. In addition, bone marrow studies of a third female patient were "suggestive" of lymphoma, ~o and in the same report, another patient, also female, and been treated for reticulum cell sarcoma of the nasopharynx 7 years before the development of her skin disorder. The pathogenesis of angioendotheliomatosis is unclear. Various stimuli, including wound healing, infection, inflammation, tumor growth, and "angiogenic factor," have been suggested to result in endothelial proliferation. 5,6,15-17In patients with angioendotheliomatosis associated with lymphoma or in those who had seemingly unrelated tumors found only at autopsy, 7'~°'~8 whether their angioen*Bhawan J: Malignant lymphoma presenting as angioendotheliomatosis proliferans systemisata. Presented at the Annual Meeting of the American Society of Dermatopathology,Nov., 1982.
dotheliomatosis represents a reactive phenomenon or a de novo endothelial proliferation remains to be clarified. Patients with angioendotheliomatosis associated with infection had been reported to respond favorably to antibiotic therapy6; however, in the majority of patients with angioendotheliomatosis the disease was not related to infection. 3 In this latter group of patients there had been no consistent response to radiation therapy or chemotherapy. It is of interest, therefore, that both the cutaneous lesions and the lymphoma of our patient apparently resolved with systemic chemotherapy, consisting of cyclophosphamide, hydroxydoxombicin, vincristine, and prednisone. The clinical response of our patient is similar to that of a previously reported patient with malignant angioendotheliomatosis, albeit without documented lymphoma, who also responded well to a combination of prednisone and doxorubicin. 9 The favorable response of our patient, taken together with the result of the previous report, 9 indicates that in patients with angioendotheliomatosis, therapy with a combination of prednisone and doxorubicin should be seriously considered, especially in those in whom infection is not present. REFERENCES 1. Pfleger L, Tappeiner J: Zur kenntnis der systemisierten endotheliomastose der cutanen blutgefasse (Reticuloendotheliose?) Hautarzt 10:359-363, 1959. 2. LeWitt PA, Forno LS, Brant-Zawadzki M: Neoplastic angioendotheliosis: A case with spontaneous regression and radiographic appearance of cerebral arteritis. Neurology (NY) 33:39-44, 1983. 3. Wick MR, Banks PM, McDonald TJ: Angioendotheliomatosis of the nose with fatal systemic dissemination. Cancer 48:25 [0-2527, 1981. 4. Pasyk K, Depowski M: Proliferating systematized angioendotheliomatosis of a 5-month-old infant. Arch Dermatol 114:1512-1515, 1978. 5. Person JR: Systemic angioendotheliomatosis" A possible disorder of a circulating angiogenic factor. Br J Dermatol 96:329-331, 1977. 6. Martin S, Pitcher D, Tschen J, Wolf JE Jr: Reactive angioendotheliomatosis. J AM ACAD DERMATOL2:117123, 1980. 7. Madara J, Shane J, Scarlato M: Systemic endotheliomatosis: A case report. J Clin Pathol 28:476-482, 1975. 8. Kauh YC, McFarland JP, Camabuci GG, Luscombe HA: Malignant proliferating angioendotheliomatosis. Arch Dermatol 116:803-806, 1980, 9. Keahey TM, Guerry D IV, Tuthill RJ, Bondi EE: Ma-
Journal of the American Academy of Dermatology
Lim and Anderson
10. 11. 12.
13. 14.
lignant angioendotheliomatosis proliferans treated with doxorubicin. Arch Derrnatol 118:512-514, 1982. Scott PWB, Silvers DN, Helwig EB: Proliferating angioendotheliomatosis. Arch Pathol 99:323-326, 1975. Wick MR, Scheithauer BW, Okazaki H, Thomas JE: Cerebral angioendotheliomatosis. Arch Pathol Lab Med 106:342-346, 1982. Fulling KH, Gersell DJ: Neoplastic angioendotheliomatosis: Histologic, immunohistochemical, and ultrastructural findings in two cases. Cancer 51:1107-1118, I983. Arnn ET, Yan LT, Li CY: Systemic angioendotheliomatosis presenting with hemolytic anemia. Am J Clin Pathol 80:246-251, 1983. Ansell J, Bhawan J, Cohen S, et al: Histiocytic lym-
15. 16. 17. 18.
phoma and malignant angioendotheliomatosis: One disease or two: Cancer 50:1506-1512, 1982. Greenblatt M, Shubik P: Tumor angiogenesis: Transfilter diffusion studies in the hamster by the transparent chamber technique. JNCI 41:111-124, 1968. Folkman J, Merler E, Abernathy C, Williams G: Isolation of a tumor factor responsible for angiogenesis. J Exp Med 133:275-288, 1971. Wolf JE Jr, Harrison RG: Demonstration and characterization of an epidermal angiogenic factor. J Invest Dermatol 61:130-141, 1973. Dolman CL, Sweeney VP, Magil A: Neoplastic angioendotheliosis: The case of the missed primary? Arch Neurol 36:5-7, 1979.
d
t.
II
Porokeratosis punctata palmaris et plantaris (punctate porokeratosis)* Case report and literature review E. L a w r e n c e S a k a s , Major, M C , U S A , * * and R i c h a r d H. G e n t r y , Lieutenant Colonel, M C , U S A * * * Honolulu, HI A case of porokeratosis punctata palmaris et plantaris (punctate porokeratosis) in a 60-year-old man of Korean ancestry is reported. The patient presented with a 15-year history of numerous asymptomatic pits measuring 1 to 3 mm in diameter and having keratotic plugs irregularly distributed on the plantar aspects of both feet and on the palmar aspects of both hands, including the flexor portions of the digits. Histologic examination revealed distinct epidermal depressions containing cornoid lamellae. Six previous case reports of this unusual dermatosis are reviewed and compared to our case. (J AM ACAD DERMATOL 13:908-912, 1985.)
Punctate p o r o k e r a t o s i s is a recently described ~ variant o f p o r o k e r a t o s i s , with only six previous c a s e s r e p o r t e d "~ (Table I). O n l y three of these From the Departments of Pathology** and Dermatology,***Tripler Army Medical Center. Reprint requests to: Dr, E. LawrenceSakas, Departmentof Pathology, Triplet Army Medical Center, HI 96859. *The opinions or assertions contained herein are the private views of the authors and are not to be construed as officialor as reflecting the view of the Department of the Army or the Department of Defense.
908
cases manifest porokeratotic i n v o l v e m e n t limited to the hands and feet. 1,z.4 Described herein are the clinical and histologic features of an additional case o f punctate porokeratosis involving only the hands and feet. CASE R E P O R T Clinical history. A 60-year-old man of Korean ancestry who had noticed, for at least 15 years, multiple small "rough spots" on his palms and soles was seen in May, 1983, by the dermatology service at Tripler
Angioendotheliomatosis is a rare disease process characterized by multifocal intravascular proliferation of endothelial cells. The term was first used by Pfleger and Tappeiner 1 in 1959; however, a patient with similar histopathologic changes was described a year earlier, t To date, over forty cases have been reported? There is no sexual predilection, and the majority of the patients are over 50 years old; however, onset as early as 5 months of age has been reported. 3.4 On the basis of the clinical features, angioendotheliomatosis has been divided into two categories: a more common malignant, aggressive form and a benign type2 '6 We report a patient with cutaneous lesions consistent histologically, ultrastructurally, and immunohistochemically with angioendotheliomatosis, which appeared 14 months prior to the diagnosis of histiocytic lymphoma of the retroperitoneum. Both the cutaneous lesions and the lymphoma responded well to systemic chemotherapy consisting of cy-
Fig.1. Indurated, yellow patch with poorly defined border on medial aspect of thigh. Multiple firm, movable, nontender subcutaneous nodules were palpated in indurated area. clophosphamide, hydroxydoxorubicin, vincristine, and prednisone. CASE REPORT
From the Divisions of Dermatology* and Hematology-Oneology,** Department of Medicine, University of California. Reprint requests to: Dr. Henry W. Lira, Division of Dermatology, H-81 l-J, University of California Medical Center, 225 Dickinson St., San Diego, CA 92103/61%294-5580. tGottron HA, Nikolowski W: Extrarenale L6hlein-Herdnephritis der haut bei endocarditis. Arch Klin Exp Dermato1207:156-176, 1958.
The patient, a 66-year-old white woman, was referred to the University of California, San Diego (UCSD), Dermatology Service in April, 1983, for the evaluation of asymptomatic skin lesions on the medial aspects of her thighs of 13 months' duration. The only significant past medical history is the resection of adenocarcinoma of the sigmoid colon in 1976, which was 903
904
Lim and Anderson
Journal of the American Academy of Dermatology
Fig. 2. Marked proliferation of endothelial cells of dermal capillaries, resulting in obliteration of capillary lumina. (Original magnification, x 100.) classified as Dukes' type C2 (positive regional lymph nodes). This was followed by a 1-year course of intermittent 5-fluorouracil as an adjuvant therapy. Since then she had been followed up by her private physician with annual colonoscopic or proctoscopic examinations, without any evidence of recurrence. Repeated determinations of serum carcinoembryonic antigen, a tumor marker, were also negative. Skin examination revealed that the patient had asymptomatie, indurated patches with poorly defined borders on the medial aspect of her thighs. Each patch measured 12 × 8 cm and had an intact epidermis and yellow discoloration; many dilated capillaries were observed on the surface (Fig. 1). In addition, multiple firm, movable, nontender subcutaneous nodules, each measuring 1 to 1.5 cm in diameter, were palpated in the indurated areas. On both legs there were also three reddish yellow indurated patches, each measuring 5 × 4 cm. The rest of the skin examination was unremarkable. Biopsies of the skin lesion were performed on April 15, 1983. On her return visit on April 22, 1983, the patient was noted to have puffiness of the face and eyelids and marked edema of the feet and legs in association with a 20-pound weight gain, anorexia, and nausea. She was referred to the medical service for further evaluation. Complete physical examination performed on April 25, 1983, showed a well-developed, well-nourished white woman with a blood pressure of 110/80 mm Hg, a pulse of 110 beats/min, and a temperature of 36 ° C. Abnormal physical findings were skin lesions and edema, as noted previously, and a finn, right-sided pelvic mass. The rest of her physical examination, in-
cluding neurologic evaluation, was within normal limits. Five days later the patient had a syncopal episode and developed severe, persistent lower abdominal pain radiating to the back, as well as nausea, vomiting, and urinary hesitancy. She was admitted to the UCSD Medical Center. On admission, the physical findings were unchanged from those of April 25, 1983. Pertinent abnormal laboratory data were as follows: hematocrit, 28%: hemoglobin, 9.5 gm/dl; white blood count, 2,800/mm 3 with segmented neutrophils 44%, bands 12%, lymphocytes 29%, mononuclear cells 11%, and eosinophils 4%; erythrocyte sedimentation rate (Westergren), 66 mm/hr; serum sodium, 126 mEq/L; serum potassium, 3.9 mEq/L; lactic dehydrogenase, 472 IU/L; and serum albumin, 2.2 gm/dl. Results of the remainder of the laboratory studies, including the coagulation profile and determinations of the other liver enzymes, were within normal limits. Chest roentgenogram was unremarkable. Abdominal and pelvic ultrasound studies disclosed moderate right hydronephrosis and a soR tissue mass posterior to the urinary bladder. Barium enema, flexible sigmoidoscopic examination of the colon to 33 cm, and biopsy of the anastomotic site of the sigmoid colon revealed no evidence of recurrence of the colonic cancer. At laparotomy the pelvic mass arising from behind the bladder extended upward along the course of the right ureter. The liver, spleen, mesentery, and intestine were normal in appearance; no other abdominal mass was observed. Biopsy of the retroperitoneal mass showed cells with large, vesicular, folded nuclei, prominent eosinophilic nucleoli, and pale, eosinophilic cy-
Volume 13 Number 5, Part 2 November, 1985
Angioendotheliomatosis with histiocytic lymphoma 90S
Fig. 3. Electron micrograph showing capillary in which endothelial proliferation has almost obliterated lumen. (Original magnification, x 32,000.) toplasm. The cell borders were indistinct, and there was a high mitotic index. These findings were diagnosed as those of diffuse, large-cell histiocytic lymphoma. Faintly positive staining of the tumor cells with antibodies to lamda and mu chains of the immunoglobulin were noted by immunoperoxidase method, consistent with changes observed in poorly differentiated large-cell lymphoma. Systemic chemotherapy every 21 days was begun, with cyclophosphamide, 750 mg/m 2 given intravenously, hydroxydoxorubicin, 50 mg/m 2 given intravenously, vincristine, 2 mg/m2 given intravenously on day 1 of each cycle, and prednisone, 50 mg/m 2 given orally on days 1 to 5 of each cycle. On day 5 of the first course of chemotherapy, the patient experienced the sudden onset of dysarthria, decreased recent memory, right-sided facial weakness, left-sided hypoglossal weakness, and hyperreflexia of the right arm. Her hematologic profile was as follows: hematocrit, 39.4%; hemoglobin, 13.3 gm/dl; white blood cell count, 5,100 cells/mm3 with segmented neutrophils of 92% and lymphocytes of 8%; platelet count, 71,000 cells/mm3; normal prothrombin time; and normal partial thromboplastin time. Computed tomographic scan of the head, which was normal on admission, showed hemorrhage into the left internal capsule. No lymphomatous cells were observed on examination of the cerebrospinal fluid. It was believed that the patient's symptoms were due to the involvement of the microvasculature of the central nervous system with either angioendotheliomatosis or lymphoma. The
neurologic impairment resolved gradually in a few weeks, while the patient continued her chemotherapy. The patient completed six courses of systemic chemotherapy. Her generalized edema resolved after the first course. In March, 1984, a computed tomographic scan of the head showed nearly complete resolution of the previously described abnormality in the region of the left internal capsule, and her retroperitoneal mass was no longer detectable by computed tomography. In July, 1984, the results of complete physical examination, complete blood count, and blood chemistry studies were normal. Only a slight yellow discoloration was observed at the sites of skin lesions on her thighs; the subcutaneous nodules on the thighs and the skin lesions on the legs had resolved completely. Skin biopsies. Studies were performed on the skin biopsy specimens obtained from the indurated lesion on the thigh. Examination of tissue sections stained with hematoxylin and eosin showed superficial and deep perivascular lymphohistiocytic infiltrate with many plasma cells. The blood vessels were dilated, and many were engorged with erythrocytes. Some of the vessels had marked proliferation of endothelial cells, which obliterated the lumina (Fig. 2). Some fibrin thrombi were observed, and rare mitotic figures were seen. These changes were interpreted to represent those of angioma, possibly angioendotheliomatosis. With the use of the immunoperoxidase technic, the cells lining the vessel walls stained positively with anti-factor VIII antibody, confirming the endothelial origin of these
906
Lira and Anderson
Journal of the American Academy of Dermatology
Fig. 4. High-power electron micrograph showing detail from endothelial cell. Membrane-
associated pinocytotic vesicles (arrow) and intracytoplasmic filaments are present. (Original magnification, x 44,000.) cells. Furthermore, they also stained positively with B271 antibody, which was relatively specific for endothelial cells. Examination of a section 1 ~m in thickness showed proliferation of endothelial cells of dermal capillaries, with prominent vascular walls and narrow lumina; this was confirmed by electron microscopic examination (Fig. 3). The proliferating cells at the capillary wails had many pinocytotic vesicles, intracytoplasmic filaments, and, in some of them, Weibel-Palade bodies, which are intracytoplasmic inclusions diagnostic of endothelium (Fig. 4). The changes were consistent with those of proliferating angioendotheliomatosis. DISCUSSION
Since angioendotheliomatosis was first recognized in 1959, ~ this entity has been described under various terms, including "proliferating," ' 'reactive, . . . . malignant," ' 'neoplastic," or ' 'systematized . . . . angioendotheliomatosis," "endotheliomatosis," "angioendotheliosis," or "endotheliosis."216 In addition, because of variations in clinical manifestations and biologic behavior, cases were reported not only in the dermatology literature but also in neurology and pathology journals. Both of these factors may account for the discrepancy of the total number of reported cases, which varies from eighteen to over forty cases in articles published just 6 months apart. 2'9 Two of the most common clinical manifestations of angioendotheliomatosis are cutaneous lesions and neurologic impairments, either or both of
which occurred in over 50% of the cases reported? '6 However, involvement of heart, lungs, liver, spleen, pancreas, gastrointestinal tract, adrenals, kidneys, genitourinary tract, lymph nodes, blood vessels, and bone has also been reported. Most of the cutaneous lesions are plum-colored, red, or purple firm patches, nodules, or plaques. The lesions may be ecchymotic, and some are tender. Dilated, tortuous blood vessels are noted on the surface of some of the lesions. The cutaneous lesions sometimes are associated with edema of the legs. Lesions are predominantly located on the extremities and trunk. The most common neurologic manifestation of angioendotheliomatosis is dementia, which occurred in 25% of the patients. 3 Other signs and symptoms of neurologic involvement include syncope, seizure, visual and auditory impairments, sensory loss, hyperreflexia, paraparesis, and hemiparesis. In addition, many of the patients also had fever, malaise, weight loss, myalgia, and arthralgia. The varied clinical manifestations of angioendotheliomatosis share similar histologic changes. 6"~° There is dilatation of small vessels in the dermis, occluded by round-to-ovoid cells with large nuclei, prominent nucleoli, and basophilic cytoplasm. Fibrin thrombi and occasional mitotic figures are seen. On electron microscopy, these cells have an ovoid nucleus, and the cytoplasm contains dilated mitochondria, prominent rough endoplasmic retic-
Volume 13 Number 5, Part 2 November, 1985
Angioendotheliomatosis with histiocytic lymphoma 907
ulum, and pinocytotic vesicles. 6'~° Rodlike cytoplasmic inclusions, consistent in appearance with Weibel-Palade bodies, which are characteristic of endothelial cells, have also been observed.~t The results of immunohistochemical staining for factor VIII-related antigen, an endothelial cell marker, have been variable, probably reflecting the degree of differentiation of the neoplastic cells. ~H3 On the basis of the clinical features, it has been proposed that angioendotheliomatosis can be divided into two groups, a malignant, progressive form, which usually is rapidly fatal, and a benign form, often associated with subacute bacterial endocarditis. 5'6 Histologic and ultrastructural changes in both groups are indistinguishable. The majority of the reported cases is the malignant form. The overall mortality rate for both groups is over 80%, and many of the patients died within 1 year2 The clinical manifestations of the disease and the histologic, ultrastructural, and immunohistochemical findings of the skin lesions in our patient are consistent with those of angioendotheliomatosis. However, this patient also had histiocytic lymphoma, and the appearance of her cutaneous lesions preceded the diagnosis of lymphoma by 14 months. There have been two other reported patients with angioendotheliomatosis associated with lymphoma. ~4.. Both were female, and one had histiocytic lymphoma of the abdominal nodes, whereas the other had lymphoma of the gastrointestinal tract. In addition, bone marrow studies of a third female patient were "suggestive" of lymphoma, ~o and in the same report, another patient, also female, and been treated for reticulum cell sarcoma of the nasopharynx 7 years before the development of her skin disorder. The pathogenesis of angioendotheliomatosis is unclear. Various stimuli, including wound healing, infection, inflammation, tumor growth, and "angiogenic factor," have been suggested to result in endothelial proliferation. 5,6,15-17In patients with angioendotheliomatosis associated with lymphoma or in those who had seemingly unrelated tumors found only at autopsy, 7'~°'~8 whether their angioen*Bhawan J: Malignant lymphoma presenting as angioendotheliomatosis proliferans systemisata. Presented at the Annual Meeting of the American Society of Dermatopathology,Nov., 1982.
dotheliomatosis represents a reactive phenomenon or a de novo endothelial proliferation remains to be clarified. Patients with angioendotheliomatosis associated with infection had been reported to respond favorably to antibiotic therapy6; however, in the majority of patients with angioendotheliomatosis the disease was not related to infection. 3 In this latter group of patients there had been no consistent response to radiation therapy or chemotherapy. It is of interest, therefore, that both the cutaneous lesions and the lymphoma of our patient apparently resolved with systemic chemotherapy, consisting of cyclophosphamide, hydroxydoxombicin, vincristine, and prednisone. The clinical response of our patient is similar to that of a previously reported patient with malignant angioendotheliomatosis, albeit without documented lymphoma, who also responded well to a combination of prednisone and doxorubicin. 9 The favorable response of our patient, taken together with the result of the previous report, 9 indicates that in patients with angioendotheliomatosis, therapy with a combination of prednisone and doxorubicin should be seriously considered, especially in those in whom infection is not present. REFERENCES 1. Pfleger L, Tappeiner J: Zur kenntnis der systemisierten endotheliomastose der cutanen blutgefasse (Reticuloendotheliose?) Hautarzt 10:359-363, 1959. 2. LeWitt PA, Forno LS, Brant-Zawadzki M: Neoplastic angioendotheliosis: A case with spontaneous regression and radiographic appearance of cerebral arteritis. Neurology (NY) 33:39-44, 1983. 3. Wick MR, Banks PM, McDonald TJ: Angioendotheliomatosis of the nose with fatal systemic dissemination. Cancer 48:25 [0-2527, 1981. 4. Pasyk K, Depowski M: Proliferating systematized angioendotheliomatosis of a 5-month-old infant. Arch Dermatol 114:1512-1515, 1978. 5. Person JR: Systemic angioendotheliomatosis" A possible disorder of a circulating angiogenic factor. Br J Dermatol 96:329-331, 1977. 6. Martin S, Pitcher D, Tschen J, Wolf JE Jr: Reactive angioendotheliomatosis. J AM ACAD DERMATOL2:117123, 1980. 7. Madara J, Shane J, Scarlato M: Systemic endotheliomatosis: A case report. J Clin Pathol 28:476-482, 1975. 8. Kauh YC, McFarland JP, Camabuci GG, Luscombe HA: Malignant proliferating angioendotheliomatosis. Arch Dermatol 116:803-806, 1980, 9. Keahey TM, Guerry D IV, Tuthill RJ, Bondi EE: Ma-
Journal of the American Academy of Dermatology
Lim and Anderson
10. 11. 12.
13. 14.
lignant angioendotheliomatosis proliferans treated with doxorubicin. Arch Derrnatol 118:512-514, 1982. Scott PWB, Silvers DN, Helwig EB: Proliferating angioendotheliomatosis. Arch Pathol 99:323-326, 1975. Wick MR, Scheithauer BW, Okazaki H, Thomas JE: Cerebral angioendotheliomatosis. Arch Pathol Lab Med 106:342-346, 1982. Fulling KH, Gersell DJ: Neoplastic angioendotheliomatosis: Histologic, immunohistochemical, and ultrastructural findings in two cases. Cancer 51:1107-1118, I983. Arnn ET, Yan LT, Li CY: Systemic angioendotheliomatosis presenting with hemolytic anemia. Am J Clin Pathol 80:246-251, 1983. Ansell J, Bhawan J, Cohen S, et al: Histiocytic lym-
15. 16. 17. 18.
phoma and malignant angioendotheliomatosis: One disease or two: Cancer 50:1506-1512, 1982. Greenblatt M, Shubik P: Tumor angiogenesis: Transfilter diffusion studies in the hamster by the transparent chamber technique. JNCI 41:111-124, 1968. Folkman J, Merler E, Abernathy C, Williams G: Isolation of a tumor factor responsible for angiogenesis. J Exp Med 133:275-288, 1971. Wolf JE Jr, Harrison RG: Demonstration and characterization of an epidermal angiogenic factor. J Invest Dermatol 61:130-141, 1973. Dolman CL, Sweeney VP, Magil A: Neoplastic angioendotheliosis: The case of the missed primary? Arch Neurol 36:5-7, 1979.
d
t.
II
Porokeratosis punctata palmaris et plantaris (punctate porokeratosis)* Case report and literature review E. L a w r e n c e S a k a s , Major, M C , U S A , * * and R i c h a r d H. G e n t r y , Lieutenant Colonel, M C , U S A * * * Honolulu, HI A case of porokeratosis punctata palmaris et plantaris (punctate porokeratosis) in a 60-year-old man of Korean ancestry is reported. The patient presented with a 15-year history of numerous asymptomatic pits measuring 1 to 3 mm in diameter and having keratotic plugs irregularly distributed on the plantar aspects of both feet and on the palmar aspects of both hands, including the flexor portions of the digits. Histologic examination revealed distinct epidermal depressions containing cornoid lamellae. Six previous case reports of this unusual dermatosis are reviewed and compared to our case. (J AM ACAD DERMATOL 13:908-912, 1985.)
Punctate p o r o k e r a t o s i s is a recently described ~ variant o f p o r o k e r a t o s i s , with only six previous c a s e s r e p o r t e d "~ (Table I). O n l y three of these From the Departments of Pathology** and Dermatology,***Tripler Army Medical Center. Reprint requests to: Dr, E. LawrenceSakas, Departmentof Pathology, Triplet Army Medical Center, HI 96859. *The opinions or assertions contained herein are the private views of the authors and are not to be construed as officialor as reflecting the view of the Department of the Army or the Department of Defense.
908
cases manifest porokeratotic i n v o l v e m e n t limited to the hands and feet. 1,z.4 Described herein are the clinical and histologic features of an additional case o f punctate porokeratosis involving only the hands and feet. CASE R E P O R T Clinical history. A 60-year-old man of Korean ancestry who had noticed, for at least 15 years, multiple small "rough spots" on his palms and soles was seen in May, 1983, by the dermatology service at Tripler