Anaplastic Large Cell Lymphoma Involving the Urinary Bladder: A Case Report and Review of the Literature Haiyan Chen, M.D., Ph.D.,1* Yanxia Li, M.D., Ph.D.,2 Sucha Nand, M.D.,3 Marcus L. Quek, M.D.,3 Ameet R. Kini, M.D., Ph.D.,1 €liz A. Barkan, M.D.1* and Gu
T cell-derived malignant lymphoma is rarely detected as a bladder neoplasm. A literature review for anaplastic large cell lymphoma (ALCL) involving urinary bladder reveals only seven previously reported cases. Here, we report a case of a 59-yearold HIV-negative man with ALK-positive ALCL. He presented an unusual clinical course with initial consideration of adult onset Still’s Disease (AOSD) due to his negative results searching for malignancy and infectious diseases. He rapidly developed macrophage activation (hemophagocytic) syndrome and experienced an unusual rapid disease progression and died in 39 days after onset of symptoms. Compared to previously reported cases, the current case of ALK-1-positive ALCL is a rare case with an unusual presentation. From this case, we learned that ALCL is one malignancy that should be considered and screened in patients with suspected AOSD. Also, T-cell lymphoma associated hemophagocytic syndrome should be considered in a patient with sustained corticosteroid-resistant spike fever, high serum ferritin, and rapid exacerbation of the disease course. Diagn. Cytopathol. 2015;43:60–65. VC 2014 Wiley Periodicals, Inc. Key Words: anaplastic large cell lymphoma; anaplastic lymphoma kinase; urinary bladder; T-cell lymphoma-associated hemophagocytic syndrome
It has been found that urogenital involvement by malignant lymphoma was present in approximately 7% of 1 Department of Pathology, Loyola University Medical Center, Maywood, Illinois 2 Department of Medicine, Loyola University Medical Center, Maywood, Illinois 3 Department of Urology, Loyola University Medical Center, Maywood, Illinois *Correspondence to: Haiyan Chen, MD, PhD, Department of Pathology, Loyola University Medical Center, 2160 S First Ave, Maywood, IL 60153, USA. E-mail: [email protected] or G€ uliz A. Barkan, MD, Department of Pathology, Loyola University Medical Center, 2160 S First Ave, Maywood, IL 60153, USA. E-mail: [email protected] Received 11 May 2013; Revised 12 December 2013; Accepted 16 January 2014 DOI: 10.1002/dc.23126 Published online 13 March 2014 in Wiley Online Library (wileyonlinelibrary.com).
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autopsies.1 Amongst the primary bladder lymphomas, the most frequently reported subtype is B-cell low-grade lymphoma of the mucosa-associated lymphoid tissue type.2 Anaplastic large cell lymphoma (ALCL) is a pleomorphic large cell lymphoma, usually of T or null cell origin, with constitutive expression of high level of the CD30 molecule.3 ALCL rarely originates as a bladder neoplasm, and to date, only seven cases of ALCL have been reported to show involvement of the urinary bladder.4–10 Except for a 78-year-old female, six of these cases were males with an age range of 22–45 years, which is consistent with the previous observation that the peak incidence of primary systemic ALCL was in childhood and young male adults.11,12 To the best of our knowledge, our patient is the first reported case of ALCL with involvement of bladder in a male over 50 years old. Anaplastic lymphoma kinase (ALK) protein expression can be detected in 60% of cases of all ALCL.13 In general, ALK-positivity is associated with better response to treatment and prognosis.11,14 However, a recent report showed no difference in prognosis between ALK-positive and ALK-negative cases in ALCL patients aged 40 years or older.15 Here, we reported a patient who had an ALK-positive ALCL, presented an unusual short disease course, and died 39 days after the onset of the first symptom of fever.
Case Report A 59-year-old man presented with fever, chills, and drenching sweats to an outside institution. Initial urine analysis revealed microscopic hematuria. Because of the concern for prostatitis, the patient received ciprofloxacin for three days, but the symptoms were not ameliorated. Chest X-ray revealed left lower lobe infiltrate and the patient was treated with clarithromycin (Biaxin), followed by azithromycin, which also did not resolve fever and chills. Laboratory studies revealed a leukocytosis of C 2014 WILEY PERIODICALS, INC. V
Diagnostic Cytopathology DOI 10.1002/dc
ANAPLASTIC LARGE CELL LYMPHOMA INVOLVING THE URINARY BLADDER
12,000–15,000/lL with a dominance of granulocytes (86–97%), as well as mildly elevated transaminases, lactate dehydrogenase (LDH), C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR). Extensive laboratory tests performed to rule out infectious diseases and autoimmune etiologies were negative. Serum protein electrophoresis and immunofixation did not show any monoclonal protein. A computed tomography (CT) chest/ abdomen/pelvis with contrast showed significant paraaortic lymphadenopathy. An exploratory laparotomy was performed and a para-aortic lymph node was biopsied, which showed a reactive lymph node without malignancy. Bone marrow biopsy was also negative for malignancy. The patient was transferred to our hospital 20 days after the onset of fever. He was still having fever and complained the increased urinary frequency. Urine analysis showed intermittent pyuria and hematuria. Laboratory data showed leukocytosis, anemia, mildly elevated liver enzymes, ESR, CRP, and markedly increase of serum ferritin (2213 lg/L, normal 20–300 lg/L). Adult Onset Still’s Disease (AOSD) was tentatively considered clinically. The patient received empirical treatment with prednisone. However, his fever persisted and his condition exacerbated quickly. The patient became hypotensive and developed renal and respiratory failure. His urine became grossly hemorrhagic. Serum ferritin gradually went up to 49,713 lg/L within two weeks. While AOSD with macrophage activation syndrome was considered, search for an underlying malignancy was continued. A repeat CT scan revealed extensive mesenteric, periportal, pericaval, periaortic, peripancreatic, and bilateral external iliac chain lymphadenopathy with a retroperitoneal lymph node mass measuring 4.7 cm 3 1.8 cm. Abdominal ultrasonography revealed bilateral hydronephrosis. The patient was taken for cystoscopy, which revealed that bladder wall was erythematous diffusely, mucosa was friable, and neither of the two ureteral orifices was identifiable. Bladder barbotage was performed, and the barbotage specimen was processed in the usual manner, and a Thin PrepTM smear was stained with the Papanicoalou method. Cytological examination of the bladder barbotage specimen identified rare highly atypical non-cohesive cells with moderate to high nuclear to cytoplasmic ratio, irregular nuclear contours, hyperchromatic nuclei, and inconspicuous nucleoli in a background of abundant mature-appearing lymphocytes (Fig. 1A). The differential diagnosis for this malignant process is broad including urothelial carcinoma, sarcomatoid carcinoma, lymphoepithelial-like carcinoma, neuroendocrine carcinoma, sarcoma, lymphoma, and metastatic malignancies especially melanoma. The features of urothelial carcinoma in urine cytology have been well described including plasmacytoid, pleomorphic with irregular nuclear membrane, and dark chromatin with prominent nucleoli.16 The cytology of our case made us favor for
non-urothelial carcinoma malignancy. Metastatic melanoma is not favorable because the patient had no history of melanoma and the cytology was not characteristic for typical melanoma which usually shows moderate amount of cytoplasma and prominent nucleoli. Although the discohesive nature of the maligant cells was suggestive of lymphoma, we could not classify further other than nonurothelial carcinoma malignancy due to the paucicellular nature of maligant cells in the urine specimen. We closely followed up the concomitant bladder biopsies which were fixed in buffered formalin and embedded in paraffin. Tissue was sectioned at a thickness of 5 mm, and stained with hematoxylin–eosin (HE). It was found a mostly denuded urothelial mucosa and an undermining densely infiltrative, partly necrotic neoplastic process involving muscularis propria of the urinary bladder. The infiltrating cells were large with abundant pale to clear cytoplasm, nuclear hyperchromasia, pleomorphism, and occasional prominent nucleoli. Vasocentric infiltration and destruction were noted (Fig. 1B). Initial immunohistochemical studies including AE1/AE3 for carcinoma, synaptophysin, chromogranin, and CD56 for neuroendocrine tumor and leukocyte common antigen (CDA or CD45) for hematopoietic malignancy showed the neoplastic cells were only positive for CD45. These results rendered the immediate intradepartmental hematopathology consult. Further staining with a panel of antibodies including CD3, CD4, CD5, CD30, ALK, CD20, CD8, CD34, TdT, was performed. The neoplastic cells were positive for CD3 (Fig. 2A), CD4, and CD5, but negative for CD8 (results not shown). The neoplastic cells showed strong immunoreactivity of CD30 with membrane and Golgi zone staining pattern (Fig. 2B). ALK revealed a diffuse cytoplasmic and nuclear staining (Fig. 2C), rendering a diagnosis of ALK-positive ALCL. The staining results are summarized in the last column of Table I, in the comparison of the previously reported seven cases. Unfortunately, the patient expired the day after his cystoscopy and the family declined an autopsy.
Discussion ALCL accounts for 2% of adult and 10–15% of pediatric/ adolescent non-Hodgkin lymphomas.12 It is known to be more common in children and young adults, but can occur in older adults with a bimodal age distribution.12 The majority of patients (60–70%) with systemic ALCL present with advanced stage III to IV disease showing peripheral and abdominal lymphadenopathy, frequently associated with extranodal and bone marrow involvement. Extranodal disease is often seen in skin, bone, soft tissue, lung, and liver in a descending order of frequency. ALK protein expression in tissues other than brain is usually observed in t(2:5)-associated NPM-ALK gene fusion and related pathological conditions.13 It has been estimated that 60% of ALK-positive ALCL show extranodal Diagnostic Cytopathology, Vol. 43, No 1
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CHEN ET AL.
Fig. 1. A: Atypical cells (arrow) identified in the sample obtained from bladder barbotage shows irregular nuclear contours and nuclear hyperchromasia, compared to the adjacent mature-appearing lymphocytes (Papanicolaou staining, 6003). B: The bladder biopsy tissue shows extensive infiltration of the tumor cells in the muscularis propria. These cells are large with abundant cytoplasm, nuclearpleomorphism, and hyperchromasia (HE staining, B:1003; B0 : 4003). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
involvement.17 ALCL rarely shows involvement of urinary bladder, but 7 of the 8 reported cases (87.5%) of ALCL detected in bladder showed positivity of ALK expression (Table I). To date, it remains unclear whether there is an association between ALK-positive-ALCL and its first detection in the bladder, which needs the accumulation of more cases. Interestingly, it has also reported that ALK expression was detected in bladder inflammatory myofibroblastic tumors,18 which should be taken into consideration of differential diagnosis.4 62
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Regarding the origin of the urinary bladder ALCL, it has been mainly considered a secondary presentation of nodal lymphoma in the previous reported cases (Table I). For the current case, although it was first detected in the bladder, we think it was a systemic disease process based on the following reasons. First, a bladder lymphoma is considered as a primary one only if the presenting symptoms are confined to bladder without involvement of the adjacent organs and no any evidence of lymphoma elsewhere at the time of diagnosis.7 In the current case, the
Diagnostic Cytopathology DOI 10.1002/dc
ANAPLASTIC LARGE CELL LYMPHOMA INVOLVING THE URINARY BLADDER
Fig. 2. Immunohistochemical staining reveals CD3 immunoreactivity in neoplastic cells (A: 1003; A0 : 4003). B: Immunohistochemical staining reveals CD30 in neoplastic cells with a cytoplasmic and Golgi zone staining pattern (4003). C: Immunohistochemical staining reveals diffuse presence of ALK in cytoplasm and nucleus in neoplastic cells (4003). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary. com.]
first biopsy of para-aortic lymph node did not reveal malignancy, but the second CT within one month revealed para-aortic merged mass and enlarged lymph nodes in other locations. It was suggested that the lymphoma may already existed in the lymph nodes before it was first detected in the bladder. In addition, the current patient showed “B” group symptoms of fever, chills, drenching sweat, and weight loss, which was not observed in any of 12 patients with the primary bladder lymphomas.7 Furthermore, it has generally been thought that primary bladder lymphoma is an indolent and curable disease because these lymphomas are confined to one organ and respond well to chemotherapy.2,7,9 In contrast, secondary involvement of bladder usually showed a poor prognosis. The condition of the current patient was progressively exacerbated in a very short course, and ultimately complicated with respiratory and renal failure, shock, and deceased on the 39th day since the onset of the fever. Such a short disease course did not fit the scenario of a primary bladder lymphoma. Lastly, ALK-1 positivity in extranodal ALCL is also considered an implication of a systemic lymphoma,19 and moderate expression of ALK-1 was detected in this case. Collec-
tively, in agreement with the literature in which only one case of bladder ALCL was suspected to be primary,7 we consider our patient had a bladder lymphoma derived from a more advanced systemic ALCL, although it has not been confirmed by autopsy which was declined by the family. It is worthwhile to point out that this patient was considered as AOSD because of his sustained high fever, leukocytosis, lymphadenopathy, abnormal liver function test, and negative rheumatoid factor and antinuclear antibodies. According to the most widely used Yamaguchi’s criteria for AOSD,20 it is reasonable to consider AOSD under the circumstance of lacking of the definitive evidence of infectious diseases and malignancy. This tentative clinical diagnosis was further supported by progressive hyperferritinemia, which has been well documented to be used as a diagnostic parameter for AOSD.21 However, before the ALCL was diagnosed according to pathological examination results, our patient had already expired. From this case, we learned that ALCL is one malignancy that should be screened in patients with suspected rheumatologic conditions after initial exclusion of infectious or neoplastic etiologies. Diagnostic Cytopathology, Vol. 43, No 1
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NA NA Systemic NA NA Yes No Claimed primary Excision, Chemo 7 years, NED NA NA Systemic Chemo 33 months, NED Hematuria Upper tract obstruction Lymphoma Involvement Treatment Outcome
ALK, anaplastic lymphoma kinase; EMA, epithelial membrane antigen; PALP, placental alkaline phosphatase; NA, not available; ND, not done; Chemo, Chemotherapy; NED, no evidence of disease, CK, cytokeratin; CG, Chromogranin; SP, Synaptophysin; OK, Oankeratin.
CD5 CD20, CD8, CD34, TdT, CD56, OK, SP, CG Yes Yes Systemic ND Died TCR-g CD20, CG, CK, SP, Cam5.2, 34bE12 NA Yes Systemic Chemo 4 months Alive CD2, CD7, CD8, CD10, CD34, TdT, CD79 Yes Yes Systemic Chemo NA NA CD20, CD79a, CD5, CD8, CD15, CD68, CK Yes Yes Systemic Chemo 1 year, NED NA CD43, CD20, CK
NA NA
TiA1, CD2, CD5 NA
HIV CD2, CD5, CD7, CD8, CD20, CD79a, CK, PLAP, S-100 NA Yes Systemic Chemo 9 months, Died
1 1 1 1 1 ND ND 1 1 2 NA 2 1 1 1 1 1 1 NA NA NA 1 1 2 1 1 NA 1 1 1 2 NA 1 NA 1
1 1 NA NA NA NA NA
1 1 1 NA NA 1 1
1 2 2 2 2 2 NA
59 M 45 M 26 M 39 M 28 M 78 F
Age (years) Gender Markers CD30 ALK CD3 CD4 CD45 Granzyme B EMA Other 1 2
22 M
27 M
Murphy8 Allory4 Hughes7 Pai9 Case
Table I. Reported Cases of Anaplastic Large Cell Lymphoma Involving the Urinary Bladder
Proca10
Blick5
G omez-Rom an6
Current case
CHEN ET AL.
In addition to the AOSD-like presentation, the patient’s rapidly progressive exacerbation, and sudden multi-organ system failure strongly support the diagnosis of T-cell lymphoma-associated hemophagocytic syndrome (T-LAHS), which is known for an extremely poor prognosis.22 In Tong’s study,22 all of 28 studied T-LAHS patients exhibited increased serum ferritin, and 11 of them died of multiorgan failure before medical treatment and the median survival of the LAHS were 40 days. Although we do not have definitive diagnostic evidences, such as postmortem examination for bone marrow, liver, lymph nodes, and CSF, the rapid disease course and laboratory results strongly supported the presence of T-LAHS. It has been thought that ALK-1 positive ALCL is generally associated with better diagnosis,11,14,19 and T-LAHS is usually seen in ALK-1 negative ALCL.22 Interestingly, our patient showed moderate ALK-1 positivity. Therefore, another important insight we learned from this case report is that T-LAHS should be in the differential diagnosis for a patient with sustained corticosteroid-resistant spike fever, high serum ferritin, and rapid exacerbation of the disease. In summary, we reported a patient who had an ALKpositive ALCL that first was detected in urinary bladder and presented an unusual short disease course and died 39 days after the onset of the first symptom of fever. From this case, we learned that the urinary system could be involved by ALCL and potentially be the first site from which the diagnosis of ALCL was established. The diagnosis of ALCL should be considered and screened in patients with suspected AOSD. T-LAHS should be considered in a patient with sustained corticosteroid-resistant spike fever, high serum ferritin, and rapid exacerbation of the disease course.
References 1. Weimar G, Culp DA, Loening S, Narayana A. Urogenital involvement by malignant lymphomas. J Urol 1981;125:230–231. 2. Kempton CL, Kurtin PJ, Inwards DJ, Wollan P, Bostwick DG. Malignant lymphoma of the bladder: Evidence from 36 cases that low-grade lymphoma of the MALT-type is the most common primary bladder lymphoma. Am J Surg Pathol 1997;21:1324–1333. 3. Falini B, Pileri S, Pizzolo G, et al. CD30 (Ki-1) molecule: A new cytokine receptor of the tumor necrosis factor receptor superfamily as a tool for diagnosis and immunotherapy. Blood 1995;85:1–14. 4. Allory Y, Merabet Z, Copie-Bergman C, Lange F, Yiou R, Gaulard P. Sarcomatoid variant of anaplastic large cell lymphoma mimics ALK-1-positive inflammatory myofibroblastic tumor in bladder. Am J Surg Pathol 2005;29:838–839; author reply 839. 5. Blick C, Abdelhadi S, Bailey D, Muneer A. Anaplastic, T-cell, non-Hodgkin’s Lymphoma presenting with haematuria. Sci World J 2008;8:342–345. 6. Gomez-Roman JJ, Cobo ML, Val-Bernal JF. Anaplastic lymphoma kinase-positive anaplastic large cell lymphoma presenting as a bladder neoplasm. Pathol Int 2008;58:249–252. 7. Hughes M, Morrison A, Jackson R. Primary bladder lymphoma: Management and outcome of 12 patients with a review of the literature. Leuk Lymphoma 2005;46:873–877.
Diagnostic Cytopathology DOI 10.1002/dc
ANAPLASTIC LARGE CELL LYMPHOMA INVOLVING THE URINARY BLADDER 8. Murphy AJ, O’Neill P, O’Brien F, et al. Anaplastic large cell lymphoma: A unique presentation with urinary bladder involvement: A case report. Int J Surg Pathol 2005;13:369–373.
16. McCroskey Z, Mehta V, Wojeck EM, et al. Myeloid Leukemia in a urine specimen: a case report and review of the literature. Diagn Cytopathology 2013. [Epub ahead of print].
9. Pai SA, Naresh KN, Patil PU. Systemic anaplastic large cell lymphoma presenting as a bladder neoplasm. Leuk Lymphoma 2004; 45:841–843.
17. Falini B, Martelli MP. Anaplastic large cell lymphoma: Changes in the World Health Organization classification and perspectives for targeted therapy. Haematologica 2009;94:897–900.
10. Proca DM, De Renne L, Marsh WL, Jr, Keyhani-Rofagha S. Anaplastic large cell lymphoma in a human immunodeficiency viruspositive patient with cytologic findings in bladder wash: A case report. Acta Cytol 2008;52:83–86. 11. Piccaluga PP, Gazzola A, Mannu C, et al. Pathobiology of anaplastic large cell lymphoma. Adv Hematol 2010;2010: 345053. 12. Kinney MC, Higgins RA, Medina EA. Anaplastic large cell lymphoma: Twenty-five years of discovery. Arch Pathol Lab Med 2011;135:19–43. 13. Falini B, Bigerna B, Fizzotti M, et al. ALK expression defines a distinct group of T/null lymphomas (“ALK lymphomas”) with a wide morphological spectrum. Am J Pathol 1998;153:875–886. 14. Stein H, Foss HD, Durkop H, et al. CD30(1) anaplastic large cell lymphoma: A review of its histopathologic, genetic, and clinical features. Blood 2000;96:3681–3695. 15. Savage KJ, Harris NL, Vose JM, et al. ALK-anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK1 ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project. Blood 2008;111:5496–5504.
18. Freeman A, Geddes N, Munson P, et al. Anaplastic lymphoma kinase (ALK 1) staining and molecular analysis in inflammatory myofibroblastic tumours of the bladder: A preliminary clinicopathological study of nine cases and review of the literature. Mod Pathol 2004;17:765–771. 19. Ten Berge RL, Oudejans JJ, Ossenkoppele GJ, et al. ALK expression in extranodal anaplastic large cell lymphoma favours systemic disease with (primary) nodal involvement and a good prognosis and occurs before dissemination. J Clin Pathol 2000;53:445–450. 20. Yamaguchi M, Ohta A, Tsunematsu T, et al. Preliminary criteria for classification of adult Still’s disease. J Rheumatol 1992;19:424– 430. 21. Meijvis SC, Endeman H, Geers AB, ter Borg EJ. Extremely high serum ferritin levels as diagnostic tool in adult-onset Still’s disease. Neth J Med 2007;65:212–214. 22. Tong H, Ren Y, Liu H, et al. Clinical characteristics of T-cell lymphoma associated with hemophagocytic syndrome: Comparison of T-cell lymphoma with and without hemophagocytic syndrome. Leuk Lymphoma 2008;49:81–87.
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T cell-derived malignant lymphoma is rarely detected as a bladder neoplasm. A literature review for anaplastic large cell lymphoma (ALCL) involving urinary bladder reveals only seven previously reported cases. Here, we report a case of a 59-yearold HIV-negative man with ALK-positive ALCL. He presented an unusual clinical course with initial consideration of adult onset Still’s Disease (AOSD) due to his negative results searching for malignancy and infectious diseases. He rapidly developed macrophage activation (hemophagocytic) syndrome and experienced an unusual rapid disease progression and died in 39 days after onset of symptoms. Compared to previously reported cases, the current case of ALK-1-positive ALCL is a rare case with an unusual presentation. From this case, we learned that ALCL is one malignancy that should be considered and screened in patients with suspected AOSD. Also, T-cell lymphoma associated hemophagocytic syndrome should be considered in a patient with sustained corticosteroid-resistant spike fever, high serum ferritin, and rapid exacerbation of the disease course. Diagn. Cytopathol. 2015;43:60–65. VC 2014 Wiley Periodicals, Inc. Key Words: anaplastic large cell lymphoma; anaplastic lymphoma kinase; urinary bladder; T-cell lymphoma-associated hemophagocytic syndrome
It has been found that urogenital involvement by malignant lymphoma was present in approximately 7% of 1 Department of Pathology, Loyola University Medical Center, Maywood, Illinois 2 Department of Medicine, Loyola University Medical Center, Maywood, Illinois 3 Department of Urology, Loyola University Medical Center, Maywood, Illinois *Correspondence to: Haiyan Chen, MD, PhD, Department of Pathology, Loyola University Medical Center, 2160 S First Ave, Maywood, IL 60153, USA. E-mail: [email protected] or G€ uliz A. Barkan, MD, Department of Pathology, Loyola University Medical Center, 2160 S First Ave, Maywood, IL 60153, USA. E-mail: [email protected] Received 11 May 2013; Revised 12 December 2013; Accepted 16 January 2014 DOI: 10.1002/dc.23126 Published online 13 March 2014 in Wiley Online Library (wileyonlinelibrary.com).
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autopsies.1 Amongst the primary bladder lymphomas, the most frequently reported subtype is B-cell low-grade lymphoma of the mucosa-associated lymphoid tissue type.2 Anaplastic large cell lymphoma (ALCL) is a pleomorphic large cell lymphoma, usually of T or null cell origin, with constitutive expression of high level of the CD30 molecule.3 ALCL rarely originates as a bladder neoplasm, and to date, only seven cases of ALCL have been reported to show involvement of the urinary bladder.4–10 Except for a 78-year-old female, six of these cases were males with an age range of 22–45 years, which is consistent with the previous observation that the peak incidence of primary systemic ALCL was in childhood and young male adults.11,12 To the best of our knowledge, our patient is the first reported case of ALCL with involvement of bladder in a male over 50 years old. Anaplastic lymphoma kinase (ALK) protein expression can be detected in 60% of cases of all ALCL.13 In general, ALK-positivity is associated with better response to treatment and prognosis.11,14 However, a recent report showed no difference in prognosis between ALK-positive and ALK-negative cases in ALCL patients aged 40 years or older.15 Here, we reported a patient who had an ALK-positive ALCL, presented an unusual short disease course, and died 39 days after the onset of the first symptom of fever.
Case Report A 59-year-old man presented with fever, chills, and drenching sweats to an outside institution. Initial urine analysis revealed microscopic hematuria. Because of the concern for prostatitis, the patient received ciprofloxacin for three days, but the symptoms were not ameliorated. Chest X-ray revealed left lower lobe infiltrate and the patient was treated with clarithromycin (Biaxin), followed by azithromycin, which also did not resolve fever and chills. Laboratory studies revealed a leukocytosis of C 2014 WILEY PERIODICALS, INC. V
Diagnostic Cytopathology DOI 10.1002/dc
ANAPLASTIC LARGE CELL LYMPHOMA INVOLVING THE URINARY BLADDER
12,000–15,000/lL with a dominance of granulocytes (86–97%), as well as mildly elevated transaminases, lactate dehydrogenase (LDH), C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR). Extensive laboratory tests performed to rule out infectious diseases and autoimmune etiologies were negative. Serum protein electrophoresis and immunofixation did not show any monoclonal protein. A computed tomography (CT) chest/ abdomen/pelvis with contrast showed significant paraaortic lymphadenopathy. An exploratory laparotomy was performed and a para-aortic lymph node was biopsied, which showed a reactive lymph node without malignancy. Bone marrow biopsy was also negative for malignancy. The patient was transferred to our hospital 20 days after the onset of fever. He was still having fever and complained the increased urinary frequency. Urine analysis showed intermittent pyuria and hematuria. Laboratory data showed leukocytosis, anemia, mildly elevated liver enzymes, ESR, CRP, and markedly increase of serum ferritin (2213 lg/L, normal 20–300 lg/L). Adult Onset Still’s Disease (AOSD) was tentatively considered clinically. The patient received empirical treatment with prednisone. However, his fever persisted and his condition exacerbated quickly. The patient became hypotensive and developed renal and respiratory failure. His urine became grossly hemorrhagic. Serum ferritin gradually went up to 49,713 lg/L within two weeks. While AOSD with macrophage activation syndrome was considered, search for an underlying malignancy was continued. A repeat CT scan revealed extensive mesenteric, periportal, pericaval, periaortic, peripancreatic, and bilateral external iliac chain lymphadenopathy with a retroperitoneal lymph node mass measuring 4.7 cm 3 1.8 cm. Abdominal ultrasonography revealed bilateral hydronephrosis. The patient was taken for cystoscopy, which revealed that bladder wall was erythematous diffusely, mucosa was friable, and neither of the two ureteral orifices was identifiable. Bladder barbotage was performed, and the barbotage specimen was processed in the usual manner, and a Thin PrepTM smear was stained with the Papanicoalou method. Cytological examination of the bladder barbotage specimen identified rare highly atypical non-cohesive cells with moderate to high nuclear to cytoplasmic ratio, irregular nuclear contours, hyperchromatic nuclei, and inconspicuous nucleoli in a background of abundant mature-appearing lymphocytes (Fig. 1A). The differential diagnosis for this malignant process is broad including urothelial carcinoma, sarcomatoid carcinoma, lymphoepithelial-like carcinoma, neuroendocrine carcinoma, sarcoma, lymphoma, and metastatic malignancies especially melanoma. The features of urothelial carcinoma in urine cytology have been well described including plasmacytoid, pleomorphic with irregular nuclear membrane, and dark chromatin with prominent nucleoli.16 The cytology of our case made us favor for
non-urothelial carcinoma malignancy. Metastatic melanoma is not favorable because the patient had no history of melanoma and the cytology was not characteristic for typical melanoma which usually shows moderate amount of cytoplasma and prominent nucleoli. Although the discohesive nature of the maligant cells was suggestive of lymphoma, we could not classify further other than nonurothelial carcinoma malignancy due to the paucicellular nature of maligant cells in the urine specimen. We closely followed up the concomitant bladder biopsies which were fixed in buffered formalin and embedded in paraffin. Tissue was sectioned at a thickness of 5 mm, and stained with hematoxylin–eosin (HE). It was found a mostly denuded urothelial mucosa and an undermining densely infiltrative, partly necrotic neoplastic process involving muscularis propria of the urinary bladder. The infiltrating cells were large with abundant pale to clear cytoplasm, nuclear hyperchromasia, pleomorphism, and occasional prominent nucleoli. Vasocentric infiltration and destruction were noted (Fig. 1B). Initial immunohistochemical studies including AE1/AE3 for carcinoma, synaptophysin, chromogranin, and CD56 for neuroendocrine tumor and leukocyte common antigen (CDA or CD45) for hematopoietic malignancy showed the neoplastic cells were only positive for CD45. These results rendered the immediate intradepartmental hematopathology consult. Further staining with a panel of antibodies including CD3, CD4, CD5, CD30, ALK, CD20, CD8, CD34, TdT, was performed. The neoplastic cells were positive for CD3 (Fig. 2A), CD4, and CD5, but negative for CD8 (results not shown). The neoplastic cells showed strong immunoreactivity of CD30 with membrane and Golgi zone staining pattern (Fig. 2B). ALK revealed a diffuse cytoplasmic and nuclear staining (Fig. 2C), rendering a diagnosis of ALK-positive ALCL. The staining results are summarized in the last column of Table I, in the comparison of the previously reported seven cases. Unfortunately, the patient expired the day after his cystoscopy and the family declined an autopsy.
Discussion ALCL accounts for 2% of adult and 10–15% of pediatric/ adolescent non-Hodgkin lymphomas.12 It is known to be more common in children and young adults, but can occur in older adults with a bimodal age distribution.12 The majority of patients (60–70%) with systemic ALCL present with advanced stage III to IV disease showing peripheral and abdominal lymphadenopathy, frequently associated with extranodal and bone marrow involvement. Extranodal disease is often seen in skin, bone, soft tissue, lung, and liver in a descending order of frequency. ALK protein expression in tissues other than brain is usually observed in t(2:5)-associated NPM-ALK gene fusion and related pathological conditions.13 It has been estimated that 60% of ALK-positive ALCL show extranodal Diagnostic Cytopathology, Vol. 43, No 1
61
Diagnostic Cytopathology DOI 10.1002/dc
CHEN ET AL.
Fig. 1. A: Atypical cells (arrow) identified in the sample obtained from bladder barbotage shows irregular nuclear contours and nuclear hyperchromasia, compared to the adjacent mature-appearing lymphocytes (Papanicolaou staining, 6003). B: The bladder biopsy tissue shows extensive infiltration of the tumor cells in the muscularis propria. These cells are large with abundant cytoplasm, nuclearpleomorphism, and hyperchromasia (HE staining, B:1003; B0 : 4003). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
involvement.17 ALCL rarely shows involvement of urinary bladder, but 7 of the 8 reported cases (87.5%) of ALCL detected in bladder showed positivity of ALK expression (Table I). To date, it remains unclear whether there is an association between ALK-positive-ALCL and its first detection in the bladder, which needs the accumulation of more cases. Interestingly, it has also reported that ALK expression was detected in bladder inflammatory myofibroblastic tumors,18 which should be taken into consideration of differential diagnosis.4 62
Diagnostic Cytopathology, Vol. 43, No 1
Regarding the origin of the urinary bladder ALCL, it has been mainly considered a secondary presentation of nodal lymphoma in the previous reported cases (Table I). For the current case, although it was first detected in the bladder, we think it was a systemic disease process based on the following reasons. First, a bladder lymphoma is considered as a primary one only if the presenting symptoms are confined to bladder without involvement of the adjacent organs and no any evidence of lymphoma elsewhere at the time of diagnosis.7 In the current case, the
Diagnostic Cytopathology DOI 10.1002/dc
ANAPLASTIC LARGE CELL LYMPHOMA INVOLVING THE URINARY BLADDER
Fig. 2. Immunohistochemical staining reveals CD3 immunoreactivity in neoplastic cells (A: 1003; A0 : 4003). B: Immunohistochemical staining reveals CD30 in neoplastic cells with a cytoplasmic and Golgi zone staining pattern (4003). C: Immunohistochemical staining reveals diffuse presence of ALK in cytoplasm and nucleus in neoplastic cells (4003). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary. com.]
first biopsy of para-aortic lymph node did not reveal malignancy, but the second CT within one month revealed para-aortic merged mass and enlarged lymph nodes in other locations. It was suggested that the lymphoma may already existed in the lymph nodes before it was first detected in the bladder. In addition, the current patient showed “B” group symptoms of fever, chills, drenching sweat, and weight loss, which was not observed in any of 12 patients with the primary bladder lymphomas.7 Furthermore, it has generally been thought that primary bladder lymphoma is an indolent and curable disease because these lymphomas are confined to one organ and respond well to chemotherapy.2,7,9 In contrast, secondary involvement of bladder usually showed a poor prognosis. The condition of the current patient was progressively exacerbated in a very short course, and ultimately complicated with respiratory and renal failure, shock, and deceased on the 39th day since the onset of the fever. Such a short disease course did not fit the scenario of a primary bladder lymphoma. Lastly, ALK-1 positivity in extranodal ALCL is also considered an implication of a systemic lymphoma,19 and moderate expression of ALK-1 was detected in this case. Collec-
tively, in agreement with the literature in which only one case of bladder ALCL was suspected to be primary,7 we consider our patient had a bladder lymphoma derived from a more advanced systemic ALCL, although it has not been confirmed by autopsy which was declined by the family. It is worthwhile to point out that this patient was considered as AOSD because of his sustained high fever, leukocytosis, lymphadenopathy, abnormal liver function test, and negative rheumatoid factor and antinuclear antibodies. According to the most widely used Yamaguchi’s criteria for AOSD,20 it is reasonable to consider AOSD under the circumstance of lacking of the definitive evidence of infectious diseases and malignancy. This tentative clinical diagnosis was further supported by progressive hyperferritinemia, which has been well documented to be used as a diagnostic parameter for AOSD.21 However, before the ALCL was diagnosed according to pathological examination results, our patient had already expired. From this case, we learned that ALCL is one malignancy that should be screened in patients with suspected rheumatologic conditions after initial exclusion of infectious or neoplastic etiologies. Diagnostic Cytopathology, Vol. 43, No 1
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NA NA Systemic NA NA Yes No Claimed primary Excision, Chemo 7 years, NED NA NA Systemic Chemo 33 months, NED Hematuria Upper tract obstruction Lymphoma Involvement Treatment Outcome
ALK, anaplastic lymphoma kinase; EMA, epithelial membrane antigen; PALP, placental alkaline phosphatase; NA, not available; ND, not done; Chemo, Chemotherapy; NED, no evidence of disease, CK, cytokeratin; CG, Chromogranin; SP, Synaptophysin; OK, Oankeratin.
CD5 CD20, CD8, CD34, TdT, CD56, OK, SP, CG Yes Yes Systemic ND Died TCR-g CD20, CG, CK, SP, Cam5.2, 34bE12 NA Yes Systemic Chemo 4 months Alive CD2, CD7, CD8, CD10, CD34, TdT, CD79 Yes Yes Systemic Chemo NA NA CD20, CD79a, CD5, CD8, CD15, CD68, CK Yes Yes Systemic Chemo 1 year, NED NA CD43, CD20, CK
NA NA
TiA1, CD2, CD5 NA
HIV CD2, CD5, CD7, CD8, CD20, CD79a, CK, PLAP, S-100 NA Yes Systemic Chemo 9 months, Died
1 1 1 1 1 ND ND 1 1 2 NA 2 1 1 1 1 1 1 NA NA NA 1 1 2 1 1 NA 1 1 1 2 NA 1 NA 1
1 1 NA NA NA NA NA
1 1 1 NA NA 1 1
1 2 2 2 2 2 NA
59 M 45 M 26 M 39 M 28 M 78 F
Age (years) Gender Markers CD30 ALK CD3 CD4 CD45 Granzyme B EMA Other 1 2
22 M
27 M
Murphy8 Allory4 Hughes7 Pai9 Case
Table I. Reported Cases of Anaplastic Large Cell Lymphoma Involving the Urinary Bladder
Proca10
Blick5
G omez-Rom an6
Current case
CHEN ET AL.
In addition to the AOSD-like presentation, the patient’s rapidly progressive exacerbation, and sudden multi-organ system failure strongly support the diagnosis of T-cell lymphoma-associated hemophagocytic syndrome (T-LAHS), which is known for an extremely poor prognosis.22 In Tong’s study,22 all of 28 studied T-LAHS patients exhibited increased serum ferritin, and 11 of them died of multiorgan failure before medical treatment and the median survival of the LAHS were 40 days. Although we do not have definitive diagnostic evidences, such as postmortem examination for bone marrow, liver, lymph nodes, and CSF, the rapid disease course and laboratory results strongly supported the presence of T-LAHS. It has been thought that ALK-1 positive ALCL is generally associated with better diagnosis,11,14,19 and T-LAHS is usually seen in ALK-1 negative ALCL.22 Interestingly, our patient showed moderate ALK-1 positivity. Therefore, another important insight we learned from this case report is that T-LAHS should be in the differential diagnosis for a patient with sustained corticosteroid-resistant spike fever, high serum ferritin, and rapid exacerbation of the disease. In summary, we reported a patient who had an ALKpositive ALCL that first was detected in urinary bladder and presented an unusual short disease course and died 39 days after the onset of the first symptom of fever. From this case, we learned that the urinary system could be involved by ALCL and potentially be the first site from which the diagnosis of ALCL was established. The diagnosis of ALCL should be considered and screened in patients with suspected AOSD. T-LAHS should be considered in a patient with sustained corticosteroid-resistant spike fever, high serum ferritin, and rapid exacerbation of the disease course.
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18. Freeman A, Geddes N, Munson P, et al. Anaplastic lymphoma kinase (ALK 1) staining and molecular analysis in inflammatory myofibroblastic tumours of the bladder: A preliminary clinicopathological study of nine cases and review of the literature. Mod Pathol 2004;17:765–771. 19. Ten Berge RL, Oudejans JJ, Ossenkoppele GJ, et al. ALK expression in extranodal anaplastic large cell lymphoma favours systemic disease with (primary) nodal involvement and a good prognosis and occurs before dissemination. J Clin Pathol 2000;53:445–450. 20. Yamaguchi M, Ohta A, Tsunematsu T, et al. Preliminary criteria for classification of adult Still’s disease. J Rheumatol 1992;19:424– 430. 21. Meijvis SC, Endeman H, Geers AB, ter Borg EJ. Extremely high serum ferritin levels as diagnostic tool in adult-onset Still’s disease. Neth J Med 2007;65:212–214. 22. Tong H, Ren Y, Liu H, et al. Clinical characteristics of T-cell lymphoma associated with hemophagocytic syndrome: Comparison of T-cell lymphoma with and without hemophagocytic syndrome. Leuk Lymphoma 2008;49:81–87.
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