Idea Transcript
Dermatopathology Specialty Conference 104th USCAP Annual Meeting March 23th, 2015 Carlos A Torres‐Cabala, MD Associate Professor Departments of Pathology and Dermatology The University of Texas – M.D. Anderson Cancer Center
Case 9 • 60 year old male presenting with multiple, rapidly progressing skin plaques on his head, arms, torso, buttocks, and legs.
MITF
CD3
CD4
CD8
CD56
TCR‐beta
TCR‐gamma
• The histopathological changes seen in this skin punch biopsy are subtle • Mild epidermal hyperplasia is seen • A very sparse lymphoid infiltrate involves superficial dermis and extends into the epidermis
• The lymphocytes are small to medium size hyperchromatic cells • Perinuclear haloes are also seen. • Immunohistochemical studies reveal the atypical intraepidermal hyperchromatic cells to be mostly positive for CD3 and CD7
• The atypical intraepidermal lymphocytes are mostly negative for both CD4 and CD8; rare intraepidermal lymphocytes are weakly positive for CD4 • The CD4:CD8 ratio of T‐cells in the dermis is about 3:1
• The intraepidermal atypical lymphocytes are positive for TCR gamma, and negative for betaF1 and CD56 • MITF‐1 highlights mildly increased small junctional melanocytes.
Differential diagnosis • Mycosis fungoides, patch lesion • Drug eruption • Spongiotic dermatitis (such as allergic contact dermatitis, lymphomatoid allergic contact dermatitis) • Interface dermatitis • Early vitiligo • Cutaneous gamma/delta T cell lymphoma • Cutaneous T cell lymphoma, NOS
Diagnosis CUTANEOUS GAMMA/DELTA T‐CELL LYMPHOMA
Discussion • The histopathological and immunohistochemical are interpreted as those of a cutaneous T‐cell lymphoma showing epidermotropism by atypical hyperchromatic cells with perinuclear haloes • On histological grounds alone, mycosis fungoides, patch lesion, is possible.
• When evaluating a skin biopsy showing these features, correlation with clinical findings is extremely important • Paying attention to the expression of T cell markers by the atypical cells will avoid misinterpretation of the phenotype of the lesion • The fact that the atypical lymphocytes are double negative for CD4 and CD8 should prompt the pathologist to further evaluate the lesion for a gamma‐delta phenotype
• BetaF1 and TCRgamma should be performed. CD56 and cytotoxic markers could also be included • Molecular studies for TCR gamma and beta chain gene rearrangements may also be required • A lymphoid proliferation with gamma‐delta phenotype in the setting of a clinically aggressive disease should raise CGDTCL as a diagnostic possibility.
• Overall, the histopathological and clinical findings in this case indicate a cutaneous T‐cell lymphoma with aggressive behavior and gamma/delta phenotype, with loss of expression of CD4 and CD8 • Primary cutaneous gamma/delta T‐cell lymphoma is favored.
• A concurrent left groin lymph node specimen showed involvement by lymphoma with gamma‐delta immunoprofile • Multiple treatments were initiated, including methotrexate, interferon, bexarotene, gemcitabine, and electron beam radiation, with no response • The patient was lost after 12 months of follow up.
CD20
CD3
CD4
CD8
CD56
Beta F1
TCRgamma
• EBER was negative
Discussion • Gamma‐delta T lymphocytes represent only 1 to 5% of the total circulating lymphocytes • However, in organs such as the skin, they may account for up to 30% of the total number of T‐cells • The 2008 WHO classification incorporated cutaneous gamma‐delta () T‐cell lymphoma (CGDTCL) as a well‐defined entity.
• CGDTCL is considered a rare subtype of T cell lymphoma, accounting for less than 1% of the T cell lymphomas; however, it is being increasingly recognized by using the available TCR immunohistochemical study on paraffin sections • Of note, other T‐cell lymphomas may occasionally express TCR, so expression of the marker by itself should not be considered diagnostic of CGDTCL
• Early studies already identified 3 histopathological patterns of CGDTCL: epidermotropic, dermal, and subcutaneous, demonstrating the complexity of this group of lymphomas • Skin lesions can be sometimes display only very subtle histopathological changes despite poor clinical outcome
• After that, she noted more lesions arise about every 3 weeks on the left breast, right nostril, right suprapubic region, left heel, and the left calf. • A punch biopsy of the lesion on the left breast was performed.
CD 7
CD 8
• Reported immunohistochemical studies were “CD8+, CD7+, many CD4+, CK7‐, EMA‐” • Outside pathology diagnosis was “mycosis fungoides, possible Woringer Kolopp”
• A new biopsy from her left leg was performed
CD3
CD4
CD8
CD5
CD30
• Diagnosis? – Mycosis fungoides – Pagetoid reticulosis, disseminated (Ketron‐ Goodman) – Aggressive epidermotropic CD8+ T cell lymphoma (Berti’s) – Cutaneous T cell lymphoma, NOS – Other
CD56
B F1
TCR gamma
TCR gamma
TIA‐1
Granzyme B
• She underwent MRD allogeneic BM transplant • Shortly after transplant she present with an ulcer on her buccal mucosa and multiple scattered pink papules on the arms, trunk, and lower extremities • A punch biopsy from a lesion on her left wrist was taken
CD3
CD4
CD8
CD30
TCR gamma
• Reports of patients with long histories of clinically indolent cutaneous T‐cell lymphoma and late “transformation” to CGDTCL open up the question of the existence of a subset of cases with a different biologic behavior
• It seems that patients presenting with lesions clinically similar to mycosis fungoides (MF) have an overall better prognosis • However, in general, CGDTCL should be considered as a potentially aggressive T‐cell lymphoma, with heterogenous clinical and histopathological presentation, that needs to be further defined.
Take home message • Pathologists should be aware of the heterogenous histopathological and clinical presentation of CGDTCL • This case illustrates the purely epidermotropic variant of CGDTCL that, albeit a bland histopathological presentation, was associated with an aggressive clinical behavior
• Correlation with clinical information and appropriate immunohistochemical and molecular workup are of crucial importance when interpreting these biopsies
Case 9 Panel Diagnoses A
It looks like MF but the history does not fit. I wonder if this patient is on Phenytoin
B
CD4/CD8 double‐ negative epidermotropic cutaneous T‐cell lymphoma
C
CD4/CD8 negative CTCL
D
CTCL
Case 10
• 60 year‐old Caucasian male who presents with fatigue, extreme weight loss, and a coin size red patch on upper arm • His local physician started treatment with antibiotics without any response. A CT scan revealed hepatosplenomegaly. New lesions developed on his trunk, buttocks, and legs • Skin and liver biopsies were taken.
• The skin biopsy reveals interface changes (vacuolar degeneration, dyskeratotic/apoptotic keratinocytes) and a superficial and deep perivascular lymphocytic infiltrate • The infiltrate is also periadnexal • The lymphocytes are mainly small to medium size with rare large atypical forms
• Interstitial increased mucin is present • Based on these findings, the outside pathology diagnosis was that of interface dermatitis with increased mucin, possibly lupus erythematosus.
CD3
CD3
CD3
CD20
CD4
CD4
CD8
CD8
CD56
CD56
CD56
CD56
TIA‐1
TIA‐1
TIA‐1
BF1
BF1
BF1
TCRgamma
TCRgamma
TCRgamma
EBER
• Numerous CD3‐positive T cells, predominantly expressing CD4, with a CD4:CD8 ratio of about 3:1 • The larger atypical cells were mostly negative for CD3, and negative for CD4, CD8, and CD30, while they were positive for CD56 and TIA‐1 • The large atypical cells were negative for both TCR gamma and betaF1 • EBER ISH was negative.
Differential diagnosis • Lupus erythematosus • Lichenoid drug eruption • Cutaneous T cell lymphoma – – – – – – – –
Mycosis fungoides, lichenoid Angioimmunoblastic T cell lymphoma Gamma/delta T cell lymphoma PTCL, NOS Blastic plasmacytoid dendritic cell neoplasm NK/T cell lymphoma, nasal type Aggressive NK/T cell lymphoma/leukemia Other
NK‐CELL LYMPHOMA/LEUKEMIA, EBV‐ NEGATIVE
CD 3
CD 4
CD 8
CD 56
CD 56
CD 30
CD 2
CD 34
Lysozyme
MPO
CD 123
Beta F1
Beta F1
TCR gamma
TCR gamma
TIA‐1
TIA‐1
Granzyme
Granzyme B
EBER
EBER Control
• Liver biopsy: T/NK‐cell neoplasm involving liver, sinusoidal pattern • Bone marrow biopsy: NK/T‐cell lymphoproliferative disorder comprising 20‐ 30% of marrow cellularity
TIA‐1
Granzyme B
• IHC: CD2+, CD3+, TIA‐1+, Granzyme B+, mostly CD4‐/CD8‐, CD30‐, EBER‐ • Flow cytometry: CD2+, CD26+, CD52+, CD56+, CD94+, CD3 surface ‐, CD4‐, CD8‐, CD7‐, CD16‐ , CD25‐, CD30‐, CD57‐ • No TCR gamma or beta chain rearrangements
• Peripheral blood flow cytometry: NK cell CD56 71.8%, CD3+/CD4+ 15.5%, CD3+/CD8+ 4.7% • CD16 dim/partial, CD26 bright, CD52, CD56 bright, CD94 bright. Negative for: surface CD3, CD4, CD5, CD7, CD8, CD14, CD30, CD57, and TCRs alpha‐beta and gamma‐delta
NK‐CELL LYMPHOMA/LEUKEMIA, EBV‐ NEGATIVE (favor aggressive NK‐cell lymphoma/leukemia)
• Our patient was initiated on hyper‐CVAD plus bortezomib, with initial partial response • Unfortunately, the disease progressed rapidly and the patient expired seven months after initial diagnosis.
BEFORE
AFTER
Discussion • This biopsy was initially interpreted by an outside pathologist as an interface dermatitis, consistent with lupus erythematosus • The clinical presentation, however, should raise the concern for a more aggressive condition, such as a hematolymphoid proliferation • A subsequent inhouse biopsy and the liver biopsy both showed involvement by hematolymphoid proliferation
• Additional immunohistochemical studies performed in this biopsy revealed a subpopulation of medium to large atypical cells expressing CD56 and TIA‐1, and negative for CD4, CD8, TCRgamma, and betaF1 • These atypical cells were interpreted as NK neoplastic cells • The same proliferation was identified in concurrent bone marrow biopsy and peripheral blood
• This is a very challenging and unique case. The findings in this initial skin biopsy are extremely mild and can be overlooked • High level of suspicion for a systemic neoplastic process is based on the clinical presentation of the disease; if clinical information is not taking into account, a misdiagnosis of an inflammatory condition can be easily made.
• Once the diagnosis of a hematolymphoid proliferation of NK lineage is established, subclassification of this process may be attempted • The fact that EBER is negative in the current and subsequent skin, liver, and bone marrow biopsies, poses an additional diagnostic dilemma since the two main differential diagnoses, extranodal NK/T lymphoma/leukemia, nasal type, and aggressive NK‐cell lymphoma/leukemia, are both highly associated with EBV.
Oshimi K. Progress in understanding and managing natural killer‐cell malignancies. Br J Haematol. 2007 Nov;139(4):532‐44. Epub 2007 Oct 3. Review.
• Promising new markers for ENKTL are – T‐bet, a transcription factor involved in the differentiation of lymphocytes, positive in 96% of ENKTL and more specific than CD2 or CD3 (Li et al. Am J Surg Path 2013) – ETS‐1, a cofactor of T‐bet that regulates the cytotoxic function of NK cells (64% of ENKTL, Li et al. Am J Surg Path 2013)
• The immunophenotype displayed by the neoplastic cells in both processes is identical and the distinction is mainly based on clinical presentation. • We decided to call our case NK‐cell lymphoma/leukemia involving skin
• Clinical presentation usually helps in this distinction • While ENKTL is characterized by cutaneous lesions at presentation, ANKL presents with peripheral blood involvement, hepatosplenomegaly, and partial involvement of the bone marrow • In some cases, however, overlap exists between the two entities, illustrating the complexity of the relationship among NK‐cell malignancies
• Secondary cutaneous involvement is possible since the patient presented with hepatosplenomegaly and evidence of lymphoma/leukemia was recorded in the liver and bone marrow • It is important to consider, however, that cutaneous NK/T lymphoma/leukemia, nasal type, can involve extracutaneous sites at presentation or soon afterward • Rare cases of these two entities have been reported to be negative for EBV (EBER).
• The 2008 WHO classification of skin lymphomas indicates that ENKTL, nasal type, is universally associated with EBV • ANKL is also considered to have a strong association with EBV infection • However, cases of EBV‐negative ENKTL and ANKL have been recorded in the literature
• A series of cutaneous ENKTL was claimed to show positivity for EBER in only 45% of the cases (5/11, Natkunam, Am J Surg Path 1999) • More recent reports seem to indicate that the percentage of EBV‐positive ENKTL cases is much higher than that, in the range of 89 to 100% • Similarly, rare cases of EBV‐negative ANKL have been reported
Ko et al.
• Although EBV negativity has been suggested to carry a better prognosis for ENKTL and ANKL, a case of EBV‐negative ANKL in a Caucasian patient had a very rapid and fatal clinical course (Perkovic et al. Hematology Reports 2012)
Take home message • Cases of NK/T cell lymphoma/leukemia involving the skin can pose a diagnostic dilemma for pathologists • Correlation with clinical presentation is extremely important for a correct interpretation of the dermatopathological findings, which may be easy to overlook
• The appropriate immunohistochemical and molecular studies need to be performed for a correct evaluation of these biopsies • Negativity for EBER adds to the diagnostic difficulty in this case • Despite the fact that aggressive NK processes in the skin are typically positive for EBV, it is important to remember that rare cases of NK lymphoma/leukemia are negative for EBER.
Case 10 Panel Diagnoses A
If CD123(+), this would be Blastoid plasmacytoid dendritic cell neoplasm. However, the clinical history is more consistent with gamma/delta T‐cell lymphoma. Provided TCR gamma IHC is not clear (it looks positive)
B
CD4+ CD56+ hematodermic/ plasmacytoid dendritic cell tumor. Would order CD123
C
Gamma/delta T‐cell lymphoma
D
Blastic plasmacytoid dendritic cell neoplasm
Acknowledgements • Dr. Victor Prieto • Dermatopathology Section – – – – – –
Dr. Victor Prieto Dr. Doina Ivan Dr. Jonathan Curry Dr. Michael Tetzlaff Dr. Phyu Aung Dr. Priya Nagarajan
• Hematopathology Department – Dr. Jeffrey Medeiros – Dr. Roberto Miranda – Dr. John Manning
Fellows ‐ Dr. Ren ‐ Dr. Mudaliar