High Grade Prostatic Intraepithelial Neoplasia (HGPIN)

High Grade Prostatic Intraepithelial Neoplasia (HGPIN):
Common questions asked about HGPIN are :
-How do we as pathologists make these diagnoses?
-What do they mean for the patient in terms of cancer risk?
-What is/are the optimal strategies for follow-up so that if cancer does eventually develop it is caught at an early, curable stage?

Pathology criteria for diagnosis of HGPIN:

-Architecturally benign acini/ducts lined by atypical cells.
-These cells show large nuclei and prominent nucleoli (cytologic features of carcinoma).
-Generally at least 10% of the luminal cells should show these features to make the diagnosis.


Diagnosis of HGPIN has been shown to be reproducible. Low grade prostatic intraepithelial neoplasia has poor reproducibility (even among experts), ill defined diagnostic criteria, and no true clinical relevance. It is for these reasons that I do not personally diagnose LGPIN.

Risk of subsequent cancer:

-In previous studies the risk of carcinoma on follow-up biopsy for a HGPIN diagnosis has been reported to be as high as 50%, however, when the data is based on series with increased case numbers, this decrease to around 25%.

-Number of cores with high grade PIN predicts risk of subsequent cancer (1 core-30%, 3 cores-40%, 4+ cores-75%).In addition, morphologic patterns of HGPIN (i.e. flat, tufted, micropapillary, cribriform) have not been shown to be predictive of subsequent carcinoma.

Follow up strategy for patients with HGPIN:

Although there have been several follow-up strategies for patients with a diagnosis of HGPIN, many recommend re-biopsy within 3-6 months. One protocol includes biopsies at 3-6 months for 2 years, followed by yearly biopsies for life.
In a recent study, recommendation was made that in the absence of other clinical indicators worrisome for cancer, men do not need a routine repeat biopsy within a year following a HGPIN diagnosis. As the natural history of HGPIN in any given patient is not known, the decision to take additional biopsies past 1 year is best made on a patient by patient basis with a frank discussion between the physician and patient.

Various studies have shown that in patients with prior diagnosis of HGPIN, cancer is often diagnosed in adjacent sites and even within the contralateral lobe. It is for this reason that when re-biopsy is performed for HGPIN sampling should be concentrated in the region of the previous HGPIN with the rest of the gland sampled so as not to miss small foci of cancer. Specimens should be meticulously labeled as to site (in addition to patient identification) and optimally no more than 2 cores should be submitted per container.

Summary:

1. HGPIN is characterized by architecturally benign glands lined by cells which are morphologically similar to prostate cancer, and is the putative precursor of prostate cancer.

2. Unlike HGPIN the diagnosis of LGPIN is not reproducible and carries no clinical significance.

3. While earlier reports described the risk of cancer following a diagnosis of HGPIN as high as 50%, more current reviews suggest that the risk may be much lower.

4. Men with a diagnosis of HGPIN (especially those with HGPIN focally) may not need re-biopsy for up to one year after initial diagnosis. Repeat biopsies should concentrate on the area of previous HGPIN, but also include sampling of the entire gland.
(Thanks to Dr.Dharam Ramnani for allowing to use the above images for this site.)
References:
1. Epstein JI, Herawi M. Prostate needle biopsies containing prostatic intraepithelial neoplasia or atypical foci suspicious for carcinoma: implications for patient care. The Journal of Urology 2006; 175: 820-834.
2. Bishara T, Ramnani DM, Epstein JI. High grade prostatic intraepithelial neoplasia on needle biopsy risk of cancer on repeat biopsy related to number of involved cores and morphologic pattern. The American Journal of Surgical Pathology 2004; 28: 629-633.
3. Bostwick DG, Qian J. High-grade prostatic intraepithelial neoplasia. Modern Pathology 2004; 17: 360-379.

Desmoplastic melanoma, a common missed diagnosis.

Introduction:

Although desmoplastic melanoma represents less than 2 percent of all melanomas, it's frequently misdiagnosed, due to a lack of distinctive clinical presentation features. Histologic diagnosis is rarely straightforward either.

Patients are often middle age-to-elderly and present with the tumor most often on the head and neck region. The lesion may resemble a scar as it is often a hard nodule or plaque.
Pigmentation is variable but often absent. The tumor has ill-defined margins and is very infiltrative, making local control difficult. Sentinel lymph node excision is routinely performed but rarely positive.

Histology :
The histology can also masquerade as a scar . The epidermis is often atrophic and may or may not have a precursor (in situ) lesion. Characteristically, the tumor is in the dermis as spindled melanocytes resembling fibroblasts.Often, there is an edematous or desmoplastic stroma with
scattered lymphoid aggregates. Perineural invasion is common.In about one third of the lesions, there are foci of epithelioid or conventional melanoma.

S-100 and HMB45 immunohistochemical stains can help differentiate tumor from scar.
At low power, there is a fibrotic lesion in the dermis with scattered lymphoid aggregates.

The lesion is paucicellular, but there is cellular atypia .

Reporting of the histologic subtype of melanoma is common practice, but it is unclear what impact, if any, it has on management decisions. One possible exception is desmoplastic melanoma, a distinct subtype with a unique biologic behavior. It is now recognized that desmoplastic melanomas present with greater tumor thickness (Breslow level) than their conventional counterparts but fail to demonstrate a corresponding higher sentinel lymph node involvement or higher mortality.

Some authors have further subdivided desmoplastic melanomas into "pure" and "mixed" forms. Pure (primarily fibrotic) and mixed varieties, which include features common to conventional melanoma and desmoplastic areas. As per these recent studies only 1% of pure desmoplastic melanomas metastasized to regional lymph nodes compared to 10% with mixed histology.

References:
1. Attis MG, Burchette JL, Selim MA, et al. Differential expression of N-cadherin distinguishes a subset metastasizing desmoplastic melanoma.
2. Davison JM, Rosenbaum E, Barrett TL, et al. Absence of V599E BRAF mutations in desmoplastic melanomas. Cancer. 2005 103:788.
3. Hawkins WG, Busam KJ, Ben-Porat L, et al. Desmoplastic melanoma:a pathologically and clinically distinct form of melanoma. Ann Surg Oncol. 2005 12:207.

Dysplasia in Inflammatory Bowel Disease

As we all know, chronic inflammatory bowel disease (IBD) presents a risk for dysplasia and subsequent malignancy in patients with long standing disease.

The risk for adenocarcinoma increases with a number of factors including

• 
  
  the linear extent of disease within the bowel,
• 
  
  early age at onset of disease,
• 
  
  severity of disease and duration of disease.

The pathologic reporting of endoscopic biopsy specimens with inflammatory bowel disease must convey the information the clinician needs in a clear and consistent manner in order to properly manage the patient's disease.

Every biopsy report should, of course, give an assessment of the disease activity and distribution. In addition, the pathologist must render an opinion on the presence or absence of dysplasia. The "second line" diagnosis must reflect one of three choices regarding dysplasia in the biopsy:

1. Negative for dysplasia

2. Indefinite for dysplasia

3. Positive for dysplasia

• Low grade
• High grade

Agreeing on the terminology is relatively easy. Agreeing on the morphologic presence or absence of dysplasia is another issue.

Studies have shown poor interobserver reproducibility with regard to recognizing and diagnosing dysplasia. Low grade dysplasia (LGD), as one might guess, suffers from the worst interobserver variability.

The more marked the cytologic changes (high grade dysplasia) the easier it is to recognize and agree upon amongst pathologists.

This variability is one reason that many suggest surveillance for LGD. The histologic parameters which define dysplasia in the colon are consistent regardless of the subtype of IBD - Crohn's colitis or ulcerative colitis.

Negative for dysplasia

The lack of dysplasia in a chronic IBD biopsy is stated as "negative for dysplasia". That phrase should be included in biopsies that are completely normal or indistinguishable from non-IBD biopsies. This could be found in biopsies obtained from an area of the colon that is not affected by the disease or in an area that is completely quiescent perhaps from treatment.

Reactive changes that can and areseen in colitis biopsies are also included in the "negative for dysplasia" category. Some refer to such changes as "baseline atypia"; regardless, that limited spectrum is devoid of dysplasia and falls under the heading of "negative".

Indefinite for dysplasia

This category sometimes suffers from a lack of respect or credibility; however, it is a defined, accepted and even required category in properlyinterpreting dysplasia in IBD.

It is not a crutch upon which uncertain and weak willed pathologists lean. The changes that are included in the indefinite category must be recognized as such lest one either overcalls or undercalls dysplasia when it cannot be unequivocally determined whether it is present or absent. One such example is when dysplasia shows partial surface maturation. That is, the involvement of the surface epithelium by dysplastic change and not just the basal, proliferating portions of crypts is required to make a diagnosis of dysplasia. If the surface is partially involved or shows incomplete maturation then indefinite is the proper designation.

A biopsy that shows marked acute inflammation, erosion or ulceration that has cytologic changes that absent the inflammation would be called dysplastic must be designated as indefinite. This use is intended to recognize that the presence of inflammation makes diagnosing dysplasia with certainty nearly impossible.

Positive for dysplasia- low and high grade .

If there is flat dysplasia present in a biopsy, then one of the above choices (low grade or high grade) ought to appear in the report.

Criterias:

Low grade dysplasia: basally oriented nuclei; mild nuclear enlargement, nuclear crowding and hyperchromasia; decreased intracellular mucin High grade dysplasia: prominent nuclear stratification (compared to low grade) with many nuclei in luminal half of cell; more significant hyperchromasia and pleomorphism; may have marked architectural distortion with a villous or nodular growth pattern resembling adenoma or with cribriforming
The best tool that a pathologist has in effectively interpreting IBD biopsies for dysplasia is the most basic one - the simple hematoxylin and eosin stained tissue section. Ancillary tests such as immunohistochemistry have not proven as effective as the simple histologic evaluation of the H&E stain.

Experience of the pathologist in seeing and appropriately interpreting dysplasia in IBD biopsies is of critical importance.

Proper written and verbal communication between the gastrointestinal pathologist and the endoscopist is essential in going from the correct interpretation to the proper clinical course.

This is of paramount importance in interpreting polypoid dysplasia and distinguishing between a sporadic adenoma and a dysplasia associated lesion or mass (DALM).

SELECTED REFERENCES

• Riddell RH, Goldman H, Ransohoff DF, et al: Dysplasia in inflammatory bowel disease: Standardized classification with provisional applications. Hum Pathol 14:931-968, 1983.
• Bernstein CN, Blanchard JF, Kliewer E, et al: Cancer risk in patients with inflammatory bowel disease: A population-based study. Cancer 91: 854-862, 2001.
• Odze RD, Goldblum JR, Noffsinger A: Interobserver variability in the diagnosis of ulcerative colitis-associated dysplasia by telepathology. ModPathol 15:379-386, 2000.