Hillard M. Lazarus, MD, FACP

Case reviews for Elidel and lymphoma

January 11, 2005

I. Case 1:

A 61 year old woman who apparently developed histiocytic lymphoma after
only a few weeks of exposure to Elidel treatment.

1\. Additional info: Evaluating the tissue would be useful (true
histiocytic lymphoma is quite rare). Obtaining serology to document HIV
and HCV status would have been useful. What was the patient's history
for tobacco use and what was the duration of the patient's exposure to
hair dye?

2\. Causal association: in my opinion, it is extremely unlikely that
this patient developed lymphoma on the basis of Elidel therapy.

3\. Explanation: The interval between duration and development of
lymphoma is so short it is more likely that the patient already had
contracted lymphoma at the time the Elidel was initiated. In fact, there
is an association between eczema and the subsequent development of
lymphoma (see citation below).

4\. Citations:

Zhang Y, Holford TR, Leaderer B, Zahm SH, Boyle P, Morton LM, Zhang B,
Zou K, Flynn S, Tallini G, Owens PH, Zheng T. Prior medical conditions
and medication use and risk of non-Hodgkin lymphoma in Connecticut
United States women. Cancer Causes Control 2004; 15: 419-428.

\[This study showed that eczema or atopic dermatitis appears to be a
risk factor for the development of lymphoma\].

Miligi L, Seniori Costantini A, Crosignani P, Fontana A, Masala G, Nanni
O, Ramazzotti V, Rodella S, Stagnaro E, Tumino R, Vigano C, Vindigni C,
Vineis P. Occupational, environmental, and life-style factors associated
with the risk of hematolymphopoietic malignancies in women. Am J Ind Med
1999; 36: 60-69.

\[This study addressed the increased association of tobacco use as well
as hair dyes and increased risk of lymphoma\].

Morton LM, Engels EA, Holford TR, Leaderer B, Zhang Y, Zahm SH, Boyle P,
Zhang B, Flynn S, Tallini G, Owens PH, Zheng T. Hepatitis C virus and
risk of non-Hodgkin lymphoma: a population-based case-control study
among Connecticut women. Cancer Epidemiol Biomarkers Prev 2004; 13:
425-430.

Zhang Y, Holford TR, Leaderer B, Boyle P, Zahm SH, Flynn S, Tallini G,
Owens PH, Zheng T. Hair-coloring product use and risk of non-Hodgkin\'s
lymphoma: a population-based case-control study in Connecticut. Am J
Epidemiol 2004; 159: 148-154.

Schroeder JC, Olshan AF, Baric R, Dent GA, Weinberg CR, Yount B, Cerhan
JR, Lynch CF, Schuman LM, Tolbert PE, Rothman N, Cantor KP, Blair A. A
case-control study of tobacco use and other non-occupational risk
factors for t(14;18) subtypes of non-Hodgkin\'s lymphoma (United
States). Cancer Causes Control 2002; 13: 159-168.

Besson H, Renaudier P, Merrill RM, Coiffier B, Sebban C, Fabry J, Trepo
C, Sasco AJ. Smoking and non-Hodgkin\'s lymphoma: a case-control study
in the RhÃ´ne-Alpes region of France. Cancer Causes Control 2003; 14:
381-389.

II\. Case 2:

A two year old infant male developed a lymphoblastic lymphoma within 6
months after exposure to Elidel.

1\. Additional info: The biopsy should be reviewed for histology,
immunophenotyping and EBV status. Obtaining serology to HIV and HCV
would have been useful. The disease extent and sites, including
presence/absence of marrow involvement, are important factors. Further,
did this patient have any underlying medical conditions or family
history suggesting a predilection for the development of lymphoma.

2\. Causal association: in my opinion, it is extremely unlikely that
this patient developed lymphoma on the basis of Elidel therapy. This
lymphoma subtype (if confirmed histologically), although uncommon,
typically affects young individuals and presents in the mediastinum (not
an atypical location) such as in this patient.

3\. Explanation: The interval between duration of Elidel therapy and
development of lymphoma is relatively short; it appears quite unlikely
that this agent was causal. Further, eczema or atopic dermatitis appears
to be a risk factor for the development of lymphoma

4\. Citations:

Zhang Y, Holford TR, Leaderer B, Zahm SH, Boyle P, Morton LM, Zhang B,
Zou K, Flynn S, Tallini G, Owens PH, Zheng T. Prior medical conditions
and medication use and risk of non-Hodgkin lymphoma in Connecticut
United States women. Cancer Causes Control 2004; 15: 419-428.

\[This study showed that eczema or atopic dermatitis appears to be a
risk factor for the development of lymphoma\].

Chiu BC, Weisenburger DD. An update of the epidemiology of
non-Hodgkin\'s lymphoma. Clin Lymphoma 2003; 4: 161-168.

III\. Case 3:

A patient with an apparent history of vitiligo reportedly developed
lymphoma (unknown patient age, lymphoma type) after exposure to Elidel
(unknown duration of exposure).

1\. Additional info: One needs to obtain data to support the diagnosis
of lymphoma and the extent of Elidel exposure.

2\. Causal association: There are insufficient data to document the
occurrence of lymphoma.

3\. Explanation: There are no objective data to support a relationship
between lymphoma diagnosis and Elidel use. Vitiligo is an autoimmune
disorder, and the latter has been noted to be a risk factor for the
development of lymphoma.

4\. Citations:

Ramos-Casals M, Trejo O, Garcia-Carrasco M, Cervera R, De La Red G, Gil
V, Lopez-Guillermo A, Ingelmo M, Font J. Triple association between
hepatitis C virus infection, systemic autoimmune diseases, and B cell
lymphoma. J Rheumatol 2004; 31: 495-499.

Fisher SG, Fisher RI. The epidemiology of non-Hodgkin\'s lymphoma.
Oncogene 2004; 23: 6524-6534.

Hardell L, Lindstrom G, van Bavel B, Fredrikson M, Liljegren G. Some
aspects of the etiology of non-Hodgkin\'s lymphoma. Environ Health
Perspect 1998; 106 Suppl 2: 679-681.

IV\. Case 4:

A 53 year old man with a long history of generalized atopic dermatitis
treated with topical immunosuppressive therapy developed a subcutaneous
panniculitis-like T cell lymphoma within 6 months after exposure to
Elidel.

1\. Additional info: What was this man's occupation (any industrial or
agriculture exposure?). Also, obtaining serology to document HIV and HCV
status would be useful. What was the patient's history for tobacco use?

2\. Causal association: The interval between duration and development of
lymphoma is relatively short; it is more likely that the patient already
had contracted lymphoma at the time the Elidel was initiated.

3\. Explanation: This rare tumor appears to be a sub-set of peripheral T
cell non-Hodgkin's lymphoma which generally affects the dermis and
subcutaneous adipose tissue and only later affects lymph nodes. In
contrast to B cell lymphomas, risk factors for the development of T cell
lymphomas are less well defined. On the other hand, this patient has a
long history of exposure to immunosuppressive therapy, a potential
inciting factor. Further, atopic dermatitis appears to be a risk factor
for the development of lymphoma.

4\. Citations:

Purdue MP, Bassani DG, Klar NS, Sloan M, Kreiger N; The Canadian Cancer
Registries Epidemiology Research Group. Dietary factors and risk of
non-Hodgkin lymphoma by histologic subtype: a case-control analysis.
Cancer Epidemiol Biomarkers Prev 2004t; 13: 1665-1676.

\[This study showed a higher rate of the development of lymphoma in
patients with a high intake of processed meat, cheese or eggs or high
consumption of fat.\]

Hardell L, Lindstrom G, van Bavel B, Fredrikson M, Liljegren G. Some
aspects of the etiology of non-Hodgkin\'s lymphoma. Environ Health
Perspect 1998; 106 Suppl 2: 679-681.

\[This study showed that use of chronic immunosuppressive agents can
leave to the development of lymphoma.\]

Stagnaro E, Tumino R, Parodi S, Crosignani P, Fontana A, Masala G,
Miligi L, Nanni O, Ramazzotti V, Rodella S, Senoiri Constantini A,
Vigano C, Vindigni C, Vineis P. Non-Hodgkin\'s lymphoma and type of
tobacco smoke. Cancer Epidemiol Biomarkers Prev 2004; 13: 431-437.

Chiu BC, Weisenburger DD. An update of the epidemiology of
non-Hodgkin\'s lymphoma. Clin Lymphoma 2003; 4: 161-168.

Zhang Y, Holford TR, Leaderer B, Zahm SH, Boyle P, Morton LM, Zhang B,
Zou K, Flynn S, Tallini G, Owens PH, Zheng T. Prior medical conditions
and medication use and risk of non-Hodgkin lymphoma in Connecticut
United States women. Cancer Causes Control 2004; 15: 419-428.

\[This study showed that eczema or atopic dermatitis appears to be a
risk factor for the development of lymphoma\].