J Cutan Pathol 2015: 42: 188–193 doi: 10.1111/cup.12402 John Wiley & Sons. Printed in Singapore
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Journal of Cutaneous Pathology
Lymphomatoid granulomatosis presenting with cutaneous involvement: a case report and review of the literature Lymphomatoid granulomatosis (LG) is a rare Epstein–Barr virus (EBV)-associated B-cell lymphoproliferative disorder presenting in middle adulthood that nearly always affects the lungs and shows cutaneous involvement in up to 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%. Recognition by both the dermatologist and dermatopathologist is therefore crucial for early and accurate diagnosis. While skin involvement is grossly and microscopically diverse, the disease most commonly presents as erythematous subcutaneous and dermal nodules showing the classic histopathologic triad of transmural lymphocytic angiitis, atypical B-lymphocytes in a polymorphous T-cell background, and necrotic foci within lymphoid aggregates. We present a case of lymphomatoid granulomatosis initially presenting with cutaneous lesions, with an accompanying review of the literature. Keywords: dermatopathology, granulomatous inflammation, lymphoma, vasculitis Rysgaard CD, Stone MS. Lymphomatoid granulomatosis presenting with cutaneous involvement: a case report and review of the literature. J Cutan Pathol 2015; 42: 188–193. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
A 75-year-old female with a history of Darier disease treated with oral retinoids, presented to Dermatology January 2013 with a two-month history of new skin lesions. Physical examination revealed multiple erythematous to violaceous papules and firm, occasionally tender, subcutaneous nodules diffusely involving the trunk and bilateral extremities (Fig. 1). The clinical differential diagnosis included an infectious versus neoplastic panniculitis. A punch biopsy from the left leg demonstrated a diffuse lymphohistiocytic
188
Carolyn D. Rysgaard1 and Mary Seabury Stone1,2 1
Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA and 2 Department of Dermatology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
Dr. Mary S. Stone MD Department of Dermatology, Carver College of Medicine, University of Iowa, 200 Hawkins Dr., Iowa City, IA 52242, USA Tel: 219/356-3162 Fax: 219/319-356-8317 e-mail: [email protected] Accepted for publication October 25, 2014
dermal and pannicular inflammatory infiltrate (Figs. 2 and 3). The infiltrate was composed primarily of CD3/CD4-positive T-cells and scattered, atypical, CD20-positive B-cells. T-cell receptor (TCR) gene clonality studies were indeterminate. Review of her chart showed a biopsy from the leg done 2 years previously that showed nearly identical features and was interpreted as suggestive of necrobiosis lipoidica. This involvement had resolved with topical clobetasol.
Lymphomatoid granulomatosis presenting with cutaneous involvement
Fig. 3. An angiocentric lymphohistiocytic infiltrate is coupled with lymphocytic angiitis (hematoxylin-eosin, original magnification ×200). Fig. 1. Multiple erythematous to violaceous papules and subcutaneous nodules involved the left leg.
Fig. 4. The lung biopsy shows prominent angioinvasion by lymphocytes (hematoxylin-eosin, original magnification ×200). Fig. 2. A nodular lymphohistiocytic dermal infiltrate spares the epidermis (hematoxylin-eosin, original magnification ×100).
Given the non-specific nature of her skin biopsy, a computed tomography (CT) scan of the chest, abdomen and pelvis was performed to evaluate for occult malignancy or infection. Imaging revealed innumerable bilateral pulmonary nodules throughout all lobes, concerning for metastatic disease. No lymphadenopathy or other foci suspicious for metastasis were noted. Upon further questioning, the patient reported a roughly two-month history of cough productive of foamy white sputum, unresolved with antibiotics. Per her report, a chest x-ray performed at an outside institution was unremarkable. She denied shortness of breath, fever, chills and malaise. A transbronchial biopsy was non-diagnostic, showing
loose lymphohistiocytic aggregates, negative for acid fast bacilli and fungal elements. Histopathologic examination of a subsequent lung wedge excision showed features reminiscent of her skin biopsy, demonstrating a lymphocyte-rich inflammatory infiltrate with a robust proliferation of T-lymphocytes, occasional atypical, CD20-positive B-cells, and multifocal areas of necrosis and lymphocytic angiitis (Fig. 4). Epstein–Barr encoded RNA (EBER) in situ hybridization (ISH) for Epstein–Barr virus (EBV) highlighted atypical B-lymphocytes (approximately 20–30 per high power field), consistent with a diagnosis of lymphomatoid granulomatosis, grade 2 (Fig. 5). EBER ISH performed retrospectively on the original skin biopsy was negative. Following her diagnosis, the patient elected to pursue single-agent Rituximab therapy,
189
Rysgaard and Stone
Fig. 5. Epstein–Barr encoded RNA (EBER) in situ hybridization highlights scattered atypical, EBV-positive Blymphocytes in the lung biopsy (original magnification ×200)
completing four doses. Laboratory evaluation for a pre-existing immunodeficiency disorder was not performed. A follow-up CT scan six months later (in November, 2013) showed significant reduction in both the size and number of pulmonary nodules. Her skin lesions were largely unchanged and the patient was started on topical clobetasol. She returned to clinic in March, 2014 with near-complete resolution of her skin lesions. She continued to report a productive cough and chest CT showed mixed interval progression of her lung lesions with overall decreased disease burden compared to the time of diagnosis. Discussion Lymphomatoid granulomatosis is a rare angiodestructive B-cell lymphoproliferative disorder linked to EBV. Originally described in 1972, it is a multisystem disorder that primarily affects adults in the fourth-sixth decades with a male predominance of approximately 2:1.1,2 LG nearly always involves the lungs as multiple bilateral variably sized nodules and shows skin involvement in approximately 40–50% of cases.2 Involvement of the kidneys, central nervous system and gastrointestinal tract are seen to a much lesser degree. Lymphoid tissues are generally spared such that the presence of nodal involvement should prompt consideration of alternate diagnoses or transformation to large cell lymphoma. Following diagnosis of LG, underlying immunocompromise can usually be demonstrated in affected patients. Cutaneous lesions of LG have been seen in association with Wiskott–Aldrich syndrome, myeloproliferative disorders and as a form of
190
post-transplant lymphoproliferative disorder (PTLD) following organ transplantation.3 – 6 Lymphomatoid granulomatosis shows a variable clinical course ranging from spontaneous remission to progression to EBV + diffuse large B-cell lymphoma.7 Overall, LG is an aggressive disease, with a median survival of less than 2 years. The presence or absence of skin lesions does not affect overall prognosis.2,8 Aside from visible skin lesions, presenting complaints are generally non-specific and include cough, fever, malaise and weight loss. The rarity of the disease combined with its variable and often non-specific clinical presentation can lead to difficulty in diagnosis and delayed treatment for patients. Previous reports have shown that skin lesions are present at the time of diagnosis in roughly a third of cases and may precede development of lung lesions in as many as 10–15% of patients.2,8,9 Recognizing the cutaneous lesions of LG both clinically and microscopically is crucial, as it provides an opportunity for early diagnosis by the least invasive means possible. Typically multifocal and painless, the cutaneous lesions of LG exhibit a number of different clinical patterns including subcutaneous and/or dermal nodules, papules, indurated plaques and macular rashes.8 – 16 A rare case presenting as angioedema has also been described.17 The lesions can ulcerate or become necrotic. Cutaneous lesions of LG tend to be multiple and widespread, occurring most frequently on the extremities and trunk. In reviewing the prior literature, erythematous to violaceous papules and nodules appear to be the most common cutaneous patterns. In a series of 20 cases, Beaty et al. demonstrated that multiple erythematous nodules, alone or in combination with other patterns were seen in 85% of cases.8 The histopathologic features of LG are similarly varied. The microscopic hallmark of LG is an angiocentric and angioinvasive lymphocyte predominant inflammatory infiltrate with admixed histiocytes, plasma cells and, rarely, neutrophils and eosinophils.8 Small, CD4+ T-lymphocytes predominate and show infiltration into vascular walls with associated necrosis. Variable numbers of atypical CD20-positive B-lymphocytes are present. Despite the name, well-formed granulomas are rarely seen. In the skin, there is patchy involvement of the dermis and sub cutis with little to no involvement of the epidermis. The findings on skin biopsy are often more subtle than those of their counterpart lung lesions. This can make diagnosis difficult, particularly in cases where skin lesions are the
Lymphomatoid granulomatosis presenting with cutaneous involvement initial presenting symptom. When compared to lung specimens, skin biopsies of LG are less likely to show cytologic atypia and necrosis.18 Skin biopsies also show fewer EBV + atypical B-cells. Madison McNiff et al. evaluated four LG patients with both pulmonary and skin biopsies. EBV positive B-cells were present in three pulmonary specimens (75%) but in only one skin biopsy (25%). There is also considerable microscopic variability within skin lesions, which correlates with their clinical appearance. Beatty et al. demonstrated that nodular and papular eruptions were most likely to show the classic features and demonstrated EBV positivity in 37%.8 Conversely, plaque-like lesions showed sparse periadnexal lymphocytic inflammation in the superficial and mid dermis. These lesions were unlikely to show atypia, angiodestruction and necrosis. In their series, all plaque-like lesions studied were negative for EBER ISH. Therefore, if a diagnosis of LG is suspected, nodular skin lesions should be preferentially sampled whenever possible.19 Due to the high degree of variability, more than one biopsy may be needed for diagnosis and appropriate grading. Furthermore, the absence of EBV positivity in a skin biopsy with otherwise characteristic features should not be used to exclude the diagnosis of LG. Grading of LG is driven by the number of EBV-positive B-cells present.7 Grade 1 lesions contain few, if any, atypical lymphoid cells and EBER positive cells are 50 per high power field. Lesions exhibiting confluent sheets of atypical EBV-positive B-lymphocytes and lacking the typical polymorphous inflammatory infiltrate represent involvement by diffuse large B-cell lymphoma and should not be classified as lymphomatoid granulomatosis. Wegener granulomatosis is a necrotizing vasculitis that shares a number of similarities to LG and is an important consideration in the differential diagnosis. Like LG, Wegener granulomatosis is a multisystem disorder of middle-aged adults with a predilection for the lungs and frequent skin involvement.20 The clinical appearance of cutaneous Wegener disease is diverse and shows overlap with LG. Patterns include purpura, papules, pustules, nodules, vesicles and ulcers. Both entities can produce necrosis and
granulomatous inflammation, but in contrast to the lymphocytic angiitis seen in LG, Wegener disease produces fibrinoid necrosis and vascular invasion by a mixed infiltrate containing neutrophils, eosinophils and plasma cells. As noted previously, vascular infiltration by polymorphonuclear cells is rare in LG. Furthermore, Wegener granulomatosis lacks atypical B-lymphocytes and is not associated with EBV. EBV-positive mucocutaneous ulcer is characterized by shallow, well-circumscribed ulcers of the skin, oropharyngeal mucosa and gastrointestinal tract that develop in immunocompromised individuals. Pathologic examination of such lesions shows a polymorphous inflammatory infiltrate with plasmacytoid-appearing apoptotic cells and scattered large B-cells that can resemble Hodgkin and Reed-Sternberg cells. Angioinvasion and necrosis can be present. The ulcers are typically solitary with a predilection for the oropharyngeal mucosa. In contrast, lesions of LG tend to be multifocal and have not been previously described in the oropharyngeal mucosa. Furthermore, unlike LG, EBER positivity is readily demonstrated in the skin lesions of EBV-positive mucocutaneous ulcer.21 EBV-positive diffuse large B-cell lymphoma is another EBV-driven lymphoproliferative disorder that involves the skin and lung as well as lymph nodes. Similar to LG, EBV-positive diffuse large B-cell lymphoma of the elderly can present as multiple subcutaneous nodules, plaques and papules.22 Pathologically, the lesions are divided into polymorphous and monomorphous subtypes. The polymorphous lesions show variable numbers of centroblasts, immunoblasts and HRS-like cells in a background of small lymphocytes, histiocytes and plasma cells with frequent necrosis and angiocentricity. The monomorphous type shows clusters or sheets of large atypical B-cells more in keeping with the traditional appearance of diffuse large B-cell lymphoma. In both types the large B-cells and HRS-like cells show a similar immunophenotype to the atypical B-cells of LG [+CD20, (+/−)CD30, (−)CD15] but are strongly and diffusely positive by EBER ISH in most cases. 23 Some T-cell and Natural Killer (NK) cell lymphoproliferative disorders can show an angioinvasive pattern of infiltration and associated necrosis, mimicking LG. These entities can be readily separated from LG on the basis of ancillary studies such as immunohistochemistry, TCR gene clonality and EBV status. Like LG, Extranodal NK/T-cell lymphoma is associated with EBV.24 The disease is predominantly
191
Rysgaard and Stone localized to the upper aerodigestive tract and rarely involves the lungs. Nodular, frequently ulcerated, skin lesions show a diffuse, angiocentric proliferation of variably sized atypical lymphoid cells exhibiting positivity for CD56, cytoplasmic CD3 and cytotoxic molecules including granzyme B and perforin. Atypical B-lymphocytes are not seen. Primary cutaneous gamma delta T-cell lymphoma presents as patches, plaques, subcutaneous or dermal nodules, largely on the extremities.25 The lesions show dermal and/or epidermal involvement by atypical lymphoid cells and frequent angioinvasion. The cells are generally positive for CD3, CD56 and TCRδ and are clonal by TCR clonality studies. The cells lack CD4, CD8, βF1 and are negative for EBV. Peripheral T-cell lymphoma, not otherwise specified, can present with robust skin involvement, manifesting as ulcerated nodules.26 The lesions are comprised of large atypical CD4+ T-cells that frequently show loss of T-cell antigens (CD3, CD5 and CD7) and are typically clonal by TCR clonality studies. Aberrant expression of CD20 can occasionally be seen, leading to confusion with B-cell entities. The background infiltrate can be angioinvasive and mimics LG, with large B-cells, small lymphocytes, epithelioid histiocytes and plasma cells. There is no association with EBV. Since its first description in 1972, there has been considerable evolution in thinking regarding the underlying etiology and pathobiology of
LG. Due to the robust number of T-lymphocytes in the inflammatory infiltrates, LG was long thought to be a T-cell lymphoproliferative disorder.27 However, T-cell clonality within the lesions could not be reliably identified in early studies. Roughly a decade following its initial description, the link between LG and EBV was first described.28 Using a combination of EBV IHC and EBER ISH, Guinee et al. demonstrated atypical EBV + B-lymphocytes in 10 of 10 pulmonary lesions of confirmed LG cases.29 Immunoglobulin heavy chain gene rearrangement for B-cell clonality was demonstrated in 6 of 9 cases tested, leading the authors to conclude that LG was in fact a B-cell lymphoproliferative disorder with a florid T-cell background. Shortly after, researchers were able to demonstrate atypical EBV-positive cells in cutaneous lesions of LG, albeit to a lesser degree. In summary, lymphomatoid granulomatosis is a rare EBV-associated B-cell lymphoproliferative disorder that can progress to large cell lymphoma in high-grade lesions. It is a multisystem disorder that primarily affects the lungs and shows skin involvement in approximately half of cases. The clinical and microscopic features can be varied, particularly in skin biopsies, but LG should be considered in the differential for patients with multiple cutaneous nodules and plaques showing mixed and granulomatous inflammation, especially with angiocentric accentuation.
References 1. Liebow AA, Carrington CR, Friedman PJ. Lymphomatoid granulomatosis. Hum Pathol 1972; 3: 457. 2. Katzenstein AA, Carrington CB, Liebow AA. Lymphomatoid granulomatosis a clinicopathologic study of 152 cases. Cancer 1979; 43: 360. 3. Kwon EJ, Katz KA, Draft KS, et al. Posttransplantation lymphoproliferative disease with features of lymphomatoid granulomatosis in a lung transplant patient. J Am Acad Dermatol 2006; 54: 657. 4. Park JH, Lee DY, Ko YH. Cutaneous lesion of lymphomatoid granulomatosis in a Korean woman with secondary myelofibrosis. J Dermatol 2011; 38: 1012. 5. Sebire MH, Haselden S, Malone M, Davies EG, Ramsay AD. Isolated EBV lymphoproliferative disease in a child with Wiskott-Aldrich syndrome manifesting as cutaneous lymphomatoid granulomatosis and responsive to anti-CD20 immunotherapy. J Clin Pathol 2003; 56: 555.
192
6. Tas S, Simonart T, Dargent J, et al. Primary and isolated cutaneous lymphomatoid granulomatosis following heart-lung transplantation. Ann Dermatol Venereol 2000; 127: 488. 7. Pittaluga S, Wilson WH, Jaffe ES. Lymphomatoid granulomatosis. In Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, eds. WHO classification of tumors of haematopoietic and lymphoid tissues. Geneva: WHO Press, 2008; 247. 8. Beaty MW, Toro J, Sorbara L, et al. Cutaneous lymphomatoid granulomatosis correlation of clinical and biologic features. Am J Surg Pathol 2001; 25: 1111. 9. James WD, Odom RB, Katzenstein AA. Cutaneous manifestations of lymphomatoid granulomatosis. Arch Dermatol 1981; 117: 196. 10. Brodell RT, Miller CW, Eisen AZ. Cutaneous lesions of lymphomatoid granulomatosis. Arch Dermatol 1986; 122: 303.
11. Carlson KC, Gibson LE. Cutaneous signs of lymphomatoid granulomatosis. Arch Dermatol 1991; 127: 1693. 12. Wood ML, Harrington CI, Slater DN, Rooney N, Clark A. Cutaneous lymphomatoid granulomatosis: a rare cause of recurrent skin ulceration. Br J Dermatol 1984; 110: 619. 13. Camisa C. Lymphomatoid granulomatosis: two cases with skin involvement. J Am Acad Dermatol 1989; 20: 571. 14. Rongioletti F, Desirello G, Nazzari G. Ulcerated plaque and nodules on the thigh of a patient with febrile pulmonary disease. Arch Dermatol 1988; 124: 572. 15. Minars N, Kay S, Escobar MR. Lymphomatoid granulomatosis of the skin. A new clinicopathologic entity. Arch Dermatol 1975; 111: 493. 16. MacDonald DM. Lymphomatoid granulomatosis. Proc R Soc Med 1975; 68: 452. 17. Torrelo A, Martin M, Rocamora A, Alleque F, Ledo A. Lymphomatoid granulomatosis presenting as angioedema. Postgrad Med J 1992; 68: 366.
Lymphomatoid granulomatosis presenting with cutaneous involvement 18. Roschewski M, Wilson WH. Lymphomatoid granulomatosis. Cancer J 2012; 18: 469. 19. Madison McNiff J, Cooper D, Howe G, et al. Lymphomatoid granulomatosis of the skin and lung. An angiocentric T-cell-rich B-cell lymphoproliferative disorder. Arch Dermatol 1996; 132: 1464. 20. Frances C, Du LTH, Piette JC, et al. Wegener’s granulomatosis. Dermatological manifestations in 75 cases with clinicopathologic correlation. Arch Dermatol 1994; 130: 861. 21. Dojcinov SD, Venkataraman G, Raffeld M, Pittaluga S, Jaffe ES. EBV positive mucocutaneous ulcer-a study of 26 cases associated with various sources of immunosuppression. Am J Surg Pathol 2010; 34: 405. 22. Martin B, Whittaker S, Morris S, Robson A. A case of primary cutaneous senile EBV-related diffuse large B-cell lymphoma. Am J Dermatopathol 2010; 32: 190.
23. Oyama T, Ichimura K, Suzuki R, et al. Senile EBV + B-cell lymphoproliferative disorders. A clinicopathologic study of 22 patients. Am J Surg Pathol 2003; 27: 16. 24. Chan JKC, Quintanilla-Martinez L, Ferry JA, Peh SC. Extranodal NK/T-cell lymphoma, nasal type. In Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, eds. WHO classification of tumors of haematopoietic and lymphoid tissues. Geneva: WHO Press, 2008; 285. 25. Gaulard P, Berti E, Willemze R, Jaffe ES. Primary cutaneous peripheral T-cell lymphomas, rare subtypes. In Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, eds. WHO classification of tumors of haematopoietic and lymphoid tissues. Geneva: WHO Press, 2008; 302. 26. Pileri SA, Weisenburger DD, Sng I, et al. Peripheral T-cell lymphoma, not otherwise specified. In Swerdlow SH, Campo E,
Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, eds. WHO classification of tumors of haematopoietic and lymphoid tissues. Geneva: WHO Press, 2008; 306. 27. Lipford EH Jr, Margolick JV, Longo DL, Fauci AS, Jaffe ES. Angiocentric immunoproliferative lesions: a clinicopathologic spectrum of post-thymic T-cell proliferations. Blood 1988; 72: 1674. 28. Veltri RW, Raich PC, McClung JE, Shah SH, Sprinkle PM. Lymphomatoid granulomatosis and Epstein-Barr virus. Cancer 1982; 50: 1513. 29. Guinee D Jr, Jaffe E, Kingma D, et al. Pulmonary lymphomatoid granulomatosis. Evidence for a proliferation of Epstein-Barr virus infected B-lymphocytes with a prominent T-cell component and vasculitis. Am J Surg Pathol 1994; 18: 753.
193
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Journal of Cutaneous Pathology
Lymphomatoid granulomatosis presenting with cutaneous involvement: a case report and review of the literature Lymphomatoid granulomatosis (LG) is a rare Epstein–Barr virus (EBV)-associated B-cell lymphoproliferative disorder presenting in middle adulthood that nearly always affects the lungs and shows cutaneous involvement in up to 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%. Recognition by both the dermatologist and dermatopathologist is therefore crucial for early and accurate diagnosis. While skin involvement is grossly and microscopically diverse, the disease most commonly presents as erythematous subcutaneous and dermal nodules showing the classic histopathologic triad of transmural lymphocytic angiitis, atypical B-lymphocytes in a polymorphous T-cell background, and necrotic foci within lymphoid aggregates. We present a case of lymphomatoid granulomatosis initially presenting with cutaneous lesions, with an accompanying review of the literature. Keywords: dermatopathology, granulomatous inflammation, lymphoma, vasculitis Rysgaard CD, Stone MS. Lymphomatoid granulomatosis presenting with cutaneous involvement: a case report and review of the literature. J Cutan Pathol 2015; 42: 188–193. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
A 75-year-old female with a history of Darier disease treated with oral retinoids, presented to Dermatology January 2013 with a two-month history of new skin lesions. Physical examination revealed multiple erythematous to violaceous papules and firm, occasionally tender, subcutaneous nodules diffusely involving the trunk and bilateral extremities (Fig. 1). The clinical differential diagnosis included an infectious versus neoplastic panniculitis. A punch biopsy from the left leg demonstrated a diffuse lymphohistiocytic
188
Carolyn D. Rysgaard1 and Mary Seabury Stone1,2 1
Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA and 2 Department of Dermatology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
Dr. Mary S. Stone MD Department of Dermatology, Carver College of Medicine, University of Iowa, 200 Hawkins Dr., Iowa City, IA 52242, USA Tel: 219/356-3162 Fax: 219/319-356-8317 e-mail: [email protected] Accepted for publication October 25, 2014
dermal and pannicular inflammatory infiltrate (Figs. 2 and 3). The infiltrate was composed primarily of CD3/CD4-positive T-cells and scattered, atypical, CD20-positive B-cells. T-cell receptor (TCR) gene clonality studies were indeterminate. Review of her chart showed a biopsy from the leg done 2 years previously that showed nearly identical features and was interpreted as suggestive of necrobiosis lipoidica. This involvement had resolved with topical clobetasol.
Lymphomatoid granulomatosis presenting with cutaneous involvement
Fig. 3. An angiocentric lymphohistiocytic infiltrate is coupled with lymphocytic angiitis (hematoxylin-eosin, original magnification ×200). Fig. 1. Multiple erythematous to violaceous papules and subcutaneous nodules involved the left leg.
Fig. 4. The lung biopsy shows prominent angioinvasion by lymphocytes (hematoxylin-eosin, original magnification ×200). Fig. 2. A nodular lymphohistiocytic dermal infiltrate spares the epidermis (hematoxylin-eosin, original magnification ×100).
Given the non-specific nature of her skin biopsy, a computed tomography (CT) scan of the chest, abdomen and pelvis was performed to evaluate for occult malignancy or infection. Imaging revealed innumerable bilateral pulmonary nodules throughout all lobes, concerning for metastatic disease. No lymphadenopathy or other foci suspicious for metastasis were noted. Upon further questioning, the patient reported a roughly two-month history of cough productive of foamy white sputum, unresolved with antibiotics. Per her report, a chest x-ray performed at an outside institution was unremarkable. She denied shortness of breath, fever, chills and malaise. A transbronchial biopsy was non-diagnostic, showing
loose lymphohistiocytic aggregates, negative for acid fast bacilli and fungal elements. Histopathologic examination of a subsequent lung wedge excision showed features reminiscent of her skin biopsy, demonstrating a lymphocyte-rich inflammatory infiltrate with a robust proliferation of T-lymphocytes, occasional atypical, CD20-positive B-cells, and multifocal areas of necrosis and lymphocytic angiitis (Fig. 4). Epstein–Barr encoded RNA (EBER) in situ hybridization (ISH) for Epstein–Barr virus (EBV) highlighted atypical B-lymphocytes (approximately 20–30 per high power field), consistent with a diagnosis of lymphomatoid granulomatosis, grade 2 (Fig. 5). EBER ISH performed retrospectively on the original skin biopsy was negative. Following her diagnosis, the patient elected to pursue single-agent Rituximab therapy,
189
Rysgaard and Stone
Fig. 5. Epstein–Barr encoded RNA (EBER) in situ hybridization highlights scattered atypical, EBV-positive Blymphocytes in the lung biopsy (original magnification ×200)
completing four doses. Laboratory evaluation for a pre-existing immunodeficiency disorder was not performed. A follow-up CT scan six months later (in November, 2013) showed significant reduction in both the size and number of pulmonary nodules. Her skin lesions were largely unchanged and the patient was started on topical clobetasol. She returned to clinic in March, 2014 with near-complete resolution of her skin lesions. She continued to report a productive cough and chest CT showed mixed interval progression of her lung lesions with overall decreased disease burden compared to the time of diagnosis. Discussion Lymphomatoid granulomatosis is a rare angiodestructive B-cell lymphoproliferative disorder linked to EBV. Originally described in 1972, it is a multisystem disorder that primarily affects adults in the fourth-sixth decades with a male predominance of approximately 2:1.1,2 LG nearly always involves the lungs as multiple bilateral variably sized nodules and shows skin involvement in approximately 40–50% of cases.2 Involvement of the kidneys, central nervous system and gastrointestinal tract are seen to a much lesser degree. Lymphoid tissues are generally spared such that the presence of nodal involvement should prompt consideration of alternate diagnoses or transformation to large cell lymphoma. Following diagnosis of LG, underlying immunocompromise can usually be demonstrated in affected patients. Cutaneous lesions of LG have been seen in association with Wiskott–Aldrich syndrome, myeloproliferative disorders and as a form of
190
post-transplant lymphoproliferative disorder (PTLD) following organ transplantation.3 – 6 Lymphomatoid granulomatosis shows a variable clinical course ranging from spontaneous remission to progression to EBV + diffuse large B-cell lymphoma.7 Overall, LG is an aggressive disease, with a median survival of less than 2 years. The presence or absence of skin lesions does not affect overall prognosis.2,8 Aside from visible skin lesions, presenting complaints are generally non-specific and include cough, fever, malaise and weight loss. The rarity of the disease combined with its variable and often non-specific clinical presentation can lead to difficulty in diagnosis and delayed treatment for patients. Previous reports have shown that skin lesions are present at the time of diagnosis in roughly a third of cases and may precede development of lung lesions in as many as 10–15% of patients.2,8,9 Recognizing the cutaneous lesions of LG both clinically and microscopically is crucial, as it provides an opportunity for early diagnosis by the least invasive means possible. Typically multifocal and painless, the cutaneous lesions of LG exhibit a number of different clinical patterns including subcutaneous and/or dermal nodules, papules, indurated plaques and macular rashes.8 – 16 A rare case presenting as angioedema has also been described.17 The lesions can ulcerate or become necrotic. Cutaneous lesions of LG tend to be multiple and widespread, occurring most frequently on the extremities and trunk. In reviewing the prior literature, erythematous to violaceous papules and nodules appear to be the most common cutaneous patterns. In a series of 20 cases, Beaty et al. demonstrated that multiple erythematous nodules, alone or in combination with other patterns were seen in 85% of cases.8 The histopathologic features of LG are similarly varied. The microscopic hallmark of LG is an angiocentric and angioinvasive lymphocyte predominant inflammatory infiltrate with admixed histiocytes, plasma cells and, rarely, neutrophils and eosinophils.8 Small, CD4+ T-lymphocytes predominate and show infiltration into vascular walls with associated necrosis. Variable numbers of atypical CD20-positive B-lymphocytes are present. Despite the name, well-formed granulomas are rarely seen. In the skin, there is patchy involvement of the dermis and sub cutis with little to no involvement of the epidermis. The findings on skin biopsy are often more subtle than those of their counterpart lung lesions. This can make diagnosis difficult, particularly in cases where skin lesions are the
Lymphomatoid granulomatosis presenting with cutaneous involvement initial presenting symptom. When compared to lung specimens, skin biopsies of LG are less likely to show cytologic atypia and necrosis.18 Skin biopsies also show fewer EBV + atypical B-cells. Madison McNiff et al. evaluated four LG patients with both pulmonary and skin biopsies. EBV positive B-cells were present in three pulmonary specimens (75%) but in only one skin biopsy (25%). There is also considerable microscopic variability within skin lesions, which correlates with their clinical appearance. Beatty et al. demonstrated that nodular and papular eruptions were most likely to show the classic features and demonstrated EBV positivity in 37%.8 Conversely, plaque-like lesions showed sparse periadnexal lymphocytic inflammation in the superficial and mid dermis. These lesions were unlikely to show atypia, angiodestruction and necrosis. In their series, all plaque-like lesions studied were negative for EBER ISH. Therefore, if a diagnosis of LG is suspected, nodular skin lesions should be preferentially sampled whenever possible.19 Due to the high degree of variability, more than one biopsy may be needed for diagnosis and appropriate grading. Furthermore, the absence of EBV positivity in a skin biopsy with otherwise characteristic features should not be used to exclude the diagnosis of LG. Grading of LG is driven by the number of EBV-positive B-cells present.7 Grade 1 lesions contain few, if any, atypical lymphoid cells and EBER positive cells are 50 per high power field. Lesions exhibiting confluent sheets of atypical EBV-positive B-lymphocytes and lacking the typical polymorphous inflammatory infiltrate represent involvement by diffuse large B-cell lymphoma and should not be classified as lymphomatoid granulomatosis. Wegener granulomatosis is a necrotizing vasculitis that shares a number of similarities to LG and is an important consideration in the differential diagnosis. Like LG, Wegener granulomatosis is a multisystem disorder of middle-aged adults with a predilection for the lungs and frequent skin involvement.20 The clinical appearance of cutaneous Wegener disease is diverse and shows overlap with LG. Patterns include purpura, papules, pustules, nodules, vesicles and ulcers. Both entities can produce necrosis and
granulomatous inflammation, but in contrast to the lymphocytic angiitis seen in LG, Wegener disease produces fibrinoid necrosis and vascular invasion by a mixed infiltrate containing neutrophils, eosinophils and plasma cells. As noted previously, vascular infiltration by polymorphonuclear cells is rare in LG. Furthermore, Wegener granulomatosis lacks atypical B-lymphocytes and is not associated with EBV. EBV-positive mucocutaneous ulcer is characterized by shallow, well-circumscribed ulcers of the skin, oropharyngeal mucosa and gastrointestinal tract that develop in immunocompromised individuals. Pathologic examination of such lesions shows a polymorphous inflammatory infiltrate with plasmacytoid-appearing apoptotic cells and scattered large B-cells that can resemble Hodgkin and Reed-Sternberg cells. Angioinvasion and necrosis can be present. The ulcers are typically solitary with a predilection for the oropharyngeal mucosa. In contrast, lesions of LG tend to be multifocal and have not been previously described in the oropharyngeal mucosa. Furthermore, unlike LG, EBER positivity is readily demonstrated in the skin lesions of EBV-positive mucocutaneous ulcer.21 EBV-positive diffuse large B-cell lymphoma is another EBV-driven lymphoproliferative disorder that involves the skin and lung as well as lymph nodes. Similar to LG, EBV-positive diffuse large B-cell lymphoma of the elderly can present as multiple subcutaneous nodules, plaques and papules.22 Pathologically, the lesions are divided into polymorphous and monomorphous subtypes. The polymorphous lesions show variable numbers of centroblasts, immunoblasts and HRS-like cells in a background of small lymphocytes, histiocytes and plasma cells with frequent necrosis and angiocentricity. The monomorphous type shows clusters or sheets of large atypical B-cells more in keeping with the traditional appearance of diffuse large B-cell lymphoma. In both types the large B-cells and HRS-like cells show a similar immunophenotype to the atypical B-cells of LG [+CD20, (+/−)CD30, (−)CD15] but are strongly and diffusely positive by EBER ISH in most cases. 23 Some T-cell and Natural Killer (NK) cell lymphoproliferative disorders can show an angioinvasive pattern of infiltration and associated necrosis, mimicking LG. These entities can be readily separated from LG on the basis of ancillary studies such as immunohistochemistry, TCR gene clonality and EBV status. Like LG, Extranodal NK/T-cell lymphoma is associated with EBV.24 The disease is predominantly
191
Rysgaard and Stone localized to the upper aerodigestive tract and rarely involves the lungs. Nodular, frequently ulcerated, skin lesions show a diffuse, angiocentric proliferation of variably sized atypical lymphoid cells exhibiting positivity for CD56, cytoplasmic CD3 and cytotoxic molecules including granzyme B and perforin. Atypical B-lymphocytes are not seen. Primary cutaneous gamma delta T-cell lymphoma presents as patches, plaques, subcutaneous or dermal nodules, largely on the extremities.25 The lesions show dermal and/or epidermal involvement by atypical lymphoid cells and frequent angioinvasion. The cells are generally positive for CD3, CD56 and TCRδ and are clonal by TCR clonality studies. The cells lack CD4, CD8, βF1 and are negative for EBV. Peripheral T-cell lymphoma, not otherwise specified, can present with robust skin involvement, manifesting as ulcerated nodules.26 The lesions are comprised of large atypical CD4+ T-cells that frequently show loss of T-cell antigens (CD3, CD5 and CD7) and are typically clonal by TCR clonality studies. Aberrant expression of CD20 can occasionally be seen, leading to confusion with B-cell entities. The background infiltrate can be angioinvasive and mimics LG, with large B-cells, small lymphocytes, epithelioid histiocytes and plasma cells. There is no association with EBV. Since its first description in 1972, there has been considerable evolution in thinking regarding the underlying etiology and pathobiology of
LG. Due to the robust number of T-lymphocytes in the inflammatory infiltrates, LG was long thought to be a T-cell lymphoproliferative disorder.27 However, T-cell clonality within the lesions could not be reliably identified in early studies. Roughly a decade following its initial description, the link between LG and EBV was first described.28 Using a combination of EBV IHC and EBER ISH, Guinee et al. demonstrated atypical EBV + B-lymphocytes in 10 of 10 pulmonary lesions of confirmed LG cases.29 Immunoglobulin heavy chain gene rearrangement for B-cell clonality was demonstrated in 6 of 9 cases tested, leading the authors to conclude that LG was in fact a B-cell lymphoproliferative disorder with a florid T-cell background. Shortly after, researchers were able to demonstrate atypical EBV-positive cells in cutaneous lesions of LG, albeit to a lesser degree. In summary, lymphomatoid granulomatosis is a rare EBV-associated B-cell lymphoproliferative disorder that can progress to large cell lymphoma in high-grade lesions. It is a multisystem disorder that primarily affects the lungs and shows skin involvement in approximately half of cases. The clinical and microscopic features can be varied, particularly in skin biopsies, but LG should be considered in the differential for patients with multiple cutaneous nodules and plaques showing mixed and granulomatous inflammation, especially with angiocentric accentuation.
References 1. Liebow AA, Carrington CR, Friedman PJ. Lymphomatoid granulomatosis. Hum Pathol 1972; 3: 457. 2. Katzenstein AA, Carrington CB, Liebow AA. Lymphomatoid granulomatosis a clinicopathologic study of 152 cases. Cancer 1979; 43: 360. 3. Kwon EJ, Katz KA, Draft KS, et al. Posttransplantation lymphoproliferative disease with features of lymphomatoid granulomatosis in a lung transplant patient. J Am Acad Dermatol 2006; 54: 657. 4. Park JH, Lee DY, Ko YH. Cutaneous lesion of lymphomatoid granulomatosis in a Korean woman with secondary myelofibrosis. J Dermatol 2011; 38: 1012. 5. Sebire MH, Haselden S, Malone M, Davies EG, Ramsay AD. Isolated EBV lymphoproliferative disease in a child with Wiskott-Aldrich syndrome manifesting as cutaneous lymphomatoid granulomatosis and responsive to anti-CD20 immunotherapy. J Clin Pathol 2003; 56: 555.
192
6. Tas S, Simonart T, Dargent J, et al. Primary and isolated cutaneous lymphomatoid granulomatosis following heart-lung transplantation. Ann Dermatol Venereol 2000; 127: 488. 7. Pittaluga S, Wilson WH, Jaffe ES. Lymphomatoid granulomatosis. In Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, eds. WHO classification of tumors of haematopoietic and lymphoid tissues. Geneva: WHO Press, 2008; 247. 8. Beaty MW, Toro J, Sorbara L, et al. Cutaneous lymphomatoid granulomatosis correlation of clinical and biologic features. Am J Surg Pathol 2001; 25: 1111. 9. James WD, Odom RB, Katzenstein AA. Cutaneous manifestations of lymphomatoid granulomatosis. Arch Dermatol 1981; 117: 196. 10. Brodell RT, Miller CW, Eisen AZ. Cutaneous lesions of lymphomatoid granulomatosis. Arch Dermatol 1986; 122: 303.
11. Carlson KC, Gibson LE. Cutaneous signs of lymphomatoid granulomatosis. Arch Dermatol 1991; 127: 1693. 12. Wood ML, Harrington CI, Slater DN, Rooney N, Clark A. Cutaneous lymphomatoid granulomatosis: a rare cause of recurrent skin ulceration. Br J Dermatol 1984; 110: 619. 13. Camisa C. Lymphomatoid granulomatosis: two cases with skin involvement. J Am Acad Dermatol 1989; 20: 571. 14. Rongioletti F, Desirello G, Nazzari G. Ulcerated plaque and nodules on the thigh of a patient with febrile pulmonary disease. Arch Dermatol 1988; 124: 572. 15. Minars N, Kay S, Escobar MR. Lymphomatoid granulomatosis of the skin. A new clinicopathologic entity. Arch Dermatol 1975; 111: 493. 16. MacDonald DM. Lymphomatoid granulomatosis. Proc R Soc Med 1975; 68: 452. 17. Torrelo A, Martin M, Rocamora A, Alleque F, Ledo A. Lymphomatoid granulomatosis presenting as angioedema. Postgrad Med J 1992; 68: 366.
Lymphomatoid granulomatosis presenting with cutaneous involvement 18. Roschewski M, Wilson WH. Lymphomatoid granulomatosis. Cancer J 2012; 18: 469. 19. Madison McNiff J, Cooper D, Howe G, et al. Lymphomatoid granulomatosis of the skin and lung. An angiocentric T-cell-rich B-cell lymphoproliferative disorder. Arch Dermatol 1996; 132: 1464. 20. Frances C, Du LTH, Piette JC, et al. Wegener’s granulomatosis. Dermatological manifestations in 75 cases with clinicopathologic correlation. Arch Dermatol 1994; 130: 861. 21. Dojcinov SD, Venkataraman G, Raffeld M, Pittaluga S, Jaffe ES. EBV positive mucocutaneous ulcer-a study of 26 cases associated with various sources of immunosuppression. Am J Surg Pathol 2010; 34: 405. 22. Martin B, Whittaker S, Morris S, Robson A. A case of primary cutaneous senile EBV-related diffuse large B-cell lymphoma. Am J Dermatopathol 2010; 32: 190.
23. Oyama T, Ichimura K, Suzuki R, et al. Senile EBV + B-cell lymphoproliferative disorders. A clinicopathologic study of 22 patients. Am J Surg Pathol 2003; 27: 16. 24. Chan JKC, Quintanilla-Martinez L, Ferry JA, Peh SC. Extranodal NK/T-cell lymphoma, nasal type. In Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, eds. WHO classification of tumors of haematopoietic and lymphoid tissues. Geneva: WHO Press, 2008; 285. 25. Gaulard P, Berti E, Willemze R, Jaffe ES. Primary cutaneous peripheral T-cell lymphomas, rare subtypes. In Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, eds. WHO classification of tumors of haematopoietic and lymphoid tissues. Geneva: WHO Press, 2008; 302. 26. Pileri SA, Weisenburger DD, Sng I, et al. Peripheral T-cell lymphoma, not otherwise specified. In Swerdlow SH, Campo E,
Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, eds. WHO classification of tumors of haematopoietic and lymphoid tissues. Geneva: WHO Press, 2008; 306. 27. Lipford EH Jr, Margolick JV, Longo DL, Fauci AS, Jaffe ES. Angiocentric immunoproliferative lesions: a clinicopathologic spectrum of post-thymic T-cell proliferations. Blood 1988; 72: 1674. 28. Veltri RW, Raich PC, McClung JE, Shah SH, Sprinkle PM. Lymphomatoid granulomatosis and Epstein-Barr virus. Cancer 1982; 50: 1513. 29. Guinee D Jr, Jaffe E, Kingma D, et al. Pulmonary lymphomatoid granulomatosis. Evidence for a proliferation of Epstein-Barr virus infected B-lymphocytes with a prominent T-cell component and vasculitis. Am J Surg Pathol 1994; 18: 753.
193
