Nonhepatosplenic/noncutaneous
Peripheral T-cell lymphomas (PTCLs) comprise a heterogeneous group of indolent and aggressive T-cell lymphomas that confer a variable prognosis [
NHNC
No cytogenetics findings unique to NHNC
As opposed to PTCL, the expression of
Patient 1 is a 31-year-old gentleman diagnosed with T-cell ALL after presenting with diffuse petechial rash, cervical lymphadenopathy, abdominal pain, and a WBC of 121 K/
Patient 1 pathological findings, by site.
Site (days from original diagnosis) | Diagnosis | Morphology | IHC (T-cell population of interest) | Flow (T-cell population of interest) | Gene rearrangements | Peripheral blood CBC with 100-cell differential count (%) |
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---|---|---|---|---|---|---|---|---|
Left iliac crest 0 days | T-cell ALL | Small- to medium-sized blast population comprising 95% of cells; marrow nearly 100% cellular | Positive: TdT, beta F1 Negative: TCR |
Positive: CD3, CD4/CD8 dual positive, CD2, CD5 (d), CD7, and TDT (d) Negative: CD1a, CD34, CD117 | T |
257 | WBCa | 18.7 |
T |
269 | Hemoglobinb | 10.5 | |||||
T |
182.9, 190.84 | MCVc | 92.8 | |||||
T |
190.94, 214.3 | Plateletsa | 211 | |||||
T |
172.9 | Lymphocytes | 15 | |||||
Atypical lymphocytes | 0 | |||||||
Blasts | 1 | |||||||
Left iliac crest 104 days | No evidence of malignancy | nc | np | nc | T |
256 | WBCa | 3.62 |
T |
126, 263.8 | Hemoglobinb | 10.8 | |||||
T |
190.63 | MCVc | 92.8 | |||||
T |
Germline | Plateletsa | 334 | |||||
T |
172.4 | Lymphocytes | 37 | |||||
Atypical lymphocytes | 0 | |||||||
Blasts | 0 | |||||||
Cerebrospinal fluid 120 days | T-cell ALL | Large granular lymphocyte-like cells with condensed chromatin, inconspicuous nucleoli, eccentric nuclei, and moderate pale blue cytoplasm with prominent azurophilic granules | np | Positive: CD3c, CD7, CD8, CD45 (b), CD4 equivocal Negative: CD3, TdT, CD34 | np | WBCa | 2.44 | |
Hemoglobinb | 9.5 | |||||||
MCVc | 88.3 | |||||||
Plateletsa | 104 | |||||||
Lymphocytes | 34.4 | |||||||
Atypical lymphocytes | 0 | |||||||
Blasts | 0 | |||||||
Right iliac crest 124 days |
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Atypical lymphohistiocytic T-cell infiltrate with granulomas; large mononuclear lymphocytes with round to irregular nuclear contours and moderate eccentric light blue pale cytoplasm and cytoplasmic granules | Positive: CD2, CD3 (>50%), CD5, CD7 (f), CD8, CD56, perforin, TIA, CD4 (equivocal) Negative: TdT, CD117, CD68, CD34, CD1a, CD99, granzyme-B, CD30, CD57, CD25, ISH EBER | Positive: CD3, CD3c, CD5, CD7, CD4 (d), CD8 (d), CD45 Negative: TdT, CD34, CD56 | T |
275 | WBCa | 2.56 |
T |
126, 258, 263.8 | Hemoglobinb | 8.7 | |||||
T |
182.92, 190.63 | MCVc | 88.1 | |||||
T |
214.13 | Plateletsa | 76 | |||||
T |
172.48 | Lymphocytes | 28.9 | |||||
Atypical lymphocytes | 0 | |||||||
Blasts | 0 | |||||||
Skin, right arm 125 days |
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Atypical lymphoid cells | Positive: CD2, CD3, CD5, CD4, CD8, CD56, TIA, CD99 (d), granzyme-B, TCRγ Negative: CD7, TdT, CD34, CD1a | nd | np | WBCa | 2.61 | |
Hemoglobinb | 9.8 | |||||||
MCVc | 87.9 | |||||||
Plateletsa | 98 | |||||||
Lymphocytes | 32.2 | |||||||
Atypical lymphocytes | 0 | |||||||
Blasts | 0 | |||||||
Skin, right flank 189 days | γδ PTCL | Atypical lymphocytic infiltrate comprised of large pleomorphic with round to irregular nuclear contours and ample cytoplasm with prominent nucleoli and elevated N:C ratio | Positive: CD3, CD4, CD8, TCRγ, CD56 Negative: TdT, Beta F1, CD20 | Positive: CD3, CD5, CD4/CD8 dual positive, CD45, CD56 Negative: CD7 (partial loss) | np | WBCa | 9.1 | |
Hemoglobinb | 10.9 | |||||||
MCVc | 95.8 | |||||||
Plateletsa | 58 | |||||||
Lymphocytes | 8 | |||||||
Atypical lymphocytes | 0 | |||||||
Blast | 0 |
Note: (b) bright; (d) dim; (f) focal; (s) positive in subset. +/− equivocal; nc, noncontributory; nd, nondiagnostic due to insufficient specimen; np, not performed. aIn k/
Patient 1, bone marrow with T-cell ALL: (a) H&E core biopsy, 500x; (b) aspirate cytology, 1000x.
Patient 1, erythematous patches and plaques of PTCL distributed predominantly on torso and upper extremities.
Patient 1, right flank skin with PTCL: (a) H&E, 100x; (b) H&E, 400x; (c) CD3, 100x; (d) TdT immunoperoxidase, 400x; (e) TCR gamma, 200x.
Patient 1, bone marrow with PTCL: (a) H&E, 40x; (b, c) aspirate cytology, 1000x; (d) CD3, 100x.
Six months after initial CR, the patient was initiated on ICE therapy and intra-Ommaya reservoir methotrexate (later switched to intrathecal cytarabine). The skin lesions and CSF involvement initially resolved; however, he developed fevers, new generalized skin
Patient 2, deceased, was a 63-year-old Caucasian female with a past medical history significant for stage III invasive ductal carcinoma, ER/PR/HER2 negative, with 1 of 9 axillary lymph nodes positive for carcinoma, diagnosed at age 52. She underwent a left segmental mastectomy (lumpectomy) procedure with axillary lymph node dissection, radiation treatment, and 4 cycles of doxorubicin and cyclophosphamide chemotherapy. Other medical problems included hypertension, hyperlipidemia, herpes zoster, childhood rheumatic fever, menopause, and hypersensitivity pneumonitis.
She initially presented with a mediastinal mass, dyspnea, and pericardial and recurrent right-sided pleural effusions. Biopsy of the mediastinal mass revealed blasts with cyCD3+, TdT+, CD4+/8+, CD7+ (Figure
Patient 2; mediastinal mass with T-cell ALL: (a) H&E, 100x; (b) cytology, 1000x; (c) CD3, 100x; (d) TdT, 100x.
She was treated with 18 cycles of hyper-CVAD followed by POMP maintenance for 18 months and remained in remission for nearly 4 years. Thereafter, she developed dyspnea, and radiographic imaging showed several simultaneous masses, including a 4.7 × 4.0 cm right atrial mass and a left flank mass, in addition to pleural effusions. Biopsy of the atrial mass was nondiagnostic showing myocardial and fibrous tissue. The chest wall (flank) mass was biopsied showing involvement by PTCL (Figure
Patient 2: (a) flank mass with PTCL, H&E, 100x; (b) flank mass, TdT immunoperoxidase, 200x; (c) pleural fluid cytospin cytology, 500x.
However, clonal TCR
Patient 2 pathological findings, by site.
Site (days from original diagnosis) | Diagnosis | Morphology | IHC (T-cell population of interest) | Flow (T-cell population of interest) | Gene rearrangements | Peripheral blood CBC with 100-cell differential count (%) |
Cytogenetics | |||
---|---|---|---|---|---|---|---|---|---|---|
5/2009 | Mediastinal mass | T-cell ALL | Monotonous population of immature lymphoid cells with high N:C ratio, round to oval nuclei, mild nuclear irregularity, and scant cytoplasm | Positive: TdT (90%) | Positive: CD2, CD3, CD5 (d), CD7, CD4, CD8, CD45, CD10 Negative: CD20, EpCAM, Cytokeratin | T |
Germline | WBCa | 6.4 | |
T |
Germline | Hemoglobinb | 12.8 | |||||||
T |
Germline | MCVc | 87.2 | |||||||
T |
Germline | Plateletsa | 209 | |||||||
T |
185.23, 193.82 | Lymphocytes | 18.7 | |||||||
Atypical lymphocytes | 0 | |||||||||
Blasts | 0 | |||||||||
Pleural fluid 17 days | T-cell ALL | Immature lymphoid blasts | Positive: CD3, CD4, CD8, TdT, CD99 Negative: CD79a | np | np | nc | No mitotic activity | |||
Right iliac crest 18 days | T-cell ALL | Sheets of lymphoblasts with high N:C ratio, immature chromatin, visible nucleoli, scant cytoplasm with occasional cytoplasmic vacuoles | np | Positive: CD45 (d), cyCD3, CD7, CD4, CD8, TdT (d), CD117, CD10 Negative: CD20, CD34; loss of surface CD3 and CD5 | np | WBCa | 9.94 | |||
Hemoglobinb | 13.9 | |||||||||
MCVc | 86.2 | |||||||||
Plateletsa | 262 | |||||||||
Lymphocytes | Few | |||||||||
Atypical lymphocytes | 22 | |||||||||
Blasts | 0 | |||||||||
9/2009 | Left iliac crest 131 days | Normocellular marrow with NEM | nc | nc | nc | Germline | nc | Normal | ||
3/2013 | Right iliac crest† 1417 days | Normocellular marrow with NEM | nc | np | nc | T |
262.3 | WBCa | 6.39 | |
T |
261.10, 266.54 | Hemoglobinb | 1.7 | |||||||
T |
188.74 | MCVc | 90.6 | |||||||
T |
Germline | Plateletsa | 165 | |||||||
T |
174.32 | Lymphocytes | 19.7 | |||||||
Atypical lymphocytes | 0 | |||||||||
Blasts | 0 | |||||||||
Pleural fluid 1419 days | PTCL, NOS with 75% large T-cells | Abundant large lymphoid cells with condensed chromatin, markedly irregular nuclear contours, frequent horseshoe-shaped nuclei, occasional binucleation, inconspicuous nucleoli, moderate-to-abundant pale blue cytoplasm, and cytoplasmic azurophilic granules | np | Positive: CD3c, CD8, CD45 Negative: CD3, CD7, CD4, TdT, CD117, CD20, CD34, CD56 | T |
259.6 (+/−) | WBCa | 6.12 | SNP ARRAY | |
T |
252.79, 272.24 | Hemoglobinb | 10.4 | |||||||
T |
326.3 | MCVc | 91.5 | |||||||
T |
208.3, 216.77 | Plateletsa | 190 | |||||||
T |
Germline | Lymphocytes | 19.6 | |||||||
Atypical lymphocytes | 0 | |||||||||
Blasts | 0 | |||||||||
3/2013 | Left chest wall mass 1419 days | PTCL, NOS |
Skeletal muscle extensively involved by a diffuse infiltrate of large lymphoid cells with granular chromatin, marked nuclear pleomorphism, markedly irregular nuclear contours, occasional horseshoe-shaped nuclei, and occasional conspicuous nucleoli | Positive: CD2, CD3, CD8 (b), ki67 (80%) Negative: CD5, CD7, CD4, TdT, CD15, CD20, CD30, CD34, CD56, pan-keratin, PAX5, EBV-LMP, EBER | np | np | nc | |||
Left flank mass | PTCL, NOS | Large lymphoid cells with granular chromatin, marked nuclear pleomorphism, markedly irregular nuclear contours, occasional horseshoe-shaped nuclei, occasional conspicuous nucleoli, moderate pale eosinophilic cytoplasm, and abundant cytotoxic granules | Positive: CD3 (b), granzyme-B Negative: CD5, TdT, CD20, CD30, CD34, ALK-1, CD1a, myeloperoxidase, EBER ISH | Not representative |
Note: (b) bright; (d) dim; (f) focal; (s) positive in subset; +/− equivocal. NEM, no evidence of malignancy; nc, noncontributory; nd, nondiagnostic due to insufficient specimen; np, not performed. aIn k/
In both cases, there was relapse as PTCL manifested with skin involvement and an overt shift from blastic morphology to “LGL-like” mature T cells with ample cytoplasm and abundant azurophilic granules. Phenotypically, expression of immature markers such as TdT was lost in both cases. Both patients reasonably represent a novel phenomenon of clonal transformation from T-ALL to PTCL which has rarely been reported in the literature. In patient 1, there is clear evidence of a clonal relationship as demonstrated by identical monoclonal TCR peaks. Also, both PTCL and T-ALL cases demonstrated the relatively immature CD4+/CD8+ immunophenotype. HSTL
Morphologically,
If this truly represents transformation, we must consider the pathophysiology of such conversion. It may be postulated that chemotherapy may have forced the original T-ALL cells to undergo some degree of maturation. However, the disparate chemotherapy regimens in both cases, lack of similar conversions in other patients treated with these typical chemotherapy regimens, and temporal distance of relapse in patient 2 (3-4 years) do not support this speculation. More likely, acquisition of additional mutations in T-cell differentiation genes may have created a genetic context to allow for such transdifferentiation. This is supported by SNP array analysis performed on patient 2’s PTCL showing clonal evolution. Another possibility is that malignant clones of T-ALL and PTCL developed separately from a common precursor sharing an initial transforming event. Subsequently, T-cell ALL and PTCL could evolve secondary to additional and separate transforming events.
The transformation into more aggressive disease is a rare event in T-cell lineage-derived hematologic malignancies compared to B-cell neoplasms. A patient with
Besides the pathophysiology, the clinical and biological nature of these transformed PTCLs can be considered challenging. Should these cases be considered “ALL-like” disorders given their putative clonal derivation from T-ALL or do they represent a new entity with unique biology? The second case was considered to be a new entity with unique biology, hence the aggressive, chemotherapy refractory course that resulted.
In summary, we report two cases of NHNC PTCL arising in patients with established diagnoses T-ALL which, in at least one case, is clonally related. This raises the possibility of a novel pathologic phenomenon with associated diagnostic and biological implications.
The authors declare that they have no conflicts of interest.
The authors thank the supporting staff at the Moffitt Cancer Center including the departments of Malignant Hematology and Hematopathology.