Breast Pathology

Metastatic Carcinoid Tumor

Carol A. Reynolds
Mayo Clinic
Rochester, MN


Clinical History:
55 year old woman with a small nodule noted by ultrasound in the left breast. Ultrasound-guided core needle biopsy performed.


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Figure 1a
Ultrasound of left breast.
Figure 1b
Low power image of infiltrating tumor composed of solid, irregular nests separated by intervening dense fibrous stroma. The tumor borders appear well-delineated.
Figure 1c
Medium power image of variable sized solid nests composed of tumor cells with mild pleomorphism. Tumor nuclei round to oval with stippled (salt-and-pepper) chromatin pattern.
Figure 1d
High power image of large distended duct with rosette-like lumen formation.

Figure 2
Chromogranin. The tumor cells demonstrate strong chromogranin expression. Synaptophysin and NSE showed similar staining result.
Figure 3
Calponin stain. The infiltrating tumor cells and the distended ducts with rosette-like lumen formation lack a basal layer of myoepithelial cells. Calponin highlights the vessels in the stroma.
Figure 4
CDX2. The tumor cells demonstrate diffuse nuclear staining against CDX2.


Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
The low power image shows an infiltrative process with a slightly circumscribed border. This tumor is composed of variable sized solid, irregular nests of tumor cells infiltrating through a fibrous stroma. At higher magnification, the tumor cells exhibit mild pleomorphism with little variation in cell size and a moderate amount of eosinophilic cytoplasm. The tumor nuclei are round to oval with stippled chromatin and small inconspicuous nucleoli. Mitotic activity is low. The infiltrating tumor is associated with what appears to be solid type ductal carcinoma in situ characterized by distended ducts with rosette-like microlumen formation composed of similar neoplastic cells. A panel of immunohistochemical stains was performed. The tumor cells lacked expression for CK7 and CK20. Myoepithelial markers were negative around the tumor nests, including what appeared to be an intraductal component. Immunohistochemical stains for estrogen receptor and progesterone receptor were negative. Neuroendocrine markers were diffusely and strongly positive. TTF-1 was negative. The tumor cells demonstrated diffuse expression for CDX2.

Differential Diagnoses:
Differential diagnostic considerations include:
  • Infiltrating ductal carcinoma, NOS The infiltrating nests of tumor cells and the distended ducts of what appears to be ductal carcinoma in situ could easily be considered. The majority of NOS infiltrating ductal carcinoma are CK7 positive, CK20 negative. [1] The absence of estrogen receptor expression in this low grade tumor would be unusual. The larger distended ducts within the current case mimics solid type ductal carcinoma in situ. The lack of myoepithelial cells at the periphery of these larger nests would exclude an intraductal component. These features should prompt one to perform additional immunohistochemical stains and to obtain a more detailed clinical history.

  • Infiltrating mammary carcinoma with neuroendocrine features Similar to infiltrating ductal carcinoma, NOS, this tumor could represent an infiltrating mammary carcinoma with neuroendocrine features. Up to 20% of mammary carcinomas can show neuroendocrine differentiation. [2] Those tumors that express neuroendocrine markers in more than 50% of the cell population represent about 2-5% of primary breast carcinomas (WHO, 2003). The majority of these neuroendocrine carcinomas are estrogen receptor positive. [3] The presence of ductal carcinoma in situ would confirm the mammary origin of this tumor. The current case demonstrates neuroendocrine differentiation, but lacks an intraductal component, is estrogen receptor negative, and shows diffuse staining for CDX2, which is not a feature of mammary carcinoma with neuroendocrine features.

  • Alveolar variant of infiltrating lobular carcinoma This tumor displays discrete groups of tumor cells separated by bands of fibrous stroma. The tumor cells have uniform, round central nuclei. This variant of invasive lobular carcinoma is typically seen admixed with "classical" type of invasive lobular carcinoma and/or lobular carcinoma in situ. These tumors are CK7 positive, estrogen receptor positive, and e-cadherin negative. Although a small subset of infiltrating lobular carcinomas, in particular pleomorphic type, can express chromogranin, the staining pattern is weak and focal (<5%). [4] The current case was CK7 negative, estrogen receptor negative, and diffusely and strongly positive for neuroendocrine markers.

  • Solid papillary carcinoma These tumors are composed of circumscribed nodules of neoplastic cells which are ovoid or spindle-shaped and show low nuclear grade. Extracellular and intracellular mucin production is a common feature. [5] These tumors usually show neuroendocrine expression and frequently coexist with mucinous carcinomas. [6] These tumors are always estrogen receptor positive. [6] These latter features are not present in the current case. The current case was negative for estrogen receptor and strongly reactive for CDX2.

  • Solid variant of mammary adenoid cystic carcinoma This tumor can be lobulated and show irregular nests of tumor cells infiltrating through a fibrotic stroma. The morphology of the tumor cells is usually characterized by moderate to marked nuclear atypia and scant eosinophilic cytoplasm. Some of the solid distended nests show ductule formation which can be highlighted with CK7. Pseudoglandular structures can occasionally be seen with the tumor nests and these contain homogenous, eosinophilic material. [7] These tumors are characterized by nuclear atypia and brisk mitotic rate, which are not present in the current case.

  • Metastatic carcinoid tumor This tumor is composed of solid, irregular nests of tumor cells with uniform cytology. The tumor nuclei are round or oval with stippled chromatin and inconspicuous nucleoli. Larger nests of tumor cells can have rosette-like lumen mimicking solid type ductal carcinoma in situ. The majority of carcinoid tumors are positive for neuroendocrine markers (chromogranin, synaptophysin, NSE). These tumors more often than not are negative for CK7 and CK20. Estrogen and progesterone receptors are frequently negative. Additional immunohistochemical markers (CDX2, TTF-1) can be useful in determining the primary tumor site. While "classic" adenocarcinomas from the gastrointestinal tract rarely metastasize to the breast, carcinoid tumors have been reported to be a more frequent source of metastasis. [8]

Final Diagnosis:
Metastatic Carcinoid Tumor

Case Discussion:
Metastases to the breast are uncommon and comprise less than 2% of all malignant breast tumors based on histological diagnosis in clinical studies. [9] Breast metastases from the contralateral breast are the most common; and in decreasing order of frequency, breast metastases from nonmammary sites include hematopoietic neoplasms, malignant melanoma, lung carcinoma, gastric carcinoma, and renal cell carcinoma. [10] While "classic" adenocarcinomas from the gastrointestinal tract rarely metastasize to the breast, carcinoid tumors have been reported to be a more frequent source of metastasis.8 Carcinoid tumors are slow growing neoplasms derived from enterochromaffin cells, most commonly of the gastrointestinal tract, pancreas, or lung. Patients usually present with a painless, palpable mass and breast imaging is an important diagnostic tool. [11] The most common mammographic appearance is of one or more well- circumscribed masses without spiculation, calcifications, or other signs that characterize the majority of primary breast carcinomas. [12] These tumors can clinically be interpreted as fibroadenoma, medullary carcinoma, or mucinous carcinoma. [13] Carcinoid syndrome occurs in approximately 5% of patients with intestinal carcinoid tumor and manifests as episodes of diarrhea, abdominal pain and flushing. [14] Although this finding is highly suggestive of metastases from gastrointestinal origin, carcinoid syndrome may be produced without hepatic metastases when the primary tumor is extraintestinal. [15] Unfortunately, clinical information regarding the patient's symptoms are not consistently reported to the pathologist. The morphology is generally similar to that of primary carcinoid. Since many other tumors may have nests, acini, cords, and trabeculae, the differential diagnosis of metastatic carcinoid is broad. Metastatic carcinoid is often misdiagnosed as a primary breast carcinoma. More than 59 cases of primary and/or metastatic carcinoid tumors have been reported in the literature. [16] It is important to differentiate between primary carcinoid tumor and metastatic carcinoid to the breast to ensure appropriate management. [8, 9, 16, 17, 18]

Histopathology
The most helpful data in making the diagnosis of metastasis to the breast are the clinical history and the morphologic assessment of the tumor. Since metastatic lesions generally present as well-circumscribed masses, the presence of a circumscribed tumor at low power magnification may be the first clue that one is dealing with a metastasis. Carcinoid tumors can have a variety of growth patterns. The tumor can grow in solid, irregular nests, cords or trabeculae. The potential confusion arises when the distended ducts or small glands show an acinar pattern mimicking solid type ductal carcinoma in situ. The tumor cells are oval to columnar with speckled (salt-and- pepper) nuclear chromatin pattern. Occasional single cells are seen infiltrating the stroma. Delicate blood vessels surround the tumor cell nests. The intervening stroma can be hyalanized or fibrous which is a characteristic feature of metastatic carcinoid tumor, unlike the desmoplastic stromal reaction seen in infiltrating breast carcinomas.

Immunophenotype
Immunohistochemistry, in conjunction with morphology and clinical history, plays a major role in distinguishing between a primary breast carcinoma and a metastasis to the breast. Carcinoid tumors are frequently chromogranin and synaptophysin positive. The cytokeratin profile, in particular the combination of CK7 and CK20, is useful in categorizing carcinomas. [19] While carcinoid tumors are generally negative for CK7 and CK20, primary breast carcinomas are typically CK7 positive and CK20 negative.[1] Estrogen and progesterone receptors in generally are negative in metastatic carcinoid tumor, but show expression in 75-80% and 55-60% of mammary carcinomas, respectively. [20] However, there are several reports that have reported positive estrogen receptor staining in extramammary neuroendocrine tumors, [21] including pulmonary neuroendocrine tumors. [22] The absence of an intraductal component is helpful in distinguishing a primary from metastatic carcinoma. Myoepithelial markers such as p63, calponin, or smooth muscle myosin are valuable in recognizing an intraductal component. The finding of a myoepithelial layer at the periphery of the distended tumor nests confirms the mammary origin of the tumor. Additional immunohistochemical markers (CDX2 and TTF-1) can provide some insight to the primary site of carcinoid tumors. CDX2 expression is found regularly in intestinal and appendiceal carcinoid tumors, and infrequently in gastric and rectal carcinoid tumors. TTF-1 expression has been found in up to 30% of pulmonary carcinoids, [23] but others have reported lack of TTF-1 staining in typical pulmonary carcinoids. [24]

Primary versus Metastatic Carcinoid Tumor
The entity of primary carcinoid tumor in the breast is an area of controversy in surgical pathology. Several authors believe primary carcinoid tumors exist based on the finding of an intraductal component, lack of clinical evidence of a primary carcinoid at a distant site, or no metastatic disease after several years of follow up. [25, 26, 27] It is unclear from the reported cases in the literature whether a complete work up to rule out an occult primary tumor elsewhere was performed. Of the reported cases where an intraductal component was identified, no myoepithelial markers were performed to support this finding. Given the tendency for primary carcinoid in the gastrointestinal tract and respiratory system to be small in size, yet have the capacity to metastasize, one might assume that many of the reported breast primary carcinoid tumors are in fact metastatic disease to the breast from a small occult primary elsewhere.

Review of the Literature/Treatment Options:
Patients with metastatic carcinoid to the breast should undergo wide local excision alone. Axillary dissection is not necessary unless there is concern or axillary adenopathy. Mastectomy is rarely the course of action, but may be needed for treatment of numerous or very large metastatic carcinoid tumors of the breast.

Conclusion(s):
In summary, metastatic lesions to the breast are uncommon. The diagnosis of metastatic carcinoid can be difficult to render due to histologic similarities between metastatic carcinoid tumor and a variety of primary breast carcinomas. Without a history of previously resected carcinoid tumor or clinical history of carcinoid syndrome, these tumors are often misdiagnosed as a primary breast carcinoma. An accurate diagnosis is important due to differences in management and prognosis.

Key Points:
  • It is important to differentiate primary breast carcinoma from metastatic disease to the breast due to the differences in management and prognosis.

  • In patients with a breast mass and known history of carcinoid tumor, a high index of suspicion for metastatic disease is warranted.

  • Additional immunohistochemical studies (CK7, CDX2, TTF-1 and estrogen receptor) may be warranted in breast carcinomas with morphologic features of neuroendocrine differentiation to rule out metastatic carcinoid tumor.

  • Identification of an in situ component (confirmed by myoepithelial markers) support mammary origin.

  • Treatment is wide excision alone.

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