Discussion
Immunity may be impaired in patients with thymoma. Thymoma-associated
immunodeficiency is known as Good’s syndrome and includes
hypogammaglobulinaemia, decreased or absent B lymphocytes,
CD4+/CD8+ inversion and decreased T
lymphocytes. In addition, autoimmune manifestations may
occur4. The etiology of thymoma related PWCA is still
unknown, but it appears to have an autoimmune background. Growth
inhibition of granulocytic and macrophage colony-forming units exposed
to different concentrations of serum from these patients has been
observed. This finding suggests the presence of an immunoglobulin
against immature myeloid cells, indicating an alteration of B cells and
humoral immunity5. Conversely, the response to
anti-calcineurin immunosuppressors in these cases, as in PRCA, points to
an alteration in T cells and cellular immunity6.
Thymus is the organ where T cell maturation and TCR gene rearrangement
occurs. Besides, it is the place where negative selection of
autoreactive T cells and positive selection of T cells capable of
recognising MHC presented antigens take place7. In
this sense, several causal mechanisms for the loss of self-tolerance in
thymoma patients have been proposed: (1) Immaturity of neoplastic T
cells that would allow the escape of autoreactive lymphocytes, (2)
Neoplastic genetic alterations that would predispose to the appearance
of autoimmunity such as decreased expression of HLA-DR and (3) Theory of
combined dysregulation of cellular and humoral immunity, an autoreactive
T cell would activate a B cell to produce
autoantibodies8.
Surgery to resect tumour tissue is the standard treatment for patients
with thymoma. Thymectomy appears to have a positive impact on the
autoimmune clinic by removing the neoplastic tissue, which seems to
provide the antigenic stimulus for autoreactive cells. It has been
reported the case of a patient with thymoma and granulocytopenia in whom
a decrease in anti-pANCA antibody titre and elevation of granulocytes in
peripheral blood was observed after thymectomy9.
However, in other cases neutropenia has not resolved after thymectomy
and a second line of treatment is necessary10,11. The
medical treatment of these patients is not established currently, due to
low incidence of cases. Several strategies have been used to increase
granulocyte counts (Table I) . GCS-F and IVIG normally have no
impact in granulocytic count12. Of the 24 patients
collected 13 survive, all of them receive some immunosuppressive
treatment (CyA 6 patients, Azathioprine 2, Corticoid 2, Alemtuzumab 1,
Chemoterapy 1 and plasmapheresis 1) which reinforces the idea of a
combined surgical and immunosuppressive treatment for these patients.
CyA has demonstrated favourable responses in these patients. It has been
used with target trough levels of 200-400 ng/mL and monitoring
toxicities. Granulocytic recovery occurs within 7 to 10 days.
Maintenance treatment has usually been applied, with CyA tappering until
its total suspension after 4-6 months5,10. Others have
used extended treatment with CyA and prednisone in decreasing doses for
up to 20 months after thymectomy12.
Alemtuzumab has been successfully used as an immunosuppressor in
autoimmune bone marrow failures. In two cases of PWCA Alemtuzumab has
achieved complete response in the first month13.
Alemtuzumab has been useful in the treatment of a patient with PWCA and
thymoma, after failure of G-CSF and plasmapheresis, achieving
granulocyte recovery in 12 days. However, agranulocytosis relapsed 5
months later and was treated with a new cycle of Alemtuzumab associated
with CyA and maintenance mycophenolate14.
A case has been described of a paciente with MG thymectomised, who
relapsed after 12 years with MG and de novo PWCA. In this case,
plasmapheresis was started with improvement of the MG symptoms as
diagnosis, but there was no change in the granulocyte count after 15
sessions. Azathioprine 2.5 mg and prednisone mg/kg were started,
obtaining an increase in the granulocyte count 4 months
later15. It suggests that plasmapheresis alone is not
a good option for the treatment of PWCA and the use of concomitant
inmunosupressor is needed.
Thymectomy is a major surgery with high complexity and infectious risks.
We consider that the appropriate management would be the resolution of
the PWCA prior to surgery. According to our review, treatments with
immunosuppressive drugs are associated with better outcome. In our
patient, we have obtained a good response with CyA, which supports the
existing literature as the most successful therapeutic option.
Furthermore, it is a drug with a known safety profile, extensive
experience in its use and the possibility of measuring levels.
Therefore, we suggest the use of CyA as a first-line drug with the
concomitant use of G-CSF from granulocyte recovery onwards. Long-term
follow-up of thymoma and immunological status is advisable because
relapses have been observed in these patients.
Conflict of interest : Authors report no conflicts of interest
associated with this publication.
Author contributions : Roberto Céspedes López is the main
author, was involved in patient care, provided necessary data for the
article, and was involved in manuscript preparation. Elena Amutio Díez
is the main reviewer, was involved in manuscript preparation, checked
grammatical and data errors, and patient care. Xabier Martín Martitegui
was involved in patient care and provided data for the article. Amaia
Balerdi Malcorra was invoveld in patient care. Lucía Insunza Oleaga was
involved in patient care. Maite Moreno Gámiz was involved in patient
care. Javier Arzuaga Méndez was involved in patient care. Juan Carlos
García-Ruíz checked the manuscript for grammatical and secientific
errors.
Ifrah Malik checked the manuscript for grammati-cal and scientific
errors
Ethical approval: Appropriate informed consent was taken for
publication of this report and the associated images. Authors have
confirmed that patient consent has been signed and collected in
accordance with the journal consent policy.