—  SPECIALTY CONFERENCE  —

Cardiovascular Pathology

Case 2 - Deep and Exuberant Quilty Lesions

Marc K. Halushka
Johns Hopkins Medical Institutions
Baltimore, MD





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Clinical History
A 60-year-old white woman underwent a routine endomyocardial surveillance biopsy to monitor for cardiac transplant rejection. It had been 4 years since her cardiac transplantation for ischemic cardiomyopathy.


Case 2 - Slide 1
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Case 2 - Figure 1
Endomyocardial biopsy findings
Case 2 - Figure 2
Endomyocardial biopsy findings
Case 2 - Figure 3

Case 2 - Figure 4


Histologic Diagnosis
Deep and exuberant Quilty lesions

Discussion
Large endocardial infiltrates, Quilty lesions (QLs), have long been an enigma in cardiac rejection surveillance biopsies. QLs were named after the first patient in which they were described by Dr. Margaret Billingham in 1981. Beyond that point, what QLs are, where they come from, what they correlate with, and where they are located all remain open areas of investigation.

What are QLs? QLs are collections of inflammatory cells usually found along the endocardium, but sometimes extending deeper into tissues, that can mimic acute rejection. To determine the components of QLs and differentiate it from acute cellular rejection, multiple studies have been performed. Generally, QLs are comprised of T lymphocytes, B lymphocytes, capillaries with "high" endothelial cells and fibrosis. By immunohistochemical study, QLs have more CD4+ cells compared to CD8+ cells, and more CD3+ cells compared to CD20+ cells. [1] An immunohistologic study comparing QLs with acute rejection found fewer RANTES+ leukocytes, fewer macrophages, but more T cells in QLs. [2] Conversely, an earlier study demonstrated more B-cells in QLs compared to rejection. [3]

Where do QLs come from? QLs were initially believed to be the result of cyclosporine use, however that belief was not borne out. [4] An infectious etiology was also considered, however this was not supported by studies of the presence of EBV and CMV. [4, 5] Other ideas proposed but not proven include the premise the lesions are the result of blocked lymphatic drainage of the heart or the possibility these are lymphoma precursors.

What are QLs associated with? Many studies have attempted to demonstrate QLs are a form of acute cellular rejection. Several have found this association, [5, 6, 7, 8] but many others have not. [4, 9, 10] More recently, groups have investigated a relationship between QLs and humoral (antibody-mediated) rejection. In patients with QLs, there was an increase in transplant vasculopathy at 5 years and an increase in coronary intimal thickness by IVUS at 1 year in separate studies. [8, 11] There is also a reported association of QLs with microvasculopathy. [12]

Where are QLs located? Historically, QLs have been defined as being attached to the endocardium, although from this position, they could extend deep into the cardiac tissue. In the first ISHLT classification system, QLs were designated as Quilty A or Quilty B effect based on this extension. Quilty A lesions represented those that were confined to the endocardium, whereas Quilty B lesions extended deeper into the underlying myocardium. [13] Peri-Quilty myocyte injury could be observed in Quilty B type lesions. The more recent ISHLT classification, on finding no clinical distinction between the entities, no longer separates between Quilty types, labeling the entire entity as the Quilty effect. [14] Generally QLs located beyond the endocardial layer are not described. There has been one case report describing a QL within a coronary artery in an 8-year-old girl. [15]

This case presentation was of a QL deep within the myocardium (Fig 1). I describe this entity as a "deep and exuberant" QL for lack of better nomenclature. The key point of this case is to demonstrate that typical QLs can rarely be deep and not attached to the endocardium. In this location, and on a biopsy specimen, a QL could be mistaken from acute cellular rejection. In one explant for graft failure (Fig 2) and in one autopsied transplant heart (Fig 3), we have noted these deep and exuberant QLs throughout the myocardium. In both cases, the patients had a history of QLs on surveillance heart biopsies. In the second case, well-formed germinal centers could be appreciated (Fig 4). How common are these deep and exuberant QLs? Likely rare. We have seen these lesions at autopsy or in second heart transplantations in 2/43 (5%). We have identified 10 cases of deep and/or exuberant QLs in surveillance biopsies in the case files of our institution covering over 450 transplantations. Not surprisingly, in these 10 subjects, QLs are usually seen on multiple biopsies.

In summary, many questions pertaining to QLs remain unresolved. Where QLs come from and what they indicate remain two topics still open for debate. This case furthers the mystery of QLs by now showing that QLs can be found deep within the myocardium, far away from the endocardial surface. Importantly, they also clearly demonstrate that QLs must be excluded in cases of acute cellular rejection, even if the infiltrate is not attached to the overlying endocardium. HHoadfsfdddHHHS

References:
  1. Gopal S, Narasimhan U, Day JD, Gao R, Kasper EK, Chen CL, Cina S, Robertson AL, Hruban RH: The Quilty lesion enigma: focal apoptosis/necrosis and lymphocyte subsets in human cardiac allografts, Pathol Int 1998, 48:191-198

  2. Michaels PJ, Espejo ML, Kobashigawa J, Alejos JC, Burch C, Takemoto S, Reed EF, Fishbein MC: Humoral rejection in cardiac transplantation: risk factors, hemodynamic consequences and relationship to transplant coronary artery disease, J Heart Lung Transplant 2003, 22:58-69

  3. Radio SJ, McManus BM, Winters GL, Kendall TJ, Wilson JE, Costanzo-Nordin MR, Ye YL: Preferential endocardial residence of B-cells in the "Quilty effect" of human heart allografts: immunohistochemical distinction from rejection, Mod Pathol 1991, 4:654-660

  4. Joshi A, Masek MA, Brown BW, Jr., Weiss LM, Billingham ME: "Quilty" revisited: a 10-year perspective, Hum Pathol 1995, 26:547-557

  5. Costanzo-Nordin MR, Winters GL, Fisher SG, O'Sullivan J, Heroux AL, Kao W, Mullen GM, Johnson MR: Endocardial infiltrates in the transplanted heart: clinical significance emerging from the analysis of 5026 endomyocardial biopsy specimens, J Heart Lung Transplant 1993, 12:741-747

  6. Pardo-Mindan FJ, Lozano MD: "Quilty effect" in heart transplantation: is it related to acute rejection? J Heart Lung Transplant 1991, 10:937-941

  7. Smith RN, Chang Y, Houser S, Dec GW, Grazette L: Higher frequency of high-grade rejections in cardiac allograft patients after Quilty B lesions or grade 2/4 rejections, Transplantation 2002, 73:1928-1932

  8. Chu KE, Ho EK, de la Torre L, Vasilescu ER, Marboe CC: The relationship of nodular endocardial infiltrates (Quilty lesions) to survival, patient age, anti-HLA antibodies, and coronary artery disease following heart transplantation, Cardiovasc Pathol 2005, 14:219-224

  9. Suit PF, Kottke-Marchant K, Ratliff NB, Pippenger CE, Easely K: Comparison of whole-blood cyclosporine levels and the frequency of endomyocardial lymphocytic infiltrates (the Quilty lesion) in cardiac transplantation, Transplantation 1989, 48:618-621

  10. Kottke-Marchant K, Ratliff NB: Endomyocardial lymphocytic infiltrates in cardiac transplant recipients. Incidence and characterization, Arch Pathol Lab Med 1989, 113:690-698

  11. Yamani MH, Ratliff NB, Starling RC, Tuzcu EM, Yu Y, Cook DJ, Crow T, Hobbs R, Rincon G, Bott-Silverman C, McCarthy PM, Young JB: Quilty lesions are associated with increased expression of vitronectin receptor (alphavbeta3) and subsequent development of coronary vasculopathy, J Heart Lung Transplant 2003, 22:687-690

  12. Hiemann NE, Knosalla C, Wellnhofer E, Lehmkuhl HB, Hetzer R, Meyer R: Quilty indicates increased risk for microvasculopathy and poor survival after heart transplantation, J Heart Lung Transplant 2008, 27:289-296

  13. Billingham ME, Cary NR, Hammond ME, Kemnitz J, Marboe C, McCallister HA, Snovar DC, Winters GL, Zerbe A: A working formulation for the standardization of nomenclature in the diagnosis of heart and lung rejection: Heart Rejection Study Group. The International Society for Heart Transplantation, J Heart Transplant 1990, 9:587-593

  14. Stewart S, Winters GL, Fishbein MC, Tazelaar HD, Kobashigawa J, Abrams J, Andersen CB, Angelini A, Berry GJ, Burke MM, Demetris AJ, Hammond E, Itescu S, Marboe CC, McManus B, Reed EF, Reinsmoen NL, Rodriguez ER, Rose AG, Rose M, Suciu-Focia N, Zeevi A, Billingham ME: Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection, J Heart Lung Transplant 2005, 24:1710-1720

  15. Truell JS, Fishbein MC: Case report of a Quilty lesion within a coronary artery, Cardiovasc Pathol 2006, 15:161-164