T-Cell Prolymphocytic Leukemia Involving Extramedullary Sites

Jose R. Valbuena, MD; Marco Herling, MD; Joan H. Admirand, MD; Anthony Padula, MD; Dan Jones, MD, PhD; L. Jeffrey Medeiros, MD


Am J Clin Pathol. 2005;123(3):456-464. 

In This Article


The study group included 8 women and 6 men with a mean age of 65.4 years (range, 49-77 years). At the time of initial diagnosis, all 14 patients (100%) had clinical evidence of extramedullary disease, including lymphadenopathy (n = 9), maculopapular skin lesions (n = 7), splenomegaly (n = 4), pleural effusion (n = 3), ascites (n = 1), hepatomegaly (n = 1), and a paraspinal mass (n = 1). However, none of these sites was biopsied at the time of diagnosis because the diagnosis was established by examination of peripheral blood and bone marrow samples.

At the time of biopsy of an extramedullary site, all patients had clinical evidence of disease progression, following complete or partial clinical remission ( Table 2 ). At this time, the WBC count ranged from 2,100 to 286,000/µL (2.1-286.0 × 109/L); 12 patients had an elevated WBC count. T-PLL was persistent in a diffuse pattern in the bone marrow in 11 of 13 patients assessed. However, in 2 patients (cases 3 and 5), there was no morphologic evidence of disease in peripheral blood or bone marrow samples, although extramedullary sites of disease were proven by biopsy. In 1 patient, bone marrow was not assessed; this patient had a WBC of 230,000/µL (230.0 × 109/L). Clinically, 9 patients had peripheral lymphadenopathy, 8 had hepatomegaly, and 6 had splenomegaly. Pleural effusions were present in 6 patients, and 1 patient had ascites.

Clinical follow-up data were available for all 14 patients. Nine were alive at the time of last follow-up, with a mean survival of 22.5 months. Five patients (cases 1-3, 9, and 10) died by the time this study was completed, with a mean survival of 13.6 months from the time of initial diagnosis. The causes of death were sepsis and multiorgan system failure (case 1); overwhelming sepsis due to Aspergillus fumigatus infection with extensive residual T-PLL involving bone marrow, liver, spleen, lymph nodes, lungs, and colon (case 2); sepsis with multiorgan system failure due to coagulase-negative Staphylococcus aureus infection (case 10); and disease progression in 2 patients (cases 3 and 9). One patient (case 3) had skin tumors and lymphadenopathy, and fine-needle aspiration of a cervical lymph node immediately preceding death demonstrated T-PLL. This patient did not have peripheral blood lymphocytosis or bone marrow involvement. In case 9, no additional details of the clinical findings at time of death are available.

The most common anatomic site biopsied was skin: 10 specimens obtained from 7 patients. One patient (case 5) had 4 skin biopsy specimens. In this subgroup, the pattern of involvement in 6 biopsy specimens (from 4 patients) consisted of an infiltrate of atypical lymphocytes in the superficial dermis, with a perivascular and periadnexal distribution (Figure 1). Other histologic features in these cases included a variable degree of stromal edema surrounding blood vessels with minimal endothelial damage and a few scattered extravasated erythrocytes. In 3 biopsy specimens, the neoplasm infiltrated the dermis in a diffuse pattern (Figure 2), and in 1 biopsy specimen (case 5), T-PLL cells formed a subcutaneous mass (Figure 3). The latter patient also had 3 other skin lesions with dermal perivascular and periadnexal involvement as mentioned. A subset of 2 skin biopsy specimens had foci of epidermotropism, one with a dermal perivascular and periadnexal pattern (case 13) and the other with diffuse dermal involvement (case 12) (Figure 4). The epidermis was otherwise unremarkable except for the presence of parakeratosis and hyperkeratosis in 2 specimens (cases 3 and 12).

(Case 5) T-cell prolymphocytic leukemia involving skin. The most common pattern of skin involvement was a dermal infiltrate with a perivascular and periadnexal pattern, associated with variable stromal edema (H&E, ×100).

(Case 11) T-cell prolymphocytic leukemia involving skin. A , In this case, the neoplasm diffusely infiltrated the dermis (H&E, ×200). B , High-power magnification revealed that the neoplastic cells had slightly irregular nuclear contours and a subset of cells had distinct nucleoli (H&E, ×1,000).

(Case 5) T-cell prolymphocytic leukemia involving skin and forming a subcutaneous mass (H&E, ×200).

(Case 12) T-cell prolymphocytic leukemia involvingthe skin with focal epidermotropism (H&E, ×500).

The second most commonly biopsied sites were liver (n = 3) and lymph node (n = 3). The pattern of infiltration in 3 liver needle biopsy specimens was mostly periportal. In 2 cases with less extensive disease, T-PLL was confined predominantly to portal tracts, with minimal portal tract expansion or sinusoidal involvement (Figure 5). Blood vessels within portal tracts were distended by T-PLL cells in 1 of these specimens. In the third liver biopsy specimen, there was extensive involvement and expansion of portal tracts by T-PLL with disruption of the limiting plates. Obvious sinus-oidal involvement also was present, although to a lesser degree. Nonspecific histologic features in these specimens included edema and cholestasis in all 3 cases, with the degree of these changes correlating with the amount of involvement by neoplasm.

(Case 7) T-cell prolymphocytic leukemia involving liver. In this case, portal tracts were expanded moderately and blood vessels in the portal tract were dilated (left) by neoplastic cells. Only minimal sinusoidal involvement was present (H&E, ×200).

In the 3 lymph node biopsy specimens, T-PLL had a diffuse pattern and subtotally replaced the normal architecture in a paracortical distribution. In all cases, a few residual lymphoid follicles and patent sinusoids were identified (Figure 6). The T-PLL cells were monomorphous in 2 specimens but showed some variability in size in 1 specimen (case 10) (Figure 7). Mitotic figures were identified easily in all 3 specimens, ranging from 1 to 2 mitoses per 10 high-power fields (×400) to greater than 10 mitoses per 10 high-power fields (case 9).

(Case 9) T-cell prolymphocytic leukemia involving lymph node. The neoplasm subtotally replaced the lymph node but spared occasional lymphoid follicles (1 reactive follicle is left center). The neoplastic cells were monomorphous, and most cells had prominent nucleoli, barely visible in some cells at this magnification (H&E, ×200).

(Case 10) T-cell prolymphocytic leukemia involving lymph node. The neoplastic cells showed greater variation in size (than the case in Image 6), and only a subset of cells had prominent nucleoli (H&E, ×1,000).

Other anatomic sites involved by T-PLL were single biopsy specimens obtained from 3 patients. One patient with splenomegaly developed splenic rupture and underwent splenectomy. The spleen weighed 832 g, and T-PLL cells diffusely infiltrated the white pulp with lesser involvement of the red pulp. The neoplasm in the red pulp had a vaguely nodular pattern. A second patient had bilateral pleural effusions and interstitial infiltrates in the lung shown by radiologic studies. A transbronchial biopsy specimen showed small, discrete aggregates of T-PLL in the bronchial mucosa. A third patient had persistent diarrhea that led to endoscopy of the colon. Endoscopy showed superficial ulcers in the cecum and small, discrete aggregates of T-PLL in the lamina propria; no lymphoepithelial lesions were identified (Figure 8).

(Case 2) T-cell prolymphocytic leukemia involving the cecum. Small aggregates of neoplastic cells were present in lamina propria (H&E, ×400).

In all biopsy specimens, the T-PLL cells were small to medium-sized. Nuclear contours were relatively round in 16 specimens and highly irregular or Sézary cell–like in 3 specimens. All 3 specimens with Sézary cell–like cells were obtained from the skin. Nucleoli were identified in at least a subset of cells in 11 biopsy specimens, and nucleoli were prominent in virtually all cells in 3 specimens. In these 3 specimens, the nucleoli could be observed at ×400 magnification. In the remaining biopsy specimens with nucleoli, ×1,000 (oil immersion) magnification was required to adequately detect the nucleoli in the T-PLL cells. The 8 biopsy specimens in which nucleoli were not prominent included skin (n = 4), liver (n = 2), lymph node (n = 1), and cecum (n = 1).

Additional histologic material was reviewed from an autopsy performed on 1 patient (case 2). Multiple organs showed extensive involvement by T-PLL. The bone marrow was involved in an interstitial and diffuse pattern. There was extensive infiltration of the lungs in a perivascular and peribronchial distribution, associated with interstitial edema, and perihilar lymph nodes were infiltrated diffusely. The spleen was congested markedly and depleted of lymphocytes. However, T-PLL cells were observed in the residual white pulp around blood vessels. In the liver, discrete periportal infiltrates with minimal sinusoidal involvement were observed. Patchy atypical lymphoid aggregates were observed within the lamina propria of the colon. No other sites were involved.

Immunohistochemical studies were performed on fixed, paraffin-embedded tissue sections of all extramedullary biopsy specimens. However, the antibody panel used was limited and highly variable. In each specimen, the neoplasm was shown to be of T-cell lineage. All biopsy specimens assessed were positive for CD3 (n = 18), CD4 (n = 9), and CD5 (n = 8) and negative for CD20 (n = 14), CD8 (n = 9), and TdT (n = 5). S-100 protein was negative in all 10 biopsy specimens assessed.

TCL-1 expression was assessed in 12 extramedullary biopsy specimens (cases 1, 2, 4, 5, 7-14); 6 were positive (Figure 9) and (Figure 10). As part of an earlier study by Herling and colleagues,[8] bone marrow biopsy specimens of many of these patients (cases 1-8 and 11-14) also were assessed, and 7 were positive for TCL-1. In sum, TCL-1 was positive in at least 1 biopsy specimen from 9 (64%) of 14 patients.

(Case 12) T-cell prolymphocytic leukemia involving skin with focal epidermotropism. The neoplastic cells were strongly positive for T-cell leukemia–1 with a nuclear pattern of staining (immunohistochemical analysis with hematoxylin counterstain, ×500).

(Case 9) T-cell prolymphocytic leukemia involving lymph node (same case as Image 6). The neoplastic cells were strongly positive for T-cell leukemia–1 with a nuclear pattern of staining. A reactive follicle (upper half of field) was mostly negative with some positive cells (immunohistochemical analysis with hematoxylin counterstain, ×200).

Flow cytometry immunophenotypic studies were performed on cell suspensions prepared from extramedullary biopsy specimens from 4 patients. In each specimen, the neoplastic cells had a mature T-cell immunophenotype similar to that determined on bone marrow aspirate specimens at the time of initial diagnosis.

In all 4 extramedullary biopsy specimens (from 3 patients) assessed by polymerase chain reaction, monoclonal TCR g chain gene rearrangements were identified. In 1 biopsy specimen, 2 discrete bands were identified on the ethidium-stained gel. Vg family use was not determined. In 2 skin biopsy specimens from the same patient, 2 identical monoclonal rearrangements that used the VgI family were identified. In another biopsy specimen, a single monoclonal band that used the VgII family was detected.

Conventional cytogenetics analysis was performed on peripheral blood (n = 1) or bone marrow (n = 7) aspirate material at the time of initial diagnosis in 8 patients and on 1 extramedullary biopsy specimen (the subcutaneous mass) at the time of disease progression. Three neoplasms had the inv(14)(q11q32), and 3 neoplasms had complex karyotypes with chromosome 14 abnormalities, including add(14)(q32) and monosomy 14. In the remaining 3 neoplasms assessed, 2 had a normal karyotype and 1 showed loss of the Y chromosome (case 13), a common finding in elderly men that is thought not to be of clinical significance. The complete karyotypes are listed in Table 1 .


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