Superseded Local Coverage Determination (LCD)

Special Histochemical Stains & Immunohistochemical Stains

L36234

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Superseded
To see the currently-in-effect version of this document, go to the section.

Contractor Information

LCD Information

Document Information

LCD ID
L36234
LCD Title
Special Histochemical Stains & Immunohistochemical Stains
Proposed LCD in Comment Period
N/A
Source Proposed LCD
DL36234
Original Effective Date
For services performed on or after 12/06/2015
Revision Effective Date
For services performed on or after 12/11/2022
Revision Ending Date
N/A
Retirement Date
N/A
Notice Period Start Date
10/27/2022
Notice Period End Date
12/10/2022
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Issue

Issue Description

Special stains are called “special” because they are dyes used to stain particular tissues, structures or pathogens such as bacteria that may not be visible by routine H&E staining. Likewise, IHC is a powerful tool for identifying substances and cells in tissue sections using the specificity of antigen-antibody reactions, where the antibody is linked to a colored indicator (stain) that can be seen with a microscope. This Special Histochemical Stains & Immunohistochemical Stains LCD identifies the medically necessary criteria for the use of special stains and/or IHC stains and addresses, based on claims review, the scenarios that may be driving medically unnecessary over-utilization or incorrect billing of these services. The services addressed in this LCD have recently been a topic of discussion among all the MACs. Through a literature review, it was identified that the LCD and Billing and Coding Article as written do not reflect the current standard of practice. Through data analysis, it was identified that the LCD and corresponding Billing and Coding Article also do not have a significant impact on Medicare expenditures. Therefore, this LCD and the corresponding Billing and Coding Article are being considered for retirement.

CMS National Coverage Policy

This LCD supplements but does not replace, modify or supersede existing Medicare applicable National Coverage Determinations (NCDs) or payment policy rules and regulations for Special Histochemical Stains & Immunohistochemical Stains. Federal statute and subsequent Medicare regulations regarding provision and payment for medical services are lengthy. They are not repeated in this LCD. Neither Medicare payment policy rules nor this LCD replace, modify or supersede applicable state statutes regarding medical practice or other health practice professions acts, definitions and/or scopes of practice. All providers who report services for Medicare payment must fully understand and follow all existing laws, regulations and rules for Medicare payment for Special Histochemical Stains & Immunohistochemical Stains and must properly submit only valid claims for them. Please review and understand them and apply the medical necessity provisions in the policy within the context of the manual rules. Relevant CMS manual instructions and policies may be found in the following Internet-Only Manuals (IOMs) published on the CMS Web site. 

Internet Only Manual (IOM) Citations:  

  • CMS IOM Publication 100-02, Medicare Benefit Policy Manual,
    • Chapter 15, Section 80.1 Clinical Laboratory Services and Section 80.6.5 Surgical/Cytopathology Exception
  • CMS IOM Publication 100-08, Medicare Program Integrity Manual,
    • Chapter 13, Section 13.5.4 Reasonable and Necessary Provision in an LCD 

Social Security Act (Title XVIII) Standard References:

  • Title XVIII of the Social Security Act, Section 1862(a)(1)(A) states that no Medicare payment shall be made for items or services which are not reasonable and necessary for the diagnosis or treatment of illness or injury. 
  • Title XVIII of the Social Security Act, Section 1862(a)(7). This section excludes routine physical examinations. 
  • Title XVIII of the Social Security Act, Section 1833(e) states that no payment shall be made to any provider for any claim that lacks the necessary information to process the claim. 

Federal Register References: 

  • Code of Federal Regulations (CFR), Title 42, Volume 2, Chapter IV, Part 410.32 Diagnostic x-ray tests, diagnostic laboratory tests, and other diagnostic tests: Conditions.

Coverage Guidance

Coverage Indications, Limitations, and/or Medical Necessity

This LCD does not designate specific special histochemical stains (aka special stains) and/or immunohistochemical (IHC) stains that should be used in the differential diagnosis of tissues or neoplasms because this information is readily available in text books and various scientific publications. This LCD identifies the medically necessary criteria for the use of special stains and/or IHC stains and addresses, based on claims review, the scenarios that may be driving medically unnecessary over-utilization or incorrect billing of these services including:

  • Reflex templates or pre-orders for special stains and/or IHC stains prior to review of the routine hematoxylin and eosin (H&E) stain by the pathologist; or
  • Use of special stains and/or IHC stains without clinical evidence that the stain is actionable or provides the treating physician with information that changes patient management, or
  • Use of added stains when the diagnosis is already known based on morphologic evaluation of the primary stain.

History/Background and/or General Information

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

Special stains are called “special” because they are dyes used to stain particular tissues, structures or pathogens such as bacteria that may not be visible by routine H&E staining. Special stains can identify whether a substance is present or absent, where the substance is located in the tissue specimen, and frequently, how many or how much of a substance is present. There are special stains to identify bacteria, yeast and fungi; for connective tissue, muscle, collagen, lipid and fibrin; for nuclei acids; and multi-purpose stains to identify basement membranes, mucins, and various other cellular constituents.

IHC is a powerful tool for identifying substances and cells in tissue sections using the specificity of antigen-antibody reactions, where the antibody is linked to a colored indicator (stain) that can be seen with a microscope. More than 400 distinct antibody targets are currently available with varying sensitivity and specificity for a given target. A major use of IHC is to identify poorly differentiated malignant neoplasms (tumors) such as a carcinoma, lymphoma, melanoma and sarcoma. Some IHC stains are useful in determining the primary site of a metastatic neoplasm, and others are used to guide specific therapies (e.g., Her2 IHC to determine potential response to trastuzumab).

Medical Necessity of Services Performed

There are many different relationships that exist in providing the provision of pathology services in the United States. Some physicians, groups, laboratories and hospitals submit global claims for the services described in this LCD. In other instances, there are separate individuals or entities providing the professional and the technical services. It is the obligation of each billing party to recognize that they are responsible for the medical necessity of the charges submitted. For example, when a physician or physician group bills for the professional component of services described in this LCD and another entity bills for the technical services, it is the obligation of each entity to independently assure the medical necessity of the services rendered and billed. 

Special Stains/IHC Medical Necessity

For information regarding additional tests that may need to be performed by the pathologist in relation to the original tests ordered by providers, please refer to CMS IOM Publication 100-02, Medicare Benefit Policy Manual, Chapter 15, Section 80.6.5 Surgical/Cytopathology Exception. 

Reflex templates or pre-orders for special stains and/or IHC stains prior to review of the routine hematoxylin and eosin (H&E) stain by the pathologist are not reasonable and necessary. A pathologist must first review the H&E stain prior to ordering special stains or IHC.

Exceptions do exist and are recognized standards of care in the practice of pathology. These exceptions include but are not limited to renal, liver, and neuromuscular biopsies, and for the suspicion of an infectious disease, particularly in an immune compromised patient. In certain clearly defined circumstances, it may be reasonable to perform some IHC on sentinel lymph nodes when the frozen sections show they are free of tumor.

IHC for Breast Pathology

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

Estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor 2 (Her2) are well- established prognostic markers in invasive breast cancer management. The triple negative breast carcinoma subtype (ER-/PR-/Her2-) has been associated with worse overall prognosis in comparison with other subtypes in study populations consisting of ethnic minorities and young women. 

Ki-67 expression is a biomarker for proliferation and has been associated with response to therapy, but methods of measurement are controversial. In December, 2013, the CAP reported that there is “a lack of consensus on scoring, definition of low versus high expression, an appropriate cut point for positivity, or which part of the tumor should be scored (e.g., leading edge, hot spots, overall average). There is also paucity of data on the effects of pre-analytical variables (e.g., ischemic time, length of fixation, antigen retrieval) on Ki-67 staining. For these reasons, routine testing of breast cancers for Ki-67 expression is not currently recommended by either ASCO or the NCCN." Consequently, Ki-67 is not reasonable and necessary for breast cancer and will not be covered by Medicare. 

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

In the absence of professional guidelines based on proven scientific literature, standing orders from clinicians for such tests as Ki-67 and EGFR on every breast cancer are not reasonable and necessary, and are not a covered Medicare service. 

In addition, basal phenotype markers (e.g., IHC for CK5) are not routinely necessary. Neither are IHC stains such as E-cadherin, p27, or high molecular weight cytokeratin to distinguish ductal from lobular differentiation necessary on every breast case, nor are myoepithelial cell markers such as p63 or smooth muscle myosin heavy chain necessary on every case. 

Special Stains and/or IHC for GI Pathology

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

Ordering special stains or IHC stains prior to review of the routine H&E stain is not reasonable and necessary. For most esophageal, gastric and duodenal specimens, it is not reasonable or necessary to perform special stains such as alcian blue – periodic acid Schiff (AB-PAS), or other mucin stains, such as diastase – PAS (D-PAS), or IHC stains such CDX-2 to determine if clinically meaningful intestinal metaplasia is present. In addition, it is not usually reasonable and necessary to perform special stains or IHC to determine the presence of H. pylori organisms. 

Other examples of special stains or IHC that are not reasonable and necessary on every specimen 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
  • Colon – CD3, p53 trichrome
  • Hyperplastic polyps – Ki67, CK20, p53, CEA, BRAF
  • Tubular or tubulovillous adenoma – Ki-67, CK20, CEA, p53, MMR 

If special stains or IHC are needed in addition to the routine H&E for gastric specimens, specific documentation to justify the medical necessity for the stain is required in the pathology report. Cases that may require special stains or IHC include but are not limited to the following:

  • Detection of H. pylori in an appropriate milieu when organisms are not seen on H&E stained slides;
  • Evaluating atrophic gastritis for evidence of autoimmune etiology and for enterochromaffin-like (ECL) cell hyperplasia/carcinoid tumor
  • Characterizing a carcinoma, lymphoma, melanoma or sarcoma
  • Defining a GIST tumor and to distinguish it from mimics
  • Ki-67 by IHC in the differential diagnosis of certain neuroendocrine tumors of the gut 

Scientific data demonstrates that the combined number of gastric biopsies requiring special stains or IHC is roughly 20% of biopsies received and examined in a pathology practice. GI specialty practices with a large GI referral base or GI consultant pathologists may sometimes exceed this relative number of special stains/IHC, but one would not expect to see routine high utilization of special stains or IHC. 

Over-utilization of special stains has also been observed with duodenal biopsies where CD3 and AB/D-PAS are reportedly used to help exclude intraepithelial lymphocytosis and gastric metaplasia. Both of these conditions, if present, are easily recognizable on H&E morphology. Mucin stains such as AB-PAS or DPAS would be reasonable and necessary in limited circumstances, and rarely is CD3 warranted on duodenal biopsies which show villous architectural abnormalities. 

Architectural and histologic features define colonic polyps including hyperplastic, inflammatory, and adenomatous lesions. Special stains and/or IHC stains are not reasonable and necessary for colon polyps despite text books noting, for example, thickened subepithelial collagen demonstrated by trichrome or collagen staining in hyperplastic polyps, or carcinoembryonic antigen (CEA) overexpression in hyperplastic polyps. While the information is of academic interest, special stains are not reasonable and necessary to make the diagnosis of various colonic polyps. 

Lynch Syndrome tumor screening 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 individuals with colorectal cancer diagnosed at age ≤70 years of age, and those >70 years of age who meet the revised Bethesda guidelines OR
  • Individuals with endometrial cancer 

No definitive algorithm for LS screening has been recommended. However, if IHC is done first and is abnormal, MSI testing is not warranted. If IHC is normal, MSI may be warranted. IHC testing Lynch syndrome is qualitative and does not require the use of tumor morphometry. 

Special Stains and/or IHC for Prostate Pathology

The accuracy of the pathologic diagnosis of prostate cancer is critical for optimal patient care. The diagnosis can usually be made on morphologic features such as growth pattern, nuclear atypia and the absence of basal cells. However, it may be difficult to reach a firm diagnosis by routine H&E stain for small foci of cancer in needle biopsies because many benign conditions can mimic prostate cancer. 

The immunohistochemical diagnosis of prostate cancer largely depends on panels of markers because no absolutely specific and sensitive marker for prostate cancer has yet been identified. These panels usually include at least one basal cell marker, such as high-molecular-weight cytokeratin (HMWCK) or p63, and the prostate cancer-specific marker, alpha-methyl-CoA-Racemase (AMACR). Although AMACR is considered a useful IHC marker for prostate cancer, because of non-standardized immunostaining protocols, interpretation criteria and heterogeneous staining pattern, there is wide variation in the sensitivity and specificity of AMACR immunoreactivity in prostate biopsies. Furthermore, because AMACR expression has been demonstrated in high-grade PIN, atypical adenomatous hyperplasia/adenosis and nephrogenic adenoma, it is recommended that AMACR is best restricted to the evaluation of morphologically highly suspicious foci in which negative immunoreactivity of basal cell markers alone is insufficient to establish a diagnosis of cancer. 

PTEN and MYC may provide some prognostic information but neither is part of any standard treatment protocol and neither should be routinely performed. ERG is another IHC that is more likely to be positive in cancer than in benign tissue, but it does not add information to conventional PIN4 testing. Similarly, neuroendocrine markers, such as IHC for synaptophysin, may be indicated in cases of recurrent/metastatic prostate carcinoma that have undergone small cell transformation after hormone therapy. The latter marker is only necessary for high grade, undifferentiated tumors and should not be used routinely. 

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

It is not reasonable and necessary to bill for IHC testing (either single antibody or antibody cocktails) on cases with morphologically negative cores. It is not reasonable and necessary to bill for IHC testing in a negative or a suspicious core biopsy when obvious prostate cancer is present in other cores. While the pathologist may choose to confirm a suspicious focus in one or more cores in a case where the diagnosis of cancer has already been made, it is not a Medicare covered service because it provides no additional actionable information to the treating physician. 

Prostate cases that may require reasonable and necessary IHC staining include but are not limited to the following: 

  • Indeterminate/suspicious focus and no other cores are positive for cancer;
  • Single worrisome core with minimal % tumor (roughly <5%);
  • Worrisome cores contralateral to a positive core
  • In a multi-part biopsy with Gleason 3+3=6 cancer in 1 part, and atypical small acinar proliferation (ASAP) suspicious for Gleason 3+3=6 cancer in other part(s); the number of positive biopsy sites and % core involvement of these sites can affect therapeutic choices for active surveillance (AS), focal therapy or surgery;
  • In a multi-part biopsy with 4+3=7 or 4+4=8 cancer in 1 part, and ASAP suspicious for the same grade cancer in other part(s); workup is justified since the extent of high grade cancer affects treatments;
  • Identify tumor invasion of adjacent structures;
  • Determine origin of undifferentiated/poorly differentiated neoplasm, such as bladder vs prostate;
  • Other unexpected results when specific cell stains would be necessary 

Prostate cases when IHC workup is Not Reasonable and Necessary include the following: 

  • In a multi-part biopsy with >3+4=7 cancer in 1 part, and ASAP suspicious for 3+3=6 cancer in other part(s), because stains are unlikely to change treatment; or
  • In a multi-part biopsy with >4+3=7 cancer in 1 part, and "atypical cribriform lesion" (ACL) suspicious for intra- ductal carcinoma versus invasive, Gleason pattern 4 cancer in other part(s), because intra-ductal carcinoma is almost always closely associated with invasive high-grade cancer. 

The International Society of Pathology (ISUP) recommendations state that at the current time, there are no prognostic IHC or molecular studies that are recommended to be routinely performed on biopsy or resection specimens. 

The surgical pathology report is expected to designate the specific block(s) upon which IHC testing is performed, the reason for IHC testing, the specific markers, and whether single antibody(ies) or a cocktail of antibodies is utilized. A statement alone in the pathology report that states “IHC confirms the diagnosis” will not be covered as reasonable and necessary. 

Special Stains and/or IHC for Lung Cancer

The diagnostic challenge of a lung biopsy can often prompt the need for additional stains to define the neoplasm. Two important considerations need to be considered in this regard: 

  • The diagnosis of squamous cell cancer can often be made without the use of any special stains, and
  • The diagnosis of non-small cell carcinoma often requires additional stains but it is essential that tumor tissue be carefully triaged to allow the patient’s sample to be tested for molecular markers (EGFR, ALK, and others) when clinically indicated. 

Experts in pulmonary pathology recommend starting the evaluation of non-small cell carcinomas with a combination of TTF-1 and p40 or p63 IHCs. Often these two stains are all that are needed to come to a reasonable diagnosis and retain enough tumor sample to complete molecular studies. In rare patients, a few additional IHCs or mucin stains may be needed. 

Ki-67/MIB-1

Ki-67 and MIB-1 monoclonal antibodies are directed against different epitopes of the same proliferation-related antigen. These stains are used to determine the proliferative rate of a tumor. Ki-67 antigen or protein (hereafter Ki-67) is present during all active phases of the cell cycle (G1, S, G2, and mitosis), but is absent from resting cells (G0). By measuring the amount of tumor cells expressing Ki-67, an estimate of DNA synthesis can be determined which has been found comparable to a mitotic count performed on a standard H&E slide. Furthermore, Ki-67/MIB-1 antibodies have suffered from a lack of international standardization which has limited their clinical usefulness. This is noted above in the discussion of breast cancers. 

Classification of lung neuroendocrine (NE) tumors is a step-wise process with four tumor categories being identified by morphology, namely: 

  • Typical carcinoid (TC),
  • Atypical carcinoid (AC),
  • Large cell NE carcinoma, and
  • Small cell lung carcinoma (SCLC). 

Ki-67 has potential usefulness in a narrow range of pathologic lung cases. Namely, it allows better classification of atypical and typical lung carcinoid tumors, and in pulmonary neuroendocrine tumors with extensive crush artifact. (As noted above, Ki-67 may be useful in the classification of some gut neuroendocrine tumors.) 

Ki-67 by IHC has clinical utility in the workup of lymphomas. Ki-67 has several established applications including: 

  • Final confirmation for the diagnosis of any low-grade lymphoma. A number of publications show a worse prognosis for follicular lymphomas which appear to be grade 1 or 2 but demonstrate high Ki-67 labeling. Similarly, small lymphocytic lymphomas/CLL with a high proliferative rate (“prolymphocytic progression”) may be best detected with Ki-67.
  • Distinguishing higher versus lower grade mantle cell lymphoma. A small percentage of cases behave as low grade rather than intermediate grade, and Ki-67 is the most accurate means to detect this subgroup. In addition, distinguishing the highly aggressive blastoid variant is aided by Ki-67 IHC testing.
  • Recognizing Burkitt and Burkitt-like grouping as distinct from diffuse large B-cell type. One of the most important qualifying criteria is Ki-67 labeling at greater than 90%.
  • Plasma cell myeloma proliferative rate has long been established as one of the most accurate prognostic markers. 

IHC for Chemosensitivity and Resistance Tumor Profiling 

ER, PR, and Her2 hormonal receptor status have demonstrated clinical utility in invasive breast cancer, as well as ER, and PR when appropriate, for in-situ breast cancer. ER and PR are performed by IHC specifically for tamoxifen therapy. Her2 testing has proven clinical utility in esophago-gastric and gastric cancers to determine response to trastuzumab. ER, PR and Her2 testing for the purpose of identifying patients likely to respond to hormonal therapy, biologics or chemotherapy is a covered Medicare service when medically necessary for breast and gastric adenocarcinoma. 

Similarly, the efficacy of imatinib, a CD117 inhibitor, is determined by the mutation status of CD117 expression (c- KIT mutation). CD117 by IHC has a proven clinical benefit in gastrointestinal stromal tumors (GIST), some advanced dermatofibrosarcoma protuberans (DFSP), some lymphoblastic and myeloid leukemias, and mast cell tumors, and is a covered Medicare service when medically necessary. 

However, IHC testing as above is distinctly different from chemotherapy sensitivity and/or resistance testing profiles offered by some labs to assist physicians in their selection of specific chemotherapeutic agents based on IHC antigen or protein expression in individual tumors. The goal stated by these profiles is to select a drug or combination of drugs from a panel of drugs to which a tumor has greater expression, and to avoid drugs to which the tumor has less expression. 

Neither the ASCO nor the NCCN has endorsed chemosensitivity tumor profile testing by IHC. ASCO has stated, "the use of CSRA's (chemosensitivity and resistance assays) to select chemotherapeutic agents for individual patients is not recommended outside of the clinical trial setting." While the NCCN's Guidelines for Ovarian Cancer (V3.2014) states "chemosensitivity/resistance and/or other biomarker assays are being used in some NCCN member institutions for decisions related to future chemotherapy in situations where there are multiple equivalent chemotherapy options available. The current level of evidence is not sufficient (Category 3) to supplant standard of care chemotherapy." The NCCN panel also stated that in vitro chemosensitivity testing as part of a chemotherapy regimen for recurrent disease should not be recommended due to lack of demonstrated efficacy. Such IHC panels include but are not limited to the following biomarkers for specific drugs: 

  • ALK for crixotinib, pemetrexed
  • Androgen receptor (AR) for goserelin, leuprolide, gonadorelin, flutamide, bicalutamide, abiraterone;
  • Androgen receptor for bicalutamide, flutamide, abiraterone and enzalutamide;
  • AREG for cetuximab, panitumumab
  • BRAF for venurafenib and dabrafenib
  • BRCA1 for cisplatin, carboplatin
  • cKIT for sorafenib, sunitinib, imatinib
  • cMET for erlotinib, gefitinib
  • EGFR for gefitinib, panitumumab, erlotinib, cetuximab, FOLFIRIEGFRVIII
  • EGFRvIII, GNA11, GNAQ, IDH2 – for clinical trials
  • ER and PR for tamoxifen, gefitinib, toremifene, fulvestrant, letrozole, anastrozole, exemestrane, megestrol acetate, erlotinib, panitumumab, medroxyprogesterone;
  • ERCC1 for oxaliplatin, cisplatin, carboplatin, CAPOX, FOLFOX
  • EREG for cetuximab, panitumumab
  • Her2 (ErbB2), PGP and TOP2A (topoisomerase IIA) for doxorubincin, liposomal-doxorubicin, epirubicin;
  • Her2 or labatinib; epirubicin, pertuzumab, trastuzumab, liposomal doxorubicin, doxorubicin,
  • KRAS for panitumumab, cetruximab, gefitinib, erlotinib, sorafenib
  • MGMT for temozolomide and dacarbazine
  • MRP1 for vinorelbine, vincrisxtine, doxorfubicin, epirubicin, vinblastine, methotrexate
  • NRAS for cetuximab, panitumumab
  • PDGFRA for imatinib
  • PGP (aka MDR1 and ABCB1) for doxorubicin, vincristine, vinblastine, eptoposide, liposomal doxorubicin, paclitaxel , docetaxel, vinorelbine, epirubicin;
  • PIK3CA for lapatinib, panitumumab, trastuzumab, cetuximab, temsirolimus
  • PTEN for getitinib, cetuximab, erlotinib, trastuszumab, panitumumab, everolimus, temsirolimus
  • RET for vandetanib
  • ROS1 for crizotinib
  • RRM1 for gemcitabine;
  • SPARC (monoclonal and polyclonal) for nab-paclitaxel;
  • TLE3, TUBB3 for docetaxel, paclitaxel;
  • TOPO1 for irinotecan, topotecan, FOLFIRI;
  • TS (thymidylate synthase or TYMS) for fluorouracil, capecitabine and pemetrexed 

Chemosensitivity profile tumor panels, regardless of whether it is performed by IHC or chromogenic in-situ hybridization (CISH), is not reasonable and necessary for the reasons cited above, and is not a Medicare covered service. 

Note, some of these markers are legitimate biomarkers for specified drugs when performed by mutation analysis or FISH testing. 

IHC for Cervical/Gyn/Bladder/Kidney Tumors 

A variety of IHC stains have found limited use in cervical, gynecologic, and urologic tumor settings. In unusual cases of cervical dysplasia, markers or surrogate markers for HPV may be useful where the diagnosis on conventional H&E stain cannot be made with certainty. These markers are clearly not reasonable and necessary on all biopsies. Claims data indicate combinations of gram stain, PAS, Ki-67, p16 and ProExC stains on all cervical biopsies from select pathology practices, and combinations of p53, Ki-67, CD20 and CD44 on bladder biopsies from select pathology practices. 

Similarly, it is rare to need stains to prove that an endometrial or ovarian cancer is a serous cancer or that a kidney neoplasm is an oncocytoma or an eosinophilic or chromophobic renal cell cancer. The use of IHC stains in these circumstances requires adequate documentation in the pathology report, such as “Because the differential histologic diagnosis is between an endometrioid carcinoma and a serous carcinoma, I performed an xxx stain. The controls worked appropriately and the results were positive indicating the tumor is a yyy.” 

IHC for Skin & Cutaneous/Soft Tissue/CNS & Peripheral Nervous System Lesions

It is well recognized that most skin lesions are diagnosed with routine H&E slides. That is the case for most melanomas and other pigmented lesions as well. A minority of skin lesions require immunostains (e.g., atypical fibroxanthomas, Merkel cell lesions, lymphomas). Most common skin lesions (e.g., seborrheic keratosis) do not require IHC stains. Use of IHC morphometric codes for skin lesions is incorrect coding. 

Similarly, most soft tissue lesions do not require IHC stains or other “special” stains. Soft tissue masses may require stains (e.g., smooth muscle differentiation in a malignant mass) but the most do not. 

Many CNS and peripheral nervous system lesions are readily diagnosed with routine stains. It is unusual for a meningioma to require an IHC. The primary role of IHC for CNS and peripheral nervous system lesions is to differentiate primary from metastatic lesions. 

IHC for Bone Marrow Samples 

Most bone marrow samples are diagnosed with the use of Wright’s stained smears and the use of H&E stained slides with an iron stain supplementing the battery. The use of IHC stains may assist in the interpretation of cases where flow cytometry (FC) does not fit with the routine slide interpretation, when flow cytometry was not obtained or for the evaluation of cell types that are not detected or significantly underrepresented in FC studies, such as large lymphocytes, plasma cells and Reed-Sternberg cells. IHC stains are generally not needed to confirm the results of FC and cytogenetic studies. When medically indicated, justification for the use of both methods must be stated in the pathology report and billed accordingly. 

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

Summary of Evidence

The FCSO LCD L36234 Special Histochemical Stains & Immunohistochemical Stains was established after Palmetto identified issues in their jurisdictions. It has recently been the topic of several inquiries and an All-MAC workgroup. As was discussed by the workgroup, five MACs (FCSO, Palmetto, WPS, Noridian, and GCS) have LCDs in place. Each of the LCDs identified contain similar content, with a discussion of IHC for breast, GI, and prostate pathology, lung cancer, Ki-67/MIB-1, chemosensitivity and resistance tumor profiling, cervical/gyn/bladder/kidney tumors, skin/soft tissue/CNS/peripheral nervous system lesions, and bone marrow samples. The FCSO LCD also offers more detailed coding guidance and documentation requirements. Each of the MACs LCAs contains the same 7 CPT codes (88312, 88313, 88341, 88342, 88344, 88360, and 88361). No ICD-10 codes are listed (no procedure-to-diagnosis code editing is in place). There is very little information about special histochemical stains, immunohistochemical stains, or the related procedure codes in policies from major commercial payers (Aetna, Cigna, United Healthcare, and Florida Blue).

Data analysis was conducted for the time period February 2021 through January 2022, and the most notable information obtained is the inconsistency of JN billing patterns vs JH/JL or the national average. It should be noted that while JN has an enumerated LCD regarding special histochemical and immunohistochemical stains, JH and JL do not.

Part A Discussion:

With one exception in each case, JN Part A is both allowing more services per bene than the national average (the exception being CPT code 88360), and denying less services per bene than the national average (the exception in this case being 88344). JN Part A services allowed per 1,000 bene are very comparable to JH numbers. JN Part A services allowed per 1,000 bene are lower overall than JL numbers. JN denial rate is comparable to that of JH, with numbers being equivalent/slightly higher/slightly lower. The exceptions to this are CPT code 88344 (JN denial rate is 2.1%, while JH's is 0.5%) and CPT code 88361 (JN denial rate is 0.2%, while JH's is 1.6%). JN denial rate is equivalent or lower than JL for all CPT codes. With one notable exception, JN amounts allowed, denied, and paid are significantly lower than JH (the outliers in question are amount denied for 88344 [JN has a significantly higher amount denied than JH] and 88361 [despite a lower number of services billed, JN has a higher total amount paid than JH]). JN amounts allowed, denied, and paid are all significantly lower than JL.

Part B Discussion:

For JN Part B, CPT code 88361 is the only one of the 7 analyzed that JN Part B was both allowing more and denying less services per bene than the national average (for that particular code JN Part B is both allowing and denying less services than the national average). JN Part B services allowed per 1,000 bene are, for the most part, equivalent or higher than JH Part B. JN Part B services allowed per 1,000 are sometimes higher than JL (in the case of 88312, 88341, 88342, and 88361) and sometimes lower than JL (in the case of 88313, 88344, and 88360). JN denial rate is lower than JH for all CPT codes except 88342. JN denial rate is lower than JL for all CPT codes. JN has a higher amount allowed and amount paid for CPT codes 88312 and 88341 than JH. All other amounts allowed, denied, and paid are lower. JN has a higher amount allowed and amount paid for CPT codes 88312 and 88361 than JL, as well as a higher amount denied for CPT code 88361.

The inconsistencies identified reflect that the JN Special Histochemical Stains & Immunohistochemical Stains LCD is not effectively saving CMS dollars or preventing aberrancies.

Analysis of Evidence (Rationale for Determination)

As discussed on the All-MAC Special Histochemical Stains & Immunohistochemical Stains workgroup call (2/16/22), no MAC is using procedure-to-diagnosis code editing, however there are multiple NCCI edits in place (edits based on HCPCS/CPT procedure code definition, or mutually exclusive procedures). For both JN Part A and Part B, average allowed stains per bene is significantly lower than the MUE value. For JN Part A and Part B, the highest utilization of the procedure codes listed was for 88341 (with the highest quantity of services billed and highest quantity of services allowed). That said, there is no noted procedure code utilization aberrancy. Furthermore, no concerns exist related to access of care or health disparities; because no procedure-to-diagnosis code editing is in place, therefore retiring the LCD would not change coverage.

Feedback was solicited from Medical Review, Appeals, ALJ, Prior Auth, and UPIC, with no significant concerns noted. Medical Review states they have no reviews planned for the impacted procedure codes; Appeals states the only recent appeals for the identified procedure codes were for duplicates; these were allowed for being performed as billed. ALJ reported there had been one hearing in January 2022 (CPT code 88342) utilizing LCD L36234, but there are no other hearings planned regarding the impacted procedure codes. Prior Auth reports no issues, and the identified procedure codes are not on the current prior authorization list. JN UPIC CMD Mark Pilley responded to the request on 4/13/22, indicating that while the services included in this LCD are not under review or being investigated by their jurisdiction at this time, should they be in the future, the LCD and its corresponding Billing and Coding Article would be helpful in determining coverage guidelines and supporting the medical review process. Dr. Pilley also indicated that the current LCD and LCA provide an appreciated level of detail.

However, a concern exists that the level of detail provided in the Special Histochemical Stains & Immunohistochemical Stains LCD as it is written does not reflect the current standard of practice. There was no Summary of Evidence or Analysis of Evidence in the current LCD. All literature is from 2005-2015. The literature cited in LCD L36234 Special Histochemical Stains & Immunohistochemical Stains was reviewed along with other MACs LCDs on the same topic. PubMed and Google Scholar were searched for new and valid peer-reviewed literature that would reinforce either the continuation of services or retirement of LCD L36234 and its corresponding article. The search did not reveal literature that was supportive of the LCD as it currently stands. One article by Dinehart et al. specifically stated that the “existing LCDs regarding IHC utilization in melanoma do not reflect the current state of practice.”1 Beyond literature written prior to the establishment of LCD L36234, there are not enough new and relevant studies supportive of the use of histochemical and immunohistochemical stain services. Overall, the literature (or lack thereof) supports the retirement of LCD L36234 and its corresponding billing and coding article.

General Information

Associated Information

Documentation Requirements

Please refer to the Local Coverage Article: Billing and Coding: Special Histochemical Stains & Immunohistochemical Stains (A57708) for documentation requirements that apply to the reasonable and necessary provisions outlined in this LCD.

Utilization Guidelines

Please refer to the Local Coverage Article: Billing and Coding: Special Histochemical Stains & Immunohistochemical Stains (A57708) for utilization guidelines that apply to the reasonable and necessary provisions outlined in this LCD.

Sources of Information
  1. Allred DC, et al. NCCN Task Force Report: Estrogen Receptor and Progesterone Receptor Testing in Breast Cancer by Immunohistochemistry. JNCCN 2009;7[Suppl 6]:S1–S21).
  2. Batts K, et Appropriate use of special stains for identifying Helicobacter pylori: recommendations from the Rodger C. Haggitt Gastrointestinal Pathology Society. Am J Surg Pathol 2013;37(11):e12-22.
  3. Burstein HJ, et al. American Society of Clinical Oncology clinical practice guideline update on the use of chemotherapy sensitivity and resistance assays. J Clin Oncol 2011;29:3328-30.
  4. CAP Cancer Biomarker Reporting Templates.  
  5. Chitkara Y. Upfront special staining for Helicobacter pylori in gastric biopsy specimens is not indicated. AJCP 2015;143:84-8.
  6. Epstein JL, et al: Best practices recommendations in the application of immunohistochemistry in the prostate: report from the International Society of Urologic Pathology consensus conference. Am J Surg Pathol 2014;38(8):e6-e19.
  7. Fitzgibbons PL, et al: Template for reporting results of biomarker testing of specimens from patients with carcinoma of the breast. Arch Pathol Lab Med 2014;138(5):595-601.
  8. Hartman DJ, et al. Are routine ancillary stains required to diagnose Helicobacter infection in gastric biopsy specimens? Am J Clin Path 2012;137:255-60.
  9. Lotan TL, Gurel B, Sutcliffe S, et al., PTEN protein loss by immunostaining: analytic validation and prognostic indicator for a high risk surgical cohort of prostate cancer patients. Clin Cancer Res 2011;17:6563-73.10.
  10. Morais C, Han JS, Gordetsky J, et al. Utility of PTEN and ERG immunostaining for distinguishing high-grade PIN and intraductal carcinoma of the prostate on needle biopsy. Am J Surg Pathol 2014;Dec 16. Epub.
  11. Pelosi G, et al: Ki-67 in lung neuroendocrine tumors. J Thorac Oncol 2014;9(3):273-84.
  12. Shah RB. Clinical applications of novel EGR immunohistochemistry in prostate cancer diagnosis and management. Adv Anat Pathol 2013;20:117-24.
  13. Smith SB, et al. Helicobacter pylori. To stain or not to stain? Am J Clin Path 2012;137:733-8.
  14. Travis WD, et al: Diagnosis of lung cancer in small biopsies and cytology: implications of the 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification. Arch Pathol Lab Med. 2013;137(5):668-84.
  15. Varma M, Jasani B. Diagnostic utility of immunohistochemistry in morphologically difficult prostate cancer: review of current literature. Histopathol. 2005;47:1-16.
  16. Wright CL, et al. The use of routine special stains for upper gastrointestinal biopsies. Am J Surg Pathol 2006;30:357-61.
  17. Yan S. Diagnostic role of immunohistochemistry in prostate cancer. CAP Newspath.
  18. Other sources for general information included websites for Medscape, Biological Stain Commission, National Comprehensive Cancer Network, and Carcinoid.
Bibliography
  1. Dinehart MS, Dinehart SM, Sukpraprut-Braaten S, High WA. Immunohistochemistry Utilization in the Diagnosis of Melanoma. Journal of Cutaneous Pathology. 2020;47(5):446-450. doi:10.1111/cup.13648

Revision History Information

Revision History DateRevision History NumberRevision History ExplanationReasons for Change
12/11/2022 R4

LCD posted for notice of retirement on 10/27/2022. LCD will be retired effective for dates of service on and after 12/11/2022.

This LCD is being retired secondary to data analysis and a review of the current literature, which revealed that the LCD and its corresponding Billing and Coding Article are neither reflective of the current standard of practice nor having a significant impact on Medicare expenditures.

6/9/2022 DL36234 Proposed LCD posted for comment.

  • Other (LCD being considered for retirement)
11/28/2019 R3

Revision Number: 3
Publication: November 2019 Connection
LCR A/B2019-075

Explanation of Revision: Based on Change Request (CR) 10901, the LCD was revised to remove all billing and coding and all language not related to reasonable and necessary provisions (“Bill Type Codes,” “Revenue Codes,” “CPT/HCPCS Codes,” “ICD-10 Codes that Support Medical Necessity,” “Documentation Requirements” and “Utilization Guidelines” sections of the LCD) and place them into a newly created billing and coding article. In addition, the Social Security Act, Code of Federal Regulations, and IOM reference sections have been updated and language from the CMS IOM was removed and instead the applicable manual reference was listed. The effective date of this revision is for claims processed on or after January 8, 2019, for dates of service on or after October 3, 2018.

At this time 21st Century Cures Act will apply to new and revised LCDs that restrict coverage which requires comment and notice. This revision is not a restriction to the coverage determination and therefore not all the fields included on the LCD are applicable as noted in this LCD.

  • Other (Revision based on CR 10901)
01/22/2019 R2

Revision Number: 2
Publication: February 2019 Connection
LCR A/B2019-007

Explanation of Revision: Based on review of the LCD, grammatical errors were corrected. In addition, the “Coverage Indications, Limitations, and/or Medical Necessity” section of the LCD was revised under subtitle “Special Stains and/or IHC for Prostate Pathology” to change “=3+4=7” to “≥3+4=7” and “=4+3=7” to “≥4+3=7”. The effective date of this revision is based on process date.

01/22/2019: At this time 21st Century Cures Act will apply to new and revised LCDs that restrict coverage which requires comment and notice. This revision is not a restriction to the coverage determination and therefore not all the fields included on the LCD are applicable as noted in this LCD.

  • Other (Revisions based on review)
03/08/2016 R1 Revision Number: 1
Publication: March 2016 Connection
LCR A/B2016-051

Explanation of Revision: Age requirement changed from ≤ 50 to ≤ 70 for Lynch Syndrome testing verbiage for Special Stains and/or IHC for GI Pathology under the ‘Special Stains/IHC Medical Necessity’ section. The effective date of this revision is for claims processed on or after 3/8/2016, for dates of service on or after December 6, 2015.
  • Provider Education/Guidance
  • Public Education/Guidance

Associated Documents

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Public Versions
Updated On Effective Dates Status
12/11/2022 12/11/2022 - 12/11/2022 Retired View
10/21/2022 12/11/2022 - N/A Superseded You are here
11/21/2019 11/28/2019 - 12/10/2022 Superseded View
Some older versions have been archived. Please visit the MCD Archive Site to retrieve them.

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