Splenic Angiosarcoma and Iron Deficiency Anemia in a 43-Year-Old Man.

ABSTRACT: Thrombocytopenia and microcytic anemia are two laboratory findings that alone or together suggest an underlying disease process. Both are found throughout particular age groups and have broad differential diagnoses. Angiosarcomas are rare neoplasms from the lining of blood vessels. Primary splenic angiosarcoma is an even rarer neoplasm, first reported in the late 1870s. We report a case of primary splenic angiosarcoma in a patient with thrombocytopenia, microcytic anemia, and splenomegaly.

HEMANGIOSARCOMAS ARE RARE neoplasms arising from the endothelial lining of blood vessels. These malignant vascular neoplasms are a homogeneous group with regard to pathology and clinical presentation. Viscera and deep tissues can be involved, but skin and superficial soft tissues appear to be the most common sites of disease. The first reported case of primary splenic hemangiosarcoma was in 1879 by Langhans. [1] More than 100 cases have been reported since that time. Median survival ranges from 4.4 months to 14.4 months. [2,3] Cytopenias and coagulation disturbances also can occur with these neoplasms. [4,5]

Anemia is defined as a hemoglobin or hematocrit level below the normal laboratory range for a patient's sex and age group. Anemia in the United States is estimated to occur in 30 per 1,000 females (of all ages), 6 per 1,000 men younger than 45 years of age, and 18.5 per 1,000 men older than 75 years. [6] The most common cause of anemia worldwide is iron deficiency. [7] In children, this disorder is typically caused by diet. [8] In adults, it is considered to be caused by blood loss until proven otherwise. Premenopausal women are prone to iron deficiency anemia due to blood loss from the menstrual cycle.

We report a case of primary splenic hemangiosarcoma, long-standing thrombocytopenia, and iron deficiency anemia. Pathologic evaluation of the spleen revealed substantial deposition of iron within the splenic parenchyma. After splenectomy and without evidence of metastatic disease, the anemia resolved and has not recurred in more than 18 months.

CASE REPORT

Our patient was a 40-year-old white man with a history of thrombocytopenia and questionable splenomegaly dating back to 1987. He was first seen in 1996 for a "low iron level" and was prescribed oral iron sulfate. Laboratory evaluation from October 1996 showed normal vitamin [B.sub.12], folate, and hemoglobin [A.sub.2] levels; normal prothrombin time/partial thromboplastin time; and normal results on hemoglobin electrophoresis, peripheral immunophenotyping, and liver function tests. Testing for human immunodeficiency virus 1 and 2, antinuclear antibodies, anti-smooth muscle antibodies, and IgG and 1gM platelet antibodies yielded negative results. A complete blood count and iron studies from the same time revealed the following values: serum iron 36 [micro]g/dL (normal, 45 to 150 [micro]g/dL), total iron-binding capacity 278 [micro]g/dL (normal, 250 to 460 [micro]g/dL), ferritin 50 ng/mL (normal, 12 to 540 ng/mL), white blood cells 5,900/[mm.sup.3] (normal, 5,000 to 10,000/[mm.sup.3]), hemoglobin 10.8 g/dL (no rmal, 14.0 to 18.0 g/dL), hematocrit 32.1% (normal, 40% to 54%), mean corpuscular volume 73.2 fL (normal, 82 to 99 fL), platelets 42,000/[mm.sup.3] (normal, 150,000 to 400,000/[mm.sup.3]), and iron saturation 12% (normal, 20% to 55%). The laboratory findings were suggestive of iron deficiency anemia, combined iron deficiency anemia and anemia of chronic disease, or anemia of a chronic disease state (Table 1).

The patient was employed as a pilot and denied any drug ingestion, drug use, toxic chemical exposure, or family history of anemia. The only significant physical finding was splenomegaly, palpated about 10 cm below the costal margin. In November 1996, the patient had further evaluation of the anemia and thrombocytopenia. A gastrointestinal tract evaluation, which included upper endoscopy, colonoscopy, and an upper gastrointestinal series with small bowel follow-through, showed no source of blood loss. A bone marrow biopsy revealed hematopoietic hyperplasia, cellularity of 70% and absent stainable iron, and normal-to-increased megakaryocytes, which confirmed iron deficiency anemia and did not suggest decreased production as the cause of thrombocytopenia. Computed tomography (CT) of the abdomen showed hepatosplenomegaly (liver 25 cm, spleen 24 cm craniocaudally) and a nodular spleen with many lesions. Magnetic resonance imaging of the liver and spleen revealed numerous masses in the spleen, and the parenchymal signal was reported to be unusual, suggestive of fibrotic material, metals, or calcium as components of the masses (Fig 1).

The patient had splenectomy in March 1997, and 6 days postoperatively platelet count was 210,000/[mm.sup.3] Pathology was positive for an intermediate grade angiosarcoma, and a supplemental iron stain showed marked deposition of iron. Biopsy of a lymph node and a wedge specimen of the liver were negative for tumor, and the liver biopsy showed no iron deposition.

The spleen weighed 2,110 g (normal, 50 to 250 g) and measured 26 x 20 x 9.5 cm. The capsule was smooth, glistening, and slightly thickened. Serial sections of the parenchyma revealed multiple dark red nodules that ranged in size from 0.9 to 5.5 cm and occupied it completely (Fig 2). No areas of hemorrhage or necrosis were grossly present. The histologic sections showed diffuse infiltration of the spleen by a neoplasm composed of irregular anastomosing vascular channels (Fig 3). The vascular channels were lined by plump columnar cells with enlarged and irregular nuclei. There was tufting of the cells into the lumen of the vascular spaces (Fig 4). Dark brown, pigment-laden macrophages were present in the lumen, and this pigment was also identified in the neoplastic cells. An iron stain showed marked iron deposition (Fig 5). The neoplastic cells were positive for CD3l (DAKO, Carpinteria, Calif), a marker of endothelial differentiation, and weakly positive for CD34 (Zymed, San Francisco, Calif) and factor VIII ( DAKO). These markers confirmed the vascular nature of the neoplasms and the diagnosis of angiosarcoma, intermediate grade.

Staging studies after the operation included CT of the chest and a bone scan, which were both negative for metastatic disease. The patient was not given adjuvant chemotherapy or radiation. Follow-up to the present time has shown no recurrence of anemia or thrombocytopenia and no evidence of tumor recurrence.

DISCUSSION

Angiosarcoma of the spleen is a rare neoplasm, but it is the most common primary, malignant nonhematopoietic tumor of the spleen. The spleen is often enlarged (weight [greater than]250 g), and some patients have a massively enlarged spleen. Most commonly angiosarcomas manifest as single or multiple hemorrhagic nodules; rarely, the neoplasm involves the spleen diffusely. Hemorrhage, infarct, and necrosis may be present.

Angiosarcomas of the spleen show highly variable microscopic findings, with the most important criterion for diagnosis being vascular differentiation, either as well-formed vascular spaces or poorly formed lumina lined by malignant cells. Several growth patterns and cell populations can be present in a single case. In a large series [3] of 40 cases of angiosarcoma, a spongiform or honeycomb-like proliferation of endothelial cells forming an irregular network of capillary or slit-like vascular channels was the pattern found in most of the cases. Areas that have a cavernous appearance with expanded lumens and pseudosinusoidal structures that simulate normal splenic sinuses have been described. Papillary formation lined by proliferating tumor cells protruding into vascular lumens and cystic spaces is another histologic pattern that can be present. Some have sheet-like areas of polygonal or epithelioid tumor cells. Solid areas that resemble high-grade sarcoma, with a herringbone or storiform pattern, can be pres ent. Poorly differentiated angiosarcomas should be extensively sampled to identify the vascular forming areas, which are usually present but can be focal. [9,10]

Cytologically the malignant cells can be epithelioid, spindle, polygonal, or primitive round cells. The presence of multinucleated giant tumor cells has been described. Mitoses, usually conspicuous, are not required for a diagnosis of malignancy. Necrosis usually is not a prominent feature, except with infarction. Hemophagocytosis has been described and in some cases has been prominent. [9]

Angiosarcomas can have histologically bland areas that may raise the possibility of a benign diagnosis of hemangioma; therefore, sampling should be adequate to identify the higher-grade areas. Also included in the differential diagnosis is bacillary angiomatosis and hairy cell leukemia. [9]

As previously stated, iron deficiency anemia is the most common cause of anemia worldwide. [7] It results from an imbalance between iron requirements and supply. The most common cause is blood loss, in which case the iron is not retrievable. In men and postmenopausal women, iron deficiency anemia is highly suggestive of gastrointestinal blood loss." Iron deficiency anemia can be the first sign of an occult malignancy. Other causes of iron deficiency anemia are listed in Table 2. In addition, gastric surgery (partial or total gastrectomy and gastroenterostomy for bypass of the duodenum) may be a causative factor in abnormal iron absorption, leading to or contributing to iron deficiency. [12] Signs and symptoms are variable and are dependent on the degree and rate of development of the anemia. These can include pallor, palpitations, tinnitus, weakness, dizziness, and fatigue. Laboratory evaluation will often reveal a hypochromic/microcytic anemia, elevated red cell distribution width, thrombocytosis, decreased ferritin and serum iron, and an elevated total iron-binding capacity. Bone marrow biopsy will reveal decreased sideroblasts and absent stainable iron. Treatment consists of iron supplementation orally or parenterally (intra-muscular injection is also an option, though less favored) and treatment, if possible, of the underlying cause (eg, gastrointestinal blood loss).

Thrombocytopenia is caused by one or more of three mechanisms: decreased production, increased destruction, or sequestration. There are many causes of thrombocytopenia, including drugs, hypersplenism, and autoimmune disorders. In our case, the normal bone marrow megakaryocytes suggested that thrombocytopenia was due to splenic sequestration.

CONCLUSION

Our patient's history of thrombocytopenia and splenomegaly began at least 9 years before the diagnosis of angiosarcoma. We can conclude that, at the time of surgery, sequestration by the tumor-infiltrated spleen was the cause of thrombocytopenia. There was no evidence of other causes of this abnormality. The exact mechanism and etiology of the iron deposition within the tumor is unclear. There was no history of blood loss, malabsorption, or pica, so we can conclude that the deposition of iron in the spleen was the cause of the iron deficiency anemia. The lack of metastatic disease allowed splenectomy to be a curative measure with regard to the malignancy. Additionally, this intervention was curative for thrombocytopenia and iron deficiency anemia.

References

(1.) Langhans T: Pulsating cavernous neoplasm of the spleen with metastatic nodules to the liver. Virchows Arch 1879; 75:273-291

(2.) Buckner JW 111, Porterfield G, Williams GR: Spontaneous splenic rupture secondary to angiosarcoma. J Okla State Med Assoc 1990; 83:211-213

(3.) Falk S, Krishman J, Meis JM: Primary angiosarcoma of the spleen: a clinicopathologic study of 40 cases. Am J Surg Pathol 1993; 17:959-970

(4.) Donald S, Dawson AA: Microangiopathic hemolytic anaemia associated with malignant haemangiosarcoma. J Clin Pathol 1971; 24:456-459

(5.) Michot F, Brugisser D, Fehr H, et al: Mikroangiopathische hamolytische anamie, erythrophagozytose and verbrauchskoagulopathie bei vinylchloridinduziertem von Milz und Leber. Schweiz Med Wochenschr 1987; 117:990-995

(6.) Current Estimates From the National Health Interview Survey, 1994. Hyattsville, Md, National Center for Health Statistics, centers for Disease control and Prevention, Department of Health and Human Services Publication No. 95-152 1, 1995

(7.) Brown RG: Anemia. Family Medicine: Principles and Practice. Taylor BR (ed). New York, Springer-Verlag, 4th Ed, 1994, pp 997-1005

(8.) Centers for Disease Control and Prevention: Guidelines for school health programs to promote life-long healthy eating. MMWR Morb Mortal Wkly Rep 1996; 45(FR-9):1-41

(9.) Warnke RA, Weiss LM, Chan JKC, et al: Tumors of the lymph nodes and spleen. Atlas of Tumor Pathology. Third Series, fasicle 14. Washington, DC, Armed Forces Institute of Pathology, 1995, pp 499-500

(10.) Rosai J: Ackerman's Surgical Pathology. St. Louis, CV Mosby, 8th Ed, 1996, p 1791

(11.) Singer JA, Plaut AG, Kaplan MM: Hepatic failure and death from erythropoietic protoporphyria. Gastroenterology 1978;74:588

(12.) Hastka D, Granick S: The occurrence and determination of delta-amino-levulinic acid and porphobilinogen in urine. J Biol Chem 1956; 219:435

TABLE 1. Outpatient Laboratory Values
                                         Date
Reference                      Range    10/96  12/96  3/17/97  3/22/97
WBC (x [10.sup.12]/L)        5.0-10.0     5.9   7.0     8.3     13.2
Hemoglobin (g/dL)            14.0-18.0   10.8  10.9    11.2     10.3
Hematocrit (%)               40.0-54.0   32.1  31.1    33.8     31.1
Platelets (x [10.sup.12]/L)   150-400      42    43      33      210 *
MCV (per fL)                   82-99     73.2  72.2    72.9     72.6
Ferritin (ng/mL)              15-200       50    -       -        -
Iron ([micro]g/dL)            45-150       36    -       -        -
TIBC ([micro]g/dL)            250-460     278    -       -        -
Iron S (%)                   20.0-55.0   12.9    -       -        -
Reference                    6/97  12/97    4/98  10/98
WBC (x [10.sup.12]/L)         9.5   10.7     9.1   9.0

Hemoglobin (g/dL)            15.7   15.6    16.7  16.7
Hematocrit (%)               47.6   46.4    50.2  48.5
Platelets Cx [10.sup.12]/L)   350    320     337   275
MCV (per fL)                 77.6   88.5    90.0  88.0
Ferritin (ng/mL)               38     75    68.9    -
Iron ([micro]g/dL)             81     95 +    45    -
TIBC ([micro]g/dL)            363    370     385    -
Iron S (%)                     -      -       -     -
(*) Post-splenectomy (3/21/97).
(+) Oral iron therapy stopped.
WBC = White blood cell count;
MCV = mean corpuscular volume;
TIBC = total iron-binding capacity;
S = saturation.
TABLE 2. Causes of Iron Deficiency Anemia
Hiatal hernia            Inflammatory bowel disease
Esophageal varices       Duodenitis
Gastritis                Intrahepatic bleeding
Peptic ulcer disease     Sprue (celiac disease)
Diverticulosis           Gastroenteritis
Hemorrhoids              Atrophic gastritis with
                         achlorhydria
Cholelithiasis           Malabsorption
Intravascular hemolysis  Genitourinary blood loss