|Year : 2018 | Volume
| Issue : 2 | Page : 228-232
|Lymphomatoid granulomatosis: A case series from South India
Elanthenral Sigamani1, Jagan Chandramohan1, Sheila Nair1, Geeta Chacko1, Meera Thomas1, Leni Grace Mathew2, Susanne Pulimood3, Marie Therese Manipadam1
1 Department of Pathology, Christian Medical College Hospital, Vellore, Tamil Nadu, India
2 Department of Pediatric Oncology, Christian Medical College Hospital, Vellore, Tamil Nadu, India
3 Department of Dermatology, Christian Medical College Hospital, Vellore, Tamil Nadu, India
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|Date of Web Publication||20-Apr-2018|
| Abstract|| |
Context: Lymphomatoid granulomatosis (LYG) is a rare B-lymphoproliferative disorder characterised by an angiocentric and angiodestructive pattern along with Epstein - Barr virus (EBV) association. It is one of the diagnostic challenges in lymphoma pathology. Deregulation of EBV immune surveillance is one of the narrated hypotheses in the literature. Extrapulmonary manifestations are rare with LYG. Morphological grading is done based on the number of EBV-positive B cells, which is useful to strategize treatment protocol. Aims: We report here a series of nine cases of LYG to discuss the clinical, histological, and immunohistochemistry findings. Settings and Design: This is the first case series from India in published literature. Subjects and Methods: We reviewed cases of LYG diagnosed at our center for the past 11 years (2006-2016). A total of nine cases were included in this study. Histomorphology was studied in conjunction with immunohistochemistry and clinical details. Cases without classical morphology and negative for EBV immunostain were excluded from the study. Results: There were nine patients in our study (7 males and 2 female; M:F ratio 3.5:1). The age of these patients ranged from 4 years to 57 years (mean age: 30 years). The most common site involved was the lung (4, 44%), followed by the skin (2, 22%), central nervous system (2, 22%) and lymph node (1, 11%). One patient had primary immunodeficiency. Another patient had undergone renal transplant 11 years before the development of the lesion. Angiocentricity and angioinvasion were appreciated in all nine cases (9/9) with necrosis in four cases (44%) and ill-defined histiocytic aggregates in three cases (33%). The histological features were as follows: Grade 1(4 cases, 44%), Grade 2(2 cases, 22%), and Grade 3(3 cases, 33%). Conclusion: LYG is a rare EBV driven angiodestructive disease with predominantly lung involvement as well as isolated extrapulmonary sites as seen in our study. It is often progressive and ultimately fatal in the absence of appropriate treatment. Grading of the lesion helps to initiate the appropriate treatment of choice.
Keywords: Angiodestructive, Epstein-Barr virus, Lymphomatoid granulomatosis
|How to cite this article:|
Sigamani E, Chandramohan J, Nair S, Chacko G, Thomas M, Mathew LG, Pulimood S, Manipadam MT. Lymphomatoid granulomatosis: A case series from South India. Indian J Pathol Microbiol 2018;61:228-32
|How to cite this URL:|
Sigamani E, Chandramohan J, Nair S, Chacko G, Thomas M, Mathew LG, Pulimood S, Manipadam MT. Lymphomatoid granulomatosis: A case series from South India. Indian J Pathol Microbiol [serial online] 2018 [cited 2020 Apr 1];61:228-32. Available from: http://www.ijpmonline.org/text.asp?2018/61/2/228/230553
| Introduction|| |
Lymphomatoid granulomatosis (LYG) is a rare B-cell lymphoproliferative disorder known for its angiocentricity and angioinvasiveness. This disorder was initially described by Liebow et al. in 1972 as primarily involving the lungs, and it was considered to be T cell lymphoproliferative disorder in earlier days., Later Epstein-Barr Virus (EBV) association was revealed by Katzenstein et al. Eventually, the clonal atypical B cells were found to be harboring EBV infection by Guinee et al. in 1994. LYG is more frequent among males than females and generally peaks in the fifth decade; most frequently, it involves the lung, followed by central nervous system, skin, liver, and kidney. In 2001 WHO classification, LYG was considered to be a distinct disease entity with intermediate malignant potential. However, in 2008 WHO classification, it was kept under diffuse large B-cell lymphoma in the category of “other lymphomas of large B cells.” There are no changes found in 2016 update of the WHO classification. Recent studies have suggested that patients with LYG have defective immune surveillance of EBV-infected B cells, particularly by CD8 positive T cells., Grading of the lesion is important to initiate the right choice of treatment. We report here a series of nine cases of LYG to discuss the clinical, histological, and immunohistochemistry findings. This is the first case series from India in published literature.
| Subjects and Methods|| |
We reviewed cases with potential diagnoses of LYG diagnosed at our center over a period of 11 years (2006–2016). A total of 15 cases were found to have the possibility of LYG in the differential. Only nine cases were included in the study. Remaining cases were excluded due to nonavailability of tissue for immunohistochemical staining for EBV latent membrane protein-1 (LMP-1). Histomorphology was studied in conjunction with immunohistochemistry and clinical details. All sections stained for hematoxylin and eosin, and immunohistochemistry were reviewed using the criteria of the 2008 WHO classification. Although the criteria of 2008 WHO are accepted, there are clearly cases that fulfill some but not all, of the criteria. For practical purposes, Katzenstein et al. have proposed the following criteria for LYG in a recent review. According to this criteria, these two necessary findings should always be present; the presence of mixed mononuclear cell infiltrate with vascular infiltration and variable numbers of CD20-positive large B cells, often with atypia, in a background of CD3-positive small lymphocytes. Some of the supporting findings such as necrosis, positivity for EBV-encoded RNA (EBER) in situ hybridization (ISH) and multiple lung nodules in radiology, or skin or nervous system involvement may be present, but not always needed.
Histomorphology was studied to look for angiocentricity, angioinvasion, necrosis, presence of any histiocytic aggregates and grading. Grading was done by counting the number of EBV immunopositive large atypical cells per high power field, based on the WHO recommendations, with Grade 1 having less than five EBV-positive large B cells in a single high-power field, Grade 3 having greater than 50 EBV-positive cells in a high power field, and Grade 2 encompassing the remainder. Immunohistochemistry done on formalin-fixed, paraffin-embedded tissue sections included the following panel of antibodies (CD20, CD3, CD30, CD15, CD4, CD8, CD56, and EBV LMP1) and MIB-1 labeling index.
| Results|| |
The mean age of the patients included in this analysis was 30 years (range: 4–57 years) comprising 7 males and 2 females (M:F = 3.5:1). The most common site involved was the lung (4, 44%), followed by skin (2, 22%), the central nervous system (CNS) (2, 22%), and lymph node (1, 11%) [Table 1]. One of the patients was a renal allograft recipient 11 years before the development of the lesion. The youngest patient in our study had combined variable immunodeficiency syndrome (CVID), who presented with the pulmonary nodule. The renal transplant patient, who was on treatment with immunosuppressants, azathioprine and prednisolone, presented with fever, weight loss, and patchy nodular opacities in both lung fields. One patient presented with a lymph node mass along with other suspicious lesions in lung and skin, which were not biopsied.
Histomorphology and immunohistochemistry
Biopsy sections revealed characteristic histopathology with evidence of EBV. Ill-defined histiocytic aggregates were seen in two cases (one lung and one skin case). Angiocentricity and angioinvasion were appreciated in all the cases (9/9). Necrosis was seen in four cases (44%). Grading was done according to the international criteria. The distribution of the grades are as follows: Grade 1(4 cases, 44%), Grade 2(2 cases, 22%), and Grade 3(3 cases, 33%). Among the lung lesions, two were Grade 2, and the remaining two were Grade 1 and Grade 3, respectively. Two of the skin lesions and one lymph node were Grade 1. Both the CNS cases were Grade 3 correlating with its aggressive behavior. Two of the three Grade 3 lesions were in young patients. Fifty percent of the young patients had Grade 3 lesions. The patient with CVID had Grade 3 lesion. None of the patients above 50 years had Grade 3 lesion (0/3).
Angiocentricity and angioinvasion along with angiodestruction was seen in all the cases, involving small to large caliber vessels [Figure 1]a. The large atypical lymphoid cells were seen in a background of polymorphic infiltrates composed of small lymphocytes, eosinophils, and plasma cells along with focal loose collection of histiocytes. There were foci of necrosis, mostly coagulative type, seen in 4/9 cases [Figure 1]b. The extent of necrosis was corresponding to the grade of the lesion. Well-formed epithelioid granulomas or multinucleated giant cells were not seen in any case.
|Figure 1: Photomicrographs from biopsies taken from a 56-year-old woman who is a renal allograft recipient, presented with fever, weight loss, and breathlessness. Angiocentricity and angioinvasion (a, H and E, ×100). Some of the nodules showed extensive necrosis (b, H and E, ×40)|
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On immunohistochemistry, the large atypical lymphoid cells were positive for CD20 and EBV LMP1 [Figure 2]b and [Figure 2]c. EBER ISH was performed on only one case, which demonstrated the EBV infected cells. The background cells were predominantly T cells positive for CD3 [Figure 2]a and CD4>CD8. In occasional cases, the large cells were positive for CD30 but were negative for CD15. Culture studies and special stains for infectious etiology were negative in all the cases.
|Figure 2: (a) CD3-positive T-cell infiltrates, (b) CD20-positive B cells and (c) Epstein-Barr virus-latent membrane protein1 positive staining|
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| Discussion|| |
LYG is a rare EBV-mediated lymphoproliferative disorder characterized by atypical cells accumulating in the affected tissue causing an infiltrative lesion. Angiocentricity and angioinvasion by the atypical lymphoid cells in a polymorphous background is the classical histomorphology. LYG almost always involves lungs, which accounts for its most common clinical presentation as bilateral pulmonary nodules. Other commonly affected organ systems include the skin, CNS and kidney. In our study, 5/9(55%) cases had presented as isolated extrapulmonary lesions, unlike the reported case series in the literature. The rarity of this disease and its unusual presentation remains a diagnostic challenge in the field of surgical pathology. The current WHO classification places LYG into an entity called “B-cell proliferation of uncertain malignant potential.”Deregulated immune response to the EBV infection in immunodeficient state results in LYG rather than the clearing of the virus. Cases have been reported to have LYG in patients those who are on immunosuppressive therapy such as azathioprine and methotrexate. Infiltrative nodular lesions consisting of abnormal cells accumulate in the affected organs. Subsequently, a T-cell response results in the destruction of blood vessels and tissue damage. The differential diagnosis includes other EBV-positive lymphomas, Wegener granulomatosis, classic Hodgkin lymphoma, sarcoidosis and mycobacterial, and fungal infections. Prominent lymphoid infiltrate, the absence of microabscesses, and EBV positivity differentiates LYG from Wegener granulomatosis. A rarity in the lung and skin, CD15 positivity and CD20 weak and variable positivity differentiates classic Hodgkin lymphoma from LYG. In extranodal NK/T-Cell lymphoma, the atypical cells are CD56 positive cytotoxic T cells, unlike LYG, where the atypical cells are B cells. However, the sites involved, EBV positivity and angiocentricity are common for both the entities. Even though post transplant lymphoproliferative disorders are EBV positive, they do not exhibit angiocentricity and also the background is poor in T cells, unlike LYG where there is a T-cell rich background. Low grade LYG occasionally undergoes spontaneous remission and is best managed with strategies designed to enhance the host's underlying immune system, where as high-grade LYG is best managed by combination chemo-immunotherapy but has inferior outcomes. LYG can lead to progressive pulmonary failure, CNS disease, or progression to overt EBV-positive lymphoma without appropriate recognition and management. Improvements in the modern understanding of the biology of LYG, particularly the precise role of EBV in its pathogenesis, offer promise in the development of improved management strategies.
In this study, we have reviewed nine cases of LYG, which were reported over a period of eleven years. In a large case series reported in the literature, most of the patients were middle-aged with a mean age of approximately 48 years. In our study, the mean age was 30 years, the youngest being a 4-year-old child. Usually, there is a male preponderance, which is also concordant with our current study findings. Although our study also shows that the most common site is lung, isolated extrapulmonary site involvement is quite rare in the published literature. In our study, five of nine cases had isolated extrapulmonary site involvement (55%), unlike the already reported studies. LYG presenting in middle adulthood that nearly always affects the lungs and shows cutaneous involvement in upto 50% of cases. Skin lesions are present at the time of diagnosis in roughly one-third of patients and may precede the development of lung lesions in as many as 10%–15%. In relapse cases, cutaneous involvement may be the first sign. While skin involvement is grossly and microscopically diverse, the disease most commonly presents as erythematous subcutaneous and dermal nodules. One-third of our cases showed skin involvement, but all of them presented as an isolated lesion with no extracutaneous involvement. One case with lymph node involvement also had some skin lesions, which were not biopsied for diagnosis. Pediatric LYG is rare, and so far there have been only 49 cases reported in the English literature. In a review of pediatric cases of LYG by Tacke et al., the median age was 12 years, and one-third of cases were associated with immunodeficiency. Most of them presented with general symptoms followed by pulmonary and neurological manifestations. Pediatric LYG is more frequently associated with immunocompromised patients, especially patients with leukemia. In general, aggressive therapy is recommended in view of high mortality rate, in these patients.
We had two cases involving the central nervous system. One of them presented as an intra-axial mass with large central cystic/necrotic areas in frontal region on magnetic reasoning imaging (MRI), and the other one had mild diffuse hypodensity of the white matter with enhancing areas in positron-emission tomography-computed tomography (CT) with clinical suspicion of CNS lymphoma. LYG and CNS lymphoma share similar radiological features that may be difficult to differentiate on MRI and CT imaging. EBV-associated primary CNS lymphoma is a close differential diagnosis of LYG Grade III. Even though both of them show angiocentric growth pattern, primary CNS lymphomas do not show angioinvasion and angiodestruction. By altering the immune condition, LYG Grade III can undergo spontaneous regression, unlike primary CNS lymphomas.
LYG is known to occur in association with many underlying diseases. Katzenstein et al. observed LYG was associated with prior history of carcinoma, biliary cirrhosis, chronic hepatitis, ulcerative colitis, sarcoidosis, and retroperitoneal fibrosis. LYG is also known to occur in association with several immunodeficiency states, like acquired immunodeficiency syndrome as well as common variable immunodeficiency, X-linked agammaglobulinemia, and hypogammaglobunimia. In our study, we had one patient with common variable immunodeficiency who showed lung involvement. Several cases of LYG have been reported in the literature in allogeneic organ transplant recipients. We had one renal allograft recipient who presented with pulmonary LYG. LYG is also seen in association with iatrogenic immunodeficiency in patients treated with methotrexate and other immunosuppressive therapy. Patients with iatrogenic immunodeficiency are also known to have lymphoproliferative disorders with similar pathological features like LYG. Hence, it is important to consider these conditions before making the diagnosis of LYG in patients with iatrogenic immunodeficiency conditions.
Treatment details were available only for four patients and all of them were treated with cyclophosphamide, adriamycin, vincristine, and prednisone regimen primarily. The median survival[Figure 3] in the four patients with known follow-up and treatment details [Table 1] was 5 weeks with an overall survival of 25% (i.e., one of four persons survived) in 2 years duration, after which the lone surviving patient was lost to further follow-up. All the patients died while undergoing chemotherapy, of which one had clinico-radiological features of disease progression (paraaortic lymphadenopathy and obstructive uropathy with bilateral hydroureteronephrosis) at the end of 15 weeks. The other two patients died due to chemotherapy-related complication with one developing febrile neutropenia and the other succumbing to septicemia and bilateral pneumonia, at 3rd and 5th weeks respectively.
| Conclusion|| |
LYG is a multisystem lymphoproliferative disorder with uncertain malignant potential. Apart from the lung as the most common site of involvement, it involves several other systems such as skin and CNS as isolated extrapulmonary sites. It has to be differentiated from other EBV associated lymphoproliferative disorders and other immunodeficiency-associated conditions with the lymphoproliferative disease. Diagnosis of LYG requires the classical morphology composed of a polymorphic background with atypical CD20 and EBV positive large lymphoid cells, displaying angiocentricity and angioinvasion. It is important to consider the history of any organ transplant or immunodeficiency status before making the diagnosis of LYG. It is often progressive and fatal if not treated appropriately. Grading of the lesion helps to initiate the right choice of treatment.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
We would like to acknowledge our Professors Dr. Alok Srivastava, Dr. Vikram Mathews and Dr. Biju George from the department of Clinical Hematology, CMC Vellore for their support and valuable suggestions.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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Marie Therese Manipadam
Department of Pathology, 4th Floor, Asha Building, Christian Medical College Hospital, Vellore - 632 004, Tamil Nadu
Source of Support: None, Conflict of Interest: None
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