Significance of Atypical Small Acinar Proliferation (ASAP) in Prostate needle biopsy

Many time while reporting prostate needle biopsy, we come across features, which are suspicious for malignancy, but hinder a definitive diagnosis of carcinoma, because of concern about over diagnosis. These are the cases, which are labelled as ASAP, -atypical small acinar proliferation.

Diagnostic criteria for ASAP :
For pathologists, 3 questions need to be answered before the diagnosis of cancer in a small lesion:
• Would you be absolutely confident of this biopsy diagnosis if it were followed by a negative radical prostatectomy?
• Would another colleague pathologist agree with the diagnosis of cancer?
• Can you confidently support the diagnosis of adenocarcinoma based solely on this biopsy?

If the answer to any of these questions is “No,” then use of the more conservative diagnosis of ASAP is recommended.

Reasons for the Diagnosis of ASAP are :

• Small number of acini in the focus of concern.
• Small focus size, average 0.4 mm in diameter.
• Loss of focus of concern in deeper levels.
• Distortion of acini raising concern for atrophy.
• Lack of convincing features of cancer (insufficient nucleomegaly or nucleolomegaly).
• Foamy cytoplasm raising concern for foamy gland carcinoma.
• Conflicting immunohistochemical findings.

Significance of ASAP. -

Prostate cancer is found in up to 60% of repeat biopsies after the diagnosis of ASAP. Thus
ASAP in a biopsy is a significant predictor for concurrent or subsequent cancer. The high predictive value of atypical small acinar proliferation (ASAP) for subsequent adenocarcinoma indicates a need for repeat biopsy.

References:

1. Borboroglu PG, Sur RL, Roberts JL, et al. Repeat biopsy strategy in patients with atypical small acinar proliferation or high grade prostatic intraepithelial neoplasia on initial prostate needle biopsy. J Urol. 2001;166:866–870.
2. Cheville JC, Reznicek MJ, Bostwick DG. The focus of “atypical glands,suspicious for malignancy” in prostatic needle biopsy specimens: incidence,histologic features, and clinical follow-up of cases diagnosed in a community practice. Am J Clin Pathol. 1997;108:633– 640.
3. Iczkowski KA, Bassler TJ, Schwob VS, et al. Diagnosis of “suspicious for malignancy” in prostate biopsies: predictive value for cancer. Urology.1998;51:749 –757; discussion 757–748.

4. Isabelle Meiers, at el. Atypical Small Acinar Proliferation in the prostate :Pathology Case reviews • Volume 13, Number 4, July/August 2008;13: 129–134

Sentinel Lymph Node Biopsy in Melanoma (SLNB)

Clinical Significance of Sentinel Lymph node in melanoma. :

SLNB is very accurate in predicting the status of the remaining regional lymph nodes.
It is currently the most significant independent prognostic indicator for survival when compared with all other factors, including tumour thickness and the presence of ulceration.

According to some studies, the relapse rate for H&E detected SLN positive patients is higher (up to 67%), whereas the relapse rate for SLN negative patients is low (2–6%) during the same period.

Indications for SLNB procedure :

1. Primary Melanoma with thickness greater than 1.0 mm,
   or
2. Primary Melanoma less than 1mm with Clark's level four or five or presence of ulceration.

Pathology Protocol:

The current standard for the diagnosis of SLN metastasis is based on routine H&E histology and immunohistochemistry (IHC).
I follow the Cochran Method.It is as follows:
1. The lymph node is either bivalved or cut into 3 mm blocks, depending on the size of the node.
2. Sections 1, 3, and 5 are stained with haematoxylin and eosin (H&E),
3. Sections 2 and 4 are immunohistochemically stained for S-100 and HMB-45.

The sensitivity of detection is increased with IHC, multiple sectioning and reverse transcriptase polymerase chain reaction (RT-PCR) techniques. The role of such molecular genetic techniques in identifying melanoma proteins remains undefined, despite greater sensitivity.

Caution.:
‘‘Surgeons should be aware that the subcapsular region is crucial in sentinel lymph node (SLN) evaluation and the architecture of the SLN can be disrupted easily if the procedure is not carried out with care.’’

To reduce the false negative rate, surgeons should avoid crushing and excessive cautery usage to preserve the integrity of the SLN. It is also important not to cut into the SLN and complete excision of the whole SLN is crucial.

False positive results. :
False positives resulting from,

1. Benign naevic cells raise concern and necessitate further refinement. Naevic cells are usually present within the capsule (intracapsular) or within the trabeculae, and typically stain negatively, or only faintly positively, with HMB-45.


2. Reactive dendritic cells, nerve fragments, and benign naevic cells may each stain positively for S100. HMB-45 stain allowed us to differentiate benign naevic cells from their malignant counterparts.
   Examination at the subcapsular level, combined with the use of S100 staining, is the most practical and sensitive method to ensure the detection of micrometastatic nodal disease.
   

References:
· Gershenwald JE, Thompson W, Mansfield PF, et al. Multi-institutional melanoma lymphatic mapping experience: the prognostic value of sentinel node status in 612 stage I or II melanoma patients. J Clin Oncol 1999;3:976–83.
· Balch CM, Buzaid AC, Atkins MB, et al. Final version of the American joint committee on cancer staging system for cutaneous melanoma. J Clin Oncol2001;19:3635–48.
· White RR, Stanley WE, Johnson JL, et al. Long-term survival in 2,505 patientswith melanoma with regional lymph node metastasis. Ann Surg 2002;235:879–87.
· McCready DR, Ghazarian DM, Hershkop MS, et al. Sentinel lymph-nodebiopsy after previous wide local excision for melanoma. Can J Surg 2001;44:432–4.
· Cochran AJ, Huang RR, Guo J, et al. Current practice and future directions inpathology and laboratory evaluation of the sentinel node. Ann Surg Oncol 2001;8(9S):13–17.
· Jansen L, Nieweg OE, Peterse JL, et al. Reliability of sentinel lymph node biopsy for staging melanoma. Br J Surg 2000;87:484–9.
· C A Murray, W L Leong, D R McCready and D M Ghazarian Histopathological patterns of melanoma metastases in sentinel lymph nodes J. Clin. Pathol. 2004;57;64-67

Work up of Carcinoma of Unknown Primary (CUP)

It is often important to determine the site of origin of a metastatic carcinoma of unknown primary site, particularly because this may affect the choice of the treatment. Determination of the primary site may take several steps.
Clinical features, such as age, sex, and site of metastases may give a first indication.
A detailed pathologic examination of the most accessible biopsied tissue specimen is mandatory in CUP cases. Pathologic evaluation typically consists of hematoxylin-and-eosin stains and immunohistochemical tests. Electron microscopy is rarely used currently, although it may beselectively useful when making treatment decisions.
Role of Serum Tumor Markers and Cytogenetics
Most tumor markers, including CEA, CA-125, CA 19-9, and CA 15-3, when elevated, are nonspecific and not helpful in determining the primary tumor site.
Men who present with adenocarcinoma and osteoblastic metastasis should undergo a PSA test. Patients with an elevated PSA should be treated as having prostate cancer.
In patients with undifferentiated or poorly differentiated carcinoma (especially with a midline tumor), elevated Beta-human chorionic gonadotropin (B-hCG) and alpha fetoprotein(AFP) levels suggest the possibility of an extragonadal germ cell (testicular)tumor.
Cytogenetic studies had a larger role in the past, although interpretation of these older studies can be challenging. With the availability of immunohistochemical stains, cytogenetic cytogenetic analyses are indicated only occasionally.

Role of Immunohistochemistry
CK 7 and CK20 are two of the most commonly used CKs in surgical pathology.
A 5% cut-off percentage for positivity may eliminate more “false positive” results.

(1) CK7+/CK20+ in carcinomas of bile duct, lung-mucinous bronchioloalveolar, pancreas; urothelium; also primary mucinous tumors of ovary (74%), upper GI tract (78%), endocervix

(2) CK7+/CK20- in carcinomas of bile duct, breast, endocervical and endometrial adenocarcinoma, esophagus (distal,), lung (not mucinous, bronchioloalveolar), salivary gland, thyroid; also mesothelioma

(3) CK7-/CK20+ in carcinoma of colon (particularly early stage); CK20 is less sensitive for poorly differentiated colonic carcinoma; primary mucinous tumors of lower GI tract (79%,) and primary bladder adenocarcinomas (29%,)

(4) CK7-/CK20- in carcinomas of adrenal cortex and prostate

(5)CK7 and CK20 can be used to distinguish primary lung carcinoma (CK7+/CK20-) from metastatic colonic carcinoma to lung (CK7-/CK20+)

(6)CK7 cab be used to distinguish chromophobe carcinoma (diffuse CK7+ staining) and oncocytoma (usually CK7-)

(7)CK 20 can be used to distinguish Merkel cell carcinoma (CK20+, dot like, TTF1 -) and metastatic small cell carcinoma of lung (CK20-, TTF1+)

Additional immunostains for further work up.
BRST-1,ER,PR,Gross cystic disease fibrous protein-15--> Breast cancer
Thyroid transcription factor 1---> Lung and thyroid cancer
Thyroglobulin ---> Thyroid cancer
Chromogranin, synaptophysin, NSE,CD56---> Neuroendocrine cancer
CDX-2 ---> Gastrointestinal cancer
Calretinin, mesothelin---> Mesothelioma
Leukocyte common antigen---> Lymphoma
S-100, HMB-45---> Melanoma
URO-III, thrombomodulin ---> Bladder cancer
AlphaFetoprotein ---> Hepatocellular cancer, germcell cancer
Beta-Human chronic gonadotropin --->Germ cell cancer
Prostate specific antigen ---> Prostate cancer
Please review following powerpoint presentation for work up of CUP.

Use of algorithm in IHC