Treatment for Patients With Unknown Primary Cancer and Favorable Prognostic Factors

Treatment for Patients With Unknown Primary Cancer and Favorable Prognostic Factors John D. Hainswortha and Karim Fizazib Patients with carcinoma of unknown primary site are heterogeneous with respect to clinical and pathologic features. Within this diverse group, specific clinical and/or pathologic features can be used to define several subsets with favorable prognoses. Specific subsets include women with peritoneal carcinomatosis, women with isolated axillary lymph node metastases, adenocarcinoma presenting as a single metastatic lesion, young men with features of extragonadal germ cell tumor, squamous carcinoma involving cervical or inguinal lymph nodes, and neuroendocrine carcinoma. Prospective identification of patients in these favorable subgroups allows the most effective treatment to be selected. This review summarizes current recommendations for the evaluation and treatment of patients in each of these favorable prognostic subsets. Semin Oncol 36:44-51 © 2009 Elsevier Inc. All rights reserved.

Patients with unknown primary cancer are heterogeneous with respect to clinical presentation, tumor biology, and response to systemic therapy. In the large majority of patients, a primary site never becomes clinically apparent and selection of treatment has been empiric. However, several treatable subgroups of patients within this large, heterogeneous group have been recognized, and initial identification of these patients is imperative for optimal management. Treatable subsets are recognized either on the basis of specific clinical presentations, or by the use of specialized pathologic techniques that aid in tumor characterization. Identification of these patients is important, because specific treatments can improve outcome and extend survival. In this review, the clinical evaluation and management of patients in each of the recognized subsets is described. Since each of these subsets is relatively rare, treatment recommendations are often derived from standard treatments developed for more common cancer types.

occasionally produce this clinical syndrome. However, peritoneal carcinomatosis also occurs in women with normal ovaries and no other evident intra-abdominal primary site. This syndrome occasionally develops despite prophylactic oophorectomy in women from families at high risk for ovarian cancer,1 and is increased in incidence in women with BRCA-1 mutations.2 Clinical features are typical of advanced ovarian cancer, with tumor involvement usually limited to the peritoneal surfaces and elevated serum levels of CA-125 antigen. In most women with this syndrome, histologic features also resemble those of ovarian carcinoma. Papillary configuration and/or psamomma bodies are frequently visible. Because of the similar histologic features, this syndrome has often been termed “multifocal extra ovarian serous carcinoma” or “peritoneal papillary serous carcinoma.” However, other histologies are sometimes present, including poorly differentiated carcinoma.

WOMEN WITH PERITONEAL CARCINOMATOSIS

Treatment

Adenocarcinoma causing diffuse peritoneal involvement is typical of ovarian carcinoma, although carcinomas from the gastrointestinal tract, lung, or breast can aSarah

Cannon Research Institute, Nashville, TN. Gustave Roussy, Villejuif, France. Supported in part by the Minnie Pearl Cancer Foundation (J.D.H.). Address correspondence to John D. Hainsworth, MD, 250 25th Ave N, Suite 110, Nashville, TN 37203. E-mail: [email protected] 0270-9295/08/$ - see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2008.10.006 bInstitut

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Several case reports in the 1980s suggested excellent responses of patients with this syndrome when treated with chemotherapy effective against ovarian cancer. These early observations were substantiated by subsequent reports containing larger numbers of patients (Table 1). Patients in these reports were treated with optimal therapy for advanced ovarian carcinoma, including initial surgical cytoreduction followed by combination chemotherapy. Early reports used platinum/cyclophosphamide regimens, which were subsequently replaced by platinum/paclitaxel combinations.3-9 Although reported response rates varSeminars in Oncology, Vol 36, No 1, February 2009, pp 44-51

Patients with favorable prognostic factors

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Table 1. Results of Platinum-Based Therapy for Women With Peritoneal Carcinomatosis of Unknown

Primary Site Study (first author)

No. of Patients

Lele3 Strnad4 Dalrymple5 Ransom6 Fromm7 Bloss8 Piver9

23 18 31 33 74 33 46

Chemotherapy*

Complete Response Rate

Median Survival (mo)

Long-Term Survival

22% 39% 10% 13% 20% 35% 40%

19 23 11 17 24 20 19

26% 17% 6% 9% 25% 15% NR

Cisplatin-based Cisplatin-based Cisplatin-based or chlorambucil Cisplatin-based Cisplatin-based or melphalan Cisplatin-based Platinum/paclitaxel or cisplatin/ cyclophosphamide

Abbreviation: NR, not reported. *Patients in all series had surgical cytoreduction before receiving chemotherapy.

ied, a minority of patients (10%– 40%) in each reported series had a complete response to chemotherapy, and the composite median survival was 18 months. In addition, all series reported long-term survivors (⬎2 years), ranging from 6% to 26%. The peritoneal epithelium is now accepted as the site of origin for some of these carcinomas. The contiguity of the peritoneal and ovarian epithelial surfaces may explain the similar biology and response to treatment observed in these two tumor types. In fact, these tumors are now thought to be similar enough that women with peritoneal papillary serous carcinoma are routinely included in clinical trials for stage III ovarian carcinoma. At present, women with isolated peritoneal carcinomatosis should be treated according to guidelines for the management of advanced ovarian cancer. Optimal management includes initial maximal surgical cytoreduction followed by taxane/platinum chemotherapy.10,11 As in ovarian cancer, patients with minimal residual peritoneal disease following surgical cytoreduction have a higher complete response rate and longer survival after chemotherapy. As with epithelial ovarian cancer, a minority of patients (approximately 10%–15%) have prolonged disease-free survival following optimal treatment. The syndrome of peritoneal carcinomatosis with papillary serous histology and elevated serum CA-125 also may occur rarely in males.12 A similar management approach in these patients seems reasonable, particularly if tumor involvement is isolated to the peritoneum.

WOMEN WITH AXILLARY LYMPH NODE METASTASES Breast cancer should be suspected in women who have axillary lymph node involvement with adenocar-

cinoma. Recognition of this patient subset is extremely important, since curative treatment is available for a sizeable percentage. The initial clinical and pathologic evaluation should be oriented towards confirming the diagnosis of breast cancer. If routine mammography is normal, a breast magnetic resonance image (MRI) scan should be performed.13-16 Positron emission tomography (PET) scanning also may be a useful procedure but has not been completely evaluated in this setting.17 Immunohistochemical stains for estrogen and progesterone receptors should be performed on lymph node biopsy material. In addition, HER-2 testing should be done with either immunohistochemistry or fluorescence in situ hybridization assay. Either HER-2 overexpression or the presence of estrogen/progesterone receptors provides strong evidence for the diagnosis of metastatic breast cancer.

Treatment Women who have metastases isolated to axillary lymph nodes after complete staging evaluation, and who have no identifiable breast primary site after specialized imaging studies, should be managed according to standard guidelines for stage II breast cancer. Although the optimal local treatment has not been defined in large trials in this patient population, reasonable approaches include modified radical mastectomy or axillary lymph node dissection with subsequent breast radiation therapy. Axillary lymph node dissection alone is not recommended, because primary breast cancers will subsequently become manifest in approximately 50% of patients treated in this manner.18-20 When mastectomy is performed, an occult breast cancer is identified in 44% to 82% of patients, even when physical examination and mammograms are normal.18 Primary tumors are usually less than 2 cm in diameter;

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in occasional patients, only carcinoma in situ is identified in the breast.21 It should be noted that all data regarding breast recurrences and mastectomy findings in this group of patients were accumulated prior to the addition of breast MRI to the diagnostic workup. Presumably, the additional breast primaries identified by MRI will result in fewer breast recurrences in the remaining patient group. In fact, it has been suggested that local treatment to the breast be withheld in patients with no breast primary identified after full evaluation (including MRI).22 Since there are currently no data to support or refute this recommendation, routine local treatment with mastectomy or breast radiotherapy remains reasonable. Women with isolated axillary lymph node metastases should receive adjuvant therapy also, following current guidelines for patients with node-positive breast cancer. As in patients with known breast cancer, the choice of adjuvant therapy depends on multiple factors, including estrogen/progesterone receptor status, HER-2 status, number of involved lymph nodes, and patient demographic features. Prognosis is also related to several clinical factors, the most important of which is the number of involved axillary lymph nodes. Women with metastatic sites in addition to axillary lymph nodes also may have metastatic breast cancer. Women with a distribution of metastases typical of metastatic breast cancer (eg, multiple bone metastases, pleural metastases) should be particularly suspected. Again, determination of estrogen receptor, progesterone receptor, and HER-2 status is important in determining therapy. Women in this group should receive a trial of systemic therapy using guidelines for treatment of metastatic breast cancer. Patients with positive hormone receptors or HER-2 overexpression may derive particular benefit from such treatment.

MEN WITH POSSIBLE PROSTATE CARCINOMA Metastatic prostate carcinoma should be suspected in men with adenocarcinoma predominantly involving bone, particularly if the metastases are blastic. Elevated serum levels of prostate-specific antigen (PSA) or tumor staining with PSA provides confirmatory evidence of prostate cancer in this clinical setting, and subsequent treatment should follow guidelines for metastatic prostate cancer. An empiric trial of androgen suppression therapy should be considered in men with multiple blastic metastases of unknown primary site, regardless of the PSA findings. Occasionally, serum PSA levels and/or tumor PSA staining suggests the diagnosis of prostate cancer in patients with atypical clinical features.23,24 These patients usually have metastases to the lungs, mediastinal lymph nodes, or upper abdominal lymph nodes, in the

J.D. Hainsworth and K. Fizazi

absence of bone and pelvic lymph node metastases. Responses to androgen ablation therapy have been documented in such patients, and therefore this group of patients also should be treated according to guidelines for advanced prostate cancer. The majority of men with adenocarcinoma of unknown primary site and bone involvement have lytic lesions and normal serum PSA levels. These patients are unlikely to respond to androgen deprivation therapy; rather, they should be considered for a trial of empiric chemotherapy for carcinoma of unknown primary site (see Greco and Pavlidis in this issue).

ADENOCARCINOMA PRESENTING AS A SINGLE METASTATIC LESION Occasionally, only a single metastatic lesion can be identified after a complete staging evaluation. Single lesions have been described in a variety of sites, including lymph nodes, brain, lung, adrenal gland, liver, bone, and skin. The possibility of an unusual primary site (eg, primary cutaneous apocrine, eccrine, or sebaceous carcinoma) mimicking a metastatic lesion should be considered, but this possibility usually can be excluded on the basis of clinical or pathologic features. In most patients who present with a single metastatic lesion, other metastatic sites become evident within a relatively short time. However, local treatment sometimes results in long disease-free intervals, and occasional patients have prolonged survival. Prior to initiating local treatment, a PET scan is useful to rule out the presence of other unsuspected metastatic sites.25 If no other metastases are detected, the solitary lesion should be definitively resected if technically feasible. In some instances (eg, after resection of a solitary brain metastases), local radiation therapy also may be appropriate to maximize the chance of local control.26 If the solitary lesion is in an area that is not amenable to surgical resection, definitive radiation therapy should be considered. The role of systemic chemotherapy in addition to definitive local therapy is undefined. However, a short course of “adjuvant” chemotherapy, using an optimal empiric chemotherapy regimen for unknown primary cancer, is reasonable in this situation, particularly in patients with poorly differentiated carcinoma. Surprisingly, occasional patients in this group have long-term survival after definitive local therapy, and never have the appearance of a primary site or other metastases. In one reported series of patients presenting with single brain metastases of unknown primary site, 15% of patients remained tumor-free 5 years after definitive treatment of the brain metastases.26 Therefore, identification of these unusual patients and the use of appropriate local therapy is important.

Patients with favorable prognostic factors

YOUNG MEN WITH FEATURES OF EXTRAGONADAL GERM CELL TUMOR The diagnoses of extragonadal germ cell tumor should be considered in young men (ie, ⬍40 years old) with poorly differentiated carcinoma involving the mediastinum or retroperitoneum. Lung metastases also occur in this group of patients, often in conjunction with a mediastinal or retroperitoneal mass. In this setting, elevated levels of either human chorionic gonadotrophin (HCG) or alpha-fetoprotein (AFP) further support the diagnosis of extragonadal germ cell tumor. Histologic examination in these patients almost always reveals a poorly differentiated carcinoma. Additional pathologic evaluation is necessary; although there are no immunoperoxidase stains that are entirely specific, staining for HCG, AFP, or OCT4 (Octomer 4, a homeodomain transcription factor of the PO4 family) supports the diagnosis of germ cell tumor27-29 (see Oien in this issue). Even after standard pathologic evaluation, it is now well recognized that some patients have extragonadal germ cell tumors with atypical pathologic features. Some of these patients can be identified by the presence of an i(12p) chromosomal abnormality on molecular genetic analysis.30 In a treatment series reported by Motzer et al, young men with poorly differentiated carcinoma involving the mediastinum and/or retroperitoneum had biopsy specimens tested for the presence of an i(12p) chromosomal abnormality.31 Twelve patients were diagnosed in this manner after other pathologic evaluation had been inconclusive. Nine of these 12 patients identified had excellent responses to testicular cancer chemotherapy regimens, with several longterm survivors. Therefore, these unusual patients with extragonadal germ cell tumor can be identified only by molecular genetic analysis but have the ability to respond to the same treatments effective in more typical germ cell tumors. If molecular genetic analysis is not available in clinical practice, young men with clinical features of an extragonadal germ cell tumor should receive a trial of treatment for poor-prognosis germ cell carcinoma. Initial treatment should include a combination of cisplatin, etoposide, and bleomycin,32 or a regimen of equivalent efficacy. Patients who have a good response after four courses of chemotherapy but who have residual radiographic abnormalities should be considered for definitive surgical resection, again following guidelines for the treatment of germ cell carcinoma. The percentage of patients with these clinical features who have highly responsive tumors is difficult to estimate, since reports have generally contained a few selected patients.33-35 However, it is clear that patients with multiple features of extragonadal germ cell tumors are those most likely to have highly responsive carcinomas. The major benefits obtained by responsive

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patients warrant a treatment trial for this broader group of patients, in the absence of any method of definitively predicting the responsive patients. Although extremely rare, this syndrome is occasionally seen in women.

SQUAMOUS CARCINOMA INVOLVING CERVICAL LYMPH NODES Squamous carcinoma of unknown primary site is relatively uncommon, accounting for approximately 5% of all unknown primary cancers. The cervical lymph nodes are by far the most common metastatic site for squamous carcinoma of unknown primary origin. Patients are usually middle-aged or elderly, and most have risk factors for head and neck cancer (tobacco, alcohol use). In most patients, unilateral involvement of upper or mid-cervical lymph nodes is evident at presentation. Appropriate diagnostic evaluation results in identification of a primary site, usually in the head and neck, in the large majority of these patients.36 Optimal evaluation includes a thorough examination of the oropharynx, hypopharynx, nasopharynx, larynx, and upper esophagus by direct endoscopic visualization, with biopsy of any suspicious areas. Computed tomography of the neck is useful in defining the extent of disease, and occasionally identifies a primary site. PET scanning identifies a primary site in approximately 25% of patients even after other procedures are unrevealing, and therefore should be included as standard diagnostic imaging.37 When lower cervical or supraclavicular lymph nodes are involved, a primary lung cancer should be suspected. Fiberoptic bronchoscopy is indicated if chest radiography and the head and neck examination described above are unrevealing. Empiric tonsillectomy is recommended by many authors, and is revealing of a primary tonsillar carcinoma in approximately 25% of patients.38-40 Patients with adenopathy in the subdigastric, submandibular, or midjugular areas are more likely to have a tonsillar primary site.38 Several molecular diagnostic assays have been described that sometimes assist in identifying a head and neck primary site. First, the detection of the EpsteinBarr viral genome in tumor tissue is specific for a nasopharyngeal primary site.41 This assay should be considered particularly in young patients with poorly differentiated squamous carcinoma or poorly differentiated carcinoma involving cervical lymph nodes. Second, the presence of human papilloma virus-16 in the lymph node biopsy specimen is specific for a primary site in the oropharynx.42 Both of these assays can be performed on tissue obtained by fine-needle aspiration biopsy. Finally, chromosomal abnormalities may be detected in histologically benign tissue taken from normal areas during endoscopy.43 These abnormalities are predictive of subsequent tumor development at that site. For patients in whom no primary site is identified, treatment should proceed according to guidelines for

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locally advanced squamous carcinoma of the head and neck. Treatment with definitive local radiation therapy to the pharyngeal axis and bilaterial neck, radical neck dissection, or a combination of these local modalities results in long-term disease-free survival for 30% to 60% of these patients.44-48 Combined modality therapy with concurrent chemotherapy and radiation therapy is now the treatment of choice for patients with locally advanced head and neck cancer.49 Although there is limited experience using combined modality therapy in patients with cervical adenopathy and an occult primary site,50-52 this approach also seems reasonable in these patients. As in patients with head and neck cancer, extensive involvement in neck lymph nodes and poorly differentiated tumor histology are adverse prognostic features.48,53 Patients with low cervical or supraclavicular lymph nodes are more likely to have a primary lung cancer, and treatment results are inferior for this group of patients. Nevertheless, patients with no detectable disease below the clavicles should be treated with the approach recommended for patients with higher cervical nodes, since occasional patients have long-term disease-free survival.

SQUAMOUS CARCINOMA INVOLVING INGUINAL LYMPH NODES Most patients with squamous cell carcinoma involving inguinal lymph nodes have a detectable primary site in the genital or anorectal areas. Careful examination of the vulva, vagina, uterine cervix, penis, and scrotum is important, with biopsy of any suspicious areas. Digital rectal examination and anoscopy should be performed routinely to exclude lesions in the anorectal area. Identification of a primary site in these patients is important, since potentially curative therapy is available for patients with carcinoma of the anus, vulva, vagina, or cervix, even after spread to regional lymph nodes. For the occasional patient in whom no primary site is identified, definitive local therapy with inguinal lymph node dissection or radiation therapy can result in long-term survival.54 In recent years, combined modality therapy with concurrent chemotherapy and radiotherapy has improved prognosis for several primary cancers arising in this region (anus, cervix, bladder). Therefore, similar systemic treatment should be considered for patients with metastatic squamous carcinoma in inguinal lymph nodes who have no defined primary site.

NEUROENDOCRINE CARCINOMA WITH AN UNKNOWN PRIMARY SITE A broad spectrum of neuroendocrine carcinoma is now recognized, in part due to improved pathologic diagnostic methods (see Oien in this issue). Well-differ-

J.D. Hainsworth and K. Fizazi

entiated (ie, carcinoid type) neuroendocrine carcinomas, as well as poorly differentiated neuroendocrine carcinomas, can present with an unknown primary site. A complete discussion of this interesting and responsive subset of patients is reviewed by Spigel et al in this issue and will not be discussed further here.

POORLY DIFFERENTIATED CARCINOMA Individuals with poorly differentiated carcinoma comprise approximately 20% of patients with carcinoma of unknown primary site. Although this is a heterogeneous group, some of the patients have neoplasms that are highly sensitive to chemotherapy; therefore, most patients in this group should receive a trial of empiric combination chemotherapy. Appropriate clinical and pathologic evaluation is necessary in this patient group, in order to identify subsets with potentially responsive tumors. In addition to light microscopic examination, immunoperoxidase studies should be routinely performed; in one series, specific diagnoses other than poorly differentiated carcinoma (eg, poorly differentiated neuroendocrine cancer, lymphoma, melanoma) were made in 18% of patients.55 Identification of young men with features of extragonadal germ cell tumor is also important, as described above. In addition to computed tomography scans of the chest and abdomen, all patients in this group should have measurement of serum HCG and AFP.

Treatment When specialized pathologic studies identify a treatable neoplasm, therapy should be administered following guidelines established for the specific tumor identified. Examples of treatable tumor types occasionally identified in this group of patients include lymphoma, Ewing’s tumor, neuroendocrine carcinoma, thymic carcinoma, and a variety of primitive sarcomas. In addition, young men with features of extragonadal germ cell carcinoma should receive treatment for poor-prognosis germ cell carcinoma, even if this diagnosis cannot be made after pathologic evaluation. Treatment of patients with poorly differentiated carcinoma of unknown primary site who do not have characteristics of extragonadal germ cell tumor remains a subject of controversy. A high overall response rate of 62%, with 26% complete responses, was reported in a selected group of 220 patients treated with testicular cancer regimens.56 A subgroup of these patients (14%) remained tumor-free after minimum follow-up of 8 years.35 Only a few patients in this group had clinical features that were strongly suggestive of an extragonadal germ cell tumor; however, the median age was young (39 years), and 40% of patients had their

Patients with favorable prognostic factors

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Table 2. Favorable Subsets in Unknown Primary Cancer: Evaluation and Treatment

Histopathology Adenocarcinoma

Recommended Evaluation*

Clinical Subset

Women with isolated adenopathy Breast MRI ER/PR/Her-2 stains Women with peritoneal CA-125 carcinomatosis Men with blastic bone metastases — or elevated serum PSA Single metastatic site PET scan

Squamous carcinoma Cervical adenopathy

ENT endoscopy, PET scan, ? tonsillectomy —

Inguinal adenpathy

Poorly differentiated carcinoma

Neuroendocrine carcinoma

Young men, mediastinal and/or retroperitoneal mass All others with good performance status See Spigel et al in this issue

HCG, AFP HCG, AFP

Treatment Treat as stage II breast cancer

Treat as stage III ovarian cancer Treat as metastatic prostate cancer Definitive local therapy ⫾ chemotherapy Treat as locally advanced head/neck cancer Inguinal node dissection ⫾ radiotherapy ⫾ chemotherapy Treat as extragonadal germ cell tumor Treat with empiric UPC regimen

Abbreviaitons: MRI, magnetic resonance imaging; ER, estrogen receptor; PR, progesterone receptor; PSA, prostate-specific antigen; ENT, ear, nose, throat; HCG, human chorionic gonadotrophin; AFP, alpha-fetoprotein; UPC, unknown primary cancer. *In addition to standard evaluation for unknown primary cancer.

predominant tumor location in lymph nodes, mediastinum, or retroperitoneum. In a retrospective analysis of a large series of patients with unknown primary cancer, Lenzi and colleagues could not identify a subset of patients with poorly differentated carcinoma and long-term survival following chemotherapy.57 In this group, patients with clinical features of extragonadal germ cell tumor were excluded. In addition, patients received a wide variety of empiric treatment regimens, and only a few patients were given cisplatin-based therapy used in the treatment of germ cell tumors. Although no long-term survivors were identified, several favorable prognostic factors were detected, including tumor location in lymph nodes, fewer metastatic sites, younger age, female sex, and poorly differentiated carcinoma histology (versus poorly differentiated adenocarcinoma). In a third study performed by Saghatchian and colleagues, patients with poorly differentated carcinoma were treated with a cisplatin/etoposide-containing regimen while patients with adenocarcinoma received cisplatin/5-fluorouracil. No survival differences were seen between these two groups of patients.58 At present, a trial of combination chemotherapy

should be considered for patients with poorly differentiated carcinoma of unknown primary site, particularly when involving nodal sites. Patients with clinical features of extragonadal germ cell tumors should receive cisplatin-based chemotherapy with a regimen used for the treatment of poor-prognosis germ cell tumors. For the remaining patients in this group, cisplatin-based regimens also have yielded relatively high response rates. Substitution of carboplatin for cisplatin decreases toxicity, and has produced similar treatment results in multiple other tumor types. Taxane/platinum-based combination regimens have yielded high response rates with moderate toxicity, and are also a good choice for this group of patients (see Greco and Pavlidis in this issue).

CONCLUSION Table 2 provides a summary of the various treatable subsets of patients described here, with brief treatment recommendations. For several of these subsets, treatment recommendations parallel those for specific carcinomas of known primary site. As treatment evolves and improves for these cancers, the treatment ap-

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proach for the much less common unknown primary counterparts should change as well. Since many of these subsets are relatively rare, it is unlikely that definitive treatment series will be available to substantiate the advantages of such treatment changes. Ultimately, better treatment of unknown primary cancer will parallel improvements in therapy for more common advanced solid tumors. With recent improved understanding of the neoplastic process, further treatment improvements based on introduction of new targeted agents are likely in the near future.

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