A 72-year-old lady presented with pneumonia. Chest X-ray (Fig. 10.1a) showed a right lung mass. CT-guided biopsy showed moderately differentiated adenocarcinoma. Immunohistochemistry was strongly and diffusely positive for CDX2, cytokeratin (CK) 20, villin, and carcinoembryonic antigen (CEA) and negative for CK7 and TTF-1. CT chest showed a right upper lobe mass (Fig. 10.1b). PET showed an intensely FDG-avid lung mass but no evidence of distant metastases (Fig. 10.1c, d). Colonoscopy and upper gastrointestinal endoscopy were performed and were normal. The patient received four cycles of mFOLFOX6 chemotherapy in neoadjuvant setting and had a partial response (Fig. 10.1e). The patient then underwent en bloc right upper lobe lobectomy with mediastinal lymph node dissection. Pathology showed poorly differentiated adenocarcinoma with 11 lymph nodes without any evidence of malignancy. The patient was then followed closely with surveillance scans, and PET-CT 4-year status postsurgery showed no evidence of recurrent or metastatic disease (Fig. 10.1f).

Select patients with CUP who present with a solitary site of disease represent a unique favorable subset that benefit substantially from aggressive therapy involving systemic chemotherapy, radiation, and surgery and can attain prolonged disease-free intervals with multidisciplinary care. Comprehensive pathological evaluation can help with neoadjuvant or adjuvant therapy planning, and given the unknown biology of CUP, a detailed discussion with the patients regarding the rationale for this approach is necessary.

Men presenting with adenocarcinoma of unknown primary with predominant osteoblastic metastases, elevated serum PSA, and immunophenotypic expression of prostate-specific tumor markers should be considered a favorable subset of CUP given the ease of management with initial hormonal therapy and expected benefit with treatment. Treatment guidelines for advanced prostate cancer are followed for the course of the disease.

Women presenting with CUP and isolated axillary lymphadenopathy are a unique favorable subset of CUP, in whom management should be designed in accordance with treatment of locally advanced breast cancer. When breast markers are not positive on immunohistochemistry, especially in patients with poorly differentiated carcinoma, it can present a challenge for management and most would treat it as breast cancer in the absence of an identifiable putative primary with additional studies. With aggressive local management (breast surgery and ALND with or without radiation) and chemotherapy, these patients are expected to have prolonged survival.

A 54-year-old lady presented with progressively worsening abdominal pain for the past 3 weeks. She had no significant medical history, and total abdominal hysterectomy and bilateral salpingo-oophorectomy was performed 12 years ago for uterine fibroids. CT abdomen and pelvis showed a 3.8 × 6 cm mass in the omentum, left of midline in the lower abdomen with some nonspecific lymphadenopathy (Fig. 10.3a, b). Mammography, upper GI endoscopy, and colonoscopy were performed and were normal. An ultrasound-guided biopsy of this omental mass showed a poorly differentiated carcinoma. The immunohistochemical profile was not specific and showed malignant cells positive for CK7 and ER (about 90 %) and negative for synaptophysin, CK20, TTF-1, CD56, PR, GCDFP15, P63, P40, mammaglobin, and CK5/CK6. Due to the presence of peritoneal carcinomatosis, additional staining was performed and showed tumor cells to be positive for WT-1 and PAX-8 and negative for inhibin. The histopathology and immunophenotype was most consistent with a high-grade serous carcinoma of Mullerian origin (peritoneal/ovary). CA 125 was found to be 220.5 U/ml (reference range: 0.0–35.0) (Fig. 10.3d). Preoperative PET scan showed FDG-avid disease in the peritoneum without any evidence of distant metastases (Fig. 10.3c). The patient underwent diagnostic laparoscopy, exploratory laparotomy, omentectomy, and resection of the anterior abdominal wall mass with optimal tumor reductive surgery. No additional metastatic disease was noted in the peritoneum. Pathology showed high-grade serous carcinoma. Postoperatively, CA 125 decreased to 89.1 U/ml (Fig. 10.3d). She was then treated with systemic chemotherapy with carboplatin and paclitaxel, but chemotherapy was held after two cycles due to poor tolerance. The patient has since been on surveillance for the past 1.5 years without any signs of local or distant recurrence.

Poorly differentiated carcinoma/adenocarcinoma of unknown primary presenting with peritoneal involvement in women and having clinicopathological features suggestive of serous ovarian neoplasms represent a favorable subset of CUP similar to primary peritoneal carcinoma with long-term remission seen in about 15 % of cases. This subset should be treated as stage III–IV ovarian cancer using cytoreductive surgery and platinum-taxane-based chemotherapy.

Young patients with poorly differentiated carcinoma predominantly involving mediastinal, retroperitoneal lymph nodes should be evaluated for the possibility of extragonadal germ cell cancer syndrome with tumor markers, immunohistochemistry, and if needed chromosomal analysis and can be treated as per guidelines for poor-risk germ cell tumors with platinum-based combination chemotherapy.