—  SPECIALTY CONFERENCE  —

Cardiovascular Pathology

Case 4 - Lesion of Aggregated Monocytes and Mesothelial Cells (LAMM)

Henry Tazelaar
Mayo Clinic
Rochester, MN


Click on each slide thumbnail image for an enlarged view
Clinical History
An 80 year-old man with a history of prostate cancer presented with fatigue and dysuria. He was found to have a urinary tract infection and was treated with antibiotics. One month later he developed chills, sweats and cough. He also had been noticing some mild right-sided weakness. A work up revealed another urinary tract infection and a large vegetation on the atrial side of the anterior leaflet of the mitral valve, which in addition was moderate to severely regurgitant. Blood cultures grew out Streptococcus agalactiae. He underwent valve replacement and at the time of surgery was diagnosed with mitral valve prolapse and vegetations as described above. Two specimens were submitted to surgical pathology: a myxomatous valve with a focus of subacute endocarditis and separate "yellow to white purulent appearing "vegetation" measuring 2.5 x 2.0 x 0.2 cm. Sections are from this latter specimen.


Case 4 - Figure 1 - "Vegetation from" mitral valve. Note vacuoles and focus of dense connective tissue (x 20)
Case 4 - Figure 2 - The "vegetation" is composed predominantly of oval to round cells with abundant pink cytoplasm (x 40)
Case 4 - Figure 3 - Interspersed among the round cells are clusters and strips of columnar cells, some of which have prominent nucleoli (x 200)



Case 4 - Figure 4 - The columnar cells are reactive with antibodies to CK 5/6 (x 400)
Case 4 - Figure 5 - The round cells are reactive with antibodies to CD 68 (x400)

Diagnosis: Lesion of aggregated monocytes and mesothelial cells, LAMM (a.k.a. cardiac MICE mesothelial/monocytic incidental cardiac excrescence)

Discussion:
In 1990, Luthringer, et al reported a lesion originally thought to resemble a histiocytoid (epithelioid hemangioma) occurring within the cardiovascular system, particularly the heart. The authors suggested that the lesions, in part, showed mesothelial differentiation. Two additional reports (Veinot, Courtice) confirmed the presence of mesothelial cells in these lesions. Courtice, et al suggested that the lesions were best regarded as "pseudotumors" and in most instances, were artifactually produced. Following publication of this article, several other authors have recognized the histiocytic and mesothelial components of this lesion.

In the earliest reported examples of this lesion, they were referred to as histiocytoid hemangiomas. Additional cases were originally diagnosed as "chemoreceptor tissue" and "metastatic adenocarcinoma". Thus, it is clear that these lesions have caused at least some confusion to experienced surgical and cardiovascular pathologists and continue to be the subject of case reports. These lesions have been identified in cardiac chambers, on cardiac valves, in the pericardial sac, in specimen jars submitted to pathology, in the ascending aorta, in the mediastinum, and in the pleural space. They have also been identified in microscopic sections of tissue taken by right ventricular endomyocardial biopsy and transbronchial biopsy. Similar lesions have been identified incidentally at the time of surgery for pulmonary disease and submitted as lymph nodes, and are similar, if not identical, to lesions described as "nodular histiocytic/mesothelial hyperplasia" in the general surgical pathology literature.

The lesions are usually identified incidentally and are often described as being "free floating" by the surgeon. The lesions range in size from microscopic up to 3 cm in diameter. Grossly, they vary from gray white to dark red to brown and are frequently associated with obvious thrombus.

The nodules are usually discrete and distinct from other tissue submitted at the same time (e.g. valves, myocardial biopsies, portions of the aorta). The lesions are composed of two predominant cell types, a histiocytoid cell and a taller columnar or cuboidal cell. The histiocytoid cells are round to oval and have pink cytoplasm, well-defined nuclei with prominent nuclear grooves and occasional nucleoli. They have a low nuclear to cytoplasmic ratio and are positive for CD68 and lysozyme. Electron microscopically, these cells have features typical of histiocytes with convoluted nuclei, prominent nucleoli, cytoplasm rich in reticulin and surface pseudopodia. The second, less numerous cells, are usually present in small groups, strips, or tubular arrangements, have smaller amounts of eosinophilic cytoplasm and have small, round, non-cleaved nuclei with inconspicuous nucleoli. These cells are reactive with antibodies for keratin, calretinin, CK 5/6 and fail to react with antibodies for CEA, CD15, Factor VIII related antigen, multiple hematolymphoid markers, CD68, lysozyme and CD45. Electron microscopically, these cells have haphazardly arranged intermediate filaments and surface microvilli. Well-developed desmosomes and intercellular connections may also be present. These features are consistent with mesothelial cells. The cells may be associated with small numbers of neutrophils, occasional lymphocytes, and eosinophils, and are sometimes arranged around spaces or adipocyte-like vacuoles. Occasionally, foreign material may be intermixed.

The authors of the original two studies (Luthringer and Veinot) suggested that these lesions might represent a form of mesothelial hyperplasia, possibly representing a reactive process in response to previous cardiac catheterization, as 75 percent of patients in one series had such a previous history. An additional hypothesis has been put forward by Courtice, et al as a result of their examination of material found in extracorporal bypass pumps and material adherent to mediastinal and pericardial drains. Based on their study, in which such lesions were found in 82% of bypass pumps and 13% of mediastinal and pericardial drains following cardiac surgery, they suggested that these lesions were produced the cardiotomy suction tip. They hypothesized that compaction and agglomeration of friable mesothelial strips, other tissue, debris, and fibrin could be transported around the operative site and thus, be found "free floating" by either the surgeon or the pathologist. This hypothesis probably explains the majority of examples of this lesion. Further support for this hypothesis comes from Suarez-Vilela and Izquierdo-Garcia who observed aberrant expression of the adhesion molecule CD34 on the mesothelial cells of an example of nodular histiocytic-mesothelial hyperplasia identified in a hernia sac. The Courtice hypothesis does not, however, account for material obtained by right ventricular endomyocardial biopsy or transbronchial biopsy. Therefore, rare examples of this lesion may represent the result of perforation of a hollow viscus into a mesothelial space which, along with fibrin and previously circulating macrophages and rare inflammatory cells, may coalesce to form a pseudoneoplasm.

As emphasized by Courtice, et al, the lack of histologic evidence of attachment to underlying tissues and a lack of supporting fibrovascular stroma highlight the fact that the fibrin meshwork previously described is not only a prominent feature of such lesions, but is likely an essential element in their formation and adherence to other tissues. The lack of supporting stroma also makes it unlikely that these lesions actually have the "capacity to grow" other than by increasing the number of cells which adhere to the fibrin meshwork.

What is the best name for these lesions? Several authors have proposed the term "nodular histiocytic/mesothelial hyperplasia". However, this implies that the lesions actually have the capacity to grow via their own blood supply. Given the fact that the majority of these lesions do not appear to have a vascular system or blood supply and are most likely artifactually produced in some way, I prefer the term "lesion of aggregated monocytes and mesothelial cells" (LAMM) when they occur outside of the heart and MICE when they occur within the heart. Their significance, of course, lies not so much in what they are called, but what they are not called (e.g. metastatic adenocarcinoma). The majority of MICE have behaved in a benign fashion. However, there has been one report of metastatic adenocarcinoma involving a cardiac MICE (Argani et.al). In this particular example, a 0.8 cm in diameter fragment of cellular debris was found floating in the pericardial cavity which proved to contain clusters of clearly malignant cells in a patient who had a known adenocarcinoma. Therefore, not all lesions with this characteristic architecture and cell composition can be dismissed as benign. This particular case also suggests the possibility that these lesions can form by induction of thrombogenic malignancies.

Other Pseudoneoplasms
This case represents an example of a cardiac pseudoneoplasm, of which there are several (Table 1). One process which is no longer considered a pseudotumor or pseudoneoplasm is the lesion now best referred to as inflammatory myofibroblastic tumor (IMT). IMT should now be regarded as a true neoplasm and the term "inflammatory pseudotumor" discarded.

Calcified amorphous tumors of the heart (cardiac CAT). In one report (Reynolds et al), patients with these pseudoneoplasms ranged in age from 16-75 years (mean, 52 years) and included 7women and 4 men. The patients presented with a wide variety of symptoms including embolic phenomenon (50%), shortness of breath, or orthopnea (30%), a "funny sensation" in the chest (10%), and without symptoms (10%). Table 2 shows the underlying disease states present in the patients. Interestingly, a few of the associated diseases are conditions known to predispose to thrombosis while others predispose to calcification. One patient had no known pre-existing condition.

All four cardiac chambers have been the site of these lesions as well as the mitral valve (Table 2). The lesions range in size from 0.2-6.5 cm. in diameter. The largest one measured 9cm in length and extended down a central line in a patient on total parenteral nutrition. Microscopically, they are remarkably similar from case to case. All cases have had various amounts of often nodular calcium deposits set in a background of what appears to be degenerating fibrin. One case had bony metaplasia. All cases had mild to moderate numbers of chronic inflammatory cells at the base, often associated with a few capillaries. Hemosiderin deposition was absent in all but two cases. In one case cholesterol clefts were present in the degenerating fibrin. Giant cells were present surrounding the calcium deposits in the one lesion from the patient with a history of tumoral calcinosis. In fact this lesion resembled that of soft tissue tumoral calcinosis. A majority of the cases (60%) had fresh fibrin on the surface, which may have been the source of some of the emboli, another possibility being the calcium fragments themselves.

Follow-up was obtained on 9 of the patients reported by Reynolds et al from 4 months to 18 years. All patients had a benign course with respect to their cardiac lesion. A repeat echocardiogram in two patients at 11months and 3.5 years showed some residual calcium at the site of the original mass, but neither patient was symptomatic.

It is tempting to conclude that all of these lesions represent nothing more than calcified mural thrombi. In fact, most probably are, particularly those occurring in patients with underlying diseases which might predispose to thrombosis. The fibrin and red cells in these thrombi, appear to undergo mummification rather than organization. However, not all patients had such underlying conditions and two had no underlying condition at all. Additional cases will need to be studied in order to determine their pathogenesis.

The clinical differential diagnosis for these lesions includes most benign and malignant cardiac tumors, particularly myxomas, as well as a group of non-neoplastic processes which may give rise to mass-like lesions. The pathologic differential diagnosis for these lesions includes a more typical organizing thrombus, non-infectious thrombotic endocarditis, white blood clots of "white blood clot syndrome", and Echinococcus cysts.

All of the CAT's lack significant fibroblastic proliferation within the majority of the lesion characteristic of an ordinary thrombus. Non-infectious thrombotic endocarditis is usually characterized as 1-4 mm diameter granular, pink vegetations. They are most frequent on the undersurface of the atrioventricular valves but may be scattered on the valvular endocardium, chordae tendineae and on the mural endocardium. Histologically, the verrucae consist of finely granular eosinophilic fibrous material. This may be associated with an underlying valvulitis.

White clot syndrome describes the development of spontaneous major arterial and/or venous thrombosis in patients receiving heparin therapy. It is often preceded by a declining platelet count and/or increasing resistance to heparin and occurs in a small percentage of patients who develop heparin-induced thrombocytopenia. The definitive diagnosis of heparin-induced intravascular thrombosis is obtained by performing platelet aggregation tests. The fibrinogen level and prothrombin time are usually normal and the fibrin-split products are normal or slightly elevated. Complications requiring amputation, thrombectomy, or other surgery have occurred in up to 61% of the patients with mortality as high as 50%. The name comes from the fact that the thrombi ("clots") in the heparin-induced white blood clot syndrome are composed predominantly of platelet aggregates and are white grossly.

Echinococcus also can involve the heart and present similarly, but the diagnosis rests on the recognition of the wall of the hydatid cyst and the presence of scolices.

Degenerating right ventricular mural thrombi containing degenerating eosinophils can also occur in the setting of restrictive/eosinophilic heart disease and have also been reported in association with Churg Strauss Syndrome.

Table 1 - Non-neoplastic cardiac tumors, a.k.a. pseudoneoplasms

Calcified amorphous tumor (CAT)
MICE/LAMM
Atrial varix
Chiari's web with thrombus
Large Eustachian valve
Vegetations
Infective
Non-infective thrombotic
Thrombi
White clots
In setting of restrictive/eosinophilic heart disease
Echinococcal "cysts"
Wegener granulomatosis
Valvular wind-sock deformities
Apical Variant of hypertrophic cardiomyopathy
Mitral annular calcification
Lipomatous hypertrophy of atrial septum
Intramyocardial hematoma

Table 2: Diseases Present in Patients with Cardiac CAT
Prior chest radiation and chemotherapy for neuroblastoma 1
SLE with anti-cardiolipin antibodies 1
Central line for total parenteral nutrition 1
Cardiac valve disease 2
Chronic renal failure with history of tumoral calcinosis 1
Diabetes mellitus 1
None 1
Recurrent pulmonary thromboemboli 2
Coronary artery disease, congestive heart failure 1

Table 3: Location of Cardiac CAT
Right atrium 2
Right ventricle 3
Left atrium 1
Left ventricle 4
Mitral valve 1

References:

MICE

  1. Argani P, Sternberg SS, Burt M, Adsay NV, Klimstra DS. Metastatic adenocarcinoma involving a mesothelial/monocytic incidental cardiac excrescence (Cardiac MICE). Am J Surg Pathol 1997; 21(8):970-974.
  2. Bando Y, Kitagawa T, Uchara, Sano N, Satake N, Onose Y, Kitaichi T, Miki O, Katoh I, Izumi K. So-called mesothelial/moncytic incidental cardiac excrescences obtained during valve replacement surgery: report of three cases and literature review. Virchows Arch 2000, 437:331-335.
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  4. Chan JKC, Loo KT, Yau BKC, Lam SY. Nodular histiocytic/mesothelial hyperplasia: a lesion potentially mistaken for a neoplasm in transbronchial biopsy. Am J Surg Pathol 1997; 21(6):658-663.
  5. Courtice RW, Stinson WA, Walley VM. Tissue fragments recovered at cardiac surgery masquerading as tumoral proliferations: evidence suggesting iatrogenic or artefactual origin and common occurrence. Am J Surg Pathol 1994; 18:167-174.
  6. Ikeda Y, Yutani C, Imakita M, Ishibashi-Ueda H, Nakamura Y, Nishida N, Hisaki R. Two cases of mesothelial/monocytic incidental cardiac excrescences of the heart. Pathol Int 1998; 48:641-4.
  7. Luthringer DJ, Virmanti R, Weiss SW, Rosai J. A distinctive cardiovascular lesion resembling histiocytiod (epithelioid) hemangioma. Am J Surg Pathol 1990; 14:993-1000.
  8. Ordonez NG, Ro JY, Ayala AG. Lesions described as nodular mesothelial hyperplasia are primarily composed of histiocytes. Am J Surg Pathol 1998; 22(3):285-292.
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  10. Rosai J, Dehner LP. Nodular mesothelial hyperplasia in hernia sacs, a benign reactive condition simulating a neoplastic process. Cancer 1975; 35:165-75.
  11. Rosai J, Gold S, Landy R. The histiocytoid hemangioma: a unifying concept embracing several previously described entities of skin, soft tissue, large vessels, bone and heart. Hum Pathol 1979; 10:707-730.
  12. Suarez-Vilela D, Izquierdo-Garcia FM. Nodular histiocytic/mesothelial hyperplasia: a process mediated by adhesion molecules? Histopathology 2002, 40:299-300.
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Calcified Amorphous Tumors (Cardiac CAT)

  1. Abbott OA, Warshawski FE, Woodfin Cobbs B. Primary tumors and pseudotumors of the heart. Ann Surg 1962; 155:855-873.
  2. Coppock, Safford RE, Danielson GK. Intracardiac thrombosis, phospholipid antibodies, and two-chambered right ventricle. Br Heart J 1988; 60:455-458.
  3. Dean DC, Pamukcoglu T, Roberts WC. Rocks in the right ventricle: a complication of congenital right ventricular infundibular obstruction associated with chronic pulmonary parenchymal disease. Am J Cardiol 1990; 23:744-747.
  4. Ensing GJ, Driscoll DJ, Smithson WA. Left atrial mass 16 years after radiation therapy for mediastinal neuroblastoma. Pediatr Cardol 1987; 8:271-274.
  5. Reynolds C, Tazelaar HD, Edwards WD. Calcified amorphous tumor of the heart (cardiac CAT). Hum Pathol 1997; 28:601-606.

White Blood Clot Syndrome

  1. AbuRahma AF, Boland JP, Witsberger T. Diagnostic and therapeutic strategies of white clot syndrome. Am J Surg 1991; 162:175-179.
  2. Ananthasubramaniam K, Shurafa M, Prasad A. Heparin induced thrombocytopenia and thrombosis. Progr Cardiovas Dis 2000, 42:247-260.
  3. Chang JC. White clot syndrome associated with heparin-induced thrombocytopenia: a review of 23 cases. Heart & Lung 1987; 16:403-407.
  4. Hermanns B, Janssens U, Handt S. Pathomorphological aspects of heparin-induced thrombocytopenia II (HIT-II syndrome).Virchows Arch 1998; 432:541-546.

Other

  1. Eiken PW, Edwards WD, Tazelaar HD, McBane RD, Zehr KJ. Surgical pathology of nonbacterial thrombotic endocarditis in 30 patients, 1985-2000. Mayo Clin Proc 2001; 76:1204-12.
  2. Mohan JC, Agarwala R, Khanna SK. Dissecting intramyocardial hematoma presenting as a massive pseudotumor of the right ventricle. Am Heart J 1992; 124:1641-42.
  3. Ramakrishna G, Connolly HM, Tazelaar HD, Mullany CJ, Midthun DE. Churg-Strauss syndrome complicated by eosinophilic endomyocarditis. Mayo Clin Proc 2000; 75;631-35.