cpt code 88341, 88342, 88360

Procedure code and Description

88312 SPECIAL STAIN INCLUDING INTERPRETATION AND REPORT; GROUP I FOR MICROORGANISMS (EG, ACID FAST, METHENAMINE SILVER)

88313 SPECIAL STAIN INCLUDING INTERPRETATION AND REPORT; GROUP II, ALL OTHER (EG, IRON, TRICHROME), EXCEPT STAIN FOR MICROORGANISMS, STAINS FOR ENZYME CONSTITUENTS, OR IMMUNOCYTOCHEMISTRY AND IMMUNOHISTOCHEMISTRY

88341 IMMUNOHISTOCHEMISTRY OR IMMUNOCYTOCHEMISTRY, PER SPECIMEN; EACH ADDITIONAL SINGLE ANTIBODY STAIN PROCEDURE (LIST SEPARATELY IN ADDITION TO CODE FOR PRIMARY PROCEDURE)

88342 IMMUNOHISTOCHEMISTRY OR IMMUNOCYTOCHEMISTRY, PER SPECIMEN; INITIAL SINGLE ANTIBODY STAIN PROCEDURE

88344 IMMUNOHISTOCHEMISTRY OR IMMUNOCYTOCHEMISTRY, PER SPECIMEN; EACH MULTIPLEX ANTIBODY STAIN PROCEDURE

88360 MORPHOMETRIC ANALYSIS, TUMOR IMMUNOHISTOCHEMISTRY (EG, HER-2/NEU, ESTROGEN RECEPTOR/PROGESTERONE RECEPTOR), QUANTITATIVE OR SEMIQUANTITATIVE, PER SPECIMEN, EACH SINGLE ANTIBODY STAIN PROCEDURE; MANUAL

88361 MORPHOMETRIC ANALYSIS, TUMOR IMMUNOHISTOCHEMISTRY (EG, HER-2/NEU, ESTROGEN RECEPTOR/PROGESTERONE RECEPTOR), QUANTITATIVE OR SEMIQUANTITATIVE, PER SPECIMEN, EACH SINGLE ANTIBODY STAIN PROCEDURE; USING COMPUTER-ASSISTED TECHNOLOGY

Coverage Guidance
Coverage Indications, Limitations, and/or Medical Necessity

This policy 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 policy 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.


Background

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. H&E staining provides excellent detail required for tissue-based diagnosis and is NOT a separately billable service, as reimbursement for pathology services includes routine H&E staining. At least one lab has touted “acid hematoxylin” as a special stain for purposes of billing Medicare and private payers. Given that all hematoxylin stains are acidic and that this stain has never been recognized by the Biological Stain Commission, it is incorrect coding to present claims for this stain as a special stain. Hematoxylin and eosin (H&E) staining is included in the billing CPT code and is not a separately billable service.

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. Two major AMA CPT coding categories for special stains are recognized: One is specifically for microorganisms; the second code is for all other purposes (not microorganisms) and specifically excludes detection of enzyme 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 policy. In other instances, there are separate individuals or entities providing the professional (-26) and the technical services (-TC). 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 policy 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

The IOM, Benefit Policy Manual (CPT15, §80.6.5) specifies “…there may be additional tests, such as special stains, that the pathologist may need to perform, even though they have not been specifically requested by the treating physician/practitioner. The pathologist may perform such additional tests under the following circumstances:
Services are medically necessary so that a complete and accurate diagnosis can be reported to the treating physician/practitioner;

Results of the tests are communicated to and are used by the treating physician/practitioner in the treatment of the beneficiary; and

Pathologist documents in his/her report why additional testing was done.”


The above citation means that 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.

The medical necessity for the special stain or IHC studies, and the results of the stain or IHC, must be documented in the surgical pathology report.

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 Medicine 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 percent tumor (roughly <5 p="">
Worrisome core(s) contralateral to a positive core(s);

o 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;
o 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 lesson" (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 is choose 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, penetrexed

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.



Bill Type Codes:

Contractors may specify Bill Types to help providers identify those Bill Types typically used to report this service. Absence of a Bill Type does not guarantee that the policy does not apply to that Bill Type. Complete absence of all Bill Types indicates that coverage is not influenced by Bill Type and the policy should be assumed to apply equally to all claims.
N/A

Revenue Codes:

Contractors may specify Revenue Codes to help providers identify those Revenue Codes typically used to report this service. In most instances Revenue Codes are purely advisory. Unless specified in the policy, services reported under other Revenue Codes are equally subject to this coverage determination. Complete absence of all Revenue Codes indicates that coverage is not influenced by Revenue Code and the policy should be assumed to apply equally to all Revenue Codes.

N/A

CPT 81206, 81270, 81403, 81450 - BCR / ABL negative MYELOPROLIFERATIVE

Procedure codes and Description

Group 1 Codes:

81206 BCR/ABL1 (T(9;22)) (EG, CHRONIC MYELOGENOUS LEUKEMIA) TRANSLOCATION ANALYSIS; MAJOR BREAKPOINT, QUALITATIVE OR QUANTITATIVE

81207 BCR/ABL1 (T(9;22)) (EG, CHRONIC MYELOGENOUS LEUKEMIA) TRANSLOCATION ANALYSIS; MINOR BREAKPOINT, QUALITATIVE OR QUANTITATIVE

81208 BCR/ABL1 (T(9;22)) (EG, CHRONIC MYELOGENOUS LEUKEMIA) TRANSLOCATION ANALYSIS; OTHER BREAKPOINT, QUALITATIVE OR QUANTITATIVE

81219 CALR (CALRETICULIN) (EG, MYELOPROLIFERATIVE DISORDERS), GENE ANALYSIS, COMMON VARIANTS IN EXON 9

81270 JAK2 (JANUS KINASE 2) (EG, MYELOPROLIFERATIVE DISORDER) GENE ANALYSIS, P.VAL617PHE (V617F) VARIANT

81402 MOLECULAR PATHOLOGY PROCEDURE, LEVEL 3 (EG, >10 SNPS, 2-10 METHYLATED VARIANTS, OR 2-10 SOMATIC VARIANTS [TYPICALLY USING NON-SEQUENCING TARGET VARIANT ANALYSIS], IMMUNOGLOBULIN AND T-CELL RECEPTOR GENE REARRANGMENTS, DUPLICATION/DELETION VARIANTS OF 1 EXON, LOSS OF HETEROZYGOSITY [LOH], UNIPARENTAL DISOMY [UPD])

81403 MOLECULAR PATHOLOGY PROCEDURE, LEVEL 4 (EG, ANALYSIS OF SINGLE EXON BY DNA SEQUENCE ANALYSIS, ANALYSIS OF >10 AMPLICONS USING MULTIPLEX PCR IN 2 OR MORE INDEPENDENT REACTIONS, MUTATION SCANNING OR DUPLICATION/DELETION VARIANTS OF 2-5 EXONS)

81445 TARGETED GENOMIC SEQUENCE ANALYSIS PANEL, SOLID ORGAN NEOPLASM, DNA ANALYSIS, AND RNA ANALYSIS WHEN PERFORMED, 5-50 GENES (EG, ALK, BRAF, CDKN2A, EGFR, ERBB2, KIT, KRAS, NRAS, MET, PDGFRA, PDGFRB, PGR, PIK3CA, PTEN, RET), INTERROGATION FOR SEQUENCE VARIANTS AND COPY NUMBER VARIANTS OR REARRANGEMENTS, IF PERFORMED

81450 TARGETED GENOMIC SEQUENCE ANALYSIS PANEL, HEMATOLYMPHOID NEOPLASM OR DISORDER, DNA ANALYSIS, AND RNA ANALYSIS WHEN PERFORMED, 5-50 GENES (EG, BRAF, CEBPA, DNMT3A, EZH2, FLT3, IDH1, IDH2, JAK2, KRAS, KIT, MLL, NRAS, NPM1, NOTCH1), INTERROGATION FOR SEQUENCE VARIANTS, AND COPY NUMBER VARIANTS OR REARRANGEMENTS, OR ISOFORM EXPRESSION OR MRNA EXPRESSION LEVELS, IF PERFORMED

81455 TARGETED GENOMIC SEQUENCE ANALYSIS PANEL, SOLID ORGAN OR HEMATOLYMPHOID NEOPLASM, DNA ANALYSIS, AND RNA ANALYSIS WHEN PERFORMED, 51 OR GREATER GENES (EG, ALK, BRAF, CDKN2A, CEBPA, DNMT3A, EGFR, ERBB2, EZH2, FLT3, IDH1, IDH2, JAK2, KIT, KRAS, MLL, NPM1, NRAS, MET, NOTCH1, PDGFRA, PDGFRB, PGR, PIK3CA, PTEN, RET), INTERROGATION FOR SEQUENCE VARIANTS AND COPY NUMBER VARIANTS OR REARRANGEMENTS, IF PERFORMED

81479 UNLISTED MOLECULAR PATHOLOGY PROCEDURE


Coverage Indications, Limitations, and/or Medical Necessity


This policy provides coverage for multi-gene non-NGS panel testing and NGS testing for the diagnostic workup for myeloproliferative disease (MPD), and limited coverage for single-gene testing of patients with BCR-ABL negative MPD. MPD includes polycythemia vera (PV), essential thrombocytopenia (ET), and primary myelofibrosis (PMF).

For laboratories performing single gene technologies, a sequential genetic testing approach is expected. Once a positive result is obtained and the appropriate diagnosis is established, further testing should stop. Reflex testing to the next gene will be considered reasonable and necessary if the following sequence of genetic tests produce a negative result:

BCR-ABL negative test results, progress to #2

JAK 2, cv negative test results, progress to #3 or #4

JAK, exon 12 (JAK2 exon 12 is only done when PV is suspected)

CALR/MPD (CALR/MPD is only done when either ET or PMF is suspected; testing for CALR/MPD does NOT require a negative JAK2 exon 12, just a negative JAK2 V617F result)


Genetic testing of the JAK2 V617F mutation (81270) is medically necessary when the following criteria are met:
Genetic testing impacts medical management; and

Patient would meet World Health Organization’s diagnostic criteria for myeloproliferative disease (i.e. polycythemia vera, essential thrombocytopenia, primary myelofibrosis) if JAK2 V617F were identified.


Genetic testing of JAK2 exon 12 (81403), performed to identify PV, is medically necessary when the following criteria are met:
Genetic testing impacts medical management; and

Patient would meet World Health Organization’s diagnostic criteria for PV, if JAK2 exon 12 testing were positive; and

JAK2 V617F mutation analysis was previously completed and was negative.


Genetic testing of the CALR gene (81479) (only found in ET and PMF) is medically necessary when the following criteria are met:
Genetic testing impacts medical management; and

JAK2 V617F mutation analysis was previously completed and negative; and

Patient would meet World Health Organization’s diagnostic criteria for MPD (i.e. ET, PMF) if a clonal marker were identified.


Genetic testing of the MPD gene (81402) is medically necessary when the following criteria are met:
Genetic testing impacts medical management; and

JAK2 V617F mutation analysis was previously completed and negative; and

Patient would meet World Health Organization’s diagnostic criteria for MPD (i.e. ET, MPF) if a clonal marker were identified.


Note: In a single-gene sequential approach (not mandated by this policy), CALR would be a higher priority single gene test than MPD because:
CALR mutations is more prevalent than MPD mutations in ET/PMF patients; and

CALF mutations are reported to predict a more indolent disease course than patients with JAK2 mutations.


For laboratories performing next generation sequencing (NGS or “hotspot”) testing platforms: Molecular testing for BCR-ABL, JAK 2, JAK, exon 12, and CALR/MPD genes by NGS is covered as medically necessary for the identification of myeloproliferative disorders.

Background

Myeloproliferative Disorders

Myeloproliferative disorders are a group of conditions that cause abnormal growth of blood cells in the bone marrow. They include polycythemia vera (PV), essential thrombocytosis (ET), primary myelofibrosis (PMF), and chronic myelogenous leukemia (CML). The World Health Organization (WHO) further classifies PV, ET, and PMF as Philadelphia chromosome negative myeloproliferative neoplasms (MPNs). The diagnosis of an MPN is suspected based upon clinical, laboratory, and pathological findings (i.e. bone marrow morphology). MPNs are related, but distinct from, myelodysplastic syndromes (MDS). In general, MDS are characterized by ineffective or dysfunctional blood cells, while MPN are characterized by an increase in the number of blood cells.

Polycythemia Vera

Polycythemia vera is a chronic myeloproliferative disease characterized by increased hemoglobin, hematocrit, and red blood cell mass. There is an associated increased risk for thrombosis and transformation to acute myelogenous leukemia or primary myelofibrosis; however, patients are often asymptomatic. Criteria for a diagnosis of PV are based upon CBC and clinical features. The JAK2 V617F mutation is present in the vast majority of PV, accounting for approximately 90% of cases. Functionally similar mutations in JAK2 exon 12 account for most remaining cases of JAK2 V617F mutation-negative PV. Together, they are identified in 98% of PV cases and lead to high diagnostic certainty.

Among the proposed revised World Health Organization (WHO) criteria for diagnosis is presence of the somatic JAK2 V617F mutation or functionally similar exon 12 mutation. Absence of a JAK2 mutation, combined with normal or increased serum erythropoietin level, greatly decreases the likelihood of a PV diagnosis. WHO proposed revision criteria for PV do not address additional molecular markers, including CALR mutation status.

Essential Thrombocythemia

Essential thrombocythemia is a disorder of sustained increased platelet count. The majority of ET patients (60%) carry a somatic JAK2 V617F mutation, while a smaller percentage (5-10%) have activating MPD mutations. Revision to the WHO criteria for diagnosis of ET has been proposed and includes exclusion of PV, PMF, CML, myelodysplastic syndrome, or other myeloid neoplasm. Also included in the proposed major criteria for diagnosis is demonstration of somatic JAK2 V617F mutation or MPD exon 10 mutation 12. Proposed criteria additionally state that 70% of patients without a JAK2 or MPD mutation carry a somatic mutation of the calreticulin (CALR) gene. Among confirmed ET cases, mutations in CALR are more common than MPD. Positive CALR mutation status is suggested as indicating a more indolent course 5.

Primary Myelofibrosis

Primary myelofibrosis (PMF) is a rare disorder in which the bone marrow is replaced with fibrous tissue, leading to bone marrow failure. Clinical features are similar to ET. The approximate incidence is 1 in 100,000 individuals. Persons can be asymptomatic in the early stages of the disease. For such patients, treatment may not initially be necessary. Progression of the disease can include transformation to acute myeloid leukemia. Treatment is generally symptomatic and aimed at preventing complications.

Demonstration of a clonal marker is important for diagnosis. Somatic molecular markers in PMF patients are similar to those in patients with ET, and include JAK2 V617F, MPD, and CALR. Somatic mutations in JAK2 are identified in 50-60% of PMF cases, and MPD mutations in 10%. Mutations in CALR are less common than JAK2, but more common than MPD.

Molecular Genetic Testing 

One JAK2 gene mutation, V617K, is most commonly reported, occurring in over 90% of all polycythemia vera (PV) cases and about 50% of ET cases. Testing for JAK2 V617K gene mutations can be useful in diagnosis and is incorporated into the WHO’s diagnostic criteria for these conditions.

The thrombopoietin receptor MPD is one of several JAK2 cognate receptors and is considered essential for myelopoiesis. The mutation frequency of MPD mutations associated with myeloproliferative disorders is substantially less (<10 2008="" 3.="" a="" acquired="" an="" be="" british="" clonal="" committee="" criteria="" diagnostic="" disease="" e.g.="" et="" for="" gene="" genes="" group="" guideline="" health="" hematology="" identified.="" if="" in="" include="" indicated="" individuals="" jak2="" marker="" may="" meet="" modification="" mpd="" mutation="" mutations.="" myeloproliferative="" of="" or="" organization="" p="" pathogenetic="" presence="" recommended="" s="" standards="" testing="" than="" the="" therefore="" to="" were="" who="" world="" would="">Calreticulin (CALR) mutations have been identified in patients with myeloproliferative neoplasms and recent studies have investigated the utility of CALR mutation testing for the diagnosis and classification of myeloproliferative neoplasms. The mutations themselves are variable; however, generally focused in the exon 9 region.

Studies have shown that a significant proportion of patients with myeloproliferative neoplasms and normal JAK2 617F mutation testing have a CALR gene mutation. CALR mutations account for a large proportion of JAK2/MPD-negative ET and PMF cases. Approximately 60% of JAK2/MPD-negative ET patients are CALR-positive and 30% of JAK2/MPD-negative PMF patients are CALR-positive. Overall, CALR mutations are identified in approximately 21% of ET cases and 16% of PMF cases. CALR mutations have not been reported in PV case series 2.

For this reason, CALR gene testing may be indicated for individuals who would meet World Health Organization’s diagnostic criteria for myeloproliferative disease if a clonal marker were identified. Proponents have argued for revised WHO criteria that includes CALR mutation status in the classification system for ET and PMF 12. Current NCCN guidelines do not make recommendations for CALR genetic testing; however, these guidelines are specific to MDS and do not broadly address myeloproliferative neoplasms, such as ET or PMF. Somatic mutations in non-MDS genes, such as CALR, are listed as being associated with conditions that can mimic other myelodysplastic syndromes.

Aside from diagnostic utility, some research suggests distinct clinical outcomes associated with CALR mutation status; however, the findings have not been confirmed in other studies. It is suggested that ET patients with CALR mutations have lower polycythemic transformation rates, but not lower myelofibrotic transformation rate, compared with ET patients harboring a JAK2 mutation. Others reported a higher platelet count, younger age of diagnosis, lower leukocyte count, and decreased risk for thrombosis, compared with a JAK2 positive ET population 1. CALR-mutated ET has also been associated with better thrombosis-free survival and lower leukocyte counts; overall survival has been reported as not different among CALR mutated and non-mutated ET 2,15.

Although they are useful for establishing a diagnosis, the presence of specific clonal markers does not dictate treatment. Controversy exists generally regarding the treatment of asymptomatic individuals with ET. Some argue against treatment if there are no associated complications. In general, the main goal of treatment with PV and ET is to identify persons at high risk for thrombosis and prevent complications. Persons with PV and ET are determined to be at high-risk due to age >60 years and past history of thrombotic event(s). CALR mutational status is not currently used for risk stratification 11.

In summary, multiple studies have demonstrated the diagnostic value of CALR mutation status in a population of JAK2 and MPD negative patients with suspected ET and PMF. The presence of a somatic CALR mutation can prove useful in obtaining an accurate diagnosis. Emerging evidence suggests possible differences in clinical phenotype among the associated clonal markers, including CALR-positive ET cases. However, CALR mutation status is currently not incorporated into clinical risk stratification and more research is needed in this area.



ICD-10 Codes that Support Medical Necessity


ICD-10 CODE DESCRIPTION

C88.8 Other malignant immunoproliferative diseases
C92.10 Chronic myeloid leukemia, BCR/ABL-positive, not having achieved remission
C92.20 Atypical chronic myeloid leukemia, BCR/ABL-negative, not having achieved remission
C92.21 Atypical chronic myeloid leukemia, BCR/ABL-negative, in remission
C92.22 Atypical chronic myeloid leukemia, BCR/ABL-negative, in relapse
C93.10 Chronic myelomonocytic leukemia not having achieved remission
C94.40 Acute panmyelosis with myelofibrosis not having achieved remission
C94.41 Acute panmyelosis with myelofibrosis, in remission
C94.42 Acute panmyelosis with myelofibrosis, in relapse
C94.6 Myelodysplastic disease, not classified
D45 Polycythemia vera
D46.0 Refractory anemia without ring sideroblasts, so stated
D46.1 Refractory anemia with ring sideroblasts
D46.20 Refractory anemia with excess of blasts, unspecified
D46.21 Refractory anemia with excess of blasts 1
D46.22 Refractory anemia with excess of blasts 2
D46.A Refractory cytopenia with multilineage dysplasia
D46.B Refractory cytopenia with multilineage dysplasia and ring sideroblasts
D46.C Myelodysplastic syndrome with isolated del(5q) chromosomal abnormality
D46.4 Refractory anemia, unspecified
D46.Z Other myelodysplastic syndromes
D46.9 Myelodysplastic syndrome, unspecified
D47.1 Chronic myeloproliferative disease
D47.3 Essential (hemorrhagic) thrombocythemia
D47.4 Osteomyelofibrosis
D47.Z9 Other specified neoplasms of uncertain behavior of lymphoid, hematopoietic and related tissue
D47.9 Neoplasm of uncertain behavior of lymphoid, hematopoietic and related tissue, unspecified
D72.821 Monocytosis (symptomatic)
D72.829 Elevated white blood cell count, unspecified
D75.1 Secondary polycythemia
D75.81 Myelofibrosis
D75.89 Other specified diseases of blood and blood-forming organs
D75.9 Disease of blood and blood-forming organs, unspecified

CPT code 81479 - Molecular pathology procedure

Procedure Code and Descripiton

Group 1 Codes:

81479 UNLISTED MOLECULAR PATHOLOGY PROCEDURE

Coverage Indications, Limitations, and/or Medical Necessity


This LCD provides limited coverage for the GeneSight® Psychotropic (AssureRx Health, Inc, Mason, OH) gene panel. GeneSight® testing may only be ordered by licensed psychiatristsor or neuropsychiatrists contemplating an alteration in neuropsychiatric medication for patients diagnosed with major depressive disorder (MDD) (in accordance with DSM IV/V criteria) who are suffering with refractory moderate to severe depression (as defined by the 17-item Hamilton Rating Scale for Depression (HAM-D17) score of 14 or greater) after at least one prior neuropsychiatric medication failure.

Background

GeneSight® Psychotropic is a multiplex pharmacogenomic test involving the analysis of fifty alleles (SNPs) from six different genes and a clinical outcomes-based decision support modeling tool that weights the influence of the various alleles/SNPs with respect to thirty-two different psychotropic pharmaceutical agents. The test results in the differentiation of psychoactive drugs that are likely to be effective and well-tolerated by a particular patient versus those that are not. In multiple prospective clinical studies, the use of GeneSight® to guide neuropsychiatric pharmaceutical selection and prescription has demonstrated an increased patient response to treatment from 60% to 250% (as measured by the standardized 17-item Hamilton Rating Scale for Depression or HAM-17; response is defined as = 50% reduction in HAM-D17 score) versus unguided, empirical treatment (or treatment as usual).

GeneSight® has particular relevance for Medicare beneficiaries, 26% of whom experience a mental disorder each year. Additionally, six out of ten disabled Medicare beneficiaries (~3.7 million) under age 65, representing roughly 17% of all beneficiaries, have a diagnosis of mental disorder. Furthermore, the American Psychiatric Association (APA) recognizes depression as the most common mental disorder in people aged 65 and older. It frequently appears as a co-morbid symptom to other conditions and can even mimic the symptoms of dementia. As a group, seniors generally take more medications than other age groups, increasing their risk of drug-drug interactions and adverse drug events (ADEs).

The GeneSight® report segments and displays these psychotropic medications into three “traffic light” categories or “bins” - green, yellow and red. Based on the patient’s genetic make-up and the drug’s metabolic and therapeutic pathways, the green bin identifies drugs that will likely be well tolerated and efficacious for the tested patient; the yellow bin identifies drugs with an intermediate effect; and the red bin identifies drugs likely to be poorly tolerated and/or ineffective. The report also identifies common drug-drug interactions that are similarly influenced by the patient’s genetic composition.

Pine Rest Study 

The Pine Rest study was a prospective, patient- and rater-blinded, randomized controlled trial evaluating the clinical impact of GeneSight® on antidepressant selection and treatment outcomes in depressed outpatients (GeneSight®, N=25 vs treatment as usual (TAU), N=24). Patients were assessed for symptom improvement, remission and response from baseline (week 0) and at 2, 4, and 8 weeks, using the HAM-D17 rating.

Subjects in the GeneSight® arm had a greater average decrease in the 17-item Hamilton Rating Scale for Depression (HAM-D17) scores from baseline at 8 weeks (p = 0.30) and a higher response rate (p = 0.055) and significantly higher remission rate (p = 0.012) at any time point. Response rates in the GeneSight®-guided arm were 73% higher compared to the unguided TAU arm. Retrospective analysis of the TAU subjects at the end of the study after un-blinding and stratifying by GeneSight® results proved the clinical validity of GeneSight®, with 30% of subjects unknowingly on red bin medications showing a significant worsening of depressive symptoms in contrast to significant improvements in depressive symptoms experienced by 30% of subjects unknowingly on green bin medications (p = 0.07). Additionally, surveys from the treating clinicians revealed that the GeneSight® composite report had a significant influence on treatment decisions for 65% of the GeneSight® subjects.

Hamm Study

The Hamm Clinic prospective cohort study with two arms (GeneSight® (n = 22) vs. TAU (n = 22)) enrolled adult patients with a primary diagnosis of major depressive disorder utilizing DSM-IV criteria for depression not otherwise specified. GeneSight® subjects achieved greater reductions in depression symptoms between the baseline and the week 8 visits compared to TAU subjects using the Quick Inventory of Depressive Symptomatology – Clinician version (QIDS-C16) (p = 0.0024) and HAM-D17 (p = 0.042) ratings. Both the response and remission rate were more than doubled in the GeneSight® arm compared to the TAU arm. Upon unblinding the TAU group at the end of 8 weeks, TAU subjects were being prescribed significantly more red and yellow bin medications and less green bin medications compared to the GeneSight® guided subjects (p = 0.02).

La Crosse

In the La Crosse prospective cohort study (GeneSight® (n = 72) vs. TAU (n = 93)) at the Franciscan Skemp Hospital in La Crosse, Wisconsin, patients with a primary diagnosis of MDD or depression not otherwise specified with a minimum score of 14 on HAM-D17 were enrolled. Diagnosis was confirmed by checking the diagnosis reported in the physician clinical notes in the electronic medical record (EMR). Samples were collected at baseline in both arms, while only the physicians in the GeneSight® arm were provided with test results to inform treatment decisions. In addition to the prospective comparisons, retrospective analysis in the TAU subjects at the end of the study was implemented after un-blinding the GeneSight® results to test for clinical validity.

A greater reduction in depression scores from baseline to the week 8 visit was observed in the GeneSight® arm for all three measures of depression: QIDS-C16 (p < 0.0001), HAM-D17 (p < 0.0001), and PHQ-9 (p < 0.0001). In all measures, a faster reduction of symptoms was observed in the GeneSight® arm subjects compared to the TAU arm subjects (QIDS-C16 and HAM-D17 (p < 0.0001), PHQ-9 (p = 0.002)). The GeneSight® arm had a significantly higher remission rate based on the QIDS-C16 score (p = 0.03), and significantly higher response rates based on QIDS-C16 (p = 0.005), HAM-D17 (p = 0.03), and PHQ-9 (p = 0.01).

Physicians changed medications more often for subjects in the GeneSight®-guided group (57.9%) than the unguided group (25.9%) (p = 0.0007). Of the 15 GeneSight®-guided subjects classified in the red bin category at baseline, fourteen (93.3%) experienced a medication change or dose adjustment during the eight week study period, compared with 8 out of 18 subjects in the unguided group (44.4%) in the red bin category (p = 0.002). A significant association between bin status and outcome was observed within the unguided group (p = 0.028). Subjects classified in the red bin category had less improvement (11%) eight than those classified in the green or yellow categories (31.9%, p = 0.047), further demonstrating the deleterious effects of red bin medications on patient outcomes.

Dayton Study

This retrospective study, in collaboration with Union Health Services (UHS, a staff model HMO located in Chicago, Illinois), examined healthcare utilization in relation to medication categories (binning) using GeneSight®. Ninety-six patients previously diagnosed with a depressive disorder or anxiety disorder and treated with one of the medications included in the GeneSight® panel were included in the study. The GeneSight® bin assignments of patient psychiatric medications were compared to the medical records for patient medication prescriptions, healthcare utilization, medical absence days, and disability claims for the previous 12 months.

Subjects whose medication regimen included a medication in the GeneSight® red bin (“use with caution and more frequent monitoring”) had 69% more total healthcare visits (p = 0.005), 67% more general medical visits (p = 0.02), greater than 3-fold more medical absence days (p = 0.06), and greater than 4-fold more disability claims (p = 0.004) than subjects taking drugs in the green (“use as directed”) or yellow bin (“use with caution”). The mean healthcare utilization cost calculated for red bin subjects during the previous 12 month period was higher at $8,627, compared to $3,453 calculated for green bin subjects (p = 0.024) and $3,426 for yellow bin subjects (p = 0.027), yielding an average annual increase in healthcare cost of $5,188 for subjects on GeneSight® red bin medications.

Meta-analysis of GeneSight® Prospective 2-Armed Studies

In a meta-analysis of three prospective, 2-armed clinical trials (Pine Rest, Hamm, and La Crosse), use of the test to aid in therapeutic selection has improved patient responses to treatment by 73% on average, which is consistent with the results from each study individually, and is highly significant (p=0.004). These findings support the value of the GeneSight® test in improving patient outcomes.

Documentation Requirements

Documentation supporting the medical need for these tests, including substantiating documentation for the ICD-9 code(s) submitted, must be maintained in the patient’s medical record. In order to be considered medically necessary, the patient must have failed or currently be failing on at least one neuropsychiatric medication, and the healthcare provider must be contemplating an alteration in neuropsychiatric medication treatment. Prior medication failure and intent to alter medication course consistent with the test results must be documented in the patient’s medical record and noted with the test requisition.

ICD-10 Codes that Support Medical Necessity


ICD-10 CODE DESCRIPTION

F32.1 Major depressive disorder, single episode, moderate
F32.2 Major depressive disorder, single episode, severe without psychotic features
F32.3 Major depressive disorder, single episode, severe with psychotic features
F32.4 Major depressive disorder, single episode, in partial remission
F32.9 Major depressive disorder, single episode, unspecified
F33.1 Major depressive disorder, recurrent, moderate
F33.2 Major depressive disorder, recurrent severe without psychotic features
F33.3 Major depressive disorder, recurrent, severe with psychotic symptoms
F33.40 Major depressive disorder, recurrent, in remission, unspecified
F33.41 Major depressive disorder, recurrent, in partial remission
F33.9 Major depressive disorder, recurrent, unspecified

CPT code 83880 - Natriuretic peptide


Procedure Codes And Description

Group 1 Codes:
83880 NATRIURETIC PEPTIDE


Coverage Indications, Limitations, and/or Medical Necessity

Abstract:

B-type natriuretic peptide (BNP) is a cardiac neurohormone produced mainly in the left ventricle. It is secreted in response to ventricular volume expansion and pressure overload, conditions often present in congestive heart failure (CHF). Used in conjunction with other clinical information, measurement of BNP levels (either total or N-terminal) is useful in rapidly establishing or excluding the diagnosis or worsening of CHF in patients with acute exacerbation of dyspnea. Also, BNP levels determined in the first few days after an acute coronary syndrome or event (ACS) may be useful in the prediction of longer-term cardiovascular risk but this risk assessment does not change the management of ACS and is non-covered by regulation.

Indications:

BNP measurements may be considered reasonable and necessary when used in combination with other medical data such as medical history, physical examination, laboratory studies, and chest x-ray.

•to diagnose or to differentiate heart failure from other potential clinical conditions if the patient’s signs and/or symptoms are consistent with both heart failure and one or more other conditions, e.g., acute dyspnea in a patient with known or suspected pulmonary disease.

•to diagnose or differentiate worsening heart failure if use of the test replaces other diagnostic tests, such as chest film; and/or to confirm the diagnosis when other diagnostic tests are equivocal.

Limitations:

•BNP measurements must be assessed in conjunction with standard diagnostic tests, medical history and clinical findings. The efficacy of BNP measurement as a stand-alone test has not been established yet.

•BNP measurements for monitoring and management of CHF are non-covered. Treatment guided by BNP has not been shown to be superior to symptom-guided treatment in either clinical or quality-of-life outcomes.

•The efficacy but not the utility of BNP as a risk stratification tool (to assess risk of death, myocardial infarction or congestive heart failure) among patients with acute coronary syndrome (myocardial infarction with or without T-wave elevation and unstable angina) has been established. However, the assessment of BNP level has not been shown to alter patient management. The BNP is not sufficiently sensitive to either preclude or necessitate any other evaluation or treatment in this group of patients.

•Screening examinations are statutorily non-covered.


Bill Type Codes:

Contractors may specify Bill Types to help providers identify those Bill Types typically used to report this service. Absence of a Bill Type does not guarantee that the policy does not apply to that Bill Type. Complete absence of all Bill Types indicates that coverage is not influenced by Bill Type and the policy should be assumed to apply equally to all claims.

012x Hospital Inpatient (Medicare Part B only)
013x Hospital Outpatient
014x Hospital - Laboratory Services Provided to Non-patients
022x Skilled Nursing - Inpatient (Medicare Part B only)
023x Skilled Nursing - Outpatient
072x Clinic - Hospital Based or Independent Renal Dialysis Center
085x Critical Access Hospital
999x Not Applicable

Revenue Codes:

Contractors may specify Revenue Codes to help providers identify those Revenue Codes typically used to report this service. In most instances Revenue Codes are purely advisory. Unless specified in the policy, services reported under other Revenue Codes are equally subject to this coverage determination. Complete absence of all Revenue Codes indicates that coverage is not influenced by Revenue Code and the policy should be assumed to apply equally to all Revenue Codes.
Revenue codes only apply to providers who bill these services to the fiscal intermediary or Part A MAC.


0300 Laboratory - General Classification
0301 Laboratory - Chemistry
0520 Freestanding Clinic - General Classification
0521 Freestanding Clinic - Clinic Visit by Member to RHC/FQHC
0523 Freestanding Clinic - Family Practice Clinic
0525 Freestanding Clinic - Visit by RHC/FQHC Practitioner to a Member in a SNF (not in a Covered Part A Stay) or NF or ICF MR or Other Residential Facility



ICD-10 Codes that Support Medical Necessity


ICD-10 CODE DESCRIPTION

I11.0 Hypertensive heart disease with heart failure
I13.0 Hypertensive heart and chronic kidney disease with heart failure and stage 1 through stage 4 chronic kidney disease, or unspecified chronic kidney disease
I13.2 Hypertensive heart and chronic kidney disease with heart failure and with stage 5 chronic kidney disease, or end stage renal disease
I16.0 Hypertensive urgency
I16.1 Hypertensive emergency
I31.1 Chronic constrictive pericarditis
I42.0 Dilated cardiomyopathy
I42.5 Other restrictive cardiomyopathy
I42.8 Other cardiomyopathies
I50.1 Left ventricular failure
I50.21 Acute systolic (congestive) heart failure
I50.22 Chronic systolic (congestive) heart failure
I50.23 Acute on chronic systolic (congestive) heart failure
I50.31 Acute diastolic (congestive) heart failure
I50.32 Chronic diastolic (congestive) heart failure
I50.33 Acute on chronic diastolic (congestive) heart failure
I50.41 Acute combined systolic (congestive) and diastolic (congestive) heart failure
I50.42 Chronic combined systolic (congestive) and diastolic (congestive) heart failure
I50.43 Acute on chronic combined systolic (congestive) and diastolic (congestive) heart failure
I50.9 Heart failure, unspecified
J44.0 Chronic obstructive pulmonary disease with acute lower respiratory infection
J44.1 Chronic obstructive pulmonary disease with (acute) exacerbation
J45.901 Unspecified asthma with (acute) exacerbation
J98.01 Acute bronchospasm
R06.00 Dyspnea, unspecified
R06.01 Orthopnea
R06.02 Shortness of breath
R06.09 Other forms of dyspnea
R06.2 Wheezing
R06.82 Tachypnea, not elsewhere classified

CPT 22612, 22633, 22558, 22614 - LUMBAR SPINE

Procedure Codes and Description

Group 1 Codes:

22533 ARTHRODESIS, LATERAL EXTRACAVITARY TECHNIQUE, INCLUDING MINIMAL DISCECTOMY TO PREPARE INTERSPACE (OTHER THAN FOR DECOMPRESSION); LUMBAR

22534 ARTHRODESIS, LATERAL EXTRACAVITARY TECHNIQUE, INCLUDING MINIMAL DISCECTOMY TO PREPARE INTERSPACE (OTHER THAN FOR DECOMPRESSION); THORACIC OR LUMBAR, EACH ADDITIONAL VERTEBRAL SEGMENT (LIST SEPARATELY IN ADDITION TO CODE FOR PRIMARY PROCEDURE)

22558 ARTHRODESIS, ANTERIOR INTERBODY TECHNIQUE, INCLUDING MINIMAL DISCECTOMY TO PREPARE INTERSPACE (OTHER THAN FOR DECOMPRESSION); LUMBAR

22585 ARTHRODESIS, ANTERIOR INTERBODY TECHNIQUE, INCLUDING MINIMAL DISCECTOMY TO PREPARE INTERSPACE (OTHER THAN FOR DECOMPRESSION); EACH ADDITIONAL INTERSPACE (LIST SEPARATELY IN ADDITION TO CODE FOR PRIMARY PROCEDURE)

22612 ARTHRODESIS, POSTERIOR OR POSTEROLATERAL TECHNIQUE, SINGLE LEVEL; LUMBAR (WITH LATERAL TRANSVERSE TECHNIQUE, WHEN PERFORMED)

22614 ARTHRODESIS, POSTERIOR OR POSTEROLATERAL TECHNIQUE, SINGLE LEVEL; EACH ADDITIONAL VERTEBRAL SEGMENT (LIST SEPARATELY IN ADDITION TO CODE FOR PRIMARY PROCEDURE)

22630 ARTHRODESIS, POSTERIOR INTERBODY TECHNIQUE, INCLUDING LAMINECTOMY AND/OR DISCECTOMY TO PREPARE INTERSPACE (OTHER THAN FOR DECOMPRESSION), SINGLE INTERSPACE; LUMBAR

22632 ARTHRODESIS, POSTERIOR INTERBODY TECHNIQUE, INCLUDING LAMINECTOMY AND/OR DISCECTOMY TO PREPARE INTERSPACE (OTHER THAN FOR DECOMPRESSION), SINGLE INTERSPACE; EACH ADDITIONAL INTERSPACE (LIST SEPARATELY IN ADDITION TO CODE FOR PRIMARY PROCEDURE)

22633 ARTHRODESIS, COMBINED POSTERIOR OR POSTEROLATERAL TECHNIQUE WITH POSTERIOR INTERBODY TECHNIQUE INCLUDING LAMINECTOMY AND/OR DISCECTOMY SUFFICIENT TO PREPARE INTERSPACE (OTHER THAN FOR DECOMPRESSION), SINGLE INTERSPACE AND SEGMENT; LUMBAR

22634 ARTHRODESIS, COMBINED POSTERIOR OR POSTEROLATERAL TECHNIQUE WITH POSTERIOR INTERBODY TECHNIQUE INCLUDING LAMINECTOMY AND/OR DISCECTOMY SUFFICIENT TO PREPARE INTERSPACE (OTHER THAN FOR DECOMPRESSION), SINGLE INTERSPACE AND SEGMENT; EACH ADDITIONAL INTERSPACE AND SEGMENT (LIST SEPARATELY IN ADDITION TO CODE FOR PRIMARY PROCEDURE)

22800 ARTHRODESIS, POSTERIOR, FOR SPINAL DEFORMITY, WITH OR WITHOUT CAST; UP TO 6 VERTEBRAL SEGMENTS

22802 ARTHRODESIS, POSTERIOR, FOR SPINAL DEFORMITY, WITH OR WITHOUT CAST; 7 TO 12 VERTEBRAL SEGMENTS

22804 ARTHRODESIS, POSTERIOR, FOR SPINAL DEFORMITY, WITH OR WITHOUT CAST; 13 OR MORE VERTEBRAL SEGMENTS

22808 ARTHRODESIS, ANTERIOR, FOR SPINAL DEFORMITY, WITH OR WITHOUT CAST; 2 TO 3 VERTEBRAL SEGMENTS

22810 ARTHRODESIS, ANTERIOR, FOR SPINAL DEFORMITY, WITH OR WITHOUT CAST; 4 TO 7 VERTEBRAL SEGMENTS

22812 ARTHRODESIS, ANTERIOR, FOR SPINAL DEFORMITY, WITH OR WITHOUT CAST; 8 OR MORE VERTEBRAL SEGMENTS



Background: 

Initial management of low back pain can include rest, exercise program, avoidance of activities that aggravate pain, application of heat/cold modalities, pharmacotherapy, local injections, lumbar bracing, chiropractic manipulation, and physical therapy. When conservative therapy (non-surgical medical management) is unsuccessful after at least 3 to 12 months, depending on the diagnosis, lumbar spinal fusion (arthrodesis) may be considered for certain conditions.

This policy does not address:
Acute spinal fracture or neural compression after spinal fracture
Epidural compression or vertebral destruction from tumor or abscess
Spinal tuberculosis
Spinal debridement for infection (e.g., osteomyelitis)
Spinal deformity from idiopathic scoliosis over 40 degrees.
Progressive degenerative scoliosis

Surgical techniques to achieve lumbar spinal fusion are numerous, and include different surgical approaches (anterior, posterior, lateral) to the spine, different areas of fusion (intervertebral body,interbody), transverse process (posterolateral), different fusion materials (bone graft and/or metal instrumentation), and a variety of ancillary techniques to augment fusion.

Indications

Spinal stenosis for a single level (for example, L4-L5) with associated spondylolisthesis and symptoms of spinal claudication and radicular pain. These patients with associated spondylolisthesis can also have motor deficit and / or described (non-iatrogenic or iatrogenic) instability on pre-operative flexion and extension radiographs. The pain must represent a significant functional impairment despite a history of 3 months of conservative therapy (non-surgical medical management) as clinically appropriate addressing the following:

Activity lifestyle modification
Daily exercise
Supervised physical therapy (PT) (activities of daily living [ADLs] diminished despite completing a plan of care)
Anti-inflammatory medications, oral or injection therapy as appropriate, and analgesics.

Spondylolisthesis manifested by back pain with or without spinal claudication, radicular pain, motor deficit when ANY of the following criteria are met:
Confirmed progressive deformity usually Grade II or higher (slippage at 26% or greater)
Multilevel spondylolysis
Symptomatic low-grade spondylolisthesis associated with back pain and significant functional impairment despite a history of 3 months of conservative therapy (non-surgical medical management) as clinically appropriate.

Spondylolysis demonstrated on imaging studies (e.g., CT scan, MRI, bone scan, or discography) as the likely cause of pain.

Repeat lumbar fusion following prior fusion for associated spondylolisthesis (for example anterolisthesis) with all the following:

Recurrent symptoms consistent with neurological compromise
Significant functional impairment
Neural compression is documented by recent post-operative imaging
Unsuccessful improvement despite 3 months of clinically appropriate post-operative nonsurgical medical management
Patient had some relief of pain symptoms following the prior spinal surgery.

Treatment of pseudoarthrosis (i.e., nonunion of prior fusion) at the same level after 12 months from prior surgery and all of the following are met:
Imaging studies confirm evidence of pseudoarthrosis (e.g., radiographs, CT)
Unsuccessful improvement despite 3 months of clinically appropriate post-operative nonsurgical medical management
Patient had some relief of pain symptoms following the prior spinal surgery.

Limitations

Initial lumbar spinal fusion for degenerative disease of the lumbar spine is not considered medically necessary and is noncovered:

When performed with initial primary laminectomy/discectomy for nerve root decompression or spinal stenosis, without documented spondylolisthesis and/or spondylolysis.

***Spondylolishthesis and/or spondylolysis must be confirmed with appropriate pre-operative diagnostic imaging (e.g., plain film, CT, MRI, discography, bone scan, and/or gallium scan).

Percutaneous sacrioiliac minimally invasive joint stabilization for arthodesis (27279) can be indicated for the treatment of sacro-iliac joint (SIJ) pain for patients with low back/buttock pain who meet all of the following criteria:

* Diagnostic imaging studies that include all of the following:

plain radiographs and a CT or MRI of the SI joint that excludes the presence of destructive lesions (e.g. tumor, infection) or inflammatory arthropathy that would not be properly addressed by percutaneous SIJ fusion
ipsilateral hip plain radiographs to rule out osteoarthritis
lumbar spine CT or MRI to rule out neural compression or other degenerative condition that can be causing low back or buttock pain
* and, at least 80 percent reduction of pain for the expected duration of the anesthetic used following an image-guided, contrast-enhanced SIJ injection on two separate occasions



Bill Type Codes:

Contractors may specify Bill Types to help providers identify those Bill Types typically used to report this service. Absence of a Bill Type does not guarantee that the policy does not apply to that Bill Type. Complete absence of all Bill Types indicates that coverage is not influenced by Bill Type and the policy should be assumed to apply equally to all claims.
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Revenue Codes:

Contractors may specify Revenue Codes to help providers identify those Revenue Codes typically used to report this service. In most instances Revenue Codes are purely advisory. Unless specified in the policy, services reported under other Revenue Codes are equally subject to this coverage determination. Complete absence of all Revenue Codes indicates that coverage is not influenced by Revenue Code and the policy should be assumed to apply equally to all Revenue Codes.

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ICD-10 Codes that Support Medical Necessity


ICD-10 CODE DESCRIPTION
M43.00 - M43.19 - Opens in a new window Spondylolysis, site unspecified - Spondylolisthesis, multiple sites in spine
Q76.2 Congenital spondylolisthesis

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