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LCD Reference Article Response To Comments Article

Response to Comments: Special Histochemical Stains and Immunohistochemical Stains, L36353

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A54597
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Article Title
Response to Comments: Special Histochemical Stains and Immunohistochemical Stains, L36353
Article Type
Response to Comments
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10/15/2015
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Noridian’s Response to Provider Recommendations (for comment period ending 03/30/2015):

Response To Comments

Number Comment Response
1 There is no provision in the Medicare policy manual that requires review the H&E stain prior to ordering SS or IHC. Another commenter notes that obtaining special stains prior to viewing H&E slides is appropriate in select circumstances. A physician cannot reasonably establish the medical necessity to order additional testing for a patient until they have reviewed the initial test(s). The commenter has listed an example of a pulmonary lesion implying that pathologists should have the ability to order stains for AFB presumably before they have examined the pulmonary lesion’s histology. By commenter’s logic, if the pulmonary lesion were entirely cancer it would still be acceptable to order, interpret and bill for AFB (fungi and other infectious disease) stains in all such cases. Clearly such stains in this case are medically unnecessary. Exceptions do exist and are recognized standards of care in the practice of pathology. This includes but is not limited to the following:
  • Renal biopsies: Standard diagnostic interpretation of a kidney biopsy requires integration of the light microscopy (H&E, periodic acid Schiff (PAS), Masson trichrome, and Jones methenamine silver stain), immunofluorescence (IgA, IgG, IgM, C1q, C3, albumin, fibrinogen, kappa and lambda light chains), and electron microscopic findings together with the clinical and laboratory data for the patient.
  • Liver biopsies: Special stains are routinely pre-ordered for liver biopsies (trichrome, reticulin, Perl’s iron, and PAS with and without enzyme digestion), but the panel may vary according to the suspected etiology of liver disease.
  • Infectious disease: The suspicion of an infectious disease in an immunocompromised patient, where a delay in diagnosis may be life-threatening, is another exception.
2 The evidentiary requirements have not been met due to contradictory evidence, lack of consensus, and lack of practice guidelines. This policy was developed with extensive research and in concert with leading practicing pathologists with direct experience in conducting the testing addressed by this test. It included in its review and cited numerous published references, including published guidelines, in support of this LCD. The commenter cited no specific articles or guidelines that were in fact contrary to those in the policy and provided no scientific literature to refute any of the policy items. The policy was developed from claims review data showing a broad pattern of inappropriate use of special stains e.g. claims data that shows providers billing Ki-67 and p53 for 100% of ICD-9 211.3 (benign neoplasm of colon) cases, or providers billing excessive (36+) units of service for 88342 for 12 core biopsies without regards to whether prostate cancer is present or not. Additional patterns of excessive staining include the routine use of mucin stains in upper gastrointestinal biopsies when there is no medically indicated reason for doing so. These and other cases in our data are indications of routine non-medically necessary testing outside of any clinical guidance. This policy identifies those scenarios where published and standard clinical pathology practice is not being applied and not medically necessary testing is occurring.
3 It is a physician’s role in determining medical necessity for special services. Noridian agrees but in the full exercise of that responsibility expects the testing performed to be consistent with each clinical case and not patterned to always use every service regardless of the case before them. A pathologist is free to order any special stain or IHC that he/she desires. Ordering a stain does not establish medical necessity. Medical necessity is established when the scientific literature demonstrates the test result provides actionable information that improves patient outcomes. This is usually by prospective, randomized, preferably multi-center clinical trial. Any special stain or IHC without proven clinical utility is not reasonable and necessary (considered investigational) and thus, not a Medicare benefit. Consequently, testing breast lesions for Ki-67, EGFR, other single gene assays and multi-analyte analyses with or without algorithmic analysis, except where specifically covered by Noridian, are not Medicare benefits. This policy does not allow standing orders to facilitate efficiency or lab workflow. This is not an acceptable approach as it drives overutilization when a service is not medically reasonable and necessary. For example, a lab may choose to perform a mucin stain on every esophageal, gastric or duodenal biopsy to increase efficiency and/or workflow. However, the business decision does not constitute medical necessity. The peer reviewed and expert medical opinion is that a mucin stain is only rarely required to diagnose Barrett’s or intestinal metaplasia. Medicare should only be billed for those cases where medical necessity is indicated and documented in the report. Some pathology practices have developed reflex or algorithmic orders that allow additional testing when an initial test is specified as positive or negative. The formulation of evidence- based algorithms prevents the potential for overutilization and allows efficiency between the ordering provider and the pathologist, delivering results and planning treatment in the most efficient manner possible. Algorithms, based on sound medical evidence, can define the parameters for the pathologist to perform SS or IHC.
4 A commenter states that SS/IHC on all gastric biopsies are medically indicated. Citing unpublished data from their own facility, this commenter indicates that 9.3% of >82,000+ cases are positive for H pylori, and 11% of all cases had “atypical” histologic findings and would have been missed if they had not stained every case. The “atypical” features included absence of significant inflammation, presence of organisms in atypical locations (non-foveolar or surface location), presence of rare organisms (<10 per biopsy). They stated that “if stains had not been performed, these infections would have been missed”. However, the commenter has no information as to whether the patient was experiencing signs or symptoms of gastritis, or evidence that cases with atypical features are actually infections. Furthermore, the clinical significance of a few organisms in a histologically normal gastric mucosa is not known. Another commenter notes that KP Batts et al (Am J Surg Path 2013;37:e12-e22) correctly note that there is little utility on special stains if H pylori organisms are clearly identified on the H&E stain, and notes that the widespread availability of proton pump inhibitors has clearly altered the features of H. pylori infection. The commenter cites differing incidence of infection in the US and notes that the “20% incidence” in the policy is an oversimplification. Another commenter notes that “Palmetto and Noridian should recognize the reasonableness and medical necessity of IHC stains to detect or rule-out H. pylori, even when not detected on a routine H&E stain, and to acknowledge that special documentation in the pathology report for the use of IHC staining is not required.” As noted in each of our cited references, the routine use of special stains or IHC stains to document the presence or absence of H. pylori is not medically indicated. The literature is clear: Most cases of H. pylori infection can be diagnosed with routine H&E stains. (Since the publication of this LCD another article in the pathology peer-reviewed literature has been published to support this contention: Chitkara, Y: Upfront special staining for Helicobacter pylori in gastric biopsy specimens is not indicated. AJCP 143:84-88, 2015). In those less than common cases where the organisms are not seen (and the clinical and pathologic features suggest their presence), the pathologist can note in the report the necessity of the stain. No “special” documentation is required. An example of a reasonable report would be the following documentation taken directly from reports: “Because the patient has chronic active gastritis and I could not identify H. pylori on H&E stains, an IHC was done and many organisms were found.” Templates or standing orders for special stains and/or IHC stains result in overutilization of services, and are not reasonable and necessary. The American Gastroenterological Society working group is addressing this issue and related issues later this month. As with any Medicare policy, this policy is subject to reconsideration based on sound scientific data to support changing the policy.
5 The MolDX Contractor is using documentation requirements as a proxy for defining when care is “reasonable and necessary, “likely because it is unable to clearly define actual coverage criteria.” Noridian, through this policy, has clearly defined coverage criteria. Noridian recognizes that the practice of pathology is both an art and a science. Noridian recognizes there are differing levels of skill among pathologists and within this policy has provided significant clinical leeway to allow a provider to exercise their best clinical discretion in the selection of SS and IHC. Medicare expects that these decisions be documented in the medical record to support the testing performed. This policy is addressing those practitioners whose claim data shows may be performing testing that is outside or beyond any reasonable medical necessity.
6 The deviation of this draft LCD from the standard format presents unique challenges in interpreting and commenting on it, as well as in applying it to the practice of pathology. This policy is consistent with and constructed according to Medicare requirements. It provides extensive discussion by organ group to make the material relevant to each case scenario. In very simple terms there are two key points that summarize the policy:
  • Standing orders (templates based on tissue origin) for special stains and/IHC prior to review of the H&E stain are not reasonable and necessary.
  • The use of special stains and/or IHC when the diagnosis is already known based on morphologic evaluation is not reasonable and necessary.
There is nothing in this policy prohibiting a pathologist from ordering any clinically indicated and medically reasonable stain.
7 A commenter noted that the current NCCN guidelines, while emphasizing the importance of ER status in DCIS, also endorses CAP’s cancer protocol, which still specifies performance of both ER and PR in cases of DCIS. The commenter requested inclusion of PR IHC in cases of DCIS. In in situ breast lesions, the importance of ER has been established and if the ER is negative it is appropriate to test for PR.
8 A commenter expressed concern that the draft LCD does not consistently articulate the circumstances in which the SS or IHC stains would be considered reasonable and medically necessary. Examples from the commenter are as follows:
  • “In the section entitled “IHC for Breast Pathology”, the LCD notes that orders for Ki- 67, EGFR, basal phenotype markers and IHC stains (e.g., E-cadherin) on every breast cancer are not reasonable and necessary.”
  • 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 benefit.”
  • “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 as myoepithelial cell markers such as p63 or smooth muscle myosin heavy chain necessary on every case.”
  • In the section on GI pathology, the LCD notes that “it is not usually reasonable and necessary to perform SS and / or IHC to determine the presence of H. pylori organisms” but then notes examples where SS or IHC are not reasonable and necessary on every specimen.
The commenter requests an outline of the circumstances in which the use of services would be reasonable and necessary with the diagnosis of breast cancer or for GI pathology. 		In anticipation of the above comments, the policy specifies in the “Purpose of Policy” section that appropriate use of SS and IHC are “readily available in text books and various scientific publications.” This policy identifies SS and IHC that are NOT appropriately performed for all specimens for a variety of tissues. This policy identifies by tissue type a number of examples of services for which there is no medical necessity for SS and/or IHC staining. Data from Medicare claims together with medical record review illustrates inappropriate testing and billing:
  • Hyperplastic polyp - Ki-67 and p53; or Ki-67, CK20 and p53;
  • Tubular adenoma – CK7, CK20 and CEA;
  • Tubular and tubulovillous adenoma – Ki-67 and CK20;
  • Cervical biopsy – PAS, Gram stain, Ki-67 and proexC stain;
  • Duodenal biopsy – AB-PAS and CD-3; AB, PAS and CD-3; or AB, PAS, CD3, and trichrome;
  • Bladder – p53, Ki-67, CK20 and CD44;
  • Colon cancer – EGFR;
  • Prostate – 12 core biopsies; billing 36 UOS for 88342 regardless of whether all cores are positive or all cores are negative; or multiple IHC combinations including HMWCK and/or PIN on multiple cores even though they already have >5% CA by volume on at least 1 core.
9 The commenter requests revision of the LCD to give more specificity to the circumstances in which SS/IHC serves are medically necessary by adding ICD-9 codes that meet the criteria for medical necessity. Automated edits will not be used to deny claims so it is not necessary to add ICD-10 codes. This policy articulates the Medicare program’s expectation of medical necessity and puts providers on notice regarding the SS/IHC requirements for performing and documenting medical necessity. It is intended to assist reviewers and other regulatory authorities in their reviews of providers.
10 A commenter objected to the inclusion of the following statement in the LCD and asked for its removal: 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. This commenter states that the Social Security Act does not authorize Medicare contractors to establish in an LCD the expected frequency of an item or service across a population of Medicare beneficiaries. The commenter also said that “Medicare coverage of an item or service is not determined based on the frequency with which a health care provider or practitioner furnishes an item or service.” The commenter worries that a Medicare auditor might use this value as “a high water mark”. This policy is reiterating the scientific literature and is not establishing a frequency limit. Medicare reviewers do recognize and understand that a practice might have a particular referral base that necessitates greater or less percentages of staining. However, it should give providers billing SS or IHC on 80-100% of their gastric biopsies reason to pause.
11 The commenter said “We do not agree that coverage for testing for the prostate-specific marker alpha-methyl-CoA-racemace (AMACR) should be limited to only those cases of highly suspicious foci in which negative IHC of basal cell markers alone is insufficient to establish a diagnosis of cancer…. We hope that the final LCD will recognize that AMACR testing has broader utility than is suggested in the draft LCD.” The MolDX Contractor and Noridian recognize wide variation in sensitivity and specificity of AMACR immunoreactivity in prostate biopsies due to non-standardized immunostaining protocols, interpretation criteria and heterogeneous staining patterns. The statement 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” is a quote from the CAP Immunohistochemistry Committee (Yan S. Diagnostic Role of Immunohistochemistry in Prostate Cancer. CAP Newspath; http://www.cap.org/apps/docs/newspath/0708/immunohistochemistry_in_prostate_cancer.pdf), and cited by others (Varma M, Jasani B. Diagnostic utility of immunohistochemistry in morphologically difficult prostate cancer: review of current literature. Histopathol. 2005;47:1–16.)
12 “PTEN is emerging as a promising prognostic biomarker in prostate cancer, and Palmetto should acknowledge that it may be appropriate to test for the gene in some circumstances. There are numerous published studies that have shown that PTEN loss in prostate cancer is associated with poor clinical outcome [Lotan, 2011]), and when utilized in the appropriate clinical context. Even though PTEN is not currently the standard of care, when utilized in the appropriate clinical context, it can provide useful information to a urologist about prostate cancer risk stratification, and it can facilitate better treatment decisions.” Additionally, it has “value in differentiating borderline difficult lesions of high-grad PIN from intraductal carcinoma [Morais, 2014]. Finally, since the measurement of PTEN loss by IHC has been shown to be sensitive and specific surrogate of underlying genomic deletions, PTEN measurement by IHC provides a more cost-effective approach than a traditional FISH approach.” A commenter argues that ERG has “low sensitivity but high specificity for prostate cancer detection. Where a high-grade PIN is ruled out, ERG positivity in small atypical glands can be used to confirm a prostate cancer diagnosis [Shah, 2013].” Lotan and co-authors validated IHC as a method to interrogate PTEN status but recognize that the utility of this test requires future multicenter studies and clinical trials. Morais and co-authors note that PTEN loss is common in intraductal carcinoma but very rare in high-grade PIN. They note that “if confirmed in large prospective studies, these results suggest that PTEN and ERG immunostaining may provide a useful ancillary assay to distinguish intraductal carcinoma from high-grade PIN in this setting.” Shah summarizes ERG testing by noting that “with availability of highly specific anti-ERG monoclonal antibodies, there is now the unprecedented opportunities to explore and validate clinical applications of ERG antibody in routine pathology practice, which has just started.” The citations provided by the commenter to support coverage have failed to identify evidence of clinical utility in each citation. In fact, each has recognized that large clinical trials to establish clinical utility are needed. Consequently, due to the absence of clinical utility, PTEN, ERG and/or other molecular markers are considered investigational and not a Medicare benefit.
13 A commenter disagreed with the statement in the policy that flow cytometry (FC) and IHC markers are frequently duplicative. The commenter notes that the “flow cytometry allows simultaneous analysis of individual cells with multiple markers but lacks the morphologic context of IHC. In addition, there are circumstances in which cells either are underrepresented (e.g., plasma cells by flow analysis) or need additional contextual information (such as coexpression of aberrant antigens by flow cytometry, or CD7 expression by CD34 positive blasts). Furthermore, IHC stains provide the pathologist with the ability to ascertain the “location” of cells of interest and to assess the degree of marrow involvement and tumor burden accurately.” The commenter states that the draft policy contradicts the NCCI policy manual: “The physician may report both codes [for IHC and flow cytometry] if both methods are required because the initial method does not explain all the light microscopic findings.” The commenter requested that the MolDX Contractor/Noridian recognize that the use of flow and IHC in the same case may sometimes be necessary. Another commenter notes that the most common situations in which performance of the same marker by IHC and flow cytometry (FC) may be necessary for diagnosis is in the evaluation of cell types that are frequently not detected or significantly underrepresented in FC studies, such as large lymphocytes, plasma cells and Reed-Sternberg cells. The commenter notes that “although testing by both methods should be an uncommon occurrence, it is sometimes necessary, and thus should be reimbursed when appropriately used… and expect that in cases where both IHC and FC for the same marker are used, the justification for use of both methods be stated in the pathology report.” Claims review and history, particularly from reference labs, frequently show where the same marker(s) are performed by IHC and FC on every case without any documentation in the report for such testing. The MolDX Contractor and Noridian agree with the commenter that sometimes flow cytometry and IHC may be used in the same case, and that the justification must be stated in the pathology report. The policy has been changed to reflect this information.
14 The commenter notes that Ki-67 is included in the most recent CAP biomarker template (CAP, December, 2014), and indicates that the LCD stops short of stating that the use of special stains or IHC to identify such biomarkers are not covered Medicare services. A commenter requested affirmation that the decision to use a particular staining method for expression of a biomarker for a particular patient remains with the pathologist reviewing the specimen. Inclusion of a biomarker in the CAP template does not establish clinical utility or coverage by Medicare. The CAP’s biomarker protocol notes that Ki-67 is optional and is not currently recommended for all carcinomas. CAP notes “there is also a paucity of data on the effects of pre-analytic 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 National Comprehensive Cancer Network (NCCN). Ki-67 will be added as a non-covered test by Medicare for breast cancer.
15 A commenter notes that pathologists should not be reporting results of IHC if the controls do not work appropriately. In no other area of a modern hospital laboratory does a comment about routine, daily quality controls appear in patient reports. Agree. Report of “control” results has been removed for the policy.
16 A commenter urges withdrawal of this policy. This policy will not be withdrawn.
17 A commenter provided references on the potential usefulness of the Ki-67 stain in a narrow range of pathologic cases. Specifically, the commenter noted that in some cases of atypical and typical carcinoid tumor of the lung, the Ki-67 stain allows better classification of the tumor. Similarly, in cases of pulmonary neuroendocrine tumors with extensive crush artifact, the Ki-67 may allow for a better classification of the tumor. References were provided that demonstrate that in biopsies of certain neuroendocrine tumors of the gut, the Ki-67 labeling index is helpful. (Note: In each of these cases, an "eyeball estimate" is adequate and quantitative morphometry (CPT codes 88360/88361) is not required.) The literature does support the use of Ki-67 by IHC (CPT code 88342) in a narrow range of neuroendocrine tumors. The LCD has been altered to reflect this data.
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Keywords

  • Special
  • Histochemical
  • Stains
  • Immunohistochemical

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