CDX2-positive Cancer of Unknown Primary With Upper-body Paralysis Was Dramatically Improved by Colorectal Cancer Chemotherapy

Case Report

A 61-year-old female had been suffering from left shoulder pain for one month. In the manual muscle test (MMT) when she first visited our hospital, the right deltoid muscle was 5/5, the left one was 2/5, the right biceps muscle was 5/5, the left one was 1/5, and the right triceps muscle was 5/5 and the left one was 2/5. Her finger extensions on both hands were 5/5. As for leg muscle strength, the tibialis anterior, quadriceps, and iliopsoas muscles were 5/5 on both sides. Therefore, marked muscle weakness of her left upper extremity was observed (Figure 1A and B). There were no major abnormalities in laboratory data. C-reactive protein (CRP) was 0.36 (mg/dl) and D dimer was 1.34 (μg/ml), both of which were slightly high. As tumor markers, carbohydrate antigen 19-9 (CA19-9) was 570 U/ml, and soluble interleukin-2 receptor (sIL-2R) was slightly higher 550 U/ml. MRI showed osteolytic masses extending to the vertebral arch in the C5, C6, C7, and Th3 vertebral bodies (Figure 2). In addition, a thickening of the sigmoid colon was observed from the rectal area, and the boundary with the surrounding fat was unclear in computed tomography (CT), suggesting CRC (Figure 3). Colonoscopy revealed a circumferential stricture in the sigmoid colon with normal mucosa, suggestive of stricture due to dissemination. A colon biopsy revealed poorly differentiated adenocarcinoma (Figure 4A) and the vertebra excision was metastatic adenocarcinoma. However, immunohistochemically, the vertebra tumor was negative for CK7 and CK20 but positive for CDX2 (Figure 4B). Therefore, we made the diagnosis of CRC with bone metastasis. It took about 3 weeks to determine the diagnosis. There were no KRAS or BRAF mutations in the tissue.

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Figure 1.

Manual muscle test (MMT) of the right and left upper extremities. A) At the initial visit to our hospital, the MMT scores of the deltoid, biceps, and triceps muscles of the right upper extremity were all 5/5. Despite posterior stabilization, muscle weakness in the right upper limb progressed, and the right extremities could hardly move. However, chemotherapy dramatically improved the patient’s muscle weakness. With the continuation of chemotherapy, the movement of the upper right limb gradually improved. The squares represent biceps, the triangles represent triceps, and the arrows represent deltoid. B) At the initial visit to our hospital, the MMT scores of the left deltoid and triceps muscles of the left upper extremity was 2/5, while the score of the left biceps muscle was 1/5. The left upper extremity was originally recognized to have lost muscle strength earlier, and the muscle strength of the left upper extremity took longer to improve in comparison to the muscle strength of the right upper extremity. Nevertheless, chemotherapy gradually improved the movement of his left extremity. The squares represent biceps, the triangles represent triceps, and the arrows represent deltoid.

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Figure 2.

Osteolytic masses extended to the vertebral arch in the C5, C6, C7, and Th3 vertebral bodies (arrow).

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Figure 3.

Thickening of the sigmoid colon was observed from the rectal area, and the boundary with the surrounding fat was unclear on computed tomography, suggesting colorectal cancer (arrow).

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Figure 4.

Pathology of colorectal cancer and vertebra. A) Pathology of colorectal cancer. 1. Atypical cells grew in alveolar foci. Glandular formation was unclear, suggesting poorly differentiated adenocarcinoma (HE staining, ×200). 2. Cytokeratin 7 (CK7) negative (CK7 staining). 3. Cytokeratin 20 (CK20) negative (CK20 staining). Most colorectal cancers are CK7-negative and CK20-positive; thus, this case was not typical. B) Pathology of vertebra. 1. The tumor proliferated like an alveolus with some small glandular formations, suggesting moderately to poorly differentiated adenocarcinoma (HE staining, ×200). It was suspected that it was a metastatic lesion, but at this point it was not known where the metastasis came from. 2. CK7 negative (CK7 staining, ×200). 3. CK20 negative (CK20 staining, ×200). Negative results for CK7 and CK20 were consistent with colorectal cancer findings. 4. CDX2 positive. Diffuse nuclear positivity (CK20 staining, ×200). A positive CDX2 resulted in a diagnosis of colorectal cancer.

The muscle strength of the left upper extremity was weakened at the time of the first visit, but it became immobile after hospitalization. Not only the left upper extremity, but also the muscle strength and movement of the right upper extremity gradually deteriorated. Therefore, posterior stabilization was performed 6 days after admission. This approach significantly reduced pain in both shoulders, especially in her left shoulder, but the numbness remained severe. Three weeks after admission, the deltoid, biceps, and triceps MMT score on the right changed from 5/5 to 1/5 (Figure 1A and B). Around the same time, she was diagnosed with CRC, and we decided to start treatment with chemotherapy for CRC.

We told her that chemotherapy might not work, but she still wanted to do something rather than do nothing, thus we started mFOLFOX6 colorectal chemotherapy about one month after admission. Each cycle of mFOLFOX6 consisted of racemic leucovorin 200 mg/m², oxaliplatin 85 mg/m² in a 2-hour infusion, bolus fluorouracil 400 mg/m² on day 1, and a 46-hour infusion of fluorouracil 2,400 mg/m² every two weeks. She was subjected to rehabilitation of her upper and lower limbs every day. Initially, at the start of chemotherapy she could not move her left hand and her right hand could hardly hold a pen. After adding cetuximab for the third time of mFOLFOX6, the muscle contraction improved slightly from the elbow of the right upper limb to the periphery of the fingers. She gradually improved. Three days after administration of cetuximab (every 2 weeks at 500 mg/m²), she became able to bend the dorsiflexion of her right wrist joint, grasp a stick with her right hand, and move the fingertips of her left hand a little. Only one and a half months after the start of chemotherapy, she was able to press the nurse call, operate her cell phone and write letters with her right hand. Almost at the same time her left hand also became mobile, and finally she was able to do the pronation and supination movements of her left hand. Numbness was still present but was managed with pregabalin and amitriptyline hydrochloride.

As she was improving, she worked even harder on rehabilitation. In order to leave the hospital, she practiced putting on her jacket while using her right hand well since she could not use her left hand. When she ate, she used a fork or spoon that was as light as possible and tried to bring it to her mouth. It wasn’t an easy rehabilitation, but she didn’t complain and did her best.

She finally returned home after three months in the hospital. At discharge, her biceps and triceps MMT scores improved from 1 to 3 on the right hand and from 0 to 2 on the left hand. In preparation for her discharge from the hospital, we also enhanced her personal support. After discharge, she was scheduled to come to the hospital once every two weeks for chemotherapy. While at home, her aunt helped her with her needs and the visiting nurse helped her bathe. Based on the situation at home after discharge, we consulted with the rehabilitation physical therapists of the hospital in order to improve her overall ability to move.

Her hands and numbness symptoms did not change significantly, but CT showed primary tumor’s getting bigger and worsening peritoneal dissemination, forcing her to change her chemotherapy regimen. Especially, after starting Cetuximab, her hands’ symptoms improved dramatically, so we continued as long as possible. When the effect of mFOLFOX6 disappeared, we switched to FOLFIRI (racemic leucovorin 200 mg/m² in a 2-h infusion, CPT-11 150 mg/m² in a one and a half-hour infusion, bolus fluorouracil 400 mg/m² on day 1, and a 46-h infusion of fluorouracil 2,400 mg/m² every two weeks) and changed cetuximab to ramucirumab (8 kg/m², in one-hour infusion). Continuing chemotherapy sometimes made treatment impossible for more than 2 weeks, so the doses of oxaliplatin and CPT-11 were reduced by one step.

About seven months after the start of chemotherapy, there was no significant change in muscle strength, but numbness became stronger, and fever appeared. Considering a change in treatment, she became pale and had a drop in blood pressure. She noted peripheral coldness and cyanosis of her lips. No change in her consciousness was noted, but her respiratory status gradually worsened. About eight months after starting her chemotherapy, she passed away. At her family’s request, no autopsy was performed.