ANATOMIC PATHOLOGY Original Article
Breast Carcinoma Diffusely Metastatic to the Spleen A Report of Two Cases Presenting as Idiopathic Thrombocytopenic Purpura O. W. CUMMINGS, M.D., AND MICHAEL T. MAZUR, M.D.
the cellular infiltrate. These cases show that idiopathic thrombocytopenic purpura may herald the presence of diffuse splenic metastases when metastatic disease is not otherwise clinically suspected. The lack of a discrete tumor mass in the spleen in such cases may make the diagnosis of metastatic carcinoma a challenge both clinically and pathologically. Immunohistochemical and electron microscopic examinations are useful to establish the appropriate diagnosis in such cases. (Key words: Breast; Carcinoma; Spleen; Metastases; Idiopathic thrombocytopenic purpura) Am J Clin Pathol 1992;97:484-489
Epithelial tumors metastatic to the spleen were once considered rare occurrences.'"4 However, several careful autopsy studies have shown that the spleen is involved by metastatic carcinoma in 6% to 13% of tumor cases.5"8 Splenic metastases tend to occur late in the course of disease, rarely produce clinical symptoms, and therefore are seldom seen by the surgical pathologist or the clinician. Idiopathic (immune) thrombocytopenic purpura (ITP) is an antibody-mediated disorder resulting in splenic sequestration of platelets and subsequent thrombocytopenia.9 Idiopathic thrombocytopenic purpura rarely has been noted in association with solid tumors.10 We report two unusual cases of patients with a known history of breast cancer in whom the signs and symptoms of ITP
subsequently developed. The thrombocytopenia was refractory to medical management and, at splenectomy, diffuse metastatic breast cancer was discovered in the spleen.
Received May 23, 1991; manuscript accepted for publication July 8, 1991. Dr. Mazur is affiliated with the State University of New York, Syracuse, New York. Address reprint requests Dr. Cummings: Department of Pathology, University Hospital 3465, Indiana University Medical Center, 926 West Michigan Street, Indianapolis, Indiana 46202.
Case 2
CLINICAL CASE REPORTS Case 1
The patient was a 46-year-old woman who underwent left mastectomy 6 years earlier for infiltrating ductal carcinoma. At that time she was found to have bone metastases and received chemotherapy with apparent clinical response. Five years later she was seen because of bleeding gums. Her platelet count was 45 X 109 /L, and it decreased to 26 X 10' /L during the next several weeks. Her hemoglobin level and hematocrit concentration were 119 g/L and 0.34, respectively. The white blood cell count was 3.7 X 109/L with a normal differential count. The peripheral blood smear was unremarkable. Bone scan, liver/spleen scan, and bone marrow biopsy were all negative for metastatic tumor. The spleen was From the Department of Pathology, Division of Surgical Pathology, not palpably enlarged. The thrombocytopenia was managed with plasUniversity ofAlabama at Birmingham, Birmingham, Alabama, and the mapheresis, prednisone, and vincristine without clinical response. Shortly Department of Pathology, Indiana University School of Medicine, In- after splenectomy, her platelet count increased to 500 X 109/L. dianapolis, Indiana.
484
The patient was a 59-year-old woman with a left breast mass, osteoblastic lesions involving the lower cervical, thoracic, and lumbosacral spine, and Stage IIA squamous cell carcinoma of the cervix. She had a right mastectomy 13 years earlier for "benign disease." She was treated by excisional left breast biopsy with subsequent thoracic and axial ra-
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Carcinoma metastatic to the spleen is found at autopsy in 6% to 13% of patients who die of cancer, yet clinical symptoms referable to splenic metastases are unusual. Two cases of breast carcinoma metastatic to the spleen discovered incidentally at therapeutic splenectomy for idiopathic thrombocytopenic purpura are described. On gross examination, the spleens were mildly enlarged with a homogeneous congested cut surface; rare 0.2-cm white nodules were present in one case. Microscopic examination revealed large, poorly cohesive cells that diffusely involved both the red and white pulp. Histochemical, immunohistochemical, and ultrastructural analyses confirmed the epithelial nature of
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Breast Carcinoma DiffuselyMetastatic to the Spleen
MATERIALS A N D METHODS
Tissues from both splenectomy specimens were fixed in 10% (w/v) formalin and embedded in paraffin. In addition to hematoxylin-and-eosin-stained sections, periodic acid-Schiff, with and without diastase predigestion, and mucicarmine stains also were performed. Formalinfixed tissue was postfixed in 4% (w/v) formaldehyde-1% (w/v) glutaraldehyde and processed in the standard manner for electron microscopic examination. Multiple ultrathin sections were cut from several blocks to insure adequate sampling and stained with uranyl acetate and lead citrate. The immunoperoxidase studies were performed on the paraffin-embedded tissue. Antibodies directed against the following antigens were used: cytokeratin (polyclonal, DAKO Corp., Carpenteria, CA: dilution, 1:200), epithelial membrane antigen (monoclonal, DAKO; dilution, 1:40), carcinoembryonic antigen (polyclonal, DAKO; dilution, 1:700), and tumor-associated glycoprotein-72 (B72.3, monoclonal, prediluted; Biomedical Technologies, Stoughton, MA). The antibodies were applied using the avidin-biotin peroxidase complex technique with the exception of anti-carcinoembryonic antigen, which was applied using the peroxidaseantiperoxidase technique. Appropriate positive and negative controls were tested simultaneously.
congested, but no nodules were identified (Fig. \A). The spleen in case 2 weighed 350 g and measured 13.5 X 9 X 4 cm. The splenic capsule was smooth, tense, and intact. The parenchyma was dark red-purple with prominent white pulp. The organ contained several small yellowwhite nodules measuring up to 0.2 cm in diameter (Fig. IB). Microscopic Observations Poorly differentiated adenocarcinoma diffusely involved the red and white pulp in both cases. The white pulp was extensively effaced with only rare periarterial lymphoid aggregates, none of which contained germinal centers. Isolated neoplastic cells invaded these lymphoid aggregates (Fig. 2A). In both cases, the neoplastic cells focally coalesced into nodules (Fig. IB), producing a gross appearance similar to prominent white pulp. This phenomenon was much more pronounced in case 2. The red pulp was diffusely effaced by congestion and a tumor infiltrate, making differentiation of cords from sinuses difficult. The tumor cells invaded as single discohesive cells and small linear collections within the red pulp (Fig. 2A). The tumor cells had large, round-to-oval nuclei with vesicular chromatin and uniform nuclear membranes. Most
RESULTS B
Gross Observations The spleen from case 1 was uniformly enlarged and weighed 505 g. The splenic capsule was smooth and intact. The cut surface was a diffuse dark, red-brown color. The white pulp appeared unremarkable. The red pulp was
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FIGS. 1A & IB. (A) Case l. Spleen showing preservation of white pulp and congestion. (5) Case 2. Spleen with apparent white pulp accentuation and a nodule (right tip).
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diotherapy. The uterine lesion was treated by intracavitary radiotherapy. Her platelet count was 172 X 109/L and hematocrit concentration was 0.31 at this time. She did well after therapy but 6 months later her platelet count decreased to 46 X 109/L and it slowly decreased to 8 X 109/L during a 5-month period. At that time, her hematocrit concentration was 0.08, mean corpuscular volume was 105 fL, and white blood cell count was 3.6 X 109/L with a normal differential count. A peripheral blood smear showed rare schistocytes, an occasional nucleated red blood cell, and scattered Howell-Jolly bodies. Results of direct and indirect Coombs tests were negative. She had a coagulation disorder that showed features of lupus-like anticoagulant. Her fibrin split products were within normal limits with a negative anti-nuclear antibody and a nonreactive syphilis serology. Carcinoembryonic antigen was 187 mg/L. Antiplatelet antibody titers were greater than 1:1,000. A computed tomographic study showed a minimally enlarged spleen without apparent tumor and no masses in the lung, liver, kidneys, pancreas, or adrenal glands. Bone marrow biopsy showed extensive metastatic carcinoma, but megakaryocytes were present. The clinical diagnosis of ITP was made. The thrombocytopenia was unresponsive to steroids, danazol, vincristine, and gamma-globulin and she underwent therapeutic splenectomy. After splenectomy, her platelet count rose to 167 X 109/L.
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FIGS. 2A-2D. (A) Neoplastic cells scattered diffusely within congested red pulp. A rare periarteriolar lymphoid cuffis present in upper left (hematoxylin and eosin, XlOO). (B) Neoplastic cells coalescing into a nodule (hematoxylin and eosin, XlOO). (C) Large discohesive cells with vesicular nuclei encroaching on white pulp (left). Occasional mitoticfigures(arrow) are present (hematoxylin and eosin, X400). (D) Intense cytoplasmic staining of tumor cells with EMA (Avidin-biotin peroxidase complex, XlOO).
nuclei had a single prominent nucleolus. Mitotic figures were identified easily (Fig. 2C). The cytoplasm was eosinophilic and varied from scant to abundant with scattered cells showing clear cytoplasmic vacuoles. Scattered macrophages contained hemosiderin but foamy macrophages were scant. There was no evidence of extramedullary hematopoiesis or a desmoplastic stromal response. Some cells in both cases contained cytoplasmic epithelial mucin.
Immunoperoxidase
Observations
In both cases the neoplastic cells showed cytoplasmic staining for keratin, epithelial membrane antigen (Fig. 2D), and tumor-associated glycoprotein-72. Immunostaining for keratin was diffuse and of mild to moderate intensity in both cases. Case 1 showed intense staining of many cells for epithelial membrane antigen but only focal
A.J.C.P. • April 1992
CUMMINGS AND MAZUR Breast Carcinoma Diffusely Metastatic to the Spleen and weak reactivity for TAG-72. Case 2, in contrast, showed weak and focal staining for epithelial membrane antigen but diffuse, strong reactivity for TAG-72. Neither case reacted with carcinoembryonic antigen. Ultrastructural
Observations
DISCUSSION With these two cases, we report the unusual association of ITP with diffuse, clinically unsuspected, splenic metastases. Both patients had histories of mammary carcinoma, one with metastases clinically confined to the axial skeleton, but no evidence of disease at other sites. Both had ITP, refractory to medical intervention, that was managed by therapeutic splenectomy. Only after pathologic examination of the spleen was the extent of metastatic disease recognized. In the 19th century, carcinomas metastatic to the spleen were thought to be rare.1"4 Paget' examined 735 breast cancer patients at necropsy and found 241 with liver metastases but only 17 (2%) with splenic metastases. However, he did not examine the spleens microscopically, and, with the advent of more careful scrutiny, metastases were more commonly found. Berge6 showed the spleen to be involved by metastases in 7% of all cancer cases and the 10th most common organ involved by metastasis. In that study, patients with breast cancer showed splenic metastasis in 12% of cases. Multiple autopsy studies5"8
FIG. 3. Two atypical cells within an endothelial lined space. The larger cell shows a prominent intracytoplasmic lumen (Uranyl acetate-lead citrate, X6.000).
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The epithelial cell nuclei were large, two to three times the size of adjacent lymphoid nuclei, and generally roundto-oval shaped, although some had an irregular and convoluted outline. The chromatin was finely dispersed, and large, irregularly shaped nucleoli were present along the nuclear membrane. The cytoplasm was primitive, containing mitochondria and scattered bundles of intermediate filaments. Several cells contained intracytoplasmic lumina lined by microvilli. In some cells, the intracytoplasmic lumina were small, multiple, and surrounded by many clear vacuoles, whereas in other cells these lumina were single and occupied most of the cytoplasmic volume. Most cells were widely separated or clumped into small clusters of two or three cells (Fig. 3) and primitive cell junctions were present.
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The two cases of this report also illustrate that splenic metastases can be difficult to detect by light microscopic examination. In case 2, the rare tumor nodules drew attention to the diffusely scattered individual neoplastic cells. However, in case 1, many tumor cells resembled histiocytes, giving the impression of a reactive process such as fibrocongestive splenomegaly.13 Although rare cells were positive for mucin, immunoperoxidase staining highlighted the true extent of metastatic disease. Each case showed a somewhat different pattern of immunostaining. Epithelial membrane antigen staining was more diffuse and intense in case 1, whereas TAG-72 was more widely expressed in case 2. Ultrastructural examination showed the presence of rare cell junctions and intracytoplasmic lumens confirmed the epithelial nature of the lesion. The results emphasize the utility of immunohistochemical panels and electron microscopic examination in detecting and specifically categorizing unsuspected splenic disease. Splenic metastases, although not uncommon at autopsy, tend to occur late in the disease process and as such rarely produce unique clinical symptoms. Klein and associates14 studied four patients with clinical signs and symptoms related to histologically confirmed splenic metastases from primary tumors of endometrium (two), lung, and skin (melanoma). The most common clinical manifestations included left upper quadrant pain and/or splenic mass effect. Multiple case reports'5"21 of clinically detected splenic metastases confirmed those findings,
adding rupture and incidental discovery as other modes of presentation. Platelet counts were either normal or not reported in these articles. Idiopathic thrombocytopenic purpura 9 is a relatively common disorder that predominantly affects middle-aged women. It is an immune process characterized by thrombocytopenia, high titers of antiplatelet antibodies, normal numbers of marrow megakaryocytes, no evidence of active coagulation, and a clinically normal-sized spleen. Antiplatelet antibodies are produced primarily in the spleen and coat the platelets.22 These opsinized platelets are removed from circulation by the reticuloendothelial system, primarily the spleen. The factors associated with the induction of ITP are diverse and include connective tissue disease, lymphoproliferative disorders, drug reactions, and postinfectious syndromes. Often the inciting factor is unknown. Pathologically, the spleens are usually of normal size, and with microscopic examination show follicular lymphoid hyperplasia (unless treated with prednisone) and collections of sinusoidal foamy macrophages.23 Case 1 exhibited virtually all the clinical parameters of ITP. However, it might be argued that case 2 represented hypersplenism24 or microangiopathic hemolytic anemia25 rather than ITP. Although there is certain validity to that point, the clinical diagnosis of ITP was rendered because of the normal-sized spleen and the high antiplatelet antibody titers. Although patients with metastatic solid tumors often have thrombocytopenia, it is usually due to bone marrow suppression (metastatic tumor, chemotherapy) rather than ITP. Schwartz and associates10 studied eight patients with solid tumors, including one with breast cancer, associated with clinical ITP. Most patients responded to prednisone therapy and splenic metastases were not documented in any case. Idiopathic thrombocytopenia purpura associated with splenic metastases appears, to be very rare. Only two similar case reports appear in the literature. One reported case24 had some features similar to the two currently reported cases. This patient also had metastatic breast cancer that diffusely infiltrated the spleen associated with thrombocytopenia, which responded to splenectomy. In that case, however, the hematologic disorder was attributed to hypersplenism rather than ITP, a conclusion supported by massive splenomegaly (1800 g), transfusion-dependent anemia, erythroblasts in the peripheral blood, and extensive splenic extramedullary hematopoiesis. These features are not present, or only minimally so, in the current cases. Similarly, Edwards and Al-Kaisi26 reported a case of adenocarcinoma of unknown primary origin that was diffusely metastatic to the spleen. This patient, however, had signs and symptoms of thrombotic thrombocytopenic purpura.
A.J.C.P.-April 1992
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have determined the true incidence of splenic metastasis to be 6% to 13%. In autopsy studies of splenic metastases, the organ often shows obvious tumor nodules, with only moderate organomegaly, similar to metastases in any other site. However, in 30% to 50% of cases,3,8,9 the spleen is grossly unremarkable, and only with histologic study is carcinoma detected. Kettle" emphasized this point in 1913 when he reported three cases of breast cancer metastatic to the spleen, two of which were detected only with microscopic examination. In a careful study by Marymont and Gross,12 splenic metastasis were noted only with microscopic examination in one third of their cases. They subclassified these into five separate histologic groups based on which microanatomic splenic compartment was involved by tumor. The current cases would be classified within Group V, "tumor in several different elements of the spleen," which accounted for 12.8% of splenic metastases in Marymont and Gross's study. Clinical data were not evaluated in this report nor was the type of metastatic cancer reported. The two currently reported cases reinforce the findings of these previous studies, that a grossly unremarkable spleen may harbor diffuse metastatic cancer, and they emphasize the importance of careful microscopic examination of the spleen.
CUMMINGS AND MAZUR Breast Carcinoma Diffusely Metastatic to the Spleen
REFERENCES 1. Paget S. The distribution of secondary growths in cancer of the breast. Lancet 1889:571-573. 2. Herbut PA, Gabriel FR. Secondary cancer of the spleen. Arch Pathol 1942;33:917-921. 3. Warren S, Davis AH. Studies of tumor metastasis. V. The metastases of carcinoma to the spleen. Am J Cancer 1934;21:517-533. 4. Hirst AE, Bullock WK. Metastatic carcinoma of the spleen. Am J MedSci 1952;223:414-417. 5. Abrams HL, Spiro R, Goldstein N. Metastases in carcinoma. Cancer 1950;3:74-85. 6. Berge T. Splenic metastases. Acta Path Microbiol Scand Sect A 1974;82:499-506. 7. Harmon JW, Dacorso P. Spread of carcinoma to the spleen. Arch Pathol 1948;45:179-186.
8. Goldberg GM. Metastatic carcinoma of the spleen resulting from lymphogenic spread. Lab Invest 1957;6:383-388. 9. McMillan R. Immune thrombocytopenia. Clin in Haematol 1983; 12: 69-88. 10. Schwartz KA, Slichter SJ, Harker LA. Immune-mediated platelet destruction and thrombocytopenia in patients with solid tumors. Br J Haematol 1982;51:17-24. 11. Kettle EH. Carcinomatous metastases in the spleen. J Pathol Bacteriol 1913;17:40-46. 12. Marymont JH, Gross S. Patterns of metastatic cancer to the spleen. Am J Clin Pathol 1963;40:58-66. 13. Wolf BC, Neiman RS. Disorders of the Spleen (Major Problems in Pathology; Vol. 20) Philadelphia: WB Saunders, 1989, pp 181182. 14. Klein B, Stein M, Kuten A, et al. Splenomegaly and solitary spleen metastasis in solid tumors. Cancer 1987;60:100-102. 15. Morganstern L, Rosenberg J, Geller S. Tumors of the spleen. World J Surg 1985;9:468-476. 16. Dunbar WH, Beahrs OH, Morlock CG. Solitary splenic metastasis incidental to rectal carcinoma. Mayo Clin Proc 1969;44:40-45. 17. Slavin JD, Mathews J, Spencer RP. Splenectomy for splenic metastasis from carcinoma of the colon. Clin Nuc Med 1986; 11:491492. 18. Glezerman M, Yanai-Inbar I, Charuz I, et al. Involvement of the spleen in ovarian adenosquamous carcinoma. Gynecol Oncol 1988;30:143-148. 19. Al-Obaidi SM. Spontaneous rupture of the spleen due to metastatic carcinoma. Br J Clin Pathol 1989;43:385-386. 20. Horie Y, Shou T, Hirayama C, Nagasako R. Spontaneous rupture of the spleen secondary to metastatic hepatocellular Carcinoma. Am J Gastro 1982;77:882-884. 21. Jorgensen LN, Chrintz H. Solitary metastatic endometrial carcinoma of the spleen. Acta Obstet Gynecol Scand 1988;67:91-92. 22. Jandl JH. Blood. Boston: Little, Brown & Company, 1987, pp 10521067. 23. Tavassoli M, McMillan R. The structure of the spleen in idiopathic throbocytopic purpura. Am J Clin Pathol 1975;64:180-191. 24. Dunn MA, Goldwin MI. Hypersplenism in advanced breast cancer: Report of a patient treated with splenectomy. Cancer I975;35: 1149-1452. 25. Antman KH, Skarin AT, Mayer RJ, et al. Microangiopathic hemolytic anemia and cancer. Medicine 1979;58:377-383. 26. Edwards RC, Al-Kaisi N. Metastatic adenocarcinoma involving the spleen, presenting as thrombotic thrombocytopenic purpura. American Society of Clinical Pathology, check sample no. AP 90-6 (AP-198).
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The mechanism for the development of ITP in our two cases is unclear. Tissue samples of the primary breast carcinomas were not available for review, but they were both described as usual invasive ductal carcinomas. It is unlikely that these cases represent a peculiar subtype of breast cancer that is more likely to be associated with thrombocytopenia. Whatever the interaction is between the spleen, tumor, and platelets in these cases, it is most unusual. Splenic metastases in patients with widely disseminated carcinoma are not uncommon. However, splenic metastases are rarely associated with clinical symptoms. These two cases illustrate that splenic metastases can manifest clinically as ITP and that splenectomy can produce dramatic improvement in the platelet count. The diffuse infiltrative pattern may make the metastases unsuspected with clinical and pathologic examinations. Identification and study of additional cases of splenic metastases associated with ITP may help elucidate the mechanism of thrombocytopenia in these cases.
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Breast Carcinoma Diffusely Metastatic to the Spleen A Report of Two Cases Presenting as Idiopathic Thrombocytopenic Purpura O. W. CUMMINGS, M.D., AND MICHAEL T. MAZUR, M.D.
the cellular infiltrate. These cases show that idiopathic thrombocytopenic purpura may herald the presence of diffuse splenic metastases when metastatic disease is not otherwise clinically suspected. The lack of a discrete tumor mass in the spleen in such cases may make the diagnosis of metastatic carcinoma a challenge both clinically and pathologically. Immunohistochemical and electron microscopic examinations are useful to establish the appropriate diagnosis in such cases. (Key words: Breast; Carcinoma; Spleen; Metastases; Idiopathic thrombocytopenic purpura) Am J Clin Pathol 1992;97:484-489
Epithelial tumors metastatic to the spleen were once considered rare occurrences.'"4 However, several careful autopsy studies have shown that the spleen is involved by metastatic carcinoma in 6% to 13% of tumor cases.5"8 Splenic metastases tend to occur late in the course of disease, rarely produce clinical symptoms, and therefore are seldom seen by the surgical pathologist or the clinician. Idiopathic (immune) thrombocytopenic purpura (ITP) is an antibody-mediated disorder resulting in splenic sequestration of platelets and subsequent thrombocytopenia.9 Idiopathic thrombocytopenic purpura rarely has been noted in association with solid tumors.10 We report two unusual cases of patients with a known history of breast cancer in whom the signs and symptoms of ITP
subsequently developed. The thrombocytopenia was refractory to medical management and, at splenectomy, diffuse metastatic breast cancer was discovered in the spleen.
Received May 23, 1991; manuscript accepted for publication July 8, 1991. Dr. Mazur is affiliated with the State University of New York, Syracuse, New York. Address reprint requests Dr. Cummings: Department of Pathology, University Hospital 3465, Indiana University Medical Center, 926 West Michigan Street, Indianapolis, Indiana 46202.
Case 2
CLINICAL CASE REPORTS Case 1
The patient was a 46-year-old woman who underwent left mastectomy 6 years earlier for infiltrating ductal carcinoma. At that time she was found to have bone metastases and received chemotherapy with apparent clinical response. Five years later she was seen because of bleeding gums. Her platelet count was 45 X 109 /L, and it decreased to 26 X 10' /L during the next several weeks. Her hemoglobin level and hematocrit concentration were 119 g/L and 0.34, respectively. The white blood cell count was 3.7 X 109/L with a normal differential count. The peripheral blood smear was unremarkable. Bone scan, liver/spleen scan, and bone marrow biopsy were all negative for metastatic tumor. The spleen was From the Department of Pathology, Division of Surgical Pathology, not palpably enlarged. The thrombocytopenia was managed with plasUniversity ofAlabama at Birmingham, Birmingham, Alabama, and the mapheresis, prednisone, and vincristine without clinical response. Shortly Department of Pathology, Indiana University School of Medicine, In- after splenectomy, her platelet count increased to 500 X 109/L. dianapolis, Indiana.
484
The patient was a 59-year-old woman with a left breast mass, osteoblastic lesions involving the lower cervical, thoracic, and lumbosacral spine, and Stage IIA squamous cell carcinoma of the cervix. She had a right mastectomy 13 years earlier for "benign disease." She was treated by excisional left breast biopsy with subsequent thoracic and axial ra-
Downloaded from http://ajcp.oxfordjournals.org/ by guest on June 7, 2016
Carcinoma metastatic to the spleen is found at autopsy in 6% to 13% of patients who die of cancer, yet clinical symptoms referable to splenic metastases are unusual. Two cases of breast carcinoma metastatic to the spleen discovered incidentally at therapeutic splenectomy for idiopathic thrombocytopenic purpura are described. On gross examination, the spleens were mildly enlarged with a homogeneous congested cut surface; rare 0.2-cm white nodules were present in one case. Microscopic examination revealed large, poorly cohesive cells that diffusely involved both the red and white pulp. Histochemical, immunohistochemical, and ultrastructural analyses confirmed the epithelial nature of
CUMMINGS AND MAZUR
485
Breast Carcinoma DiffuselyMetastatic to the Spleen
MATERIALS A N D METHODS
Tissues from both splenectomy specimens were fixed in 10% (w/v) formalin and embedded in paraffin. In addition to hematoxylin-and-eosin-stained sections, periodic acid-Schiff, with and without diastase predigestion, and mucicarmine stains also were performed. Formalinfixed tissue was postfixed in 4% (w/v) formaldehyde-1% (w/v) glutaraldehyde and processed in the standard manner for electron microscopic examination. Multiple ultrathin sections were cut from several blocks to insure adequate sampling and stained with uranyl acetate and lead citrate. The immunoperoxidase studies were performed on the paraffin-embedded tissue. Antibodies directed against the following antigens were used: cytokeratin (polyclonal, DAKO Corp., Carpenteria, CA: dilution, 1:200), epithelial membrane antigen (monoclonal, DAKO; dilution, 1:40), carcinoembryonic antigen (polyclonal, DAKO; dilution, 1:700), and tumor-associated glycoprotein-72 (B72.3, monoclonal, prediluted; Biomedical Technologies, Stoughton, MA). The antibodies were applied using the avidin-biotin peroxidase complex technique with the exception of anti-carcinoembryonic antigen, which was applied using the peroxidaseantiperoxidase technique. Appropriate positive and negative controls were tested simultaneously.
congested, but no nodules were identified (Fig. \A). The spleen in case 2 weighed 350 g and measured 13.5 X 9 X 4 cm. The splenic capsule was smooth, tense, and intact. The parenchyma was dark red-purple with prominent white pulp. The organ contained several small yellowwhite nodules measuring up to 0.2 cm in diameter (Fig. IB). Microscopic Observations Poorly differentiated adenocarcinoma diffusely involved the red and white pulp in both cases. The white pulp was extensively effaced with only rare periarterial lymphoid aggregates, none of which contained germinal centers. Isolated neoplastic cells invaded these lymphoid aggregates (Fig. 2A). In both cases, the neoplastic cells focally coalesced into nodules (Fig. IB), producing a gross appearance similar to prominent white pulp. This phenomenon was much more pronounced in case 2. The red pulp was diffusely effaced by congestion and a tumor infiltrate, making differentiation of cords from sinuses difficult. The tumor cells invaded as single discohesive cells and small linear collections within the red pulp (Fig. 2A). The tumor cells had large, round-to-oval nuclei with vesicular chromatin and uniform nuclear membranes. Most
RESULTS B
Gross Observations The spleen from case 1 was uniformly enlarged and weighed 505 g. The splenic capsule was smooth and intact. The cut surface was a diffuse dark, red-brown color. The white pulp appeared unremarkable. The red pulp was
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FIGS. 1A & IB. (A) Case l. Spleen showing preservation of white pulp and congestion. (5) Case 2. Spleen with apparent white pulp accentuation and a nodule (right tip).
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diotherapy. The uterine lesion was treated by intracavitary radiotherapy. Her platelet count was 172 X 109/L and hematocrit concentration was 0.31 at this time. She did well after therapy but 6 months later her platelet count decreased to 46 X 109/L and it slowly decreased to 8 X 109/L during a 5-month period. At that time, her hematocrit concentration was 0.08, mean corpuscular volume was 105 fL, and white blood cell count was 3.6 X 109/L with a normal differential count. A peripheral blood smear showed rare schistocytes, an occasional nucleated red blood cell, and scattered Howell-Jolly bodies. Results of direct and indirect Coombs tests were negative. She had a coagulation disorder that showed features of lupus-like anticoagulant. Her fibrin split products were within normal limits with a negative anti-nuclear antibody and a nonreactive syphilis serology. Carcinoembryonic antigen was 187 mg/L. Antiplatelet antibody titers were greater than 1:1,000. A computed tomographic study showed a minimally enlarged spleen without apparent tumor and no masses in the lung, liver, kidneys, pancreas, or adrenal glands. Bone marrow biopsy showed extensive metastatic carcinoma, but megakaryocytes were present. The clinical diagnosis of ITP was made. The thrombocytopenia was unresponsive to steroids, danazol, vincristine, and gamma-globulin and she underwent therapeutic splenectomy. After splenectomy, her platelet count rose to 167 X 109/L.
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FIGS. 2A-2D. (A) Neoplastic cells scattered diffusely within congested red pulp. A rare periarteriolar lymphoid cuffis present in upper left (hematoxylin and eosin, XlOO). (B) Neoplastic cells coalescing into a nodule (hematoxylin and eosin, XlOO). (C) Large discohesive cells with vesicular nuclei encroaching on white pulp (left). Occasional mitoticfigures(arrow) are present (hematoxylin and eosin, X400). (D) Intense cytoplasmic staining of tumor cells with EMA (Avidin-biotin peroxidase complex, XlOO).
nuclei had a single prominent nucleolus. Mitotic figures were identified easily (Fig. 2C). The cytoplasm was eosinophilic and varied from scant to abundant with scattered cells showing clear cytoplasmic vacuoles. Scattered macrophages contained hemosiderin but foamy macrophages were scant. There was no evidence of extramedullary hematopoiesis or a desmoplastic stromal response. Some cells in both cases contained cytoplasmic epithelial mucin.
Immunoperoxidase
Observations
In both cases the neoplastic cells showed cytoplasmic staining for keratin, epithelial membrane antigen (Fig. 2D), and tumor-associated glycoprotein-72. Immunostaining for keratin was diffuse and of mild to moderate intensity in both cases. Case 1 showed intense staining of many cells for epithelial membrane antigen but only focal
A.J.C.P. • April 1992
CUMMINGS AND MAZUR Breast Carcinoma Diffusely Metastatic to the Spleen and weak reactivity for TAG-72. Case 2, in contrast, showed weak and focal staining for epithelial membrane antigen but diffuse, strong reactivity for TAG-72. Neither case reacted with carcinoembryonic antigen. Ultrastructural
Observations
DISCUSSION With these two cases, we report the unusual association of ITP with diffuse, clinically unsuspected, splenic metastases. Both patients had histories of mammary carcinoma, one with metastases clinically confined to the axial skeleton, but no evidence of disease at other sites. Both had ITP, refractory to medical intervention, that was managed by therapeutic splenectomy. Only after pathologic examination of the spleen was the extent of metastatic disease recognized. In the 19th century, carcinomas metastatic to the spleen were thought to be rare.1"4 Paget' examined 735 breast cancer patients at necropsy and found 241 with liver metastases but only 17 (2%) with splenic metastases. However, he did not examine the spleens microscopically, and, with the advent of more careful scrutiny, metastases were more commonly found. Berge6 showed the spleen to be involved by metastases in 7% of all cancer cases and the 10th most common organ involved by metastasis. In that study, patients with breast cancer showed splenic metastasis in 12% of cases. Multiple autopsy studies5"8
FIG. 3. Two atypical cells within an endothelial lined space. The larger cell shows a prominent intracytoplasmic lumen (Uranyl acetate-lead citrate, X6.000).
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The epithelial cell nuclei were large, two to three times the size of adjacent lymphoid nuclei, and generally roundto-oval shaped, although some had an irregular and convoluted outline. The chromatin was finely dispersed, and large, irregularly shaped nucleoli were present along the nuclear membrane. The cytoplasm was primitive, containing mitochondria and scattered bundles of intermediate filaments. Several cells contained intracytoplasmic lumina lined by microvilli. In some cells, the intracytoplasmic lumina were small, multiple, and surrounded by many clear vacuoles, whereas in other cells these lumina were single and occupied most of the cytoplasmic volume. Most cells were widely separated or clumped into small clusters of two or three cells (Fig. 3) and primitive cell junctions were present.
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ANATOMIC PATHOLOGY Original Article
The two cases of this report also illustrate that splenic metastases can be difficult to detect by light microscopic examination. In case 2, the rare tumor nodules drew attention to the diffusely scattered individual neoplastic cells. However, in case 1, many tumor cells resembled histiocytes, giving the impression of a reactive process such as fibrocongestive splenomegaly.13 Although rare cells were positive for mucin, immunoperoxidase staining highlighted the true extent of metastatic disease. Each case showed a somewhat different pattern of immunostaining. Epithelial membrane antigen staining was more diffuse and intense in case 1, whereas TAG-72 was more widely expressed in case 2. Ultrastructural examination showed the presence of rare cell junctions and intracytoplasmic lumens confirmed the epithelial nature of the lesion. The results emphasize the utility of immunohistochemical panels and electron microscopic examination in detecting and specifically categorizing unsuspected splenic disease. Splenic metastases, although not uncommon at autopsy, tend to occur late in the disease process and as such rarely produce unique clinical symptoms. Klein and associates14 studied four patients with clinical signs and symptoms related to histologically confirmed splenic metastases from primary tumors of endometrium (two), lung, and skin (melanoma). The most common clinical manifestations included left upper quadrant pain and/or splenic mass effect. Multiple case reports'5"21 of clinically detected splenic metastases confirmed those findings,
adding rupture and incidental discovery as other modes of presentation. Platelet counts were either normal or not reported in these articles. Idiopathic thrombocytopenic purpura 9 is a relatively common disorder that predominantly affects middle-aged women. It is an immune process characterized by thrombocytopenia, high titers of antiplatelet antibodies, normal numbers of marrow megakaryocytes, no evidence of active coagulation, and a clinically normal-sized spleen. Antiplatelet antibodies are produced primarily in the spleen and coat the platelets.22 These opsinized platelets are removed from circulation by the reticuloendothelial system, primarily the spleen. The factors associated with the induction of ITP are diverse and include connective tissue disease, lymphoproliferative disorders, drug reactions, and postinfectious syndromes. Often the inciting factor is unknown. Pathologically, the spleens are usually of normal size, and with microscopic examination show follicular lymphoid hyperplasia (unless treated with prednisone) and collections of sinusoidal foamy macrophages.23 Case 1 exhibited virtually all the clinical parameters of ITP. However, it might be argued that case 2 represented hypersplenism24 or microangiopathic hemolytic anemia25 rather than ITP. Although there is certain validity to that point, the clinical diagnosis of ITP was rendered because of the normal-sized spleen and the high antiplatelet antibody titers. Although patients with metastatic solid tumors often have thrombocytopenia, it is usually due to bone marrow suppression (metastatic tumor, chemotherapy) rather than ITP. Schwartz and associates10 studied eight patients with solid tumors, including one with breast cancer, associated with clinical ITP. Most patients responded to prednisone therapy and splenic metastases were not documented in any case. Idiopathic thrombocytopenia purpura associated with splenic metastases appears, to be very rare. Only two similar case reports appear in the literature. One reported case24 had some features similar to the two currently reported cases. This patient also had metastatic breast cancer that diffusely infiltrated the spleen associated with thrombocytopenia, which responded to splenectomy. In that case, however, the hematologic disorder was attributed to hypersplenism rather than ITP, a conclusion supported by massive splenomegaly (1800 g), transfusion-dependent anemia, erythroblasts in the peripheral blood, and extensive splenic extramedullary hematopoiesis. These features are not present, or only minimally so, in the current cases. Similarly, Edwards and Al-Kaisi26 reported a case of adenocarcinoma of unknown primary origin that was diffusely metastatic to the spleen. This patient, however, had signs and symptoms of thrombotic thrombocytopenic purpura.
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have determined the true incidence of splenic metastasis to be 6% to 13%. In autopsy studies of splenic metastases, the organ often shows obvious tumor nodules, with only moderate organomegaly, similar to metastases in any other site. However, in 30% to 50% of cases,3,8,9 the spleen is grossly unremarkable, and only with histologic study is carcinoma detected. Kettle" emphasized this point in 1913 when he reported three cases of breast cancer metastatic to the spleen, two of which were detected only with microscopic examination. In a careful study by Marymont and Gross,12 splenic metastasis were noted only with microscopic examination in one third of their cases. They subclassified these into five separate histologic groups based on which microanatomic splenic compartment was involved by tumor. The current cases would be classified within Group V, "tumor in several different elements of the spleen," which accounted for 12.8% of splenic metastases in Marymont and Gross's study. Clinical data were not evaluated in this report nor was the type of metastatic cancer reported. The two currently reported cases reinforce the findings of these previous studies, that a grossly unremarkable spleen may harbor diffuse metastatic cancer, and they emphasize the importance of careful microscopic examination of the spleen.
CUMMINGS AND MAZUR Breast Carcinoma Diffusely Metastatic to the Spleen
REFERENCES 1. Paget S. The distribution of secondary growths in cancer of the breast. Lancet 1889:571-573. 2. Herbut PA, Gabriel FR. Secondary cancer of the spleen. Arch Pathol 1942;33:917-921. 3. Warren S, Davis AH. Studies of tumor metastasis. V. The metastases of carcinoma to the spleen. Am J Cancer 1934;21:517-533. 4. Hirst AE, Bullock WK. Metastatic carcinoma of the spleen. Am J MedSci 1952;223:414-417. 5. Abrams HL, Spiro R, Goldstein N. Metastases in carcinoma. Cancer 1950;3:74-85. 6. Berge T. Splenic metastases. Acta Path Microbiol Scand Sect A 1974;82:499-506. 7. Harmon JW, Dacorso P. Spread of carcinoma to the spleen. Arch Pathol 1948;45:179-186.
8. Goldberg GM. Metastatic carcinoma of the spleen resulting from lymphogenic spread. Lab Invest 1957;6:383-388. 9. McMillan R. Immune thrombocytopenia. Clin in Haematol 1983; 12: 69-88. 10. Schwartz KA, Slichter SJ, Harker LA. Immune-mediated platelet destruction and thrombocytopenia in patients with solid tumors. Br J Haematol 1982;51:17-24. 11. Kettle EH. Carcinomatous metastases in the spleen. J Pathol Bacteriol 1913;17:40-46. 12. Marymont JH, Gross S. Patterns of metastatic cancer to the spleen. Am J Clin Pathol 1963;40:58-66. 13. Wolf BC, Neiman RS. Disorders of the Spleen (Major Problems in Pathology; Vol. 20) Philadelphia: WB Saunders, 1989, pp 181182. 14. Klein B, Stein M, Kuten A, et al. Splenomegaly and solitary spleen metastasis in solid tumors. Cancer 1987;60:100-102. 15. Morganstern L, Rosenberg J, Geller S. Tumors of the spleen. World J Surg 1985;9:468-476. 16. Dunbar WH, Beahrs OH, Morlock CG. Solitary splenic metastasis incidental to rectal carcinoma. Mayo Clin Proc 1969;44:40-45. 17. Slavin JD, Mathews J, Spencer RP. Splenectomy for splenic metastasis from carcinoma of the colon. Clin Nuc Med 1986; 11:491492. 18. Glezerman M, Yanai-Inbar I, Charuz I, et al. Involvement of the spleen in ovarian adenosquamous carcinoma. Gynecol Oncol 1988;30:143-148. 19. Al-Obaidi SM. Spontaneous rupture of the spleen due to metastatic carcinoma. Br J Clin Pathol 1989;43:385-386. 20. Horie Y, Shou T, Hirayama C, Nagasako R. Spontaneous rupture of the spleen secondary to metastatic hepatocellular Carcinoma. Am J Gastro 1982;77:882-884. 21. Jorgensen LN, Chrintz H. Solitary metastatic endometrial carcinoma of the spleen. Acta Obstet Gynecol Scand 1988;67:91-92. 22. Jandl JH. Blood. Boston: Little, Brown & Company, 1987, pp 10521067. 23. Tavassoli M, McMillan R. The structure of the spleen in idiopathic throbocytopic purpura. Am J Clin Pathol 1975;64:180-191. 24. Dunn MA, Goldwin MI. Hypersplenism in advanced breast cancer: Report of a patient treated with splenectomy. Cancer I975;35: 1149-1452. 25. Antman KH, Skarin AT, Mayer RJ, et al. Microangiopathic hemolytic anemia and cancer. Medicine 1979;58:377-383. 26. Edwards RC, Al-Kaisi N. Metastatic adenocarcinoma involving the spleen, presenting as thrombotic thrombocytopenic purpura. American Society of Clinical Pathology, check sample no. AP 90-6 (AP-198).
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The mechanism for the development of ITP in our two cases is unclear. Tissue samples of the primary breast carcinomas were not available for review, but they were both described as usual invasive ductal carcinomas. It is unlikely that these cases represent a peculiar subtype of breast cancer that is more likely to be associated with thrombocytopenia. Whatever the interaction is between the spleen, tumor, and platelets in these cases, it is most unusual. Splenic metastases in patients with widely disseminated carcinoma are not uncommon. However, splenic metastases are rarely associated with clinical symptoms. These two cases illustrate that splenic metastases can manifest clinically as ITP and that splenectomy can produce dramatic improvement in the platelet count. The diffuse infiltrative pattern may make the metastases unsuspected with clinical and pathologic examinations. Identification and study of additional cases of splenic metastases associated with ITP may help elucidate the mechanism of thrombocytopenia in these cases.
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