Download Commenatry case

Commenatry
case
By
Prof Dr /Fawzy Megahed
Asst lec /Rafaat Saied
• A 29-year-old man with metastatic thymoma
was seen in the outpatient oncology clinic
because of intractable diarrhea of 1 month’s
duration.
• The patient had received a diagnosis of
thymoma 5 years earlier, after a chest
radiograph had been obtained to evaluate
acute pain in the left shoulder.
• A frontal radiograph of the chest (Panel A)
shows a mediastinal mass (arrows), with
rightward tracheal deviation and a left pleural
effusion.
• An axial, contrast-enhanced CT scan of the
chest (Panel B) shows an anterior mediastinal
soft-tissue mass abutting the main pulmonary
artery and ascending aorta (arrows) and a left
pleural effusion
• A chemotherapy regimen of doxorubicin,
cisplatin, vincristine, and cyclophosphamide
was administered for three cycles, and then a
thymectomy was performed.
• An axial, contrast-enhanced
• CT scan of the chest (Panel E) shows a median
sternotomy wire and retrosternal surgical clips
(encircled), findings consistent with
thymectomy, as well as circumferential
nodular pleural thickening involving the
mediastinal pleura (arrows), a finding
consistent with known metastatic disease.
• Thirteen months after the patient’s initial
presentation, follow-up CT of the chest
revealed new nodular left pleural thickening, a
finding that was suggestive of metastatic
disease. Thereafter, the patient was
monitored with serial scanning.
• Approximately 2.5 years before this
presentation, episodes of nonproductive
cough developed that persisted for a few
minutes at a time and were occasionally
associated with vomiting and pain in the right
lateral chest wall; there was no dyspnea at
rest.
• Pathological examination of a core-needle
biopsy specimen of the left pleura confirmed
the presence of metastatic thymoma.
• Additional chemotherapy with doxorubicin,
cisplatin, vincristine, and cyclophosphamide
was administered, followed by sunitinib;
• there was transient improvement in the
cough.
• The treatment course was complicated by
several episodes of fever and cough (at least
three of which were documented as bacterial
pneumonia) and intermittent oral thrush.
• Six months before this presentation,
treatment with an investigational agent — a
selective inhibitor of phosphatidylinositol 3kinase (PI3K) isoform β — was begun.
• At the end of the second and fourth cycles of
therapy, restaging scans showed stable
disease.
• Four weeks before this presentation, at the
end of the fifth cycle, diarrhea developed, and
episodes increased in frequency to 10 to 12
liquid stools daily, each with an average
volume of 250 ml; there was occasional
nausea and vomiting, despite administration
of loperamide hydrochlorideand
diphenoxylate atropine.
• Stool color reportedly varied in relation to oral
intake; there was no abdominal pain,
hematochezia, or melena.
• He reported slight nausea without vomiting,
fever, or chills, as well as poor appetite,
increased fatigue, persistent chest-wall pain,
nocturnal headaches, dyspnea when climbing
stairs, and dryness of the lips and mouth and
the skin of his hands.
• He had lost 9 kg of weight in the past month
• Thirteen days before this presentation, CT of
the abdomen and pelvis revealed mild
circumferential wall thickening of the sigmoid
colon and prominence of the vasa recta,
findings that were suggestive of inflammation
(Fig. 1D). Enlarging celiac lymphadenopathy
was suggestive of progression of metastatic
disease.
• CT of the chest that was performed on the
same day revealed that the pleural and
pulmonary nodules had not changed; these
findings were consistent with stable thoracic
metastases (Fig. 1E).
• The investigational agent was stopped after a
total of five cycles of therapy, without
subsequent improvement in diarrhea.
• 1 week before this presentation, testing of a
stool specimen for Clostridiumdifficile was
negative, and a stool culture did not grow any
enteric pathogens.
• Medications were allopurinol,
hydromorphone, guaifenesin, diphenoxylate–
atro-pine, potassium chloride, and, as needed,
benzonatate for cough..
• He did not smoke, drink alcohol, or use illicit
drugs.
• His paternal grandfather had had cancer,
possibly of the prostate; other family history
was noncontributory.
Examination
• the vital signs and oxygen saturation were
normal. The abdomen was soft, with slight
tenderness on deep palpation of the upper
right quadrant and without guarding or
rebound. The remainder of the examination
was normal.
Investigations
• The hematocrit, hemoglobin level, platelet
count, and plasma anion gap were normal, as
were the blood levels of glucose, total protein,
albumin, globulin, magnesium, uric acid,
phosphorus, total and direct bilirubin, alkaline
phosphatase, and lactic dehydrogenase and
results of renal-function tests.
• Nucleic acid testing for cytomegalovirus was
negative; other test results are shown in Table
1.
• Differential Diagnosis
Differential Diagnosis
• Diarrhea in Patients with Cancer
• Immunologic Complications of Thymoma
Diarrhea in Patients with Cancer
• Systemic therapy needs to be considered as
the cause of this patient’s diarrhea;
• Immunomodulatory agents can also cause
diarrhea as a manifestation of immune-related
enteritis.
• An underlying cancer can also be responsible
for the development of diarrhea,
• infections should always be considered in a
patient with cancer.
• This patient had metastatic thymoma and
refractory diarrhea. A CT scan showed bowelwall thickening that was indicative of diffuse
colitis.
• No infectious cause was identified.
• Diarrhea may be a side effect of some of the
chemotherapy medications to which this
patient had been exposed; however,
discontinuation of these medications did not
result in improvement.
Immunologic Complications of
Thymoma
• Immunologic complications of thymoma
include
• A-immunodeficiency
• B-autoimmunity.
A-Immunodeficiency and Thymoma
• due to defects in the B cells or T cells of the
adaptive immune system.
• The association between mmunodeficiency
and thymoma is now known as
syndrome
Good’s
• The recognized features of Good’s syndrome
include
1. no or low levels of B cells in the peripheral blood,
2. low serum immunoglobulin levels,
3. CD4 lymphocytopenia,
4. an inverted ratio of CD4 to CD8 cells,
5. a clinical pattern of recurrent sinopulmonary
infections,
6. and evidence of impaired cell-mediated immunity.
• The pathophysiology of Good’s syndrome is
not clearly understood but appears to
represent a pre–B-cell developmental arrest in
the bone marrow;
• unlike the other immune-mediated cytopenias
that can be seen in patients with thymoma,
the cytopenia associated with Good’s
syndrome does not improve with
glucocorticoids or Immunosuppressive
therapy
• The results of one study suggested that T cells
that are isolated from thymomas can inhibit Bcell production of immunoglobulins and pre–
B-cell growth in healthy controls.
B- Autoimmunity and Thymoma
-Autoimmunity.
1. immune-mediated cytopenias, pure red-cell
aplasia,
2. myasthenia gravis,
3. the stiffperson syndrome,
4. oral lichen planus,
5. pemphigus vulgaris,
6. and autoimmune enteropathy
• Autoimmune problems are also linked to
thymoma, and just over half the patients with
Good’s syndrome have some manifestations of
autoimmunity,
• Noninfectious diarrhea, there have been
several reports of autoimmune enteropathy as
the cause of the diarrhea.
• Autoimmune enteropathy is characterized by
persistent watery diarrhea and
malabsorption. Autoantibodies against
enterocytes and non-enterocyte–associated
antigens can be present on
immunofluorescence studies.
• Autoimmune enteropathy has been observed
in patients with Good’s syndrome, as well as in
patients with other conditions in which the
immune regulation is disordered
•What is next
step ?
• The diagnostic procedures performed in this
case were
•colonoscopy and
esophagogastroduo
denoscopy.
• Examination of biopsy specimens of the right
and left colon and rectum revealed colonic
mucosa with reactive epithelial injury,
prominent crypt-cell apoptosis, mild
lymphocytosis, and extensive loss of goblet
cells
• The prominent crypt-cell apoptosis, which
was reminiscent of that seen in patients with
graft-versus-host disease, is a feature of
autoimmune enteropathy; this diagnosis is
further supported by the absence of goblet
cells.
• Examination of a duodenal-biopsy specimen
that was obtained a few days later revealed
chronic duodenitis with villous shortening,
reactive epithelial injury, basal-cell apoptosis,
and loss of goblet and Paneth cells these
findings are consistent with autoimmune
enteropathy.
• Immunohistochemical staining for antibodies
against enterocytes was positive on two
separate occasions.
• Flow cytometry of peripheral blood showed a
decreased total count of CD3+ T cells ,CD4+ T
cells and CD19+ B cells the total count of CD8+
T cells was within the normal range.
• Serum immunoglobulin levels were also low,.
• These findings fit with the clinical
characteristics associated with Good’s
syndrome.
• Five months after this presentation, a bone
marrow biopsy was performed because of
anemia. Examination of the biopsy specimens
are consistent with pure red-cell aplasia.
• Thymoma-associated cellular and
humoral immunodeficiency (Good’s
syndrome) and autoimmune
enteropathy.
Management
• Management of Advanced Thymoma
• Management of Immunologic Complications
of Thymoma
Management of Advanced Thymoma
• initial treatment with combination regimens
that include cisplatin
• No standard therapy exists for relapsed or
refractory thymoma.
Management of Immunologic Complications
of Thymoma
• Hypogammaglobulinemia, which is typical of
Good’s syndrome, requires immunoglobulinreplacement therapy
• Specific intervention with antimicrobial
agents, including antifungal agents.
• The autoimmune complications of thymoma
require immunosuppressive therapy
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