Neuroendocrine tumors of GI Tract.

The World Health Organization (WHO) classifies neuroendocrine neoplasms as well-differentiated neuroendocrine tumors (either the primary tumor or metastasis) and poorly differentiated neuroendocrine carcinomas.

Historically, well-differentiated neuroendocrine tumors have been referred to as “carcinoid tumors,” a term which may cause confusion because clinically a carcinoid tumor is a serotonin-producing tumor associated with functional manifestations of carcinoid syndrome.

The use of the term “carcinoid” for neuroendocrine tumor reporting is therefore discouraged for these reasons.

Immunohistochemistry and other ancillary techniques are generally not required to diagnose well-differentiated neuroendocrine tumors. Specific markers that may be used to establish neuroendocrine differentiation include chromogranin A, synaptophysin, and CD56.
Because of their relative sensitivity and specificity, chromogranin A and synaptophysin are recommended.



Recommended Grading System for Well-Differentiated Gastroenteropancreatic Neuroendocrine Tumors

Because of site-specific similarities in histology, immunohistochemistry, and histochemistry, neuroendocrine tumors of the digestive tract have traditionally been subdivided into those of foregut, midgut, and hindgut origin . In general, the distribution pattern along the gastrointestinal (GI) tract parallels that of the progenitor cell type, and the anatomic site of origin of GI neuroendocrine tumors is an important predictor of clinical behavior.

Tumor Size
For neuroendocrine tumors in any part of the gastrointestinal tract, size greater than 2.0 cm is associated with a higher risk of lymph node metastasis. For jejunoileal tumors, nodal metastases occur in about 12% of patients with tumors smaller than 1.0 cm and in most patients with tumors larger than 1.0 cm. Thus, treatment for small intestine neuroendocrine tumor includes complete resection with regional lymphadenectomy.

Immunohistochemistry in the Differential Diagnosis of Cutaneous Basal Cell Carcinoma

Basal cell carcinoma and squamous cell carcinoma are two of the most common cutaneous tumors seen by pathologists. In the large majority of cases, the distinction between these two tumors is readily made on the basis of standard H&E morphology. However, many of us see cases from time to time that for one reason or another (minuscule biopsy, mishandled specimen, crushed beyond recognition, dryed out, poorly fixed, etc., etc.), it is difficult to know for certain whether one is dealing with a squamous carcinoma or a basal cell carcinoma. This month, we discuss several immunostains that can be of utility in approaching this problem. 

It is worth mentioning that both basal cell carcinoma and cutaneous squamous cell carcinoma characteristically express strong and diffuse high molecular weight cytokeratin, cytokeratin 5 (or cytokeratin5/6) and nuclear p63, so the absence of staining with these markers (assuming adequate tissue and technique of course) should lead you to consider another diagnosis. 

EMA is a useful antibody for this problem, since basal cell carcinomas are negative for EMA, although occasionally lumina associated with sebaceous differentiation in these tumors may show EMA positivity. In contrast, most squamous cell carcinomas of the skin will have substantial EMA immunoreactivity.

Ber-EP4 is also a useful marker, as basal cell carcinomas are typically positive for this marker, unlike cutaneous squamous carcinoma. Interestingly, non-cutaneous squamous carcinomas (e.g., pulmonary squamous carcinoma) may express Ber-EP4, so conceivably reactivity of Ber-EP4 in a known cutaneous squamous tumor might suggest the possibility of metastatic squamous carcinoma, although I do not know of any published reports that have specifically addressed that question. 

Interestingly, smooth muscle actin (SMA) has been found to be expressed in a significant number of basal cell carcinomas of the skin (13 of 17 cases in one study). Indeed, we have observed strong SMA reactivity in a number of basal cell carcinomas that we have stained, although the frequency of reactivity is not as high in our hands as in some published series. Cutaneous squamous carcinomas are negative for SMA.

BCL-2 has been reported by some authors to be useful in this situation, since basal cell carcinomas are typically diffusely positive for this marker. Cutaneous squamous cell carcinomas are generally negative, although some authors describe focal positivity enough to 26% of cutaneous squamous carcinoms.

In summary, when faced with the differential diagnosis of cutaneous basal cell carcinoma versus cutaneous squamous carcinoma, a reasonable first approach would be to employ immunostains for EMA and Ber-EP4. If these results are not diagnostic, immunostains for SMA and BCL-2 would be worth a try. Again, if the tumor in question does not show strong high molecular weight cytokeratin, cytokeratin 5, cytokeratin 5/6, and nuclear p63, consideration of another diagnosis would be prudent. Results of expected staining in these tumors are listed in table below.

REFERENCES:

1. Wick MR: Practical immunohistology of cutaneous neoplasms: an update. Presentation at the American Society of Dermatopathology Companion Meeting, 2004 Annual Meeting of the United States and Canadian Academy of Patholgy, Vancouver, BC, March 7, 2004.

2. Jimenez FJ et al: Ber-EP4 immunoreactivity  innormal skin and cutaneous neoplasms. Mod Pathol8(8): 854-858, Oct 1995.

3. Peterdy G et al: Immunohistochemical separationof microcystic adnexal carcinoma from basal cellcarcinoma and squamous cell carcinoma. ModPathol 14(1):72A (abstract # 407), Jan 2001.

4. Varma M et al: Expression of smooth muscle antigensin basal cell carcinomas of skin. Mod Pathol12(1):65A (abstract # 365), Jan 1999.

5. Williams GA et al: Immunoreactivity for alphasmoothmuscle actin aids in the separation of basalcell carcinoma from both squamous cell carcinomaand trichoepithelioma. Lab Investig 78(1):54A(abstract # 303), Jan 1998.

6.Rodney T. Miller, M.D., Director of Immunohistochemistry

Tumor Size (Size of Invasive Carcinoma) in Breast Carcinoma

Breast Carcinoma reporting;

Tumor Size (Size of Invasive Carcinoma)

• The size of an invasive carcinoma is an important prognostic factor. 
• The single greatest dimension of the largest invasive carcinoma is used to determine T classification 
• The best size for AJCC T classification should use information from imaging, gross examination, and microscopic evaluation. 
• Visual determination of size is often unreliable, as carcinomas often blend into adjacent fibrous tissue. 
• The size by palpation of a hard mass correlates better with invasion of tumor cells into stroma with a desmoplastic response. 
• Sizes should be measured to the nearest millimeter. 
• In some cases, the size may be difficult to determine.

How to measure size of breast invasive carcinoma:

A. Invasive carcinoma with surrounding ductal carcinoma in situ (DCIS). The size only includes the area of the invasive carcinoma and does not include the adjacent DCIS. The size should be measured to the closest 1 mm.

Invasive carcinoma and DCIS: The size measurement includes only the largest area of contiguous invasion of stroma. Surrounding DCIS is not included in the size measurement.

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B. Small invasive carcinoma with prior core needle biopsy. The size of the carcinoma in the core needle biopsy should not be added to the size of the carcinoma in the excisional specimen, as this will generally overestimate the true size. The best size for classification must take into consideration the largest dimension of the carcinoma in both specimens as well as the size by imaging before the core needle biopsy.

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C. Small invasive carcinomas with adjacent biopsy site changes. In some excisional specimens, a small carcinoma will be present adjacent to a relatively large area of biopsy site changes. The actual size cannot be determined with certainty. The size in the core needle biopsy, in the excisional specimen, and by imaging should be considered to determine the best size for classification.

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D. Multiple invasive carcinomas. If multiple carcinomas are present, the size of the largest invasive carcinoma is used for T classification. The modifier “m” is used to indicate that multiple invasive carcinomas are present.

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E. Multiple invasive carcinomas in close proximity. It may be difficult to distinguish multiple adjacent carcinomas from one large invasive carcinoma. Careful examination of the specimen with submission of tissue between grossly evident carcinomas is essential. Correlation with imaging findings can be helpful. Generally, microscopic size confirmation of the largest grossly identified invasive carcinoma is used for T classification.

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F. Invasive carcinomas that have been transected. If an invasive carcinoma has been transected and is present in more than 1 tissue fragment, the sizes in each fragment should not be added together, as this may overestimate the true size. In many cases, correlation with the size on breast imaging will be helpful to choose the best size for classification. In other cases, the pathologist will need to use his or her judgment in assigning an AJCC T category.

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DCIS with microinvasion: 

• Microinvasion is defined by the AJCC as invasion measuring 1 mm or less in size. 
• If more than 1 focus of microinvasion is present, the number of foci present, an estimate of the number, or a note that the number of foci is too numerous to quantify should be reported.
•  In some cases, immunoperoxidase studies for myoepithelial cells may be helpful to document areas of invasion and the size of the invasive foci.
•  Invasive tumors that are larger than 1.0 mm but less than 2.0 mm are rounded up to 2.0 mm.