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97 Carcinoma of Unknown Primary

osteoporosis, the cortical bone may be preserved, whereas cortical bone destruction is usually noted with metastatic cancer. TREATMENT Metastatic Bone Disease Treatment of metastatic bone disease depends on the underlying malignancy and the symptoms. Some metastatic bone tumors are curable (lymphoma, Hodgkin’s lymphoma), and others are treated with palliative intent. Pain may be relieved by local radiation therapy. Hormonally responsive tumors are responsive to hormone inhibition (antiandrogens for prostate cancer, antiestrogens for breast cancer). Strontium-89, samarium-153, and radium-223 are bone-seeking radionuclides that can exert antitumor effects and relieve symptoms. Denosumab, a monoclonal antibody that binds to RANK ligand, inhibits osteoclastic activity and increases bone mineral density. Bisphosphonates such as pamidronate may relieve pain and inhibit bone resorption, thereby maintaining bone min­ eral density and reducing risk of fractures in patients with osteo­ lytic metastases from breast cancer and multiple myeloma. Careful monitoring of serum electrolytes and creatinine is recommended. Monthly administration prevents bone-related clinical events and may reduce the incidence of bone metastases in women with breast cancer. When the integrity of a weight-bearing bone is threatened by an expanding metastatic lesion that is refractory to radiation therapy, prophylactic internal fixation is indicated. Overall survival is related to the prognosis of the underlying tumor. Bone pain at the end of life is particularly common; an adequate pain relief regimen including sufficient amounts of narcotic analgesics is required. The management of hypercalcemia is discussed in Chap. 422. ■ ■FURTHER READING Alvarez RA et al: Optimization of the therapeutic approach to patients with sarcoma: Delphi consensus. Sarcoma 2019:4351308, 2019. Ballinger ML et al: Monogenic and polygenic determinants of sarcoma risk: An international genetic study. Lancet Oncol 17:1261, 2016. Beird HC et al: Osteosarcoma. Nat Rev Dis Primers 8:77, 2022. Gounder M et al: Nirogacestat, a γ-secretase inhibitor for desmoid tumors. N Engl J Med 388:898, 2023. Meyer M, Seetharam M: First-line therapy for metastatic soft tissue sarcoma. Curr Treat Options Oncol 20:6, 2019. Pasquali S, Gronchi A: Neoadjuvant chemotherapy in soft tissue sarcomas: Latest evidence and clinical implications. Ther Adv Med Oncol 9:415, 2017. Patel S, Reichardt P: An updated review of the treatment landscape for advanced gastrointestinal stromal tumors. Cancer 127:2185, 2021. Ratan R, Patel SR: Chemotherapy for soft tissue sarcoma. Cancer 122:2952, 2016. Wagner MJ et al: Chemotherapy for bone sarcoma in adults. J Oncol Pract 12:208, 2016. Kanwal Raghav, James L. Abbruzzese

Carcinoma of Unknown

Primary Carcinoma (or cancer) of unknown primary (CUP) is a biopsy-proven malignancy for which the anatomic site of origin remains unidenti­ fied after a standardized detailed diagnostic evaluation. CUP is one of the 10 most frequently diagnosed cancers globally, accounting for 3–5% of all malignancies. Most investigators limit CUP to epithelial

or undifferentiated cancers and do not include lymphomas, metastatic melanomas, and metastatic sarcomas because these cancers have spe­ cific histology and stage-based management guidelines, even in the absence of a primary site. CUP can occur in patients of all age groups including adolescents and young adults.

The emergence of sophisticated imaging, robust immunohisto­ chemistry (IHC), and genomic and proteomic tools has challenged the “unknown” designation. Additionally, effective targeted therapies in several cancers and tissue-agnostic biomarker-driven therapies have endorsed a change in paradigm from empiricism to a personal­ ized approach to CUP management. The reasons cancers present as CUP remain unclear. One hypothesis is that the primary tumor either regresses after seeding the metastasis or remains so small that it is not detected. It is possible that CUP falls on the continuum of cancer presentation where the primary has been contained or eliminated by the natural body defenses, including the immune system. Alterna­ tively, CUP may represent a specific malignant event that results in an increase in metastatic spread or survival relative to the primary. Whether the CUP metastases truly define a clone that is genetically and phenotypically unique to this diagnosis remains to be determined. Since liver is a common site of CUP presentation, intrahepatic chol­ angiocarcinoma (ICC) can be often misdiagnosed as CUP. Of note, the incidence of ICC is increasing, whereas at the same time, that of CUP is declining. Improvements in diagnostic technologies including nextgeneration sequencing and other molecular techniques and awareness among clinicians to differentiate the two are possibly contributing to an increased recognition and incidence of ICC. CHAPTER 97 Carcinoma of Unknown Primary CUP BIOLOGY Studies looking for unique signature abnormalities in CUP tumors have not been positive. Abnormalities in chromosomes 1 and 12 and other complex cytogenetic abnormalities have been reported. Aneu­ ploidy has been described in 70% of CUP patients with metastatic adenocarcinoma or undifferentiated carcinoma. The overexpression of various genes, including RAS, BCL2 (40%), HER2 (11%), and P53 (26–53%), has been identified in CUP samples, but they are found in many other malignancies. The extent of angiogenesis in CUP relative to that in metastases from known primaries has also been evaluated, but no consistent findings have emerged. Although current comprehen­ sive genomic profiling efforts may help identify targeted therapeutic approaches to improve outcomes for this disease as discussed below, they have failed thus far to reveal a distinct molecular signature. More comprehensive and integrated multiomic efforts are needed to provide insights into CUP biology through recognition of molecular aberra­ tions that specifically drive metastatic growth. APPROACH TO THE PATIENT Carcinoma (or Cancer) of Unknown Primary Initial CUP evaluation has two goals: search for the primary or “putative primary” tumor based on clinicopathologic evaluation of the metastases and determine the extent of disease. Focused evaluation directed by clinicopathologic cues allows for judicious and efficient use of diagnostic tests. Obtaining a thorough medical history from CUP patients is essential, including paying particular attention to risk factors, prior surgeries, and family medical history to assess potential hereditary cancers. Adequate physical examina­ tion, including a digital rectal examination in men and breast and pelvic examinations in women, should be performed based on clini­ cal presentation. Finally, all patients with CUP, in the absence of contraindication, must undergo a computed tomography (CT) scan of chest, abdomen, and pelvis as a part of their standard workup. ■ ■ROLE OF SERUM TUMOR MARKERS AND CYTOGENETICS Most tumor markers, including carcinoembryonic antigen (CEA), CA-125, CA 19-9, and CA 15-3, are nonspecific and not helpful in determining the primary site. Men who present with adenocarcinoma

and predominant osteoblastic metastasis should undergo a prostatespecific antigen (PSA) test. In patients with undifferentiated or poorly differentiated carcinoma (especially with a midline tumor), elevated β-human chorionic gonadotropin (β-hCG) and α fetoprotein (AFP) levels suggest the possibility of an extragonadal germ cell (testicular) tumor. With the availability of advanced IHC, cytogenetic studies are rarely needed.

■ ■ROLE OF IMAGING STUDIES In the absence of contraindications, a baseline intravenous (IV) con­ trast CT scan of the chest, abdomen, and pelvis is the standard of care. This helps to search for the primary tumor, evaluate the extent of disease, and select the most accessible biopsy site. With precise imag­ ing and reporting, latent primary cancers, defined as appearance of a new primary cancer after a latent period of several months to years, is uncommon and seen in ≤5% of CUP patients, usually in patients with very indolent presentations and/or highly responsive metastatic cancers that allows a latent primary to emerge (grow) over time. Mammography should be performed in women who present with metastatic adenocarcinoma, especially in those with isolated axillary lymphadenopathy. Magnetic resonance imaging (MRI) of the breast can be considered in patients with axillary adenopathy and suspected occult primary breast carcinoma following a negative mammography and ultrasound. The results of these imaging modalities can influence surgical management; a negative MRI of the breast predicts a low tumor yield at mastectomy. PART 4 Oncology and Hematology A conventional workup for a squamous cell carcinoma and cervical CUP (neck lymphadenopathy with no known primary tumor) includes a CT scan or MRI and invasive studies, including indirect and direct laryngoscopy, bronchoscopy, and upper endoscopy. Ipsilateral (or bilat­ eral) staging tonsillectomy has been recommended for these patients. 18-Fluorodeoxyglucose positron emission tomography (18-FDG-PET) scans are useful in this patient population and may help guide the biopsy; determine the extent of disease; facilitate the appropriate treat­ ment, including planning radiation fields; and help with disease sur­ veillance. Several studies have evaluated the utility of PET in patients with squamous cervical CUP, and head and neck primary tumors were identified in ~21–30%. The diagnostic contribution of PET to the evaluation of other CUP presentations (outside of the neck adenopathy indication) remains controversial and is not routinely recommended. PET-CT can be help­ ful for patients with bone metastases and those deemed candidates for aggressive multimodality therapy (surgical intervention/radiation) such as patients with solitary metastatic disease because the identifica­ tion of disease in addition to the solitary metastatic site may affect treatment planning. Invasive studies, including upper endoscopy, colonoscopy, and bronchoscopy, should be limited to symptomatic patients or those with laboratory, imaging, or pathologic abnormalities that suggest that these techniques will result in a high yield in finding a primary cancer. CK7 CK20 CK7+ CK20+ CK7+ CK20– CK7– CK20+ CK7– CK20– Lung adenocarcinoma Breast carcinoma Thyroid carcinoma Endometrial carcinoma Cervical carcinoma Salivary gland carcinoma Cholangiocarcinoma Pancreatic carcinoma Urothelial tumors Ovarian mucinous adenocarcinoma Pancreatic adenocarcinoma Cholangiocarcinoma FIGURE 97-1  Approach to cytokeratin (CK7 and CK20) markers used in adenocarcinoma of unknown primary.

TABLE 97-1  Major Histologies in Carcinoma (Cancer) of Unknown Primary HISTOLOGY PROPORTION, % Well to moderately differentiated adenocarcinoma

Squamous cell cancer

Poorly differentiated adenocarcinoma, poorly differentiated carcinoma

Neuroendocrine

Undifferentiated malignancy

■ ■ROLE OF PATHOLOGIC STUDIES A detailed pathologic examination of the most accessible biopsied tissue specimen is mandatory in CUP patients. Pathologic evaluation typically consists of hematoxylin and eosin stains and IHC tests. The importance of adequate tissue acquisition cannot be overemphasized in CUP. In addition to pathologic evaluation, tissue is also needed for molecular profiling, which can aid in identifying biomarkers suggest­ ing the primary site for effective therapeutics including targeted agents, immunotherapy, and clinical trials. Light Microscopy Evaluation  Adequate tissue obtained prefer­ ably by excisional biopsy or core needle biopsy (instead of only a fineneedle aspiration) is stained with hematoxylin and eosin and subjected to light microscopic examination. On light microscopy, 60–65% of CUP is adenocarcinoma, and 5% is squamous cell carcinoma. The remaining 30–35% is poorly differentiated adenocarcinoma, poorly differentiated carcinoma, or poorly differentiated neoplasm. A small percentage of lesions are diagnosed as neuroendocrine cancers (2%), mixed tumors (adenosquamous or sarcomatoid carcinomas), or undif­ ferentiated neoplasms (Table 97-1). Role of IHC Analysis  IHC stains are peroxidase-labeled antibod­ ies against specific tumor antigens that are used to define tumor lin­ eage. The number of available IHC stains is ever-increasing. However, a tiered and uniform approach to tissue evaluation in the CUP setting is lacking. For CUP cases, more is not necessarily better, and IHC stains should be used in conjunction with the patient’s clinical presen­ tation and imaging studies to select the best therapy. Communication between the clinician and pathologist is essential. No stain is 100% sensitive or specific, and under-/overinterpretation should be avoided. Poor differentiation, even in known primary tumors, decreases sensi­ tivity of hallmark IHC markers. PSA and thyroglobulin tissue markers, which are positive in prostate and thyroid cancer, respectively, are two of the most specific markers. However, these cancers rarely present as CUP, so the yield of these tests may be low. Figure 97-1 delineates a simple algorithm for immunohistochemical staining in CUP cases. Table 97-2 lists additional tests that may be useful to further define the tumor lineage. A more comprehensive algorithm may improve the diagnostic accuracy but can make the process complex and increase Colorectal carcinoma Merkel cell carcinoma Hepatocellular carcinoma Renal cell carcinoma Prostate carcinoma Squamous cell and small- cell lung carcinoma Head and neck carcinoma

TABLE 97-2  Select Immunohistochemical Stains Useful in the Diagnosis of CUP COMMONLY CONSIDERED IHC TO ASSIST IN DIFFERENTIAL DIAGNOSIS OF CUPa LIKELY PRIMARY PROFILE Breast ER, GCDFP-15, mammaglobin, HER2/neu, GATA3 Ovarian/müllerian ER, WT1, CK7, PAX8, PAX2 Lung adenocarcinoma TTF-1; nuclear staining, napsin A, SP-A1 Germ cell β-hCG, AFP, OCT3/4, CKIT, CD30 (embryonal), SALL4 Prostate PSA, α-methylacyl CoA racemase/P504S (AMACR/ P504S), P501S (prostein), PSMA, NKX3-1 Intestinal CK7, CK20, CDX-2, CEA Neuroendocrine Chromogranin, synaptophysin, CD56 Sarcoma Desmin (desmoid tumors), factor VIII (angiosarcomas), CD31, smooth muscle actin (leiomyosarcoma), MyoD1 (rhabdomyosarcoma) Renal RCC, CD10, PAX8, CD10 Hepatocellular carcinoma Hep Par-1, Arg-1, glypican-3 Melanoma S100, SOX-10, vimentin, HMB-45, tyrosinase, melan-A Urothelial CK7, CK20, thrombomodulin, uroplakin III Mesothelioma Calretinin, WT1, D2-40, mesothelin Lymphoma LCA, CD3, CD4, CD5, CD20, CD45 SCC p63, p40 (lung SCC), CK5/6 aPatterns emerging from coexpression of stains are better than individual stains to suggest putative primary site. Even with optimization, no IHC panel is 100% sensitive or specific (e.g., ovarian mucinous carcinoma can exhibit positivity with intestinal markers). Abbreviations: AFP, α fetoprotein; Arg-1, arginase-1; β-hCG, β-human chorionic gonadotropin; CEA, carcinoembryonic antigen; CUP, carcinoma of unknown primary; ER, estrogen receptor; GCDFP-15, gross cystic disease fibrous protein-15; IHC, immunohistochemistry; LCA, leukocyte common antigen; PSA, prostatespecific antigen; PSMA, prostate-specific membrane antigen; SCC, squamous cell carcinoma; SP-A1, surfactant protein A precursor; TTF, thyroid transcription factor; WT, Wilms’ tumor. cost. With the use of IHC markers, electron microscopic analysis, which is time-consuming and expensive, is rarely performed today. There are >20 subtypes of cytokeratin (CK) intermediate filaments with different molecular weights and differential expression in various cell types and cancers. Monoclonal antibodies to specific CK subtypes have been used to help classify tumors according to their site of origin; commonly used CK stains in adenocarcinoma CUP are CK7 and CK20. CK7 is found in tumors of the lung, ovary, endometrium, breast, and upper gastrointestinal tract including pancreaticobiliary cancers, whereas CK20 is normally expressed in the gastrointestinal epithelium, urothelium, and Merkel cells. The nuclear CDX-2 transcription fac­ tor, which is the product of a homeobox gene necessary for intestinal organogenesis, is often used to aid in the diagnosis of gastrointestinal adenocarcinomas. However, CDX-2 positivity can be seen with enteric or mucinous differentiation in tumors from diverse primary sites (e.g., mucinous ovarian cancers). Thyroid transcription factor 1 (TTF-1) nuclear staining is frequently positive in lung and thyroid cancers. Approximately 68% of adeno­ carcinomas and 25% of squamous cell lung cancers stain positive for TTF-1, which helps differentiate a lung primary tumor from metastatic adenocarcinoma in a pleural effusion, the mediastinum, or the lung parenchyma. Gross cystic disease fibrous protein-15 (GCDFP-15), a 15-kDa monomer protein, is a marker of apocrine differentiation that is detected in 62–72% of breast carcinomas. GATA3 is being increasingly used in the CUP setting when there is concern for a breast primary and can be particularly useful as a marker for metastatic breast carcinoma, especially triple-negative and metaplastic carcinomas, which lack spe­ cific endocrine markers of mammary origin. UROIII, high-molecularweight cytokeratin, thrombomodulin, and CK20 are the markers used to diagnose lesions of urothelial origin.

IHC performs the best when used in groups that give rise to patterns that are strongly indicative of certain profiles. For example, the TTF-1/ CK7+ and CK20+/CDX-2+/CK7− phenotypes have been reported as very suggestive of lung and lower gastrointestinal cancer profiles, respectively. Despite their practical utility, these patterns have not been validated prospectively in CUP patients. IHC is not without its limitations; several factors affect tissue antigenicity (antigen retrieval, specimen processing, and fixation), interpretation of stains in tumor (nuclear, cytoplasmic, membrane) versus normal tissue, inter- and intraobserver variability, variable performance of different antibodies said to recognize the same antigen, and tissue heterogeneity and inad­ equacy (given small biopsy sizes). Communication with the patholo­ gist is critical to determine if acquisition of additional tissue will be beneficial in the pathologic evaluation. Pathologic features should not always supersede clinical or radiologic findings when considering testing for biomarkers of therapeutic response (e.g., epidermal growth factor receptor [EGFR], ALK mutations, human epidermal growth fac­ tor receptor 2 [HER2]). Role of Cancer Classifier Molecular Profiling  In the absence of a known primary, developing therapeutic strategies for CUP is chal­ lenging. The current diagnostic yield with imaging and immunochem­ istry is ~20–30% for CUP patients. To reduce diagnostic uncertainty, sophisticated molecular analytics have been applied to CUP samples. These include gene expression profiling, messenger RNA (mRNA), microRNA, and genetic and epigenetic profiling to classify CUP.

CHAPTER 97 Gene expression profiles are most commonly generated using quan­ titative reverse transcriptase polymerase chain reaction (RT-PCR) or DNA microarray. Neural network programs are then used to develop predictive algorithms from the gene expression profiles. Typically, a training set of gene profiles from known cancers (preferably from metastatic sites) is used to train the software. Comprehensive gene expression databases that have become available for common malig­ nancies are then applied to CUP samples, and the program can then be used to predict the putative origin of a CUP sample. Carcinoma of Unknown Primary mRNA- or microRNA-based tissue of origin cancer classifier assays have also been studied in prospective and retrospective CUP trials. Other assays such as DNA methylation profiling predicted a primary cancer in 87% of 216 CUP patients. Incorporation of machine learning and nextgeneration sequencing has furthered prediction of these classifiers. Despite the sophistication of the cancer classifier molecular assays, most of the CUP studies have evaluated assay performance, although the challenge with validating the accuracy of an assay for CUP is that, by definition, the primary cancer diagnosis cannot be verified. Thus, current estimates of tissue of origin test accuracy have relied on indirect metrics, including comparison with pathology/IHC, clini­ cal presentation, appearance of latent primaries, and autopsies. Using these measures, the assays suggest a plausible primary in ~70–80% of patients studied. Three outcomes-based studies have been performed. First, a single-arm study reported a median survival of 12.5 months for patients who received assay-directed site-specific therapy. Second, a phase 2 trial of site-specific therapy, including molecularly targeted therapy, based on predicted tumor site from an algorithm using gene expression and alteration profile showed a 1-year survival of 53.1%. However, two randomized clinical trials evaluating site-specific therapy directed by gene expression profiling versus empirical chemotherapy with either paclitaxel plus carboplatin or gemcitabine plus cisplatin failed to show a significant improvement in survival with this approach. Firm conclusions of therapeutic impact cannot be drawn from these studies given the sample size, design, statistical biases, confounding variables including use of subsequent lines of (empiric) therapy, and heterogeneity of the CUP cancers. Additional studies are needed to bet­ ter understand the clinical impact of tissue of origin profiling tools and how these assays complement IHC and help guide therapy. Role of Next-Generation Sequencing  A significant push is being made toward personalized medicine across all cancer types with the goal of identifying driver mutation(s) in a patient who can be treated with targeted agents independent of the site of origin. A retrospective study of 200 CUP tumor specimens reported on genomic

alterations using the hybrid capture–based FoundationOne assay. The authors reported that a large number of CUP samples (85%) harbored at least one clinically relevant genomic alteration with the potential to influence and personalize therapy. The mean number of genomic alter­ ations was 4.2 per tumor, and the most common genetic alterations included TP53 (55%), KRAS (20%), CDKN2A (19%), and ARID1A (11%). The adenocarcinoma CUP tumors were more frequently driven by genetic alterations in the receptor tyrosine kinase (RTK)/Ras/mitogenactivated protein kinase (MAPK) signaling pathway than nonadeno­ carcinoma CUP tumors. Although druggable genetic lesions seen in CUP are comparable to those in known primary cancer databases, whether molecularly stratified approaches for CUP will successfully improve outcomes remains to be seen and clinical trials are needed. In a single-arm phase 2 study of 97 patients with molecularly targeted therapy, five patients were found to have targetable EGFR mutations. Of these, four patients were treated with afatinib, an anti-EGFR drug, and two patients achieved a progression-free survival of >6 months. It is anticipated that second- and third-generation drugs targeting EGFR mutations are likely to be even more effective. The emerging use of assays looking for circulating tumor DNA (ctDNA), so-called liquid biopsies, has been increasingly useful within known tumor types and has stirred interest in their potential utility in CUP (Chap. 503).

Ongoing histology and cellular-context agnostic prospective clinical trials are studying the presence of actionable mutations and matching patients to the right targeted drug. As this strategy gains traction, CUP would be a natural fit for genomic alteration–based targeted therapy independent of tumor site. Established tumor-agnostic therapies such as immune checkpoint inhibitors (pembrolizumab) for microsatellite instability high (MSI-H) or deficient mismatch repair (dMMR) tumors or tumors with high tumor mutation burden (TMB) and NTRK inhibi­ tors for NTRK fusion–positive tumors can help a small minority of CUP patients. PART 4 Oncology and Hematology TREATMENT Carcinoma (or Cancer) of Unknown Primary GENERAL CONSIDERATIONS The treatment of CUP continues to evolve, albeit slowly. The median survival of most patients with disseminated CUP is ~6–10 months. Adenocarcinoma Poorly differentiated adenocarcinoma CUP IHC to suggest “favored” primary Isolated axillary nodes in women Bone-only metastases in men (blastic) Solitary site of metastasis Peritoneal carcinoma Disseminated cancer, 2 or more sites involved Check PSA (in tumor and serum). If elevated, Rx as prostate cancer. If resectable, resect with or without prior C or CRT. If unresectable, C, RT, or CRT depending on location of tumor Breast MRI if mammogram and ultrasound are negative If PSA not elevated, C or RT as indicated MRI (+). Breast surgery or radiation. C and/or hormonal therapy for breast cancer. MRI (–). No surgery, consider radiation. C for breast cancer. FIGURE 97-2  Treatment algorithm for adenocarcinoma and poorly differentiated adenocarcinoma of unknown primary (CUP). C, chemotherapy; CRT, chemoradiation; GI, gastrointestinal; IHC, immunohistochemistry; MRI, magnetic resonance imaging; PSA, prostate-specific antigen; RT, radiation.

Squamous cell CUP Disseminated, visceral metastases Metastatic inguinal adenopathy Metastatic cervical adenopathy Directed invasive tests as needed Perineal exam, anoscopy if needed. Pelvic examination in women. PET is optional. Triple endoscopy, consider tonsillectomy. CT neck and chest. PET is optional. If no extra-cervical disease—neck dissection followed by adjuvant RT vs RT alone. C for bulky disease. If localized, lymph node dissection, followed by local RT in select patients C in good performance status patients. RT as indicated. FIGURE 97-3  Treatment algorithm for squamous cell carcinoma of unknown primary (CUP). C, chemotherapy; CT, computed tomography; PET, positron emission tomography; RT, radiation. Systemic chemotherapy is the primary treatment modality in most patients with disseminated disease, but the careful integration of surgery, radiation therapy, and even periods of observation is important in the overall management of this condition (Figs. 97-2 and 97-3). Prognostic factors include performance status, site and number of metastases, response to chemotherapy, and serum lactate dehydrogenase (LDH) levels. Culine and colleagues developed a prognostic model using performance status and serum LDH levels, which allowed the assignment of patients into two subgroups with divergent outcomes. Raghav and colleagues developed a prognostic nomogram to provide individualized survival estimates for patients with CUP based on baseline gender, Eastern Cooperative Oncology If not suggestive of primary peritoneal, GI workup for primary. C, if good performance status. If suggestive of primary peritoneal cancer, treat as ovarian cancer C, if good performance status

Group performance status, histology, number of metastatic sites, and neutrophil-lymphocyte ratio. Future prospective trials using this prognostic model are warranted. Clinically, some CUP diagno­ ses fall into a favorable prognostic subset. Others, including those with disseminated CUP, have a more unfavorable prognosis. TREATMENT OF FAVORABLE CUP SUBSETS Women with Isolated Axillary Adenopathy  Women with isolated axillary adenopathy with adenocarcinoma or carcinoma are usually treated for stage II or III breast cancer based on pathologic findings. These patients should undergo a breast MRI if mammogram and ultrasound are negative. Radiation therapy to the ipsilateral breast is indicated if the MRI of the breast is positive. Chemotherapy and/ or hormonal therapy are indicated based on patient’s age (pre­ menopausal or postmenopausal), nodal disease bulk, and hormone receptor and HER2 status (Chap. 84). It is important to verify that the pathology suggests a breast cancer profile (morphology, IHC breast markers including estrogen receptor, mammaglobin, GCDFP-15, GATA3, HER2 gene expression) before embarking on a breast cancer therapeutic program. Women with Peritoneal Carcinomatosis  The term primary peri­ toneal papillary serous carcinoma (PPSC) has been used to describe CUP with carcinomatosis with the pathologic and laboratory (elevated CA-125 antigen) characteristics of ovarian cancer but no ovarian primary tumor identified on transvaginal sonography or laparotomy. Studies suggest that ovarian cancer and PPSC, which are both of müllerian origin, have similar gene expression profiles. Like patients with ovarian cancer, patients with PPSC are candi­ dates for cytoreductive surgery, followed by adjuvant taxane- and platinum-based chemotherapy. In one retrospective study of 258 women with peritoneal carcinomatosis who had undergone cytoreductive surgery and chemotherapy, 22% of patients had a complete response to chemotherapy; the median survival duration was 18 months (range 11–24 months). However, not all peritoneal carcinomatosis in women is PPSC. Careful pathologic evaluation can help diagnose a colon cancer profile (CDX-2+, CK20+, CK7−) or a pancreaticobiliary cancer or even a mislabeled peritoneal mesothe­ lioma (calretinin, D2-40 positive; BerEp4, MOC-31 negative). Poorly Differentiated Carcinoma with Midline Adenopathy (Chap. 93)  Men with poorly differentiated or undifferentiated carcinoma who present with midline adenopathy should be evalu­ ated for extragonadal germ cell malignancy. If diagnosed and treated as such, they often experience a good response to treatment with platinum-based combination chemotherapy. Response rates of >50% have been noted, and long-term survival rates of 10–15% have been reported. Older patients, especially smokers, who present with mediastinal adenopathy are more likely to have a lung or head and neck cancer profile. Neuroendocrine Cancer (Chap. 89)  Low-grade neuroendocrine tumor (NET) often has an indolent course, and treatment decisions are based on symptoms and tumor bulk. Urine 5-HIAA and serum chromogranin may be elevated and can be followed as markers. Often the patient is treated with somatostatin analogues alone for hormone-related symptoms (diarrhea, flushing, nausea). Specific local therapies or systemic therapy would only be indicated if the patient is symptomatic with local pain secondary to significant growth of the metastasis or the hormone-related symptoms are not controlled with endocrine therapy. Novel therapy options have demonstrated benefit in patients with low-grade NET, including sunitinib (which targets the vascular endothelial growth factor pathway), everolimus (which inhibits the mammalian target of rapamycin), and lutetium-177 dotatate (a somatostatin peptide receptor radioligand). Patients with high-grade NET are treated with platinum-based doublet therapy; 20–25% show a complete response, and up to 10% patients with limited/oligo presentations survive for >5 years. Some degree of neuroendocrine differentiation can be seen in diverse poorly differentiated carcinomas.

Squamous Cell Carcinoma Presenting as Neck Adenopathy  Patients with early-stage squamous cell carcinoma involving the cervical lymph nodes are candidates for node dissection and radiation therapy, which can result in long-term survival. The role of che­ motherapy in these patients is undefined, although chemoradiation therapy or induction chemotherapy is often used and is beneficial in bulky N2/N3 lymph node disease.

Solitary Metastatic Sites  Patients with solitary metastases can also experience good treatment outcomes. Some patients who pres­ ent with locoregional disease are candidates for aggressive trimo­ dality (chemotherapy, radiation, and surgery) management—both prolonged disease-free survival and, occasionally, cure are possible. Men with Blastic Skeletal Metastases and Elevated PSA (Chap. 92)  Blastic bone-only metastasis is a rare presentation, and elevated serum PSA or tumor staining with PSA may provide con­ firmatory evidence of prostate cancer in these patients. Those with elevated levels are candidates for hormonal or other therapy for prostate cancer, although it is important to rule out other primary tumors (lung most common). MANAGEMENT OF DISSEMINATED CUP Patients who present with liver, brain, and adrenal metastatic disease usually have a poor prognosis. Patients with peritoneal carcinomatosis secondary to metastatic adenocarcinoma have a broad differential diagnosis, which includes mainly gastrointestinal cancers including gastric, appendiceal, colon, and pancreaticobili­ ary cancers. CHAPTER 97 Traditionally, platinum-based combination chemotherapy regi­ mens have been used to treat CUP. Several broadly used regimens have been studied in the past two decades; these include paclitaxelcarboplatin, gemcitabine-cisplatin, gemcitabine-oxaliplatin, and irinotecan and fluoropyrimidine-based therapies. These chemo­ therapeutic agents used as empiric regimens have shown response rates of 25–40%, and their use obtains median survival times of 6–13 months. Carcinoma of Unknown Primary Outside of favorable subsets, there is a small group of patients with a “definitive” IHC profile. These patients usually have a single diagnosis based on their clinicopathologic presentation and are often treated for the putative primary tumor. This does not guar­ antee a response, although it increases the probability of response when select drugs are chosen from a class of drugs known to be effective in that cancer type. Efforts should be made to search for biomarkers of response to tumor-agnostic effective therapies such as immunotherapy for MSI-H/dMMR tumors. Patients who do not fall into those categories are candidates for broad-spectrum platinum-based regimens, clinical trials, and additional trial-based genomic and proteomic tests. Today, we do not have many effective drugs for several CUP cancer profiles, and treatments overlap for some cancers. Immunotherapy has been an area of active interest due to robust and durable responses in cancers with known prima­ ries and has shown some activity in CUP. However, biomarkers of response and immune-sensitive subsets need to be defined within CUP. SUMMARY Patients with CUP should undergo a directed diagnostic search for the primary tumor based on clinical and pathologic data. Subsets of patients have prognostically favorable disease, as defined by clinical or histologic criteria, and may substantially benefit from aggressive treatment; in these patients, prolonged survival can be expected. How­ ever, for most patients who present with advanced CUP, the prognosis remains poor with early resistance to available cytotoxic therapy. The current focus has shifted away from empirical chemotherapeutic trials to understanding the metastatic phenotype, tissue of origin profiling in select patients, and next-generation sequencing to identify actionable mutations in CUP patients. As novel therapies evolve in cancers with known primaries, investigations to assess their value in CUP will likely have a positive impact on management of CUP patients.