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 3-kinase (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 bowel-wall 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 Good’s syndrome

• 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 B-cell 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 esophagogastroduodenoscopy.

• 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 Complicationsof Thymoma

• Hypogammaglobulinemia, which is typical of Good’s syndrome, requires immunoglobulin-replacement therapy

• Specific intervention with antimicrobial agents, including antifungal agents.

• The autoimmune complications of thymoma require immunosuppressive therapy

Thanks