Special histochemical and immunohistochemical stains (L36234) (2023)

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Special histochemical and immunohistochemical stains

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For services performed from June 12, 2015

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For services performed on or after November 12, 2022

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problem description

Specialty stains are called "special" because they are stains used to stain specific tissues, structures, or pathogens such as bacteria that may not be visible during routine H&E staining. Likewise, IHC is a powerful tool for identifying substances and cells in tissue sections using the specificity of an antigen-antibody reaction in which an antibody is combined with a colored indicator (stain) that can be seen under a microscope. This dedicated LCD display for histochemical and immunohistochemical stains identifies the medically necessary criteria for the use of specialty stains and/or IHC stains and addresses, based on a review of complaints, scenarios that may lead to unnecessary overuse from a point of view. doctor or incorrect billing for these services. The services referenced in this LCD have been a topic of discussion among all MACs lately. Based on a literature review, the text on LCDs and billing and coding did not reflect current practice. Through data analysis, it was determined that the LCD and its corresponding billing and coding articles also had no significant impact on Medicare spending. As such, this LCD and its corresponding billing and encoding item are being considered for recall.

CMS National Coverage Policy

This LCD monitor supplements, but does not replace, modify, or replace existing National Medicare Coverage Agreements (NCD) or payment policy rules and regulations for Specialty Histochemical Dyes and Immunohistochemical Dyes, but does not replace them. Federal statute and subsequent Medicare regulations for providing and paying for medical services are lengthy. They are not repeated on this LCD. Neither the Medicare Payments Policy nor this LCD supersedes, modifies or supersedes applicable state medical practice or other statutes, definitions and/or scopes of practice of health professions. All providers who report services under Medicare Payments must fully understand and comply with all existing laws, regulations, and policies regarding Medicare Payments for Specialty Histochemical Stains and Immunohistochemical Stains and must only submit valid claims to them. Please read and understand them and apply the medical necessity provisions of the policy in the context of the handbook rules. Refer to the following Internet-Only (IOM) manuals posted on the CMS website for the instructions and rules relevant to the CMS manual.

Quotes from the Internet Handbook (IOM):

  • Publication CMS IOM 100-02,Medicare Benefit Policy Handbook,
    • Chapter 15, Section 80.1 Clinical Laboratory Services and Section 80.6.5 Surgery/Cytopathology Exception
  • Publication CMS IOM 100-08,Medicare Integrity Guide,
    • Chapter 13, Section 13.5.4 Reasonable and Necessary Warranty on LCD

National Insurance Act (Title XVIII) Standard references:

  • Title XVIII of the Social Security Act, section 1862(a)(1)(A), states that no Medicare payments shall be made for items or services that are unreasonably necessary for the diagnosis or treatment of an illness. or injury.
  • Title XVIII of the Social Security Act, Section 1862(a)(7). This section does not cover routine physical exams.
  • Title XVIII of the Social Security Law, art. 1833(e) provides that no payment to any service provider is made for a request that does not have the information necessary to process the request.

References from the Federal Register:

  • Code of Federal Regulations (CFR) Title 42, Volume 2, Chapter IV, Part 410.32 Diagnostic X-ray, Diagnostic Laboratory and Other Diagnostic Tests: Conditions.

range tips

Insurance indications, limitations and/or medical necessity

This LCD does not indicate specific specialized histochemical stains (also known as special stains) and/or immunohistochemical (IHC) stains that should be used in the differential diagnosis of tissues or tumors, as this information is readily available in textbooks and various Scientific publications. This MDC identifies medically necessary criteria for the use of specialty dyes and/or IHC dyes and addresses, based on a claims analysis, scenarios that may lead to medically unnecessary overuse or incorrect billing for these services, including:

  • Reflex models or pre-orders for specialty stains and/or IHC stains prior to review of routine hematoxylin and eosin (H&E) staining by a pathologist; Or
  • Use of special dyes and/or IHC dyes without clinical evidence that the dye is applicable or provides the treating physician with information that alters patient management, or
  • Use of added dyes when the diagnosis is already known based on the morphological assessment of the primary dye.

History/Background and/or General Information

Routine hematoxylin and eosin (H&E) staining is the cornerstone of tissue-based microscopic diagnosis. Thin tissue sections are stained with H&E to visualize tissue morphology. The hematoxylin stain stains cell nuclei blue and the eosin stain stains other structures pink/red.

Specialty stains are called "special" because they are stains used to stain specific tissues, structures, or pathogens such as bacteria that may not be visible during routine H&E staining. Special dyes can determine whether or not a substance is present, where it is located in the tissue sample, and often how much or how much of the substance is present. There are special dyes to identify bacteria, yeasts and fungi; for connective tissue, muscle, collagen, lipids and fibrin; for nucleic acids; and universal stains to identify basement membranes, mucins, and various other cellular components.

IHC is a powerful tool for identifying substances and cells in tissue sections using the specificity of an antigen-antibody reaction in which an antibody is combined with a colored indicator (stain) that can be seen under a microscope. Currently, there are over 400 different target antibodies with varying sensitivity and specificity for a given target. The main application of IHC is the identification of poorly differentiated malignancies (tumors) such as carcinoma, lymphoma, melanoma and sarcoma. Some IHC dyes are useful for determining a tumor's primary metastatic site, while others are used to guide specific therapies (eg, Her2 IHC for determining potential response to trastuzumab).

Medical necessity of the services provided

There are many different relationships in the provision of pathology services in the United States. Some physicians, groups, laboratories and hospitals make global claims for the services described in this MDC. In other cases, there are separate persons or entities providing professional and technical services. It is the responsibility of each billing party to acknowledge that it is responsible for the medical necessity of the submitted bills. For example, where a physician or group of physicians bills for a professional component of the services described in this MDC and another entity bills for technical services, it is the responsibility of each entity to independently ensure the medical necessity of the services provided and billed.

Special Colors/Medical Need IHC

For information on additional tests that may be required by the pathologist, in addition to the original tests ordered by healthcare professionals, see CMS Publication IOM 100-02,Medicare Benefit Policy Handbook, Chapter 15, Section 80.6.5 Surgical/Cytopathological Exception.

Reflex stencils or pre-orders for special dyes and/or IHCbefore the reviewRoutine hematoxylin and eosin (H&E) staining by a pathologist is not warranted or required. The pathologist should review H&E staining before ordering special stains or IHC.

There are exceptions and these are recognized standards of care in pathology practice. These exceptions include, but are not limited to, renal, liver, and neuromuscular biopsies and suspected infectious disease, especially in immunocompromised patients. In certain clearly defined circumstances, IHC in sentinel lymph nodes may be warranted when frozen sections show that they are free of tumor.

IHC for breast pathology

The clinical care of a patient with breast cancer depends on accurate diagnosis and assessment of biomarkers. Hormone receptor testing and Her2 testing are recommended for all primary invasive breast cancers and for recurrent or metastatic cancers. There are currently no recommendations for testing Her2 on breast lesions in situ outside of a clinical trial. While there are many additional promising biomarkers such as Ki-67, PI3K, and gene expression assays, the College of American Pathologists (CAP), American Society of Clinical Oncologists (ASCO), and the National Comprehensive Cancer Network (NCCN) have not recognized these markers. in patient care pathways.

Estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor 2 (Her2) are recognized prognostic markers in the treatment of invasive breast cancer. The triple negative breast cancer subtype (ER-/PR-/Her2-) is associated with a worse overall prognosis compared with other subtypes in ethnic minority and study populations of young women.

Ki-67 expression is a proliferation biomarker and has been linked to response to therapy, but measurement methods are controversial. In December 2013, CAP reported that "lack of consensus on scoring, the definition of low and high expression, the appropriate cutoff for positivity, or which part of the tumor should be scored (eg, overall mean). a dearth of data on the effect of preanalytical variables (eg, time of ischemia, duration of fixation, antigen retrieval) on Ki-67 staining.For these reasons, routine breast cancer testing for Ki-67 expression is not recommended by ASCO or NCCN.

The clinical usefulness of in situ hormone receptor testing for breast cancer differs from that of invasive disease. Guidelines and peer-reviewed literature support the use of ER testing for breast cancer in situ and PR testing only when the ER status is negative (Lester, personal communication). Clinical guidelines for the use of Her2 or other biomarkers in patients with non-invasive breast cancer have not been established.

In the absence of professional guidelines based on proven scientific literature, physicians' standing orders for tests such as Ki-67 and EGFR for each breast cancer are not warranted or necessary and are not covered by Medicare.

Furthermore, primary phenotypic markers (eg, IHC for CK5) are not routinely needed. Neither IHC staining such as E-cadherin, p27 or high molecular weight cytokeratin is required in all cases of ducto-lobular differentiation, nor are myoepithelial cell markers such as p63 or smooth muscle myosin heavy chain required in all cases.

Special dyes and/or IHC for gastrointestinal pathologies

Pathologists are often called upon to microscopically diagnose abnormalities seen on endoscopy of the esophagus, stomach, duodenum, and colon. Biopsy specimens are an important diagnostic aid for the patient. Most normal and abnormal conditions of these organs can be detected by routine H&E staining.

It is unreasonable or necessary to order special stains or IHC stains before reviewing routine H&E staining. For most esophageal, gastric, and duodenal specimens, it is neither reasonable nor necessary to perform special staining, for example, staining such as CDX-2 to determine whether clinically significant intestinal metaplasia is present. In addition, it is generally unreasonable and necessary to perform specific staining or IHC to determine the presence of H. pylori organisms.

Other examples of special dyes or IHC that are not guaranteed and required in all samples include:

  • Esophagus - fungal stains, trichrome, DPAS, CDX-2 or other mucin stains
  • Gastric – AB-PAS, D-PAS, CDX-2 or other mucin stains or special stains or IHC for H. pylori or neuroendocrine markers such as synaptophysin or chromogranin
  • Duodenum - AB-PAS, D-PAS, CD3 and trichrome or other mucin stains
  • Jelito grube – CD3, p53 trichrom
  • Hyperplastic polyps – Ki67, CK20, p53, CEA, BRAF
  • Tubulo-villous adenoma – Ki-67, CK20, CEA, p53, MMR

If special stains or IHC are required in addition to routine H&E for gastric specimens, special documentation is required in the histopathology report to justify the medical need for staining. Cases that may require special stains or IHC include, but are not limited to:

  • Detection of H. pylori in the right environment when organisms are not visible on H&E stained slides
  • Evaluation of atrophic gastritis for autoimmune etiology and enterochromaffin-like cells (ECL)/carcinoid hyperplasia
  • Features of cancer, lymphoma, melanoma, or sarcoma
  • Define GIST tumor and differentiate it from mimics
  • Ki-67 according to IHC in the differential diagnosis of some intestinal neuroendocrine tumors

Evidence shows that the total number of gastric biopsies requiring special staining or IHC is approximately 20% of biopsies obtained and examined in the pathology practice. Specialist GI practices with a large GI referral base or consulting GI pathologists can sometimes exceed this relative number of specialty dyes/IHCs, but high routine use of specialty dyes or IHCs cannot be expected.

Excessive use of special dyes has also been observed in duodenal biopsies, where CD3 and AB/D-PAS are supposedly used to exclude intraepithelial lymphocytosis and gastric metaplasia. Both conditions, if present, are readily identifiable on H&E morphology. Mucin staining such as AB-PAS or DPAS would be warranted and necessary in limited circumstances, and CD3 is rarely proven in duodenal biopsies that show abnormalities in villous architecture.

Architectural and histological features define colonic polyps, including hyperplastic, inflammatory, and adenomatous lesions. Special stains and/or IHC stains are not warranted or required for colonic polyps, although textbooks note, for example, subepithelial collagen thickening as demonstrated by trichrome or collagen staining in hyperplastic polyps or overexpression of carcinoembryonic antigen (CEA) in hyperplastic polyps. While this information is of academic importance, special staining is not warranted and necessary to make a diagnosis of many colonic polyps.

Screening of Lynch syndrome tumors for DNA mismatch repair (MLH1, MSH2, MSH6, and PMS2) by qualitative IHC and/or microsatellite instability (MSI) is considered medically necessary and covered by Medicare for the following indications:

  • All persons diagnosed with colorectal cancer aged ≤ 70 years and persons aged > 70 years who meet the revised Bethesda GuidelinesLUB
  • People with endometrial cancer

No definitive LS screening algorithm has been recommended. However, if the IHC is performed first and it is abnormal, the MSI test is not warranted. If the IHC is normal, the MSI can be guaranteed. Lynch IHC Syndrome is a qualitative test and does not require tumor morphometry.

Special dyes and/or IHC for prostate pathologies

The accuracy of the pathological diagnosis of prostate cancer is critical to optimizing patient care. The diagnosis can usually be made on the basis of morphological features such as growth pattern, nuclear atypia, and absence of basal cells. However, it can be difficult to make a definitive diagnosis with routine H&E staining of small foci of cancer on needle biopsies because many benign conditions can mimic prostate cancer.

The immunohistochemical diagnosis of prostate cancer largely depends on the marker set, as an absolutely specific and sensitive prostate cancer marker has yet to be identified. These panels usually include at least one basal cell marker, such as high molecular weight cytokeratin (HMWCK) or p63, and a prostate cancer-specific marker, alpha-methyl-CoA racemase (AMACR). Although AMACR is considered a useful IHC marker for prostate cancer, due to non-standard immunostaining protocols, interpretation criteria and heterogeneous staining pattern, there is wide variation in the sensitivity and specificity of AMACR immunoreactivity in prostate biopsies. Furthermore, since AMACR expression has been demonstrated in high-grade PIN, atypical adenomatous hyperplasia/adenosis, and nephrogenic adenoma, it is recommended that AMACR be best limited to the evaluation of morphologically highly suspicious foci, where negative immunoreactivity of AMACR markers basal cells alone is insufficient for the diagnosis of cancer.

PTEN and MYC may provide some prognostic information, but neither is part of the standard care protocol and should not be routinely performed. The ERG is another IHC that is more likely to be found in cancer than benign tissue, but it does not add information to the conventional PIN4 test. Likewise, neuroendocrine markers such as IHC for synaptophysin may be indicated in cases of recurrent/metastatic prostate cancer that has undergone small cell transformation following hormone therapy. This last marker is only needed for high-grade undifferentiated tumors and should not be used routinely.

PIN4 is an IHC cocktail of CK5/14, p63 and P504S that is primarily used to differentiate between normal and neoplastic epithelial tissues. In prostate tissue, CK5 and CK14 are detected in basal cells of normal glands and in prostate intraepithelial neoplasia (PIN), a precursor lesion of prostate adenocarcinoma. However, CK5 and CK14 expression has not been identified in invasive prostate adenocarcinoma. P63 is detected in the basal epithelial nuclei of normal prostates, but is not expressed in malignant prostate tumors. As P504S (also known as AMACR) is not specific for prostate adenocarcinoma, the use of PIN4 is best limited to the evaluation of morphologically highly suspicious foci.

It is unreasonable or necessary to charge for IHC testing (single antibodies or antibody cocktails) in cases with morphologically negative cores. It is unreasonable or necessary to charge the IHC bill for a negative or suspected core needle biopsy when obvious prostate cancer is present in other cores. Although the pathologist may choose to confirm a suspected focus in one or more cores in the event that a cancer diagnosis has already been made, this is not a covered Medicare service because it does not provide the treating physician with any additional information that may be taken.

Prostate cases that may require legitimate and necessary IHC staining include, but are not limited to:

  • Unspecified/suspicious focus and no other nucleus is positive for cancer;
  • Single worrisome core with minimal percentage of tumor (approximately <5%);
  • Disturbing nuclei opposite the positive nucleus
  • In multiple biopsy with Gleason 3+3=6 in 1 part and small atypical astase proliferation (ASAP) suspect Gleason 3+3=6 in another part; the number of positive biopsy sites and the percentage of involvement of these sites may influence treatment options for active observation (AS), focal therapy, or surgery;
  • In a multiple biopsy with 4+3=7 or 4+4=8 cancer in one part and as soon as possible with suspected cancer of the same grade in another part; treatment is warranted because the stage of high-grade cancer affects treatment;
  • Identify tumor invasion of adjacent structures;
  • Identify the source of an undifferentiated/poorly differentiated tumor, such as bladder or prostate;
  • Other unexpected results where specific cell staining would be required

Prostate cases when there is ICHirrational and necessaryinclude the following elements:

  • In a multipart biopsy with cancer >3+4=7 in 1 part and suspected 3+3=6 cancer in other part(s) as soon as possible, as staining is unlikely to change treatment; Or
  • On a multipart biopsy with tumor >4+3=7 in 1 part and "atypical ethmoid lesion" (ACL) suspected intraductal carcinoma compared to invasive carcinoma, Gleason 4 pattern in different parts because intraductal carcinoma is almost always closely associated with high-grade invasive cancer.

International Society of Pathology (ISUP) recommendations state that there are currently no recommended IHC prognostic tests or molecular testsroutinelyperformed on biopsy or resection specimens.

The surgical histopathology report is expected to specify the specific blocks on which the IHC is performed, the reason for the IHC, specific markers, and whether a single antibody or a cocktail of antibodies is used. A mere statement in the histopathological report that says "IHC confirms the diagnosis" will not be considered reasonable and necessary.

Special stains and/or IHC for lung cancer

The diagnostic challenge of a lung biopsy can often require additional staining to define the tumor. There are two important points to consider in this regard:

  • Often, the diagnosis of squamous cell carcinoma can be made without the use of special dyes and
  • The diagnosis of NSCLC usually requires additional staining, but it is essential that the tumor tissue is carefully screened to allow the patient's sample to be tested for molecular markers (EGFR, ALK and others) when clinically indicated.

Experts in lung pathology recommend starting the evaluation of non-small cell carcinomas with a combination of IHC TTF-1 and p40 or p63. Often these two points are all that is needed to make a reasonable diagnosis and retain a sufficient tumor sample to complete molecular testing. In rare cases, several additional IHC or mucin stains may be required.


Ki-67 and MIB-1 monoclonal antibodies are directed against different epitopes of the same proliferation-associated antigen. These points are used to determine the rate of tumor proliferation. The Ki-67 antigen or protein (hereinafter referred to as Ki-67) is present during all active phases of the cell cycle (G1, S, G2 and mitosis), but not in resting cells (G0). By measuring the amount of tumor cells expressing Ki-67, it was possible to estimate DNA synthesis, which was comparable to a mitotic count done on a standard H&E slide. Furthermore, Ki-67/MIB-1 antibodies suffer from a lack of international standardization, which limits their clinical usefulness. This was noted above in the discussion of breast cancer.

The classification of neuroendocrine lung (NE) tumors is a stepwise process in which four categories of tumors are identified based on morphology, namely:

  • Typical carcinoid (TC),
  • atypical carcinoid (AC),
  • NE large cell carcinoma
  • Small cell lung cancer (SCLC).

Ki-67 has potential utility in a narrow range of lung pathological cases. In particular, it allows a better classification of atypical and typical lung carcinoids and neuroendocrine lung tumors with extensive crushing artifact. (As mentioned above, Ki-67 may be useful in classifying some intestinal neuroendocrine tumors.)

IHC Ki-67 has clinical utility in the treatment of lymphomas. The Ki-67 has several recognized uses, including:

  • Final confirmation of the diagnosis of any low-grade lymphoma. Several publications indicate a worse prognosis for follicular lymphomas that appear to be grade 1 or 2 but have high Ki-67 staining. Likewise, small lymphocytic lymphomas/CLLs with a high proliferative index ("pro-lymphocytic progression") may be better detected with Ki-67.
  • Distinguish between higher and lower grade mantle cell lymphoma. A small percentage of cases behave as low rather than medium, and the Ki-67 is the most accurate way to detect this subset. In addition, Ki-67 IHC tests help to distinguish the highly aggressive blastoid variant.
  • Recognition of the Burkitt portion and the Burkitt type as distinct from the diffuse large B-cell type. One of the most important eligibility criteria is a Ki-67 staining greater than 90%.
  • Myeloma plasma cell proliferation rate has long been recognized as one of the most accurate prognostic indicators.

IHC to profile tumor chemosensitivity and resistance

The hormone receptor status of ER, PR, and Her2 has demonstrated clinical utility in invasive breast cancer, as well as ER and PR, if appropriate, in breast cancer in situ. ER and PR are performed by IHC specifically for tamoxifen therapy. The Her2 test has proven clinically useful in esophageal and gastric cancer to determine response to trastuzumab. ER, PR, and Her2 testing to identify patients likely to respond to hormone therapy, biologics, or chemotherapy is covered by Medicare when clinically necessary for breast and gastric adenocarcinoma.

Likewise, the effectiveness of imatinib, a CD117 inhibitor, depends on the mutation status of CD117 expression (c-KIT mutation). IHC CD117 has proven clinical benefit for gastrointestinal stromal tumors (GIST), some advanced cutaneous nodular fibrosarcomas (DFSP), some lymphoblastic and myeloid leukemias, and mast cell tumors, and is covered by Medicare when clinically necessary.

However, the above IHC tests are distinctly different from the chemotherapy sensitivity and/or resistance test profiles offered by some laboratories to assist clinicians in selecting specific chemotherapeutic agents based on IHC antigen or protein expression in individual tumors. The purpose of these profiles is to select a drug or combination of drugs from a panel of drugs that the tumor expresses more and to avoid drugs that the tumor expresses less.

Neither ASCO nor NCCN has approved tumor profiling testing for IHC chemosensitivity. ASCO said "CSRA testing (chemosensitivity and resistance testing) is not recommended for selecting chemotherapeutic agents for individual patients outside of clinical trials." Although the NCCN Guidelines for Ovarian Cancer (Version 3.2014) state that “some NCCN member institutions use chemosensitivity/resistance testing and/or other biomarkers to make decisions about future chemotherapy when multiple equivalent chemotherapy options are available. the level of evidence is not sufficient (Category 3) to replace standard chemotherapy.” The NCCN Panel also concluded that in vitro chemotherapy susceptibility testing as part of a relapse chemotherapy regimen should not be recommended due to lack of demonstrated efficacy. These IHC panels include, but are not limited to, the following drug-specific biomarkers:

  • ALK for crixotinib, pemetrexed
  • Androgen receptor (AR) for goserelin, leuprolide, gonadorelin, flutamide, bicalutamide, abiraterone;
  • Androgenomic receptor for bicalutamide, flutamide, abiraterone and enzalutamide;
  • AREG dla cetuksymabu, panitumumabu
  • BRAF for venurafenib and dabrafenib
  • BRCA1 to cisplatin, carboplatin
  • cKIT dla sorafenibu, sunitynibu, imatynibu
  • cMET for erlotinib, gefitinib
  • Producer of EGFR gefitinib, panitumumab, erlotinib, cetuximab, FOLFIRIEGFRVIII
  • EGFRvIII, GNA11, GNAQ, IDH2 - for clinical trials
  • ER i PR dla tamoksyfenu, gefitynibu, toremifenu, fulwestrantu, letrozolu, anastrozolu, eksemestranu, octanu megestrolu, erlotynibu, panitumumabu, medroksyprogesteronu;
  • ERCC1 for oxaliplatin, cisplatin, carboplatin, CAPOX, FOLFOX
  • EREG dla cetuksymabu, panitumumabu
  • Her2 (ErbB2), PGP and TOP2A (topoisomerase IIA) for doxorubicin, liposomal-doxorubicin, epirubicin;
  • Her2 or labatinib; epirubicin, pertuzumab, trastuzumab, liposomal doxorubicin, doxorubicin,
  • KRAS products panitumumab, cetruximab, gefitinib, erlotinib, sorafenib
  • MGMT para temozolomida e dacarbazine
  • MRP1 for vinorelbine, vincristine, doxorfubicin, epirubicin, vinblastine, methotrexate
  • NRAS dla cetuksymabu, panitumumabu
  • PDGFRA for imatinib
  • PGP (also known as MDR1 and ABCB1) for doxorubicin, vincristine, vinblastine, eptoposide, liposomal doxorubicin, paclitaxel, docetaxel, vinorelbine, epirubicin;
  • PIK3CA para lapatinib, panitumumab, trastuzumab, cetuksimab, temsyrolimus
  • PTEN para getytynibu, cetuksymabu, erlotynibu, trastuzumabu, panitumumabu, ewerolimus, temsyrolimus
  • RET para vandetanibe
  • ROS1 for crizotinib
  • RRM1 para gemcitabine;
  • SPARC (monoclonal and polyclonal) for nab-paclitaxel;
  • TLE3, TUBB3 para docetaxel, paclitaxel;
  • TOPO1 para irinotecano, topotecano, FOLFIRI;
  • TS (thymidylate synthase or TYMS) for fluorouracil, capecitabine, and pemetrexed

Tumor chemosensitivity profiling panels, whether performed by IHC or chromogenic in situ hybridization (CISH), are not warranted or required for the reasons described above and are not Medicare-covered services.

It should be noted that some of these markers are legitimate biomarkers for specific drugs when performed by mutation analysis or FISH assay.

IHC for cervical/gynecological/bladder/kidney tumors

Several IHC dyes have found limited use in cervical, gynecologic, and urologic cancers. In unusual cases of cervical dysplasia, HPV markers or surrogate markers may be useful when a diagnosis cannot be made by conventional H&E staining. These markers are clearly not guaranteed and required for all biopsies. Claimed data indicate combinations of Gram, PAS, Ki-67, p16, and ProExC stains in all cervical biopsies from selected pathology offices and combinations of p53, Ki-67, CD20, and CD44 in bladder biopsies from selected pathology offices.

Likewise, staining is rarely needed to prove that an endometrial or ovarian carcinoma is a serous carcinoma or that a renal tumor is an oncocytoma or an eosinophilic or chromophobic renal carcinoma. The use of IHC staining in these circumstances requires proper documentation in the histopathology report, such as: "Since the histological differential diagnosis includes endometrioid carcinoma and serous carcinoma, I performed the xxx stain. The controls performed well and the results were positive, indicating that the tumor is yyy ."

IHC for Skin and Skin/Soft Tissue Lesions/Central Nervous System and Peripheral Nervous System

It is well known that most skin lesions are diagnosed with routine H&E slides. This also applies to most melanomas and other pigmented lesions. A minority of skin lesions require immunostaining (eg, atypical fibroids, Merkel cell lesions, lymphomas). The most common skin lesions (eg, seborrheic keratosis) do not require IHC staining. The use of IHC morphometric codes for skin lesions is incorrect.

Likewise, most soft tissue injuries do not require IHC or other "special" staining. Soft tissue masses may require staining (eg, smooth muscle differentiation into a malignant tumor), but most do not.

Many central nervous system and peripheral nervous system lesions can be easily diagnosed with routine staining. It is uncommon for a meningioma to require IHC. The basic role of the IHC in the case of CNS and peripheral nervous system lesions is to differentiate primary lesions from metastatic lesions.

IHC for bone marrow samples

Most bone marrow specimens are diagnosed with Wright-stained smears and H&E-stained slides with battery replacement iron stain. The use of IHC dyes can aid in the interpretation of cases where flow cytometry (FC) does not match the routine interpretation of slides, when flow cytometry was not obtained, or in the evaluation of cell types that were not detected or are significantly underrepresented in CF studies, such as large lymphocytes, plasma cells, and Reed-Sternberg cells. IHC staining is generally not required to confirm CF and cytogenetic results. In the case of medical indications, the justification for the use of both methods must be presented in the histopathological report and duly accounted for.

As published in CMS Publication IOM 100-08,Medicare Integrity Guide, Chapter 13, Section 13.5.4, an item or service may be covered by an LCD contractor if reasonable and necessary under section 1862(a)(1)(A) of the Social Security Act. Counterparties identify and describe the circumstances in which the item or service is considered reasonable and necessary.

summary of evidence

FCSO LCD L36234 Special Histochemical Stains & Immunohistochemical Stains was developed after Palmetto identified problems in their jurisdictions. This has been the subject of several investigations and the All-MAC working group recently. As discussed in the working group, five MACs (FCSO, Palmetto, WPS, Noridian and GCS) have LCDs installed. Each of the identified LCD screens contains similar content, with IHC coverage for breast, gastrointestinal and prostate pathologies, lung cancer, Ki-67/MIB-1, chemotherapy resistance and sensitivity profile, cervical/gynecologist/bladder tumors /kidney, skin cancer/soft tissue lesions/CNS/peripheral nervous system and bone marrow samples. FCSO LCD also provides more detailed coding guidance and documentation requirements. Each MAC LCA contains the same 7 CPT codes (88312, 88313, 88341, 88342, 88344, 88360 and 88361). No CID-10 code listed (no diagnostic procedure code edit). There is very little information about special histochemical stains, immunohistochemical stains or related procedure codes in the policies of major commercial payers (Aetna, Cigna, United Healthcare and Florida Blue).

Data analysis was carried out for the period from February 2021 to January 2022, and the most notable information obtained is the discrepancy between the settlement patterns of JN and JH/JL or the national average. Note that while JN has an LCD calculated for special histochemical and immunohistochemical stains, JH and JL do not.

Part A Discussion:

With one exception in each case, Part A JN either allows more benefits than the national average (except for CPT code 88360) or denies fewer benefits than the national average (the exception in this case is 88344). JN Part A services allowed for 1000 bene are very comparable to JH numbers. JN Part A services allowed at 1000 bene are generally lower than JL numbers. JN's bounce rate is comparable to JH's, with equivalent/slightly higher/slightly lower numbers. Exceptions are CPT code 88344 (JN refusal rate is 2.1% while JH is 0.5%) and CPT code 88361 (JN refusal rate is 0.2% while JH is 1.6%). The JN denial rate is equivalent to or less than JL for all CPT codes. With one notable exception, the allowed, rejected, and paid JN values ​​are significantly less than JH (outliers are the reject values ​​for 88344 [JN has a significantly higher reject value than JH] and 88361 [despite having fewer billed services, JN has a total amount paid greater than JH]). Allowed, rejected, and paid values ​​for JN are much lower than for JL.

Part B Discussion:

For JN Part B, CPT code 88361 is the only one of the 7 analyzed where JN Part B Part B allowed more and refused fewer services per good than the national average (for this specific JN Part B code allowed and refused less services than the national average). JN Part B services allowed at 1000 bene are mostly equivalent to or greater than JH Part B. JN Part B services allowed at 1000 are sometimes greater than JL (for 88312, 88341, 88342 and 88361) and sometimes less than JL (for 88313, 88344 and 88360). The JN denial rate is less than JH for all CPT codes except 88342. The JN denial rate is less than JL for all CPT codes. JN has a higher allowable and payable value for CPT codes 88312 and 88341 than JH. All other allowed, rejected, and paid amounts are less. JN has a higher allowed and paid amount for CPT codes 88312 and 88361 than JL, and a higher denied amount for CPT code 88361.

The identified inconsistencies reflect the fact that the JN Special Histochemical Stains & Immunhistochemical Stains LCD does not effectively save CMS dollars or prevent irregularities.

Analysis of evidence (justification of conclusion)

As discussed in the All-MAC Special Histochemical Stains & Immunhistochemical Stains working group discussion (2/16/22), no MAC uses procedural code editing for diagnosis; ). For both Part A and Part B of the JN, the allowable midpoints are much lower than the MUE value. For JN part A and part B, the highest usage of the listed procedure codes was for 88341 (with the highest number of services billed and the highest number of services allowed). That said, there is no record of misuse of procedural code. Furthermore, there are no concerns about access to care or health disparities; as there is no procedure to edit the diagnostic code, so reversing the LCD would not change the coverage.

Medical Review, Resources, ALJ, Prior Auth and UPIC were consulted without significant objections. Medical Review says it has no plans to revise the affected procedure codes; The references state that the only recent references to identified procedure codes were to duplicates; they were approved for execution according to the invoice. The ALJ reported that there was a hearing in January 2022 (CPT code 88342) using LCD L36234, but no further hearings are planned under the affected procedural codes. Pre-authorization does not report issues and the identified procedure codes are not on the current pre-authorization list. JN UPIC CMD Mark Pilley responded to the request on 4/13/22, noting that while the services included in this LCD are not being reviewed or investigated by your jurisdiction, should this be the case in the future, the LCD and its articles of billing and coding would be helpful in defining insurance coverage guidelines and supporting the medical review process. The Doctor. Pilley also pointed out that current LCDs and LCAs provide an appreciated level of detail.

However, there is concern that the level of detail presented on the Special Histochemical Stains & Immunhistochemical Stains LCD, as written, does not reflect the current standard of practice. There was no Evidence Summary or Evidence Analysis in the current LCD. All literature is from 2005-2015. The literature cited in LCD L36234 Special Histochemical Stains & Immunhistochemical Stains has been reviewed along with other MAC LCDs on the same topic. PubMed and Google Scholar were searched for important new peer-reviewed literature that would support continuation of services or withdrawal of LCD L36234 and its corresponding article. The search did not reveal any literature supporting LCD as is. An article by Dinehart et al. explicitly stated that "existing LCDs on the use of IHC in melanoma do not reflect the current state of practice".1Aside from the literature written prior to the establishment of the L36234 LCD, there is not enough new and relevant research to support the use of histochemical and immunohistochemical staining services. Overall, the literature (or lack thereof) supports the withdrawal of the L36234 LCD and its corresponding billing and encoding article.


What is the meaning of immunohistochemical stains? ›

(IH-myoo-noh-HIS-toh-KEH-mih-stree) A laboratory method that uses antibodies to check for certain antigens (markers) in a sample of tissue. The antibodies are usually linked to an enzyme or a fluorescent dye.

What are the results of immunohistochemical stain? ›

The IHC test gives a score of 0 to 3+ that measures the amount of HER2 receptor protein on the surface of cells in a breast cancer tissue sample. If the score is 0 to 1+, it's called HER2 negative. If the score is 2+, it's called borderline. A score of 3+ is called HER2 positive.

What are examples of immunohistochemical stains? ›

Common counterstains include hematoxylin, eosin, nuclear fast red, methyl green, DAPI, and Hoechst fluorescent stain. The following representative example, Hoechst fluorescent dye was used as a counterstain for IHC detection of the protein, vimentin.

What does a positive IHC mean? ›

A positive test means that a marker or receptor is found on the cell during the biopsy or indicates a certain change in the protein of the tumour. The positive result indicates that the person might have inherited a genetic condition.

What diseases can be diagnosed by immunohistochemistry? ›

Diagnosis of infectious diseases: IHC with specific antibodies against viruses, bacteria, fungi, and parasite antigens can detect and diagnose pathogenic microorganisms of many infectious diseases, such as hepatitis B virus (HBV), cytomegalovirus (CMV), and human nipples Tumor virus (HPV), herpes virus (HSV), hepatitis ...

What cancers are diagnosed using immunohistochemistry? ›

However, IHC tests are routinely used to help diagnose most types of breast cancer, including: Invasive breast cancer (when the cancer has spread within breast tissue) Metastatic breast cancer (when the cancer has spread to distant parts of the body)

What are the common immunohistochemical markers? ›

The essential immunohistochemistry panel recommended for the diagnosis and prognosis includes expression of the following markers: CK7; CK20; COX-2; TTF-1, chromogranin; synaptophysin, CD56; PSA; CA125; p53; c-erbB-2; MMP-9; and VEGF.

Why is immunohistochemistry staining important? ›

IHC allows specific tissue antigens to be recognized in a biopsy sample, and when used in conjunction with tumor morphology, can help lead us to a definitive diagnosis. For this test to be performed no additional samples need to be collected, as it is run on the original tissue sample.

What does it mean if immunohistochemical staining is positive for p16? ›

Positive immunostaining for the tumor suppressor protein p16 is associated with the presence of mucosal or alfa subtypes of human papillomavirus (HPV) in cervical and genital squamous cell carcinoma (SCC).

What is the most common histology stain? ›

Hematoxylin is the most commonly used nuclear stain in histology and pathology although, despite its long use and honorable history, the chemistry of the dye is still not fully understood.

What does her positive mean? ›

HER2-positive breast cancer is a breast cancer that tests positive for a protein called human epidermal growth factor receptor 2 (HER2). This protein promotes the growth of cancer cells.

What is the best IHC marker for multiple myeloma? ›

In addition, CD56 has a good positive predictive value for diagnosis of myeloma and correlates well with bone lesions and may be correlated with the pathogenesis of lytic lesions.

What are the indications for immunohistochemistry? ›

The main indications for IHC are: definition of histogenesis; differential diagnosis between reactive and neoplastic states; etiologic diagnosis of infectious diseases; determination of prognostic factors; determination of target therapy sites; location of primary tumors in malignant disease; determination of specific ...

How do you read a biopsy report? ›

Sections of Your Report
  1. Grade 1 or well-differentiated: Cells appear normal and are not growing rapidly.
  2. Grade 2 or moderately-differentiated: Cells appear slightly different than normal.
  3. Grade 3 or poorly differentiated: Cells appear abnormal and tend to grow and spread more aggressively.
Feb 16, 2022

What does a negative IHC test mean? ›

If your tumor, or tissue sample, does not show hormone receptors, you are ER-negative, PR-negative, or negative for both. In that case, hormone therapy will most likely not be helpful to you. IHC results for HER2 are reported as 0, 1+, 2+, or 3+. A score of 0, 1+, means the tumor is HER2-negative.

What are the two types of immunohistochemistry? ›

Immunohistochemistry (IHC) staining allows for 2 broad classes of detection: 1) chromogenic and 2) fluorescent.

Which immunohistochemical marker for squamous cell carcinoma? ›

p40, p63, cytokeratin 5/6 (CK5/6), and desmocollin-3 (DSC3) have been frequently used in the diagnosis of SQC.

How long does it take to get the results of a biopsy? ›

For most biopsy procedures, results are generally available within a few days to one week to 10 days.

Which immunohistochemical stain for squamous cells? ›

CK5/6 is the best marker for differentiating SCC and AC, irrespective of the histological grade of the tumor. Thus, the combination of CK5/6 and TTF-1 is the most recommended combination of immunohistochemical markers.

What are examples of tumor markers? ›

Tumor Markers in Common Use
  • ALK gene rearrangements and overexpression. ...
  • Alpha-fetoprotein (AFP) ...
  • B-cell immunoglobulin gene rearrangement. ...
  • BCL2 gene rearrangement. ...
  • Beta-2-microglobulin (B2M) ...
  • Beta-human chorionic gonadotropin (Beta-hCG) ...
  • Bladder Tumor Antigen (BTA) ...
  • BRCA1 and BRCA2 gene mutations.
May 11, 2021

Is immunohistochemistry a special stain? ›

An Introduction to IHC Staining

Where H&E and Special Stains are non-specific, IHC is directed to a specific protein marker or markers. IHC is used as a diagnostic tool to assist in the diagnosis of solid tumors and cytological specimens and has been used as a mainstream diagnostic tool for almost half a century.

What is the difference between immunohistochemistry and histochemistry? ›

In addition, hybridization histochemistry identifies cell bodies in which neuron-specific molecules are synthesized. In contrast, immunohistochemistry localizes sites of product accumulation which may be in cell processes distant from the cell body.

What are the three most common problem areas in IHC staining? ›

Different antibodies to the same target molecule can produce very different results, and therefore this choice is a critical one. In this review, I will focus on 3 common problems facing the diagnostic pathologist in the use of IHC: antibody selection, false-positive IHC signals, and false-negative IHC signals.

What is the most commonly used antibody for immunohistochemistry? ›

Both monoclonal and polyclonal antibodies can work in IHC. The key requirement is that the specific epitope of interest be exposed. One of the advantages of using a monoclonal antibody is that generally it is more specific, but this is associated with a higher likelihood that the one epitope it recognizes is buried.

What is the survival rate of p16 positive? ›

The 5-year overall survival (OS) was 73.0% in all patients with OPSCC (Fig. 1a), 93.9% in p16-positive patients, and 62.2% in p16-negative patients.

Is it better to be p16 positive or negative? ›

Outcomes for p16 positive, HPV negative oropharyngeal SCC are not significantly different from p16 positive, HPV positive tumors and are significantly better than for p16 negative tumors.

Is p16 negative good or bad? ›

p16 IHC can be used to screen a tumor using the same criteria as in the oropharynx. If it is negative, then one can conclude that the tumor is not related to transcriptionally active HR-HPV.

What is the most suitable stain for malignant cells? ›

H and E staining helps identify different types of cells and tissues and provides important information about the pattern, shape, and structure of cells in a tissue sample. It is used to help diagnose diseases, such as cancer. Also called hematoxylin and eosin staining.

What is the most common bacterial stain? ›

The Gram stain is the most common differential stain used in microbiology. Differential stains use more than one dye. The unique cellular components of the bacteria will determine how they will react to the different dyes. The Gram stain procedure has been basically unchanged since it was first developed in 1884.

What cancers are associated with HER2? ›

Cancers that may be HER2 positive include breast, bladder, pancreatic, ovarian, and stomach cancers. Also called c-erbB-2 positive and human epidermal growth factor receptor 2 positive.

What does it mean to be HER2 positive? ›

A positive test for HER2 means breast cancer may grow quickly and possibly come back (recur). This risk is significantly lowered with appropriate treatment. At the Abramson Cancer Center, we treat HER2-positive breast cancer with medications that work to slow or stop tumor growth.

How many cancers are HER2 positive? ›

About 15 out of every 100 breast cancers (about 15%) are HER2 positive. Testing breast cancer cells for the HER2 protein can help to show whether targeted drugs might work. Targeted cancer drugs are treatments that change the way cells work and help the body control the growth of cancer.

What is usually the first symptom of multiple myeloma? ›

What are multiple myeloma symptoms? Multiple myeloma causes many symptoms, but bone pain often is the first symptom people notice. Other symptoms include: Weakness in your arms and legs and/or a sensation of numbness in your arms and legs.

What are the red flags for multiple myeloma? ›

These 6 symptoms in turn cause other symptoms such as confusion or mental fogginess, nausea, constipation, weight-loss, loss of appetite, excessive thirst, fever and bruising.

What test confirms multiple myeloma? ›

Bone marrow biopsy

This test is required to confirm the diagnosis of multiple myeloma. A needle is inserted into the bone marrow space to remove a small sliver of bone marrow. Our hematopathologists examine the tissue under a microscope to determine if there are myeloma cells in the bone marrow.

Why is IHC test done for lymphoma? ›

IHC is essential in lymphoma diagnosis because the lymphocyte type (B or T cell) is indistinguishable on hematoxylin and eosin (H&E) stained slides.

What is immunohistochemical stain S100 positive? ›

S100 remains the most sensitive marker of melanocytic differentiation being diffusely positive in all benign and all primary and secondary malignant lesions including naevoid melanomas, and in most desmoplastic/spindle cell melanomas.

What cancers are S100 positive? ›

The role of S100 proteins has been widely examined in breast cancer, lung cancer, and melanoma, but pathologic S100 signalling could also be observed in additional cancer types, such as ovarian, colorectal, and pancreatic cancer.

What tumor is positive for S100? ›

Other S100P-positive tumor types that enter into differential diagnostic consideration with melanocytic lesions include various poorly differentiated carcinomas, selected histiocytic proliferations, malignant gliomas, peripheral nerve sheath tumors, and Langerhans' cell proliferations.

What disease is S100 protein? ›

S100 proteins, particularly calgranulins (S100A8, A9 and A12), play a major role in the mediation of the immune responses characteristic of a series of diseases, including inflammatory arthritis, atherosclerosis and microbial infections [61], as well as joint inflammation and cartilage degradation in patients with RA [ ...

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