Small Cell Variant Anaplastic Large Cell Lymphoma: Long-Term Remission after Allogeneic Peripheral Blood Stem Cell Transplant

    

    

    Figure 1:  (A) Low power view of lymph node shows dilated nodal sinuses with small cell in filtrate (H&E 10x). (B) Predominant population of small cells with scattered large cells, the latter primarily in the perivascular regions (H&E 20x). (C) CD3 staining shows these cells to be T-cells. Residual follicular structure is evident. (D) CD30 highlights the sinusoidal and perivascular infiltrate. (E and F) The malignant cells are ALK+ with a subpopulation also being EMA+.
    
    

During initial workup, leukocytosis increased and reached a peak of 69.4 K/mm³ on day 4 of hospitalization. The patient also experienced worsening abdominal pain and hypoxic respiratory failure, eventually requiring intubation. Serial CT scans showed worsening interstitial lung infiltrates. Bronchoalveolar lavage was negative for malignant cells, but pleural fluid analysis showed atypical lymphocytes consistent with a T-cell neoplasm. Patient began therapy with hyper-CVAD [12] with remarkable clearing of pulmonary infiltrates and reduction of hepatosplenomegaly and pain. She was able to be extubated on day 12 of hospitalization and discharged on day 23.

Discussion

ALCL by Morphological subgroup

There are several morphological subgroups of ALK+ ALCL: the most common classic type, and less common lymphohistiocytic and small cell variants. The classic type comprises about 70% of cases and is characterized histologically by sheets of "hallmark cells," large cells with abundant cytoplasm and a horseshoe-shaped nucleus with multiple nucleoli surrounded by a prominent, pale Golgi region [1,7]. These cells can be found in all ALCL subtypes. The lymphohistiocytic variant comprises 5-10% of cases and is characterized by tumor cells smaller than those in the common type that are often masked by a large number of histiocytes that do not proliferate despite monomorphic appearance. Immunostaining for CD-30 and Ki-67 is particularly important in this variant to identify tumor cells and to distinguish ALCL from malignant histiocytosis [1,7]. The small cell variant of ALK+ ALCL, was first described in 1993 by Kinney, et al. [9] This variant comprises 5-10% of cases, affects primarily younger patients (median age 14 [9]), and is characterized morphologically by a mixture of small, medium, and large lymphoid cells with the nuclei of the small and medium cells often being irregular [1,7]. Interestingly, while the large cells are always CD30+, the small cells are often CD30- [5]. However, in lymph nodes, the small cell variant usually has areas of large CD30+ blasts indicative of the common type of ALCL, which assists in diagnosis.

Even though all of small cell variant cases have been shown to be ALK+ [1], the prognosis is poor. Kinney, et al. discussed a series of 8 patients with small cell variant receiving combination chemotherapy of who 7 achieved CR. However, 5 relapsed within 2-21 months after remission with a median time to relapse of 10 months [9]. In another case series involving 4 patients, Youd et al. described similar survival data with 2-year OS of 50% and 3-year DFS of 25% [10]. This pattern of initial response to treatment followed by treatment-resistant relapse is in contrast to the common subtype of ALK+ ALCL. Interestingly, the survival data for small cell variant are comparable to those for ALK- ALCL rather than ALK+. In a series of 28 patients of which 4 were diagnosed with ALK- systemic ALCL, Jagasia, et al. demonstrated that 2 achieved CR with initial therapy with 1 relapsing in 212 days. Even after further treatment, OS and EFS were found to be 50% and 0% respectively for patients with ALK- ALCL [11].

ALCL with Leukemic involvement

One potential explanation for the poor prognosis and aggressive nature of small cell variant ALCL is the high incidence of leukemic involvement. While leukemic peripheral blood involvement is rare in classic ALCL, it is common with the small cell variant. In a case series of 3 patients with leukemic involvement in ALK+ ALCL by Onciu, et al. 2 of the 3 had marrow and nodal evidence of small cell variant. Neither patient achieved a lasting response after chemotherapy, so HSCT was considered. One patient underwent allogeneic transplantation and achieved CR, while the other continued to decline rapidly and died before transplant [13]. As shown by a complete review of cases by Nguyen, et al., poor prognosis is seen throughout all cases of ALCL with leukemic involvement including both the classic type and small cell variant. Of the 21 leukemic cases of ALCL reported, 18 patients had small cell variant ALCL (the other 3 had the classic type), 13 died of their disease with a median survival of 2.75 months, and 3 patients had either relapsed or were still on treatment at the time of report[14].

HSCT in ALCL

There have been a number of reports concerning the efficacy of allo HSCT in ALCL, morphological subtype unspecified. In a retrospective analysis of 27 patients with treatment-refractory ALCL, Le Gouill, et al. reported 5-year OS and EFS of 55% and 48% respectively after allogeneic HSCT [15]. Dodero et al. reported very similar results in a retrospective analysis of 11 patients with ALCL, with 5-year OS and EFS of 54% and 45% respectively post-allogeneic HSCT [16]. In a retrospective analysis of 64 patients with ALCL, He, et al. compared OS and EFS between treatment with conventional chemotherapy and allo PBSCT. Results revealed that 4-year OS and EFS from PBSCT at first remission were not significantly different (90.9% PBSCT vs. 88.3% for chemo, p = 0.580 and 81.8% vs. 70.7%, p = 0.240 respectively). However, 4-year EFS was significantly better with PBSCT for patients with B symptoms (100% vs. 50.8%, p = 0.027) and bulky disease (100% vs. 52.8%, p = 0.045) [17]. The efficacy of allogeneic HSCT for refractory or relapsed ALCL suggests a graft-versus-lymphoma effect that may also be beneficial for poorprognosis morphological subtypes of ALCL such as the small cell variant.

HSCT in small cell variant ALCL

Due to the poor prognosis and lack of continued response to chemotherapy of ALCL, small cell variant, HSCT has been explored as a potential therapy. A total of 11 cases (including this case) of small cell variant ALCL treated with HSCT (3 auto, 8 allo) have been identified in the literature and are presented in Table 1 [9,13,18-22]. Patient age ranged from 4 months to 40 years with a median age of 16 years.. Each of the 11 patients received a different treatment regimen prior to undergoing transplantation and had variable disease statuses at the time of transplant (1 active disease, 4 relapse, 4 PR, 2 CR). Of the 11 patients, 6 were in CR for a median time of 18 months at the time of report publication, with our patient achieving a remarkable 116 months of CR. There do not seem to be significant differences between responses for auto vs. allo HSCT (CR in 2 of 3 auto patients, 5 of 8 allo) or for HLA-identical vs. single-antigen mismatch donors (CR in 4 of 5 HLA-identical patients, 1 of 2 single mismatch), but the sample size is admittedly small. Interestingly, six of these cases are from the last 10 years with 5 of 6 patients having achieved CR after HSCT, potentially indicating that modern advances in the transplantation process have led to an even better response. Due to the promising data including very good recent responses, HSCT appears to be a viable option for treatment of small cell variant ALCL.

  

    
Patient 
    
Age/Ethnicity/Sex 
    
Presentation 
    
Primary Location 
    
WBC Count (x109/L) / Lymphocytes (%) / Atypical Cells (%) 
    
Therapy 
    
Type of HSCT 
    
Follow-up 
  
  

    
1 [9] 
    
4 mo M
    
NA
    
BM, LN
    
NA
    
MACOP-B; Auto HSCT x 2 after relapse
    
Auto
    
Died 10 mo after transplant
  
  

    
2 [9] 
    
12 M
    
NA
    
Bone, skin
    
NA
    
D-COMP and EBRT; ECP, Auto HSCT after relapse
    
Auto
    
CR 26 mo after diagnosis
  
  

    
3 [9] 
    
14 F
    
NA
    
LN, skin
    
NA
    
D-COMP; Allo HSCT after relapse
    
Allo
    
Died 23 mo after transplant
  
  

    
4 [18] 
    
18 Italian F
    
Few weeks of fever, weight loss, cough, LAD
    
BM, LN, lung, mediastinum, skin, relapse to CNS, skin
    
15 / 61% / 90%
    
CHOP; additional tx after relapse; Allo HSCT from HLA-identical    sibling donor while in CR
    
Allo (HLA-identical)
    
CR 18 mo after diagnosis
  
  

    
5 [18] 
    
20 mo French F
    
2 weeks of fever, LAD
    
BM, liver, LN, spleen, relapse to BM, LN, skin
    
37.9 peaking to 120 / 72% / 90%
    
COPAD-M; vinblastine then Allo HSCT from HLA-identical sibling after    relapse
    
Allo (HLA-identical)
    
Died a few mo after transplant
  
  

    
6 [13] 
    
6 F
    
Fever, LAD, progressing to respiratory distress
    
BM, LN, lung, kidneys
    
60 peaking to 216 / NA / 51%
    
APO; MIED after poor response; alternating lomustine, vinblastine, and    bleomycin and� lomustine, vinblastine,    and cytarabine after poor response; HLA-identical Allo HSCT with active    diseasea
    
Allo (HLA-identical)
    
CR 17 mo after diagnosis
  
  

    
7 [19] 
    
16 M
    
NA
    
BM, CNS, liver, LN, lungs, mediastinum, skin, spleen
    
NA
    
Unrelated single-mismatch Allo HSCT after PR to initial txb
    
Allo (single-mismatch)
    
CR 29 mo after diagnosis
  
  


    
8 [20] 
    
29 African-American M
    
1 week of fever, HA, myalgias, chills, RUQ pain, anorexia
    
BM, CNS, liver, LN, pleura, spleen
    
20 peaking to 81.3 / 17% / NA
    
Daunorubicin, vincristine, and prednisone; Hyper-CVAD and IT MTX after    re-diagnosis; multi-tx regimen after worsening statusc; unrelated    single-mismatch Allo HSCT after PRd
    
Allo (single-mismatch)
    
Died 1 mo after transplant from severe GVHD
  
  

    
9 [21] 
    
23 Japanese F
    
2 weeks of fever, weakness
    
BM, relapse to lung
    
24.5 / NA / 5.5%
    
CHOP; Auto PBSCT while in CR; CHOP after relapse
    
Auto
    
CR at time of report
  
  

    
10 [22] 
    
40 Japanese M
    
Fever, LAD, leukocytosis
    
BM, liver, LN, pleura, spleen, spread to CNS
    
34 / NA / 31%
    
Unknown induction tx; HD-MTX, HD-cytarabine, IT MTX after CNS spread;    single-mismatch sibling Allo PBSCT after PRe
    
Allo (single- mismatch)
    
CR 18 mo after diagnosis
  
  

    
11 (current case) 
    
31 Caucasian American F
    
3 weeks of fever, HA, LUQ pain, chills, NS, leukocytosis
    
BM, liver, LN, pleura, spleen, spread to skin
    
35 peaking to 69.4 / 17%� / 14%
    
Hyper-CVAD A and B and IT MTX; HLA-identical sibling Allo PBSCT after    PRf
    
Allo (HLA-identical)
    
CR 116 mo after diagnosis
  

Table 1:  Reported cases of small cell variant ALCL treated with HSCT.