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Response to Comments: MoPath: Special Histochemical Stains and Immunohistochemical Stains

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Response to Comments: MoPath: Special Histochemical Stains and Immunohistochemical Stains
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Response to Comments
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The following are comments CGS Administrators received during open comment, 06/17/2015 to 08/03/2015, for draft LCD DL35986 MoPath: Special Histochemical Stains and Immunohistochemical Stains.

Response To Comments

Number Comment Response
1

A commenter complained that the draft LCD:

  • Tells you what is not covered but does not tell you what is covered;
  • Uses terms such as “rarely” and usually are difficult to interpret when applied in day to day practice;
  • Provides no single ICD mentioned as to what is covered;
  • Serves to create confusion among practitioners;
  • Notes numerous scientific assertions in the LCD do not reflect the totality of medical evidence and consensus.
 CGS and MolDX will not be establishing automated edits to deny claims so it is not necessary to add ICD-9 codes. This policy articulates the Medicare program’s expectation of medical necessity and puts providers on notice regarding the requirement of medical necessity for special stains (SS) and immunohistochemical (IHC) staining. It is intended to assist reviewers and other regulatory authorities in their reviews of providers who have established template pre-orders for SS/IHC regardless of medical necessity and inappropriate ordering of SS/IHC for purposes of renumeration.
2 Leave the determinations of what special stains and immunohistochemical stains need to be performed to the pathologist because we are abreast of new research in our field. The LCD encroaches on the pathologists' medical judgment to order the appropriate number of stains based upon the patient tissue characteristics. There is a lack of clarity within the LCD when and under what circumstances special stains can be ordered by a pathologist. This lack of clarity leaves the provider with no method to be able to determine prospectively when a special stain may be ordered to determine the correct diagnosis in a case. In the full exercise of that responsibility, CGS and MolDX expect the testing performed to be appropriate for a clinical case, and not patterned to always use every service regardless of the case before them. A pathologist is free to order SS/IHC according to established medical practice (medical necessity) for a given specimen. Ordering a stain does not establish medical necessity. Medical necessity is established when the scientific literature demonstrates the test result provides clinically useful information that improves patient outcomes. This is usually by prospective, randomized, preferably multi-center clinical trials. 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 indicated are not Medicare benefits. This policy does not allow standing orders to facilitate efficiency or lab workflow. Standing orders (ordering a stain before seeing the biopsy or specimen) 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 (or any payer) 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.
3 The evidence for the medical overutilization is not cited so the premise of this document has not been substantiated. The similar concern applies to the assertion of incorrect billing. This policy was developed with extensive research and in concert with leading practicing pathologists (CAP & AMP members) 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. 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, and providers billing excessive (36+) units of service for 88342 for 12 core biopsies without regards to whether prostate cancer is present or not. These are just two examples of many. 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. The complainer asserts there is a lack of national consensus on whether to routinely perform mucin stains on gastrointestinal biopsies or H. pylori stains on gastric biopsies. This complaint is without foundation. All of the nation’s leading gastrointestinal pathologists agree that the routine use of mucin stains in gastrointestinal biopsies is not indicated and only rarely needed. 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.
4 In the case of small specimens it is essential that any slides for special stains be cut serially with the H&E sections, to assure that morphological features can be correlated with staining characteristics, and to avoid loss of tissue in refacing the block. It is a matter for medical judgment by the pathologist whether the likelihood of need for the special studies and/or the need for expeditious management of the patient merits special staining prior to review of the H&E sections. In some instances this pre-ordering of special stains and/or immunohistochemical studies is performed to avoid an unnecessary delay in patient care. IHC stains may also be proactively ordered after the review of core biopsy touch imprint cytology preparations that may be used to assess adequacy of a specimen at the time of invasive cancer biopsies and after the review of frozen section samples. This is performed to provide improved diagnostic turnaround time. This may actually be lifesaving, in the clinical example of superior vena cava syndrome, as an example. The ASCO/CAP HER2 guidelines dictate the HER2 be performed on all recurrent breast cancers. Medical liver biopsies and medical renal biopsies require special stains to fully evaluate the tissue and patient diagnosis is not delayed by providing the stains available at the same time as the hematoxylin and eosin stained section. The extent of the use of these techniques must be left up to the medical judgment of the pathologist responsible for rendering a diagnosis on a patient beneficiary as they are the sole responsible party to provide the most complete evaluation possible on what may be a very limited tumor sample. Additional examples are provided in the various comments on the specific subsections of this document. A physician cannot reasonably establish the medical necessity to order additional testing for a patient until they have reviewed the initial test(s) 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. Even in this circumstance, however, it is prudent to review the H&E slide prior to performing the special stains. For example, the liver biopsy may contain a tumor and not hepatocellular disease. It would not be appropriate to stain a tumor for trichrome or iron or other “liver” stains when a tumor is found.
  • Infectious disease: The suspicion of an infectious disease in an immunocompromised patient or when the treating physician is highly suspicious of infectious etiology, where a delay in diagnosis may be life-threating.
5 The meaning of the words in the context of an LCD is unclear. The contents of the proposal do not fit into the context of the definition of an LCD. The proposal also discusses what stains and immunohistochemical studies should not usually be billed, but there is minimal discussion as to what is covered. The opening sentence in the policy indicates that appropriate indications for use of special stains and IHC are addressed in textbooks and scientific articles. The purpose of this policy is to address inappropriate utilization of these ancillary stains.
6 The policy also states that, “A major use of IHC is to identify the type and origin of poorly differentiated malignant neoplasms (tumors) as carcinoma, lymphoma, melanoma and sarcoma.” This statement suggests that the rather crude diagnostic subclassification is the only medically necessary level of specificity required or desirable by Medicare recipients. This is an error of oversimplification of the diagnostic process. The commenter doesn’t understand pathology or the use of stains.
7 While it is true that CAP, ASCO and NCCN do not recommend routine performance of Ki-67 or gene assays in all patients, those organizations have not stated that these markers have no role in patient management. The statement in the LCD that these markers have no role in patient evaluation is thus a misrepresentation of the opinion of the above organizations. 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 (eg, 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 is not covered by Medicare for breast cancer.
8 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). The guidelines and references that are referred to are not specified so cannot be evaluated. A personal communication from a single practitioner does not constitute evidence of sufficient strength to warrant an LCD. Until that evaluation is enabled, the statement is overreaching. 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.
9 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. The above statement fails to acknowledge that these markers are often necessary to determine ductal vs. lobular differentiation and invasive vs. in situ disease in morphologically ambiguous cases, and should be ordered at the discretion of the pathologist. This results in information that allows the clinician to manage patients appropriately. (To achieve its purpose, an LCD needs to define the circumstances under which a test or procedure is or is not payable. Statements like ‘not routinely necessary’ or ‘not necessary in every case’ do not serve to define conditions for coverage). This statement does not provide the eligible provider or beneficiary the kind of prospective coverage information that is necessary to know if a service is covered. The very nature of these comments requires a retrospective evaluation of numerous beneficiaries’ records. In fact, the payment for the diagnostic medical evaluation of one beneficiary appears to be dependent on the complexity and extent of other beneficiaries’ diagnostic evaluation in a nearly random fashion. The commenter recognizes that these markers are only necessary in difficult or ambiguous cases. What for one pathologist may be ambiguous, may not be so for another pathologist. Thus, there is clinical decision leeway for the less experienced pathologist or truly ambiguous cases. What is important, is that it is not medically necessary for every case of breast cancer. This LCD does not limit the pathologist from performing, for example, e-cadherin stains in cases where the differential diagnosis is between invasive ductal and invasive lobular carcinoma as long as the pathologist documents in his/her report the medical necessity of doing so.
10 There is a lack of consensus in the medical community whether ordering of special stains or IHC stains prior to review of the H&E-stained slides for esophageal, gastric, and duodenal specimens is reasonable. Such discretion should be left to the individual physician. H. pylori is a treatable infectious disease that predicates severe chronic consequences (including carcinoma) and it is reasonable and necessary to assess for its presence on every gastric biopsy. As patient characteristics vary from practice to practice, the individual practitioner must determine what is appropriate for his or her particular patient population. In a recent survey of the membership of the Rodger C. Haggitt Gastrointestinal Pathology Society (GIPS), nearly 50% reported use of at least one ancillary stain to detect Helicobacter in all gastric biopsies. The GIPS survey results were included in a white paper on the use of ancillary stains for identifying H. pylori. The group concluded that, performing “up front” staining on all gastric biopsies is “generally unnecessary,” although they have outlined several instances in which staining upon review of the H&E is recommended. In contrast, a 2009 UK-based study of 167 pathology departments concluded that “there is a strong argument for the routine deployment of special stains in the oesophagus, stomach, and duodenum.” Special and/or immunohistochemical stains (e.g., AB-PAS, D-PAS, CDX2, etc.) may be used to detect intestinal metaplasia. Employment of these ancillary stains will generally assist in the detection of rare goblet cells, while more extensive intestinal metaplasia is generally detected on the H&E. For example, Harrison and colleagues, in a set of 92 cases with endoscopically apparent columnar-lined esophagus in which at least 6 biopsies had been taken, found that the addition of alcian blue/periodic-acid Schiff staining increased the rate of detection of intestinal metaplasia by 5.4%. Regarding the use of ancillary techniques for the detection of H. pylori, performance of these is often reasonable and necessary. There are clinical and pathologic associations with H. pylori infection. These may include but are not limited to the following: a) chronic active gastritis, b) chronic inactive gastritis (especially if concomitant ulcer disease, MALT lymphoma, or duodenal lymphocytosis are present; the patient has a history of treated H. pylori infection; or the patient is from an H.pylori-endemic geographic region), c) lymphocytic gastritis, d) chronic active carditis, e) chronic inactive carditis - the latter, if gastric biopsies are unavailable. It is generally accepted that either special stains or immunohistochemistry may be used to assist in the identification of H. pylori organisms. A physician cannot reasonably establish the medical necessity to order additional testing for a patient until they have reviewed the initial test(s). Review of the H&E specimen eliminates a large number of cases where H pylori stains are not necessary because the organisms can be seen via the microscope with the human eye. However, in the correct milieu, special stains or IHC are indicated. For small biopsies and issues surrounding re-facing of the block face, many practices obtain additional slides in case special stains are needed. In short, a business decision does not constitute medical necessity. The standard of care by all nationally recognized gastrointestinal pathologists is to examine the H&E stain first. When H. pylori is present, it can most often be seen on the H&E slide. In those cases where the H&E slide shows the changes of H. pylori infection (e.g., active chronic gastritis) and the organisms are not seen, a special stain can be performed and examined within four hours (the same day) confirming or denying the presence of the organism. There is no clinical significance to a four hour delay in those exceptional cases of H. pylori disease.
11 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
These statements imply that these stains are not often indicated. Several examples follow: Trichrome staining may be used to highlight a thickened subepithelial collagen table in suspected cases of collagenous gastritis. Gastrin and general neuroendocrine stains are very helpful to highlight pyloric metaplasia and neuroendocrine hyperplasia in suspected cases of atrophic gastritis. In the duodenum, CD3 staining may be useful to highlight T-cells in cases with borderline intraepithelial lymphocytosis suspicious for celiac sprue. Trichrome staining is again useful in suspected cases of collagenous sprue. Special and immunohistochemical stains for mucin and infectious agents may be needed, e.g. to establish a diagnosis of Whipple’s Disease or mycobacterial infection. In the colon, CD3 staining may again be helpful in cases with borderline intraepithelial lymphocytosis, and Trichrome staining is again useful to diagnose collagenous colitis, especially in its distinction from lymphocytic colitis. p53 staining may be useful throughout the tubal gut (especially Barrett’s esophagus, gastritis with intestinal metaplasia, and inflammatory bowel disease) to help distinguish reactive atypia from dysplasia. Immunohistochemistry is useful in the evaluation of colon polyps in multiple situations. Sessile serrated polyps are often difficult to distinguish from hyperplastic polyps; the distinction is important, with bearing on the risk of neoplastic progression and on the colonoscopic surveillance interval. Immunohistochemistry maybe useful in select cases to adjudicate this differential; potentially useful markers include Ki-67, CK20, MUC6, and annexin A10. Absence of mismatch repair (MMR) protein expression is noted in 2/3rds of adenomas from Lynch syndrome patients, and MMR testing maybe indicated to support or refute that diagnostic consideration. The NCCN Genetic/Familial High-Risk Assessment Colorecta lGuideline specifically states that “MSI and/or IHC testing of large polyps when a tumor sample is not available is justified in high-risk families”. In the duodenum, CD3 staining may be useful to highlight T-cells in select cases (e.g., borderline intraepithelial lymphocytosis suspicious for celiac sprue). Similarly, mucin stains to detect foveolar metaplasia are useful in certain circumstances. Specific references to substantiate the claim that “Overutilization of special stains has also been observed with duodenal biopsies” have not been cited. There are numerous instances where special stains and immunohistochemistry are useful in the evaluation of colon polyps. Specific examples in which ancillary techniques may be of value include, but are not limited to: a) distinction of sessile serrated polyp/adenoma from hyperplastic polyp, b) detection of deficient mismatch repair function which might suggest a diagnosis of Lynch syndrome and, c) situations where special stains maybe helpful in identifying stromal invasion and therefore establishing a diagnosis of carcinoma.		 The commenters are careful to indicate “may be useful” for specific indications. There is total agreement that stains may be useful for special indications, but the examples listed in the policy occur with 100% frequency for specific pathologists and pathology practices. The purpose of this policy is to clarify specific examples of inappropriate utilization - that billing for these services 100% of the time are not medically indicated and not a Medicare benefit.
12 Scientific data demonstrate 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 statement appears to be derived specifically from a 2006 study by CL Wright and JK Kelly published in the American Journal of Surgical Pathology entitled “The use of routine special stains for upper gastrointestinal biopsies.” This study represents the experience of two pathologists within a single anatomic pathology group (specifically at Royal Jubilee Hospital in Victoria, British Columbia), and, thus, the results are not necessarily generalizable. The quote is from the scientific literature and does not establish a frequency limit for Medicare review or audit purposes. 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 for special stains or IHC on 80-100% of their gastric biopsies reason to pause.
13 This draft LCD appears to be referencing NCCN Guidelines, although in an incomplete manner; also, these NCCN Guidelines are internally inconsistent. The Colon Cancer Guideline does recommend testing in colorectal cancer patients diagnosed at age =70 years old, as well as those >70 years old who meet Bethesda criteria. It also suggests that “MMR testing should also be considered for patients with stage II tumors,” in which case the testing, in addition to screening for Lynch syndrome, provides the additional benefit of informing the decision as to whether to pursue adjuvant therapy. Thus, in the case of a stage II colon cancer in a patient over 70 failing to meet Bethesda criteria, MMR and/or MSI testing should not be denied. The Genetics/Familial High-Risk Assessment: Colorectal Guideline similarly endorses testing in all patients <70 and in those =70 meeting Bethesda criteria. It also recommends testing in patients diagnosed with endometrial cancer diagnosed before age 50, as well as testing in two other scenarios not mentioned by the author of this draft LCD: 1. Patients with known Lynch syndrome in the family 2. Patients =5% risk of Lynch syndrome based on one of several clinical prediction models (e.g., MMRpro, PREMM,MMRpredict) As an alternative to age-based or Bethesda-guideline-driven “selective testing,” this NCCN Guideline co-endorses universal testing of colon cancer patients (i.e., screening of all colon cancers with MMR and/or MSI testing) as an alternative approach. From this and other examples addressed above and below, it is apparent that the authors of the dLCD have selected references and sections of references to support preconceived notions of appropriate utilization which may be based on financial costs rather than the statutory and regulatory standard of reasonableness and necessity. Several other groups have endorsed universal testing including the Centers-for-Disease-Control-and- Prevention-sponsored Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group and the Association for Molecular Pathology (AMP) Mismatch Repair-Defective CRC Working group. A subsequent cost-effectiveness analysis from the EGAPP demonstrated an incremental cost-effectiveness ratio for universal testing similar to that seen with screening colonoscopy. The Association for Molecular Pathology white paper specifically recommends concurrent mismatch repair protein immunohistochemistry, microsatellite instability testing, and BRAF V600E mutation analysis on all colon cancers. The NCCN Guidelines do not recommend a specific algorithm because MMR IHC-based and MSI- based algorithms have been shown to perform similarly. These tests may be performed in series, rather than in parallel, to maximize the sensitivity for detecting Lynch syndrome (i.e., we concur that if IHC is done first and is normal, MSI testing may be warranted) without having to perform MSI testing in the ~15% of colon cancers with abnormal MMR IHC results (i.e., we concur that MSI testing is generally not warranted if IHC is done first and is abnormal). Occasionally the results of either MMR IHC or MSI testing is equivocal in which case interpretation may be aided by knowledge of the results of the complementary test (e.g., in neoadjuvant- treated cancers in which MMR IHC testing may be difficult to interpret). Testing of patients without signs or symptoms of disease is ,b>screening and not a Medicare benefit.
14 We believe that prostate IHC generally requires one or two basal markers and AMACR because of the tiny size of the atypical focus and the fact that it is often present on only one or two profiles, thus, AMACR cannot be restricted to cases with negative basal markers because the markers and the AMACR are typically performed together in order to conserve the limited amount of tissue obtained through the small gauge needle used for prostate biopsy. There are indications to utilize ERG in high-grade prostatic intraepithelial neoplasia (HGPIN) diagnosed on H&E and/or immunohistochemical stains. In patients with HGPIN, those who express ERG have a higher risk of progression to developing adenocarcinoma than patients who have HGPIN and do not express ERG. Furthermore, basal cell markers are not always positive in benign acini (i.e., atrophy, inflammation, etc.) and are not always negative in cancer. The addition of AMACR adds significant information that is complementary to the basal cell markers and is required in combination in order to adjudicate between benign and malignant diagnosis. The suggestion that AMACR be used only after the use of basal cell markers is impractical as suspicious foci are typically small and may be lost on deeper levels of the paraffin tissue block. In fact, in a study by Green et al, in 52 cases of suspicious lesions, deeper sections did not contain the worrisome focus in 31 cases. 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. These markers are also necessary for accurately classifying low grade neuroendocrine tumors (carcinoid tumors) of the prostate. PIN-4 can also be used to differentiate high-grade prostatic intraepithelial neoplasia (HGPIN) from a focus of cribriform pattern of Gleason pattern 4 adenocarcinoma. Furthermore, the published literature has been unable to stratify suspicious foci into suspicious and “highly suspicious” subsets, despite repeat attempts. It is not rare to need additional IHC stains. It is not uncommon to get equivocal results on the first stains and additional ones are needed. It is frequently necessary to exclude metastatic carcinoma as part of the diagnostic workup, requiring multiple additional markers. Napsin-A is also important to make the diagnosis of pulmonary adenocarcinoma, especially in TTF-1 negative cases. Mucin stains may be utilized in some cases. In the upcoming WHO histologic classification of lung tumors, there is a comment indicating that mucin stains maybe used to exclude solid pattern ADC before performing 2 marker-panel IHC. Furthermore, the differential diagnosis of primary lung carcinoma commonly includes metastatic carcinoma. Not uncommonly, it is critical to subsequent treatment decisions to determine the origin of a carcinoma presenting as a lung mass. In various circumstances IHC stains are useful in the evaluation of cervical lesions or ovarian neoplasms. Distinction between serous carcinoma and other types of endometrial and ovarian carcinoma is clinically relevant as the results help determine the need for and type of adjuvant therapies. In morphologically ambiguous cases, immunohistochemistry performed at the discretion of the pathologist is helpful in making such a determination. Bladder: In certain situations IHC can be critical to achieving the correct diagnoses of a bladder specimen. Expert Genitourinary pathologists recently published a consensus statement regarding useful IHC stains in the context of bladder cancer and bladder biopsy IHC.1 They highlight the utility of IHC in the following contexts:
  • Confirmation of a urothelial primary at a metastatic site, or addressing the possibility of metastases to the bladder;
  • Distinction of reactive urothelial atypia from carcinoma in situ. diagnosis;
  • Role of IHC in staging bladder cancer. Experts acknowledge the utility of cytokeratin immunohistochemical staining to identify invasive tumor cells when “there are few cells, there is significant cautery artifact or there is an intense inflammatory infiltrate obscuring invasion of the tumor cell.” They mention that desmin staining could also be useful when thermophologic differential diagnosis requires separation of muscle from desmoplasia.
  • Muscularis propria invasion is an important cut-point in clinical management and prognosis for invasive urothelial carcinoma, especially in terms of surgical decision-making for cystectomy/partial cystectomy(NCCN guidelines, version 2.2104);
  • • Distinction between spindle cell lesions of the bladder. In terms of the rare but potentially malignant spindle cell lesions of the bladder (such as, but not limited to, pseudosarcomatousmyofibroblastic proliferation/inflammatorymyofibroblastic tumor (PMP/IMT), sarcomatoidurothelial carcinoma, leiomyosarcoma, and rhabdomyosarcoma), experts acknowledge that judicious IHC in the context of morphology has an important supportive role in this differential diagnosis setting, particularly among the tumors in the malignant category.
Kidney: Classification of renal tumors has changed with the characterization of important new morphologic and clinical variants of renal neoplasia, which differ in molecular genetics, prognosis and available therapies. In 2013, experts in genitourinary pathology, under auspices of the International Society of Urologic Pathology (ISUP), extensively reviewed the literature and proposed updates to the classification scheme for renal tumors. Many of these new entities were characterized based on IHC and molecular features, and as described above, have clinical relevance. Another subgroup of ISUP recently reviewed literature and surveyed experts on IHC in renal tumors, resulting in a consensus publication. The expert authors acknowledge that while morphology plays the major role in classification of renal tumors, IHC and other ancillary studies maybe helpful in the following scenarios, among others: verify histologic subtype, or to distinguish primary RCC from benign mimics and other tumor types that can occur in the kidney or from the rare metastasis to the kidney. Metastases of RCC to distant sites also usually need to be confirmed with the use of a panel of markers. The classification of the tumor type on limited material, such as core biopsies, may warrant immunohistochemical assessment from their survey, 87% of expert GU pathologists use IHC “occasionally” or “sometimes” in histologic subtyping. These experts further state that Oncocytoma, angiomyolipoma, and metanephric adenoma are benign mimics of RCC. Morphologic distinction can be problematic on occasion, and immunohistochemistry may then be required to assist in confirming the diagnosis. Several recent reviews highlight the important role of IHC in subtyping RCCs in unique settings. Ross, Martignoni and Argani (Johns Hopkins) review the differential diagnosis of RCC with both clear cell and papillary features, and the important role of IHC and other ancillary studies in classifying tumors with this rare constellation ofmorphology and outcome differences. Kryvenko et al. from the same institution review the differential diagnosis of eosinophilic renal neoplasms, including judicious use of immunohistochemistry.18 In contrast to the statement above that “it is rare to need stains to prove that….a kidney neoplasm is an oncocytoma or an eosinophilic or chromophobic renal cell cancer,” these expert authors state, “Although in excision specimens with the classic morphology of oncocytoma the use of CK7 may be avoided, in core biopsy specimens CK7 immunostain is more widely accepted to avoid misclassification of low-grade RCC as oncocytoma”. These statements are not accurate. For meningiomas, a measure of proliferation index is of prognostic significance which requires Ki-67 staining. Neuro-oncologists often request information on progesterone receptor status to guide possible treatment decisions as well. It has been established in the literature that expression of progesterone receptor may relate to tumor grade and recurrence of these neoplasms. Although some meningiomas do not require immunohistochemistry staining to identify them as meningioma, specific pathological subtypes may require immunostains to adjudicate the differential diagnosis. Similarly, for gliomas for grade II tumors, proliferation markers are prognostically important. For all gliomas, the classification and treatment decisions require knowledge of IDH1 mutation status (which can be more rapidly and more cheaply determined by immunohistochemistry stains if the canonical mutation is present). Similarly, the status for 1p/19q co-deletion is critical (and this can be approached in a surrogate manner through the use of p53 staining). There are subsets of skin biopsies in which immunohistochemistry (IHC) and special stains are required for diagnosis. The dLCD statement about only a “minority of skin lesions” requiring immunostains is vague, incomplete (for example most vesiculo-bullous and infectious diseases require immuno-fluorescence or special stains for diagnosis) and incorrect (melanocytic lesions for example may require IHC). The proportion of these cases varies from practice to practice depending on the case mix, so a uniform policy that does not take into consideration individual variations is not applicable. By way of example, a referral center for melanocytic lesions will examine a higher percentage of ambiguous melanocytic lesions that require IHCs compared to a general dermatopathology practice. Moreover, the decision as to whether IHC is needed for diagnosis in a specific case is complex and maybe dependent upon several factors including specific morphologic appearance, clinical presentation, clinical history patient demographics, anatomic location, and others. Establishing rigid exclusion criteria fails to take into consideration the complexity of this process and will likely prevent establishing the correct diagnosis in a significant number of cases. The decision to use a certain test should be left to the pathologist working on the case who is best positioned to determine the need for the test. The purpose of an LCD is to provide clear guidance on the circumstances in which it is appropriate to report services to Medicare for payment. Implementation of such sweeping guidelines in this vague and practice nonspecific form has the potential to negatively affect all pathologists in their provision of medically necessary services. The following are several more common examples in dermatopathology that routinely require the use of IHC and special stains:
  • Melanocytic lesions. Histologic diagnosis of melanocytic proliferations is difficult even by experts in the field as it requires integration of multiple criteria. While most lesions can be diagnosed by histology alone, there is a category of melanocytic lesions that cannot be reliably classified as benign or malignant by conventional histologic examination.52These lesions include dysplastic nevi with severe atypia, atypical Spitz nevi and Spitz tumors, atypical blue nevi, atypical deep penetrating nevi, clonal nevi and proliferative nodules which cannot be reliably distinguished from melanoma as well and nevoid melanomas that are often misdiagnosed as nevi. Such lesions require ancillary IHC stains to refine the diagnosis in almost all instances. The most common IHC stains used in these instances include dual labeling for Ki-67/ Melan-A, HMB-45 and p16.8,31 There are other indications for IHC in melanocytic proliferation. Desmoplastic melanomas are notoriously prone to be missed on histologic examination alone.21 IHC helps in differentiating desmoplastic/ spindle cell melanoma from a desmoplastic or sclerosing nevus (S100,MART1, HMB-45), differentiating desmoplastic melanoma from a scar (S100,SOX10, p75) or delineating the extent and depth of a desmoplastic melanoma (S100, SOX10, p75).
  • Sentinel lymph nodes. Sentinel lymph node (SLN) biopsy is routinely performed as part of the therapy and staging protocols in melanomas with a Breslow depth deeper than 1 mm, for Merkel cell carcinomas (MCC) or for other high grade cutaneous carcinomas.32,33 Typical protocols for SLN include routine IHC staining.
  • Cutaneous lymphomas, myeloid and histiocytic derived tumors. These tumors require IHC stains most of the time for a correct classification.
  • Differential diagnosis of dermal spindle cell tumors. Several spindle cell tumors involving dermis including desmoplastic melanoma, atypical fibroxanthoma, spindle squamous cell carcinoma, leiomyosarcoma and spindle cell variants of angiosarcoma have overlapping histologic features. IHC including S100, various cytokeratins, p63, smooth muscle markers and endothelial markers are usually employed to establish a diagnosis.
  • Infectious lesions. Histological identification of infectious organisms in skin biopsies most often requires the use of special stains. Common stains used are GMS and PAS for fungal elements, Ziel-Nielson and Fite for mycobacteria, Gram stain for bacteria and Giemsa stain for parasites.
  • Vesiculobullous lesions. All immunologically mediated vesiculobullous lesions require immunofluorescence for a correct diagnosis and classification.
Soft tissue tumors/skin tumors, like lymphomas, require immunophenotype for classification, prognosis and treatment. It is very important to separate tumors of different immunophenotype, even within the same diagnosis, based on syndromic associations and prognosis. In soft tissue and skin, benign and malignant tumors mimic each other and it is important to immunophenotype these tumors in order to correctly classify them and understand their behavior. Examples when a panel of immunohistochemical stains must be used include undifferentiated pleomorphic, round cell, and spindle cell soft tissue tumors. IHC helps to separate these mesenchymal tumors from spindle cell carcinoma and melanoma which have a different treatment protocol. The requirement for immunohistochemistry in soft tissue tumors is dependent upon the individual case, clinical and radiologic features, anatomic location, depth, patient demographics, and specific morphologic appearance. This decision must be made by the individual pathologist who is signing out the case and is ultimately responsible for the diagnosis. 		Medicare neither mandates nor restricts a pathologist from obtaining ,b>appropriate stains to establish a differential diagnosis or make a definitive diagnosis.
15 We disagree with the conclusion that IHC would not provide additional information if adenocarcinoma is detected on another core biopsy. For example:
  • If cancer is reported in only one core, it may appear to be a low volume tumor for which active surveillance is recommended, but confirming cancer in other cores might indicate a more extensive tumor for which surgery or radiation is considered as staging may change.
  • If the patient has only a single focus of low grade (Gleason pattern 3) carcinoma, he would probably have only active surveillance, but if an atypical focus in another core is shown to be high grade carcinoma (patterns 4 or 5), surgery or radiation would likely be recommended. In this case, IHC testing of those foci could have a major impact on patient management.
NCCN Guidelines Version 1.2015 Prostate Cancer (10/24/2014) state: For very low risk group patients, defined as T1c with Gleason score equal or less than 6, PSA less than 10 ng/m, fewer than 3 prostate biopsy cores positive, equal or less than 50% of cancer in any core, PSA density <0.15ng/mL/g, the initial therapy may consist of:
  • Active surveillance, EBRT or brachytherapy, or radical prostatectomy when expected patient survival is 20 years or more;
  • Active surveillance when expected survival is 10-20 years; observation if expected survival is less than 10 years.
For pathologists it is of the highest importance to determine the number of cores involved and the percentages of tumor in each core as this information provides actionable information to the treating physician.		 Is the commenter justifying performing IHC on the microscopically uninvolved cores if only one core is positive? If a microscopic focus is not apparent, one does not screen the other remaining cores with IHC. In the second example submitted by the commenters, a single high-grade (4 or 5) atypical focus is more likely to be evident to the eye than an intermediate grade lesion (3), and not likely to require IHC staining. The Gleason score is only one component for very low and low-risk prostate cancer.
16 There are lesions larger than 5% that can mimic prostatic adenocarcinoma on a prostate biopsy. These lesions would require immunohistochemical stains including HMWCK, p63, AMACR (racemase) or PIN-4. It is necessary to perform immunohistochemical staining of small suspicious lesions on contralateral cores in a patient with definitive adenocarcinoma diagnosed on the opposite side of the prostate gland. These stains include HMWCK, p63, AMACR (racemase) or PIN-4. There are universally accepted guidelines (NCCN) in which the urologist and/or oncologist utilizes the presence of adenocarcinoma and percentage of the core length involved with adenocarcinoma at multiple sites including but not limited to the right and left sides of the prostate gland in determining treatment. The treatment decision may include surveillance of the patient, radiation, and/or surgical resection. Clinical decisions are made based on the percentage of tumor present and the number of sites or quadrants the tumor is present in prostate biopsies of a patient. If a patient has adenocarcinoma on one side and the other side has a single atypical carcinoma, it is common practice to confirm the presence of cancer in the atypical focus. A single atypical focus does not add appreciably to the volume of tumor present. Even with a high grade focus contralateral to carcinoma, it is unlikely the patient will receive unilateral prostate irradiation therapy.
17 Ki-67 immunohistochemistry has been well-vetted, perhaps with greatest experience in gastroenteropancreatic neuroendocrine tumors, in which determination of the Ki-67 “proliferation index” is an essential component of tumor grading in the 2010WHO Classification of Tumors of the Digestive System. This system specifies that grade requires “mitotic count in at least 50 HPFs and Ki67 index using the MIB antibody as a percentage of 500-2000 cells counted in areas of strongest nuclear labeling (“hot spots”). Ongoing scientific inquiry is centered not on whether Ki-67 immunohistochemistry is valid, but rather on finer points including, a) what represent the optimal proliferation index cut points (e.g., >2% vs. >5% to assign an intermediate grade) and, more importantly, b) how the Ki-67 proliferation index will be best incorporated along with traditional histologic features (e.g.,mitotic activity, necrosis, architecture) in contemporary grading systems. In well-differentiated neuroendocrine tumors of the GI tract, the grade assigned based on the Ki-67 proliferation index has been shown to be greater than that assigned based on mitotic counting in one-third of cases, and in these instances, survival is determined by that higher grade, proving the value of Ki-67 immunohistochemistry in this setting.48 Determination of Ki-67 proliferation indices is more objective and reproducible than traditional mitotic counting, and inter-observer agreement of proliferation index determination has been proven to exceed that of mitotic counting, including in pulmonary carcinoids. The reference to a lack of international standardization appears to have been taken out of context. The relevant reference cited acknowledges that “there is no uniform methodology for Ki-67 IHC and evaluation of results,” but goes on to say, “most studies pinpointed monoclonal antibody MIB-1 on paraffin sections after antigen retrieval procedures and the assessment of the Ki-67 labeling index (LI) as the most widely agreed-upon methodologies, which have been optimized within each laboratory by longstanding experience with this marker.” This is a conspicuous example of the use of highly selective and partial literature citation, which undercuts the credibility of the purported evidence base of this dLCD. The authors of a recent publication (Alco G, et. al. Clinical and histopathological factors associated with Ki67 expression in breast cancer. Oncol Lett. 2015 Mar; 9(3): 1046–1054; 10.3892/ol.2015.2852) state that “Despite the published studies that have analyzed the prognostic role of Ki-67 in BC, uncertainty remains concerning the assessment of Ki-67, partly due to the fact that the majority of the studies were retrospective. As no clear evidence exists regarding the methodology of how to interpret and score Ki-67 levels, or a definition of set Ki-67 cut-off values, the routine use of Ki-67 is not advocated. If “testing is optimized within each lab by longstanding experience with this marker”, why would the authors of this and other scientific articles risk their credibility with making the above statement?
18 IHC for Chemosensitivity and Resistance Tumor Profiling It is difficult to comprehend what is being described in this section. The first two paragraphs discuss predictive factor testing and contrast that in the third and part of the fourth paragraphs with chemosensitivity/resistance assays. The last part of paragraph 4 is not clear due to incomprehensible sentence construction. The long bulleted list of “IHC panels” is not clearly described, does not follow what comes before, and mostly does not represent IHC assays (most of these are molecular tests). It appears to be describing acceptable companion diagnostics, but the construction of this section is such that the intent of the carrier is unclear. The commenters complain they lack understanding of the message in this section. To clarify, this section says that chemosensitivity and/or resistance tumor testing by IHC is NOT covered by Medicare.
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