Major strides for cutaneous T-cell lymphoma

Cutanteous T cell Lymphoma (CTCL) manifesting as erythroderma with leukemic blood involvement in this patient.”Researchers are making important strides in better understanding the genetics of cutaneous T cell lymphoma (CTCL). This new knowledge could have major implications for improved diagnosis and, potentially, new targeted CTCL therapies.

One such study by Yale researchers describes 17 genes in CTCL pathogenesis, including genes involved in cell activation and cell death.¹

“We performed a systematic analysis on the genetic basis of CTCL using next generation sequencing. We identified disease promoting mutations in numerous putative oncogenes and tumor suppressors that affect DNA damage repair, chromatin modification, and T cell signaling,” says the study’s lead author Jaehyuk Choi, M.D., Ph.D., assistant professor of dermatology, biochemistry and molecular genetics at Northwestern University Feinberg School of Medicine, Chicago (formerly at Yale). “Specifically, we identified novel oncogenic mutations in CD28, a critical T cell costimulatory molecule. We believe this genetic information can be a useful tool for the diagnosis of this disease. Furthermore, we believe these studies will catalyze the eventual development of precision medicine for patients with CTCL, [with] patients [receiving] the therapies that are most likely to help them.”

Answers for a diverse disease

The genetic work helps to answer important questions about this diverse disease, according to study author Michael Girardi, M.D., professor and vice chair of dermatology at Yale School of Medicine.

“By examining the coding regions of patients’ malignant cells, it was possible to identify the fuller spectrum of mutations. The mutations that were identified help explain why the CTCL cells behave as they do; why they continue to resist cell death and are in a state of perpetual activation; and why they suppress the normal T cells,” Dr. Girardi says.

READ - Cutaneous T-Cell lymphoma: Poised for a new treatment paradigm

In fact, several research groups, including at Stanford, Vanderbilt and the University of Pennsylvania, have performed similar CTCL sequencing studies on their patients. Together, these studies are helping to complete a fuller mapping of the genetic alterations possible in CTCL, according to Dr. Girardi.

“The number of genes that can be affected is mind-boggling, so it is great to see all this mutational mapping information now also coming out from different research groups,” Dr. Girardi says. “Also, recent work from the Stanford and Harvard groups on high throughput sequencing of the T cell receptor will surely also help enhance the earlier diagnosis of CTCL, and better distinguish CTCL from inflammatory diseases of the skin.”

NEXT: Difficult diagnosis

Difficult diagnosis

CTCL can be a difficult diagnosis to make, especially at the early stages, according to Dr. Choi.

“Diagnosis takes careful consideration of both the clinical presentation and the histopathology. CTCL has to be considered especially for lesions that appear in sun-protected areas such as the buttocks,” he says.

According to Susan Thornton, CEO of the Cutaneous Lymphoma Foundation, the most challenging issue dermatologists have in diagnosing cutaneous lymphomas is knowing when to look beyond what might look like a typical case of eczema, psoriasis or other more common skin rashes.

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“Cutaneous lymphomas, especially mycosis fungoides, is a great mimicker of other skin diseases. Even under the microscope it can look like other more benign skin conditions and be misdiagnosed for years, sometimes decades,” Thornton tells Dermatology Times. “The key is understanding the patient’s history, having cutaneous lymphoma as a possible diagnosis in mind, doing a punch biopsy of non-treated lesions and sending to an experienced dermatopathologist for review. Even then, the results may come back as inconclusive. This is very frustrating for patients and physicians as well, which is why is it very important that patients be referred to cutaneous lymphoma specialists if this diagnosis is suspected for a second opinion, diagnosis, proper disease staging and treatment recommendations.”

NEXT: Best practices

Best practices

Carrie Kovarik, MD, associate professor, dermatology, dermatopathology, and infectious diseases, University of Pennsylvania, says that patients with CTCL can go undiagnosed for many years, due to initial lack of diagnostic testing or non-specific biopsy results in patients with early disease or erythroderma.

“If someone has late onset eczema, psoriasis, contact dermatitis, or other inflammatory entity, do not hesitate to do a biopsy to confirm your clinical suspicion. Doing biopsies from two separate sites at once can increase your diagnostic yield. In the setting of high clinical suspicion, additional gene rearrangement studies from those two sites can aid in confirming the diagnosis.”

CTCL care should involve collaborations among dermatologists, dermatopathologists, laboratory medicine, medical oncology and radiation oncology, according to Dr. Choi.

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And when they don’t feel comfortable prescribing the medications used to treat CTCL, dermatologists should refer these patients, Dr. Choi says.

Dr. Girardi points out that “most dermatologists feel comfortable managing stage IA patients, with less than 10% body surface area involvement. The accessibility of specialized and multi-disciplinary CTCL centers is a major factor to consider for more advanced disease, as these typically provide the patient with a more comprehensive evaluation of CTCL, the latest in diagnostic testing and access to cutting-edge clinical trials.”

The National Cancer Comprehensive Network (NCCN) guidelines are a great resource for various treatment modalities available to CTCL patients based on their stage of disease, according to Dr. Kovarik. “Go to www.nccn.org, then guidelines for non-hodgkins lymphoma,” she says.

NEXT: A brighter, more targeted future

A brighter, more targeted future

In as early as the next few years, next generation sequencing will revolutionize the detection, treatment and management of CTCL, according to Dr. Choi.

“I don’t think it will be long before every patient has their CTCLs sequenced and this information is used to guide treatment strategies,” Dr. Choi says.

Best practices for diagnosing CTCL at various stages

• Respect the full disease spectrum, the numerous clinical and histologic variants of CTCL

• Recognize that CTCL may manifest as very subtle patches with a predilection for sun protected areas, as follicular papules, as erythroderma and with many other possible clinical presentations

• Perform multiple biopsies at multiple times, to provide the pathologist with as much information as possible

• Perform immunohistochemistry and molecular analysis to try to help distinguish clonal T cells from reactive T cells

• Understand that any or all of the three major compartments of skin, blood and lymph nodes may be involved

• Check flow cytometry of the blood, especially in cases of erythroderma

• Examine the lymph nodes and consider a PET/CT scan and lymph node biopsy

• Most importantly, respect that CTCL is a diagnosis that may take time, repeated visits and workups, and a full correlation of clinical, histologic and molecular analyses

NEXT: More on the topic

Read more on the topic

Cutaneous Lymphoma Foundation:  http://www.clfoundation.org

Whole-genome sequencing reveals oncogenic mutations in mycosis fungoides:

McGirt LY, Jia P, Baerenwald DA, Duszynski RJ, Dahlman KB, Zic JA, Zwerner JP, Hucks D, Dave U, Zhao Z, Eischen CM. Whole-genome sequencing reveals oncogenic mutations in mycosis fungoides. Blood. 2015 Jul 23;126(4):508-19. http://www.ncbi.nlm.nih.gov/pubmed/?term=Whole-genome+sequencing+reveals+oncogenic+mutations+in+mycosis+fungoides.

Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK-STAT pathway inSézary syndrome:

Kiel MJ, Sahasrabuddhe AA, Rolland DC, Velusamy T, Chung F, Schaller M, Bailey NG, Betz BL, Miranda RN, Porcu P, Byrd JC, Jeffrey Medeiros L, Kunkel SL, Bahler DW, Lim MS, Elenitoba-Johnson KS. Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK-STAT pathway in Sézary syndrome. Nat Commun. 2015 Sep 29;6:8470. http://www.ncbi.nlm.nih.gov/pubmed/?term=Kiel+MJ%2C+Sahasrabuddhe+AA%2C+Rolland+DC%2C+Velusamy+T%2C+Chung+F%2C+Schaller+M%2C+Bailey+NG%2C+Betz+BL%2C+Miranda+RN%2C+Porcu+P%2C+Byrd+JC%2C+Jeffrey+Medeiros+L%2C+Kunkel+SL%2C+Bahler+DW%2C+Lim+MS%2C+Elenitoba-Johnson+KS.+Genomic+analyses+reveal+recurrent+mutations+in+epigenetic+modifiers+and+the+JAK-STAT+pathway+in+S%C3%A9zary+syndrome.

Genomic analysis of mycosis fungoides and Sézary syndrome identifies recurrent alterations in TNFR2:

Ungewickell A, Bhaduri A, Rios E, Reuter J, Lee CS, Mah A, Zehnder A, Ohgami R, Kulkarni S, Armstrong R, Weng WK, Gratzinger D, Tavallaee M, Rook A, Snyder M, Kim Y, Khavari PA. Genomic analysis of mycosis fungoides and Sézary syndrome identifies recurrent alterations in TNFR2. Nat Genet. 2015 Sep;47(9):1056-60. Epub 2015 Aug 10. http://www.ncbi.nlm.nih.gov/pubmed/?term=Genomic+analysis+of+mycosis+fungoides+and+S%C3%A9zary+syndrome+identifies+recurrent+alterations+in+TNFR2.

TCR sequencing facilitates diagnosis and identifies mature T cells as the cell of origin in CTCL:

Kirsch IR, Watanabe R, O'Malley JT, Williamson DW, Scott LL, Elco CP, Teague JE, Gehad A, Lowry EL, LeBoeuf NR, Krueger JG, Robins HS, Kupper TS, Clark RA. TCR sequencing facilitates diagnosis and identifies mature T cells as the cell of origin in CTCL. Sci Transl Med. 2015 Oct 7;7(308):308ra158. http://www.ncbi.nlm.nih.gov/pubmed/?term=TCR+sequencing+facilitates+diagnosis+and+identifies+mature+T+cells+as+the+cell+of+origin+in+CTCL.

The difficult-and often delayed-diagnosis of CTCL:

Weed J, Girardi M. The difficult-and often delayed-diagnosis of CTCL. Sci Transl Med. 2015 Oct 7;7(308):308fs41. http://www.ncbi.nlm.nih.gov/pubmed/?term=Weed+J%2C+Girardi+M.+The+difficult-and+often+delayed-diagnosis+of+CTCL.

Disclosures:

Dr. Choi: none

Dr. Girardi: none

Dr. Kovarik: none

Reference:

1.     Choi J, Goh G, Walradt T, Hong BS, Bunick CG, Chen K, Bjornson RD, Maman Y, Wang T, Tordoff J, Carlson K, Overton JD, Liu KJ, Lewis JM, Devine L, Barbarotta L, Foss FM, Subtil A, Vonderheid EC, Edelson RL, Schatz DG, Boggon TJ, Girardi M, Lifton RP. Genomic landscape of cutaneous T cell lymphoma. Nat Genet. 2015 Sep; 47(9):1011-9.