Bethesda Handbook of Clinical Oncology, 2nd Edition

Other Malignancies

32

Carcinoma of Unknown Primary

Hung T. Khong

Departments of Medicine and Pharmacology, USA Cancer Research Institute, University of South Alabama, Mobile, Alabama

DEFINITION

Carcinoma of unknown primary (CUP) is defined as the detection of one or more metastatic tumors for which routine evaluation, including history and physical examination, routine blood work, urinalysis, chest x-ray (CXR), and histologic evaluation, fails to identify the primary site.

EPIDEMIOLOGY

  • Incidence: 3% of all diagnosed oncologic cases are CUP.
  • Gender: male-to-female ratio is approximately 1:1.
  • Age: highest incidence is in the sixth decade of life.

CLINICAL FEATURES AND PROGNOSIS

Clinical Features

  • At presentation, most patients (97%) complain of symptoms at metastatic site(s). Common presenting sites and common metastatic sites are listed in Tables 32.1 and 32.2.
  • Nonspecific constitutional symptoms also are common: anorexia, weight loss, and fatigue.
  • At diagnosis, more than 50% of patients (59%) have multiple sites (more than two) of metastatic involvement.

TABLE 32.1. Common Presenting Sites

Site

%

Range (%)

In each patient, the metastatic site that was apparent or symptomatic first was the only one counted. Data were collected from three series involving a total of 611 patients.
From Le Chevalier T, Cvitkovic E, Caille P, et al. Early metastatic cancer of unknown primary origin at presentation. A clinical study of 302 consecutive autopsied patients. Arch Intern Med 1988;148(9):2035–2039; Kirsten F, Chi CH, Leary JA, Ng AB, Hedley DW, Tattersall MH. Metastatic adeno or undifferentiated carcinoma from an unknown primary site-natural history and guidelines for identification of treatable subsets. Q J Med 1987;62(238):143–161; and Lyman GH, Preisler HD. Carcinoma of unknown primary: natural history and response to therapy. J Med 1978;9(6):445–459, with permission.

Lymph node

26

14–37

Lung

17

16–19

Bone

15

13–30

Liver

11

   4–19

Brain

   8

   7–10

Pleura

   7

   2–12

Skin

   5

   0–22

Peritoneum

   4

   1–6

TABLE 32.2. Common Metastatic Sites

Site

%

Range (%)

All principal metastatic sites in each patient were counted. Data were collected from two series involving a total of 1,051 patients. Data reported from subspecialty practices were excluded.
From Shildt RA, Kennedy PS, Chen TT, Athens JW, O'Bryan RM, Balcerzak SP. Management of patients with metastatic adenocarcinoma of unknown origin: a Southwest Oncology Group study. Cancer Treat Rep 1983;67(1):77–79 and Hess KR, Abbruzzese MC. Lenzi R, Raber MN, Abbruzzese JL. Classification and regression tree analysis of 1000 consecutive patients with unknown primary carcinoma. Clin Cancer Res 1999;5(11): 3403–3410, with permission.

Lymph nodes

41

20–42

Liver

34

33–43

Bone

29

29

Lung

27

26–31

Pleura

11

11–12

Peritoneum

   9

Brain

   6

6

Adrenal gland

   6

4–6

Skin

   4

Bone marrow

   3

Prognosis

  • In general, the median survival time of patients with CUP is 3 to 4 months; however, some recent studies have reported a median survival duration of 5 to 12 months.
  • Most patients (55% to 85%) die within 1 year; 5% to 10% survive at 5 years (see Fig. 32.1).
 

FIG. 32.1. Kaplan–Meier survival curve of 1,000 consecutive patients with cancer of unknown primary (CUP). Median survival is 11 months (95% confidence interval [CI], 10 to 12 months).

Poor Prognostic Factors

  • Male gender
  • Adenocarcinoma histology
  • Increasing number of involved organ sites
  • Hepatic involvement
  • Supraclavicular lymphadenopathy.

P.424

 

P.425

 

Advantageous Prognostic Factors

  • Nonsupraclavicular lymphadenopathy
  • Neuroendocrine histology
  • A recent study of 1,000 patients (from M.D. Anderson) revealed several prognostic subgroups. Some subgroups are shown in Table 32.3.

TABLE 32.3. Median Survival in Some Prognostic Subgroups

 

Median survival time (mo)

Mets, metastasis.
The median survival for all patients in this study was 11 mo.

40

24

5

5

<3 metastatic organ sites; nonadenocarcinoma; no involvement of liver, bone, adrenal, or pleura

Liver mets and nonneuroendocrine histology

Liver mets; neuroendocrine histology; age >61.5 yr

Adrenal mets

DIAGNOSIS

  • The recommended initial evaluation is listed in Table 32.4.
  • Generous tissue samples should be obtained at the first biopsy.
  • Accurate pathologic evaluation is critical.
  • Light microscopic examination: four major histologic subtypes can be identified by the initial light microscopic examination (see Fig. 32.2).
  • Immunoperoxidase staining (IPS) should be performed in all CUP cases of poorly differentiated carcinomas (PDCs). Table 32.5 lists some immunoperoxidase stains that are most useful.

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  • Electron microscopy should be considered if the tumor cannot be identified by IPS.
  • Most common primary sites are listed in Table 32.6.

TABLE 32.4. Initial Evaluation

H & P, history and physical; CBC, complete blood count; CXR, chest x-ray.

Complete H & P (attention to breast and pelvic examination in women; prostate and testicular examination in men; and head/neck and rectal examination in all patients)

CBC

Chemistry profiles

Urinalysis

Stool testing for occult blood

CXR

 

FIG. 32.2. Relative sizes of various clinical and histologic subgroups of patients with cancer of an unknown primary (CUP) site as determined by optimal clinical and pathologic evaluation. Potentially treatable subgroups are indicated in italics and comprise approximately 40% of patients. PDC, poorly differentiated carcinoma; PDA, poorly differentiated adenocarcinoma; PDMN, poorly differentiated malignant neoplasm. (From Hainsworth JD, Greco FA. Treatment of patients with cancer of an unknown primary site. N Engl J Med 1993;329:257–263, with permission.

TABLE 32.5. Immunoperoxidase Staining in the Differential Diagnosis of Carcinoma of Unknown Primary Site

 

Immunoperoxidase stains

HMB, β-hydroxy β-methylbutyrate monohydrate.

Tumor type

Cytokeratin

Leukocyte common antigen

S100 protein, HMB 45

Neuron-specific enolase, chromogranin

Vimentin desmin

Carcinoma

+

-

-

±

-

Lymphoma

-

+

-

-

-

Melanoma

-

-

+

±

-

Sarcoma

-

-

-

-

+

Neuroendocrine

+

-

-

+

-

TABLE 32.6. Primary Sites (Diagnosed During Life or at Autopsy)

Primary sites

%

Data were collected from nine series involving a total of 1,453 patients with CUP. A diagnosis was made either during life or at autopsy in 582 patients. Head/neck primary and data from subspecialty practices have been excluded in the calculation (to avoid artifactual representation of certain cancers such as the high rates of pancreatic primary reported by clinics specializing in gastrointestinal malignancy).

Lung

   23.7

Pancreas

   21.1

Ovary

   6.4

Kidney

   5.5

Colorectal

   5.3

Gastric

   4.6

Liver

   4.3

Prostate

   4.1

Breast

   3.4

Adrenal

   2.2

Thyroid

   2.2

Urinary tract/bladder

   1.9

Esophagus

   1.5

Lymphoma

   1.5

Gall bladder/biliary tree

   1.2

Testicular germ cell

   1

Mesothelioma

   0.5

Uterus

   0.3

Others

   9.3

Total

100

WELL-DIFFERENTIATED OR MODERATELY DIFFERENTIATED ADENOCARCINOMA OF UNKNOWN PRIMARY

Clinical Features

  • Typically elderly patients
  • Metastatic tumors at multiple sites
  • Poor performance status (PS) at diagnosis
  • Common metastatic sites: lymph nodes, liver, lung, and bone
  • Most common primary sites identified: the lung and pancreas (45%) (Table 32.6)
  • Poor prognosis (median survival of 3 to 4 months)
  • Primary site is rarely found (<15% before death); an exhaustive search is not indicated.

Further Workup

Additional studies that should be performed include prostate-specific antigen (PSA) serum level and/or IPS for men and mammography, serum CA 15-3, serum CA 125, and estrogen receptor/progesterone receptor (ER/PR) (IPS) for women. Computerized tomography (CT) scan of the abdomen can identify a primary site in approximately 30% of cases. In patients with CUP who have metastatic adenocarcinoma to the axillary lymph nodes and a negative mammogram, breast magnetic resonance imaging (MRI) detected a primary breast cancer in 9 (75%) of 12 patients in one study and in 19 (86%) of 22 patients in another study.

P.427

 

P.428

 

Treatment

  • Most cases (90%) of well-differentiated or moderately differentiated adenocarcinoma of unknown primary show low response rates (RRs) and few complete responses with systemic chemotherapy.
  • Patients in this group have a poor prognosis.
  • The empiric chemotherapy for CUP has been discussed in Table 32.7.
  • The various subsets of patients with different types of CUPs who can be treated are discussed in the following sections.

TABLE 32.7. Empiric Chemotherapy for Carcinoma of Unknown Primary

Drug regimen

Treatment description

Cycle

In this study, there was an overall response rate (RR) of 47%, with 13% complete responses, and a median survival of 13.4 mo. Activity was seen in both well-differentiated adenocarcinoma (45% RR) and poorly differentiated carcinoma (48% RR). AUC, area under the curve.
Adapted from Goldberg RM, Smith FP, Ueno W, et al. 5-Fluorouracil, adriamycin, and mitomycin in the treatment of adenocarcinoma of unknown primary. J Clin Oncol 1986;4(3):395–399.
From Greco FA, Hainsworth JD. Cancer of unknown primary site. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology. 5th ed. Philadelphia: Lippincott-Raven Publishers, 1997:2423–2443, with permission.
From Shepherd FA. Treatment of advanced non-small cell lung cancer. Semin Oncol 1994; 21:7–18, with permission.

EPa Cisplatin Etoposide

60–100 mg/m2 i.v. on d 1 80–100 mg/m2 i.v. on d 1–3

21 d

FAMb Fluorouracil Doxorubicin Mitomycin

600 mg/m2 i.v., d 1, 8, 29, 36 30 mg/m2 i.v., d 1, 29 10 mg/m2 i.v., d 1

8 wk

PaclitaxelcCarboplatin Etoposide

200 mg/m2 i.v. over 1 h, d 1 followed by dose calculated by Calvert formula to AUC 6 i.v., after paclitaxel 50 mg PO qd, alternating with 100 mg PO qd, d 1–10

21 d

Peritoneal Carcinomatosis in Women

Characteristics:

  • Typical of ovarian cancer
  • Occasionally associated with cancers from the gastrointestinal (GI) tract or breast
  • Serum CA125 level is often elevated.

Treatment:

  • Treatment is the same as for stage III ovarian cancer (laparotomy with surgical cytoreduction, followed by taxane or platinum-based combination chemotherapy) (see Chapter 17). It should be noted that about 20% of patients have complete remission (CR) and 16% have prolonged disease-free survival.

P.429

 

Women with Axillary Lymph Node Metastases

Characteristics:

  • Suggests breast cancer.
  • ER/PR should be checked
  • Occult breast primary is found in 55% to 75% of cases.

Treatment:

  • Axillary node metastases should be treated in the same manner as stage II breast cancer.
  • Modified radical mastectomy has been recommended.
  • Alternatively, radiation therapy (XRT) to the breast can be performed after axillary node dissection.
  • Adjuvant systemic chemotherapy should also be considered (see Chapter 17).
  • Patients with metastatic sites in addition to axillary nodes should be treated for metastatic breast cancer (see Chapter 12).

Men with Elevated Prostate-specific Antigen or Osteoblastic Bone Metastasis

  • If the PSA serum level or tumor staining is positive, a regimen of hormonal therapy similar to that used for metastatic prostate cancer (Chapter 14) should be started.
  • If osteoblastic bone metastases are present, empiric hormonal therapy should be started regardless of the PSA levels.

Patients with a Single Metastatic Site

  • Surgical excision and/or XRT is performed.

POORLY DIFFERENTIATED CARCINOMA/ADENOCARCINOMA OF UNKNOWN PRIMARY

Introduction

  • Poorly differentiated carcinoma and poorly differentiated adenocarcinoma (PDA) account for 30% of CUP (PDC accounts for two thirds of CUP and PDA accounts for one third of CUP).

P.430

 

  • Patients with PDC and PDA show poor response to fluorouracil-based chemotherapy and exhibit a short survival.
  • Some patients have neoplasms that are highly responsive to platinating agent–based combination chemotherapeutic treatments. Some long-term survivors and cures have been described for both PDC and PDA.

Clinical Features

  • Younger median age (about 40 years)
  • Rapid progression of symptoms
  • Evidence of rapid tumor growth
  • Most common sites of metastatic involvement (50% of cases): lymph nodes, mediastinum, and retroperitoneum.

Pathologic Evaluation

  • IPS is useful in the pathologic evaluation of PDC and PDA.
  • Electron microscopic evaluation should be performed if tumor cannot be identified by IPS.
  • Genetic analysis may be useful [e.g., i(12p), del(12p), or multiple copies of (12p) are diagnostic of germ cell tumor].

Further Workup

  • Additional workup should include CT scan of chest and abdomen, and serum β-human chorionic gonadotropin (β-HCG) and α-fetoprotein (AFP).

Treatment

  1. Extragonadal germ cell cancer syndrome
  • This syndrome is commonly found in young men.
  • These are predominantly midline tumors (mediastinum or retroperitoneum).
  • The syndrome is characterized by elevated levels of β-HCG, AFP, or both.
  • Genetic analysis may be diagnostic (e.g., abnormalities in chromosome 12).
  • This syndrome should be treated in the same manner as a germ cell tumor (Chapter 16).
  1. Poorly differentiated neuroendocrine carcinoma
  • These carcinomas are high-grade tumors.
  • It is characterized by multiple metastatic sites.
  • The carcinomas are highly responsive to cisplatin-based chemotherapy.
  • The overall RR for combination chemotherapy was 71% (33 of 46 patients), with a complete response (CR) in 28% (13 of 46 patients); 17% of patients (8 of 46 patients) showed durable disease-free survival.
  • Patients in this group should be treated with a regimen of combination chemotherapy including a platinating agent and etoposide (Table 32.7). It should be noted that other patients with PDC or PDA should receive an empiric therapy of platinating agent–based chemotherapy (Table 32.7). (In a prospective study of 220 patients, the overall RR was 62%, with a complete RR of 26%. Thirteen percent of patients were considered cured.)

P.431

 

POORLY DIFFERENTIATED MALIGNANT NEOPLASMS OF UNKNOWN PRIMARY

  • Poorly differentiated malignant neoplasms of unknown primary are found in 5% of all patients with CUP.
  • Specialized pathologic study found 35% to 65% of the malignant neoplasms to be lymphomas; carcinomas accounted for most of the remaining cases. Less than 15% of the neoplasms are melanoma and sarcoma.

SQUAMOUS CELL CARCINOMA OF UNKNOWN PRIMARY

Cervical Node Involvement

High Cervical Node(s)

  • Workup and treatment of squamous cell carcinoma of unknown primary in the high cervical nodes is the same as that for primary head and neck cancer (see Chapter 1).
  • High long-term survival rates (30% to 70%) have been reported after local treatment.
  • The role of chemotherapy is undetermined.

Low Cervical or Supraclavicular Node(s)

  • Histology can be either squamous, adenocarcinoma, or poorly differentiated tumors.
  • Poorer prognosis (particularly for adenocarcinoma histology) is because lung and GI tract are frequent primary sites.
  • If no other sites of disease are found, a few patients (10% to 15%) will have a long-term disease-free survival with aggressive local therapy (surgery and/or XRT).
  • The role of chemotherapy is undetermined.

Inguinal Lymph Node(s)

  • A primary site in the genital or anorectal areas is often identified in most patients.
  • Curative therapy is available for some of these patients.
  • If no primary is found, surgical node dissection (with or without XRT) can offer long-term survival.

SUGGESTED READINGS

Abbruzzese JL, Abbruzzese MC, Hess KR, et al. Unknown primary carcinoma: natural history and prognostic factors in 657 consecutive patients. J Clin Oncol 1994;12:1272–1280.

Bataini JP, Rodriguez J, Jaulerry C, et al. Treatment of metastatic neck nodes secondary to an occult epidermoid carcinoma of the head and neck. Laryngoscopy 1987;97:1080–1089.

Ellerbroek N, Holmes F, Singletary E, et al. Treatment of patients with isolated axillary nodal metastases from an occult primary carcinoma consistent with breast origin. Cancer 1990;66:1481–1491.

Eltabbakh GH, Piver MS. Extraovarian primary peritoneal carcinoma. Oncology 1998;12:813–819.

Goldberg RM, Smith FP, Ueno W, et al. 5-Fluorouracil, adriamycin, and mitomycin in the treatment of adenocarcinoma of unknown primary. J Clin Oncol 1986;4(3):395–399.

Greco FA, Hainsworth JD. Cancer of unknown primary site. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology, 5th ed. Philadelphia, PA: Lippincott–Raven Publishers, 1997:2423–2443.

Greco FA, Oldham RK, Fer MF. The extragonadal germ cell cancer syndrome. Semin Oncol 1982;9:448–455.

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Hainsworth JD, Johnson DH, Greco FA. Cisplatin-based combination chemotherapy in the treatment of poorly differentiated carcinoma and poorly differentiated adenocarcinoma of unknown primary site: results of a 12-year experience. J Clin Oncol 1992;10:912–922.

Hess KR, Abbruzzese MC, Lenzi R, et al. Classification and regression tree analysis of 1000 consecutive patients with unknown primary carcinoma. Clin Cancer Res 1999;5(11):3403–3410.

Kirsten F, Chi CH, Leary JA, et al. Metastatic adeno or undifferentiated carcinoma from an unknown primary site-natural history and guidelines for identification of treatable subsets. Q J Med 1987;62(238):143–161.

Le Chevalier T, Cvitkovic E, Caille P, et al. Early metastatic cancer of unknown primary origin at presentation. A clinical study of 302 consecutive autopsied patients. Arch Intern Med 1988;148(9):2035–2039.

Lyman GH, Preisler HD. Carcinoma of unknown primary: natural history and response to therapy. J Med 1978;9(6):445–459.

Morris EA, Schwartz LH, Dershaw DD, et al. MR imaging of the breast in patients with occult primary breast carcinoma. Radiology 1997;205(2):437–440.

Orel SG, Weinstein SP, Schnall MD, et al. Breast MR imaging in patients with axillary node metastases and unknown primary malignancy. Radiology 1999;212(2):543–549.

Shepherd FA. Treatment of advanced non-small cell lung cancer. Semin Oncol 1994;21:7–18.

Shildt RA, Kennedy PS, Chen TT, et al. Management of patients with metastatic adenocarcinoma of unknown origin: a Southwest Oncology Group study. Cancer Treat Rep 1983;67(1):77–79.

Sporn JR, Greenberg BR. Empirical chemotherapy in patients with carcinoma of unknown primary. Am J Med 1990;88:49–55.

http://www.nci.nih.gov/cancer/topics/pdq/treatment/unknownprimary/HealthProfessional, 2004.