ChatGPT Weighs In: Changing CGP Barriers at CMS to Benefit Patients

I am working to assist an organization that wants to improve CMS policy for cancer patients.  Generally, lung cancer patients need to have "comprehensive genomic testing," or CGP, which is a panel of 200 or more oncogenes to help direct the patient's therapy.  Sadly, half the time patients do not get this testing.   There are several policy reasons for this.

[accidentally hit Return]

ChatGPT

I understand your situation. Addressing policy issues for comprehensive genomic testing for lung cancer patients is a crucial and commendable effort. Here are several potential policy issues that might explain why only half of the patients are receiving this testing:

Cost and Reimbursement Policies: Comprehensive genomic testing can be expensive, and if the insurance policies, including Medicare and Medicaid, don't cover or only partially cover the cost of the test, patients might not be able to afford it.

1. Guideline and Approval Issues: If CGP isn't widely accepted or incorporated into official treatment guidelines or if it isn't FDA-approved, it may not be routinely offered to patients or covered by insurance.
2. Physician Awareness and Education: Some clinicians might not be aware of the benefits of CGP or how to interpret the results, which may prevent them from recommending the test.
3. Laboratory Infrastructure and Capacity: Some facilities might not have the necessary laboratory infrastructure or the capacity to perform CGP.
4. Policy on Off-label Drug Use: CGP can identify mutations that could potentially be targeted by drugs approved for other indications (off-label use). However, some insurance policies don't cover off-label drug use, which might discourage CGP.
5. Inequalities in Access: There might be disparities in access to CGP based on socio-economic status, geographical location, race, or other factors.
6. Data Privacy and Ethical Concerns: Some patients might refuse CGP due to concerns about genetic data privacy, potential discrimination, or ethical considerations. Clear policy guidelines need to be in place to address these issues.

Addressing these policy issues could involve advocating for change at various levels:

1. Healthcare Systems: Increase awareness of the benefits of CGP among healthcare providers, update clinical guidelines to incorporate CGP, and improve lab infrastructure.
2. Insurance Companies: Advocate for coverage of CGP and targeted therapies for off-label use.
3. Government: Advocate for legislation that requires insurance coverage for CGP, enforces genetic data privacy, and addresses health disparities. It may also be beneficial to involve patient advocacy groups in these efforts.
4. Education: Improve education on the benefits of CGP for clinicians and patients.

I hope this helps and I wish you the best in your efforts to improve access to comprehensive genomic testing for lung cancer patients!

User

Thank you!  Here are some specific policy concerns.

1.  Treating physician must order the test. CMS has a regulation, 42 CFR 410.31, that says the person ordering the test must be the treating physician who is managing the patient's illness.   (This wording is specifically meant to exclude the pathologist or radiologist).   This blocks the pathologist from ordering the CGP test, and some stakeholders thinks CMS should update this regulation.  However, the barrier and burden to getting CMS to update such a regulation is very high.

2.  Pathologist can order some tests, but only minor ones.  There is a pathologist ordering exception, but it is very limited.  CMS says a pathologist may order a test "necessary to complete a case."  CMS provides only one example, the pathologist sees like TB bacteria and orders a TB stain.  This is a trivial $10 expense, and it's not clear that CMS would belive the pathologist must order a $4000 CGP test to complete a case.   

3.  Standing orders.   There are some CMS rules around "standing orders" but they have traditionally been applied to simpler scenarios, such as ordering glucose 4 times a day while the patient is in hospital to monitor their blood sugar.   That is a 'Standing order."   Having a standing order in a hospital that all incoming cancer patients should have a $4000 CGP test, well, one or two hospitals may have adopted such a brave approach, but very few hospitals see that as a realistic meaning of "standing order."    

Giving these three policy barriers, how could we move forward? Treating physician must order; Pathologist can order [within very very limited scope], or instituational standing orders for costly test.

ChatGPT

Indeed, the policy barriers you've outlined pose challenges to increasing the accessibility of comprehensive genomic testing (CGP) for cancer patients. Here are a few potential strategies to navigate these issues:

1. Develop a Collaborative Model: Encourage a model of care where pathologists work more closely with treating physicians to ensure the latter order the CGP when appropriate. Educational initiatives could be set up to increase treating physicians' awareness of the benefits of CGP, and regular meetings or consultations could be organized between treating physicians and pathologists.
2. Advocate for Policy Changes: While changing CMS regulations is difficult, sustained advocacy can lead to eventual success. Efforts could be targeted towards expanding the role of pathologists in ordering tests, as well as broadening the interpretation of 'necessary to complete a case.' Advocacy campaigns should highlight the importance of CGP in determining appropriate therapies and improving patient outcomes.
3. Utilize Standing Orders Strategically: Standing orders could be applied for patients who meet certain criteria indicating high likelihood of benefit from CGP. For instance, all patients with a specific type or stage of cancer could be automatically recommended for CGP under a standing order. This narrower approach may be more palatable to hospitals and CMS, given the cost implications of a broader standing order policy.
4. Promote Research: Encourage and fund research demonstrating the benefits and cost-effectiveness of CGP. This evidence could be invaluable in making a case to CMS and insurance companies for more flexible policies around ordering CGP.
5. Leverage Technology: Digital health tools could be used to alert treating physicians when CGP might be beneficial for a patient, based on their specific diagnosis, stage of disease, etc. These tools could also provide physicians with information on how to interpret the results of CGP.
6. Partner with Patient Advocacy Groups: These groups can help apply pressure on policymakers and increase public awareness of the issue.

The key here is persistence, and to keep building a compelling body of evidence that demonstrates the value and necessity of CGP in treating lung cancer. This is a multi-faceted issue and will likely require a multi-pronged approach to effectively address.

User

How would the CMS agency likely respond to clarifying the rules or expanding the rules to be more friendly to CGP?  Personally, I am skeptical that CMS officials would be easy to talk to, or listen with an open mind, or actually move proactively forward.   

ChatGPT

Indeed, getting a bureaucratic institution like the Centers for Medicare & Medicaid Services (CMS) to change its policies can be a difficult process, but not an impossible one. Your skepticism is understandable, as the process often involves substantial time, effort, and evidence to convince these agencies to make a change.

CMS is fundamentally a public organization, driven by the mandate to provide effective and efficient healthcare services to the eligible population while balancing cost implications. They generally respond to changes when there's a clear evidence base that supports the efficacy, cost-effectiveness, and necessity of the proposed changes.

Here are some strategies that could potentially prompt a positive response from CMS:

Evidence-Based Approach: CMS typically requires robust clinical evidence demonstrating that a proposed change would lead to improved patient outcomes. This includes randomized clinical trials, observational studies, and cost-effectiveness analyses. A concerted effort to compile and present this evidence in a persuasive way will be important.

1. Stakeholder Support: Gathering support from a broad range of stakeholders, including patient advocacy groups, healthcare providers, and other health agencies, can amplify your voice and lend credibility to your argument. The more consensus there is among these groups about the importance of CGP, the more likely CMS is to take notice.
2. Public Comment Periods: During rulemaking periods, CMS opens up for public comments where suggestions and criticisms about proposed rules are heard. These are opportunities to submit formal comments and to encourage other stakeholders to do the same.
3. Pilot Programs: CMS might be more open to changes if they can first be tested on a small scale. If a pilot program could be established that demonstrates the benefits of more liberal CGP ordering, CMS might be more likely to consider policy changes.
4. Legislative Advocacy: CMS is bound by the laws that Congress enacts. If efforts to directly change CMS policy are unsuccessful, you could potentially advocate for legislative changes that would require CMS to modify their policies.
5. Continued Engagement: Regular communication with CMS officials to discuss your concerns, share new evidence, and maintain an open dialogue can build relationships and understanding over time.

Remember, policy change often requires persistence and time. Even if initial efforts are not successful, continued advocacy and the accumulation of evidence can eventually lead to change.

EXTRA

As we work to coordinate with other stakeholders and then bring these requests for changes to CMS, what are the biggest mistakes we could make (the "watch-outs").  How can we then mitigate those risks.

ChatGPT

As you embark on this journey to coordinate changes with CMS, it's essential to plan carefully and avoid potential pitfalls. Here are some common mistakes to watch out for and strategies to mitigate those risks:

Lack of Clear and Consistent Messaging: Miscommunication can undermine your campaign. Ensure that all stakeholders are on the same page and convey a consistent, unified message. Use clear, concise language that non-experts can understand. Mitigate this risk by having frequent meetings and updates with all stakeholders.

Not Enough Supporting Evidence: CMS will require substantial evidence of the benefits and cost-effectiveness of CGP. Not having enough data to back up your arguments will weaken your case. Mitigate this risk by proactively investing in research or leveraging existing literature and studies to strengthen your proposal.

Neglecting to Build Broad Support: If you only involve a few organizations or focus only on patient advocacy groups without engaging other stakeholders (like medical societies or pharmaceutical companies), CMS may not see the request as representative of a broader consensus. Mitigate this risk by actively reaching out to a wide range of stakeholders.

Ignoring the Cost Factor: While patient care is crucial, CMS also has to consider cost-effectiveness. Ignoring the financial implications of more widespread CGP testing could lead to a quick dismissal of your proposal. Mitigate this risk by conducting or sourcing cost-effectiveness analyses and demonstrating the potential long-term cost savings of early and precise intervention.

Overlooking the Bureaucratic Process: CMS, like any government agency, has specific procedures for changing regulations. If these processes are not followed precisely, your proposal could be dismissed on procedural grounds. Mitigate this risk by thoroughly understanding the policy change process or working with experts who do.

Underestimating Timeline: Policy change often takes longer than expected. If you underestimate the time required, you may not allocate sufficient resources to the effort, leading to burnout or loss of momentum. Mitigate this by developing a realistic timeline, having persistent follow-ups, and securing adequate resources.

Failure to Engage CMS Early: CMS should not be the last to hear about your proposal. Engage with them early and often, allowing them to provide feedback and direction to your efforts. Mitigate this by making CMS a part of your dialogue right from the early stages.

By anticipating these potential pitfalls and developing strategies to address them, you can greatly enhance your chances of successfully bringing about the policy changes you seek.

CLIA State Inspection Manuals

While we offer refer to labs operating "under CLIA regulations," those regulations are usually very short.  (Ensure appropriate controls are performed...).   There is somewhat more guidance under state inspection manuals on the CMS website.

See State Operations Manual, Chapter 6, Special Procedures for Laboratories, 256 pages, update 199, January 2020.

https://www.cms.gov/regulations-and-guidance/guidance/manuals/downloads/som107c06pdf.pdf

But "Chapter 6 Special Procedures for Laboratories" isn't the whole story.  

See also, "Survey Procedures and Interpretative Guidelines for Laboratories and Laboratory Services," which is "Appendix C" to the above.  This weighs in at 418 pages; currently Rev. 166, February 2017.

https://www.cms.gov/Regulations-and-Guidance/Guidance/Manuals/Downloads/som107ap_c_lab.pdf

Much of the quality systems in general seem to be managed at 493.1230ff (manual, p147ff).

There is a comment re standing orders, 493.1240.  There is a definition of reflex testing at page 46, and regarding quality controls at 493.801b. 

##

See my April 2022 blog.

https://www.discoveriesinhealthpolicy.com/2022/04/very-brief-blog-medicares-400-page-clia.html

MOLDX classic question "When do I submit a new TA for a new platform? How do I know?

ANSWER ONE

Today on July 11, I got a reply from the MOLDX info service and one of the senior MDs, Dr Angie Charnot-Katsikas.   She describes 3 tiers, 

• the first tier is 'do nothing', 
• the second tier is "Update text in te dex registry and email us too" and 
• the third tier is "Submit a new TA" more of an A to Z revalidation.   
• She doesn't have precise rules between these there pathways and suggests "check with MOLDX" for advice.

####

When a test has been modified in a minor way (ie change in a reagent; minor extraction protocol change) that information does not have to be provided as an update to MolDx.

 However, when a test has been modified in a significant way (ie methodology or platform has changed, for example from microarray to NGS; intended use or specimen types have changed) an email should be sent to MolDx informing us of the changes and the test information should be updated in DEX.  

A TA is required for significant changes, to ensure that they have been adequately validated and that the test still meets criteria of the policy.

###### 

ANSWER TWO

MolDx had a public webinar in June 2023 about its use of Z codes with United Healthcare, and there was a Q&A.  I asked the question about when a TA update is needed, and Dr. Bien Willner answered my question as below.  

• What amount of change to a lab procedure requires notification and new TA? Then, do you have to wait for it too come back approved, before using the test.
  • Let’s say you have a test with Z code and covered. Dr Bien Willner
  • Now you modify it. Tests are constantly being optimized.
  • In general, as long as the description of the test doesn’t change, the analytes, the intended use doesn’t change, we don’t care
  • If you change the brand of analyzer, we just assume you validated that and don’t tell us
  • You extract DNA more efficienctly, don’t tell us, your description doesn’t change
  • If you FUNDAMENTALLY change, like microarray to NGS, you drop the old version, tell us you are doing that and send us information about the validation you did to assure equivalence. It doesn’t need a new Z code. 
  •  You need to update the DEX registry (for example, your test title/description probably says microarray and must edit to read NGS)
  • If you need more, we will tell you so when we get your information
  • If you go from 12 to 25 genes, tell us what you did and why, just tell us and ask our direction what’s required. Minor = nothing for us (examples just stated.) Major = submit, but never a new Z code (perhaps very rare exceptions).

 

Inside Health Policy: ALZ CED

  July 7, 2023, 5:22 PM, Carey, Brian <BCarey@foleyhoag.com> wrote:

CMS Drafting PET Scan NCD, To Cover Alzheimer’s MRIs

By Jessica Karins<https://insidehealthpolicy.com/authors/Jessica-Karins> / July 7, 2023 at 6:48 PM

*
https://insidehealthpolicy.com/daily-news/cms-drafting-pet-scan-ncd-cover-alzheimer-s-mris?destination=node/136115 

* Share

Alongside its plan to gather observational data on potential adverse effects linked to the newly approved Alzheimer’s drug Leqembi, CMS will also soon propose a national coverage determination loosening current PET scan restrictions and will cover reasonable and necessary MRIs, a CMS spokesperson told Inside Health Policy Friday (July 7).

Currently, the spokesperson said, Medicare covers one positron emission tomography (PET) scan per lifetime to detect amyloid beta plaque, but the agency is currently reconsidering that and intends to issue a proposed NCD soon.

FDA granted full approval to Leqembi (lecanemab)<https://insidehealthpolicy.com/node/136089>, made by Biogen Inc. and Eisai Inc., Thursday (July 6). CMS immediately made available its registry for prescribing physicians, which patients must participate in as a condition of receiving Medicare coverage.

To qualify for the drug, Medicare patients will need a clinical diagnosis of mild Alzheimer's disease dementia or mild cognitive impairment due to Alzheimer’s disease, along with confirmation of amyloid beta plaque on the brain. The latter can be confirmed by biomarker testing including PET imaging, cerebral spinal fluid (CSF) studies or blood tests.

CMS also told IHP that reasonable and necessary diagnostic tests related to monitoring for adverse events will be covered, including MRIs to diagnose ARIA, CSF studies, and tests to identify the genetic marker APOE4, which is associated with negative reactions to anti-amyloid drugs.

CMS plans to conduct an observational study of patients<https://www.cms.gov/files/document/ced-study-description.pdf> using anti-amyloid drugs, based on registry and Medicare claims data. Prescribing physicians will need to submit data about patients’ cognitive function and any adverse events every six months, and initial results will be posted once a minimum sample size has been observed for 24 months.

The objectives of the study are to assess whether the treatment meaningfully improves health outcomes; how harms and benefits change over time; and whether benefits and harms vary according to the characteristics of patients, providers, and treatment settings.

“In addition to performing the required cognition and function assessments, prescribing clinicians will need to report on the patient’s use of anti-platelet and/or anti-coagulation therapy and whether the patient has developed new amyloid related imaging abnormalities (ARIA) since the last assessment data submission,” CMS wrote.

FDA issued a “black box” warning with Leqembi, meaining providers should be aware of serious safety risks. It is the most serious type of warning FDA attaches to a drug. The black box warns of brain bleeding, swelling and ARIA. It also says genetic testing should be performed before administering the drug because APOE4 are at higher risk of adverse events, but does not require the testing.

While not included in the black box warning, Leqembi’s label will also carry a warning about adverse events associated with anti-platelet or anti-coagulation blood thinners.

Diana Zuckerman, president of the National Center for Health Research (NCHR) and a critic of FDA’s decision to approve Leqembi, told Inside Health Policy she was disappointed the warning about blood thinners was not included in the black box, where providers would be most likely to see it. Although physicians should read a drug’s label in full, Zuckerman said, not all do.

Zuckerman is among several health researchers and providers who have said evidence is still limited<https://insidehealthpolicy.com/node/136112> on lecanemab’s safety and efficacy. While she said the CMS study will likely be able to identify the groups most at risk of serious side effects, she added that data without a control group likely will not produce reliable evidence of clinical benefit. -- Jessica Karins (jkarins@iwpnews.com<mailto:jkarins@iwpnews.com>

MolDx Barely Updates Infectious Panel FAQ

 MolDx has several tech assessmsent documents associated with its pathogen PCR testing LCD.   These include a FAQ.  Also a listing of non-acceptable bladder pathogen papers.

The FAQ was updated on June 19, 2023.   The last update (that I have) was December 2022.   I did a document compare, and the changes seemed very slight.  This cloud link should show the document compare:

https://draftable.com/compare/rJkWBBiozYJT

NEJM July 7, 2023: A bumpy road to diagnosis.

Complex case suspicious for lymphoma but rules in as Sarcoidosis.

I give the NEJM summary up to the diagnosis at at bottom.

https://www.nejm.org/doi/full/10.1056/NEJMcps2304844

CHAT GPT4 DISCUSSES THE CASE TO THIS POINT.

The patient's medical history, physical examination findings, and investigative results all point towards a diagnosis of Sarcoidosis. This systemic granulomatous disease often involves multiple organ systems, most commonly the lungs, skin, and lymph nodes, but can potentially affect any organ.

The noncaseating granulomas found in the excisional biopsy of the right groin lymph node, along with the extensive lymphadenopathy observed on CT and PET scans, are consistent with sarcoidosis. The lung nodules, skin changes, joint pains, elevated ACE levels, and her family history further support this diagnosis. Sarcoidosis is indeed known for its association with tattoos and could explain the skin changes overlying the tattoos.

The negative interferon gamma release assay, lack of necrosis in the biopsied lymph node, absence of pulmonary symptoms typical of tuberculosis, and the fact she has not traveled outside of Massachusetts make tuberculosis an unlikely diagnosis.

Lymphoma was another important consideration due to the systemic symptoms and lymphadenopathy. However, flow cytometry did not reveal any evidence of a lymphoproliferative disorder, and no malignant cells were found in the lymph node biopsy.

Systemic Lupus Erythematosus (SLE) was also a possibility given the patient's joint pains and rashes. However, the absence of other typical manifestations (such as photosensitivity, alopecia, Raynaud's phenomenon, or oral ulcers) and negative antinuclear antibody test make this less likely.

The next steps would be a multidisciplinary approach to manage her symptoms and the disease itself. This includes pulmonary function tests, ophthalmological evaluation, skin biopsy (if not already performed) from the affected areas, bone density test (due to the risk of osteoporosis in long-term sarcoidosis), and potentially cardiac evaluation as sarcoid can affect the heart. A treatment plan including corticosteroids or other immunosuppressive agents might be considered, based on the severity and extent of the disease. Regular follow-ups would be necessary to monitor her symptoms and the effect of treatment. Lifestyle modifications including smoking cessation will also be beneficial. Finally, genetic counseling may be of value given the family history of sarcoidosis.

Your analysis is correct.  Here is how the case continues, beyond the point that you read above. 

In this case, the combination of histologic findings (including an absence of cancer or infection), radiographic signs, and cutaneous manifestations are diagnostic of sarcoidosis.

Prednisone was prescribed at a dose of 40 mg daily, and the patient had rapid abatement of her abdominal and pulmonary symptoms. She reported no palpitations, lightheadedness, or syncope; an electrocardiogram showed no conduction abnormalities. An ophthalmologic evaluation showed no uveitis or retinal abnormalities such as “candle wax dripping” lesions (perivenous exudates associated with periphlebitis in patients with acute ocular sarcoidosis). Biopsy cultures were negative for mycobacteria after 60 days.

The patient did well for 1 year but had a recurrence of symptoms after completing a prednisone taper. Prednisone treatment was restarted, and the patient was transitioned to methotrexate (a glucocorticoid-sparing immunosuppressant)

ChatGPT4 CLOSING REMARKS

This is a classic presentation of sarcoidosis, a systemic granulomatous disease that can affect any organ system but most commonly involves the lungs and lymph nodes. The patient’s symptoms such as abdominal pain, unintentional weight loss, night sweats, skin changes, and the presence of a nonproductive cough and dyspnea suggest multi-organ involvement.

Sarcoidosis often presents with non-specific symptoms, as seen in this case, making the diagnosis challenging. The presence of non-necrotizing granulomas in biopsy samples from involved tissues is a hallmark of sarcoidosis but is not specific. Exclusion of other causes, such as infections or malignancy, is a crucial part of the diagnostic process.

It is interesting to note the patient's response to prednisone, the initial first-line therapy for sarcoidosis. Prednisone can effectively control the symptoms and inflammation associated with sarcoidosis. However, as in this case, some patients may require more prolonged treatment or additional immunosuppressive medications, like methotrexate, due to recurrence of symptoms after initial tapering of prednisone.

Methotrexate has been shown to have a steroid-sparing effect, and its use can help mitigate the long-term side effects of corticosteroids. It is generally well-tolerated and effective in the management of sarcoidosis. Regular monitoring is essential to check for potential adverse effects, such as hepatotoxicity and myelosuppression.

In summary, this case illustrates the diagnostic challenges of a disease with a highly variable presentation, and the importance of a systematic approach to investigation, including histological confirmation and exclusion of differential diagnoses. It also highlights the potential for relapse in sarcoidosis and the need for individualized long-term management plans.

##

NEJM SUMMARY UP TO DX.

In this Journal feature, information about a real patient is presented in stages (boldface type) to an expert clinician, who responds to the information by sharing relevant background and reasoning with the reader (regular type). The authors’ commentary follows.

A 32-year-old woman presented to the emergency department with a 6-month history of worsening abdominal pain. She rated the pain as 10 on a 10-point scale of severity; the pain was localized to the epigastrium and was characterized as intermittent and cramping in nature, without substantial radiation. It was not associated with eating or exertion but was associated with unintentional weight loss of 20 lb (9 kg). She reported chills, night sweats, a nonproductive cough, and intermittent dyspnea and wheezing that did not respond to inhaled albuterol. She reported that she had not had fever, headaches, vision changes, chest pain, nausea, emesis, changes in bowel habits, or genitourinary symptoms. Her menstrual cycles were normal.

Localized gastrointestinal disorders (e.g., gastritis, peptic ulcer disease, and pancreatitis) could cause chronic abdominal pain but would not explain this patient’s systemic symptoms. Chills, sweats, and weight loss suggest a systemic infectious, inflammatory, or neoplastic disease. An indolent infection, such as tuberculosis or histoplasmosis, could also explain her pulmonary symptoms. A cancer, such as a lymphoma, could cause a similar constellation of symptoms as a result of pulmonary and abdominal lymphadenopathy. Additional symptoms suggestive of autoimmune disease (Raynaud’s phenomenon, arthritis, oral ulcers, and eye or skin changes), infectious exposures, and a family history of inflammatory disease or cancer would help refine the differential diagnosis.

The patient noted intermittent joint pain in both hands but reported no color changes in the fingers or pain elsewhere in her limbs. She reported that she had had skin changes on her legs over the course of 6 months, with nonpainful bumps present at the sites of recent tattoos. She did not have dry eyes, dry mouth, oral ulcers, pleuritic chest pain, photosensitivity, or alopecia. Her medical history was notable for gastroesophageal reflux disease and constipation. She had no history of surgery. Her medications included acetaminophen twice daily for abdominal pain, with only modest effect. She had no known allergies. She identified as Black and lived in Boston; she worked as a patient care assistant and did not travel outside of Massachusetts. She was sexually active with one male partner and used condoms consistently. She had smoked a half pack of cigarettes daily for 13 years, and only rarely used marijuana or vaped. She had no known exposures to inhaled particulates such as silica or metal dusts, including beryllium. She consumed eight alcoholic drinks per week. She reported that she did not use other drugs. There was no family history of cancer or gastrointestinal disease; an aunt had sarcoidosis.

Reflux and constipation could contribute to the abdominal pain but would not explain her night sweats and weight loss. The absence of travel outside Massachusetts reduces concern for an endemic mycosis such as histoplasmosis, but her health care occupation increases her risk of tuberculosis. Although her alcohol consumption modestly exceeds “healthy” intake (<7 drinks per week in women), it is unlikely to cause alcohol-related complications at this age. Skin changes involving tattoos can be seen in infectious and inflammatory or granulomatous conditions, most classically in sarcoidosis; the family history increases concern for sarcoidosis.

Figure 1.

Skin Changes.

The patient’s oral temperature was 36.5°C, the heart rate 62 beats per minute, the blood pressure 122/66 mm Hg, the respiratory rate 16 breaths per minute, and the oxygen saturation 98% while she was breathing ambient air. Her height was 163 cm, and her weight was 58 kg, for a body-mass index (the weight in kilograms divided by the square of the height in meters) of 21.8. She was well-appearing, without cachexia. The conjunctivae, oropharynx, and parotid glands were normal. There was nontender lymphadenopathy bilaterally in the cervical, supraclavicular, axillary, and inguinal chains. Cardiac and pulmonary examinations were normal. The abdomen was soft and nondistended, with mild tenderness to deep palpation in the epigastrium without rebound, guarding, organomegaly, or other masses. The limbs showed mild tenderness to palpation in the left elbow and right knee, with a full range of motion and no erythema, swelling, or effusion; the remaining joints were unremarkable. The neurologic examination was normal. The patient’s skin was warm and dry; scattered firm, slightly eroded, nontender, erythematous and violaceous papules were present on the arms and legs, with a cluster at the right knee and overlying bilateral tattoos on the legs (Figure 1).

Although diffuse lymphadenopathy may reflect infectious or inflammatory processes, lymphoma is of particular concern. The combination of arthralgias, lymphadenopathy, and rashes could be explained by systemic lupus erythematosus even without Raynaud’s phenomenon, photosensitivity, or alopecia. The erythematous papular rash could be caused by an infection such as borreliosis or mycobacterial disease, cancers such as cutaneous marginal-zone lymphoma or T-cell lymphoma, or a dermal inflammatory reaction. An association with tattoo ink is characteristic of sarcoidosis but can also be seen in the context of cutaneous pseudolymphoma (benign lymphoproliferation in response to cutaneous antigens) or infections related to local inoculation.

Results of liver-function tests and levels of serum electrolytes, creatinine, calcium, lipase, and thyroid-stimulating hormone were normal, as were the prothrombin time and partial thromboplastin time. The white-cell count was 5240 per microliter, with 36.1% neutrophils (reference range, 48 to 76), 36.8% lymphocytes (reference range, 18 to 41), 11.6% monocytes (reference range, 4 to 11), and 14.5% eosinophils (reference range, 0 to 5); the hemoglobin level was 13.6 g per deciliter, and the platelet count 338,000 per microliter. The erythrocyte sedimentation rate was 50 mm per hour (reference range, 0 to 20), and the C-reactive protein level was normal. The lactate dehydrogenase level was 294 U per liter (reference range, 135 to 225), the angiotensin-converting enzyme level 146 U per liter (reference range, 16 to 85), and the total IgG level 2243 mg per deciliter (reference range, 700 to 1600). An interferon gamma release assay for tuberculosis was negative, as was syphilis immunoglobulin testing. Serologic testing for hepatitis A, B, and C viruses, human immunodeficiency virus, antinuclear antibody, antineutrophil cytoplasmic antibodies, and anti–double-stranded DNA antibody were negative; levels of C3 and C4 were normal. Urinalysis was normal, and a urine pregnancy test was negative.

Many of these tests suggest nonspecific increased activation of the immune system. An elevated erythrocyte sedimentation rate with a normal C-reactive protein level can be seen in the context of infections, autoimmune diseases such as systemic lupus erythematosus, and cancers with overproduction of immunoglobulins (e.g., Waldenstrom’s macroglobulinemia and multiple myeloma). Eosinophilia can occur with cancers, including lymphomas; in inflammatory disorders, such as sarcoidosis; or in infections (typically parasitic infections, but also others, including fungal infections). An elevated serum level of angiotensin-converting enzyme is also nonspecific and inadequate for a diagnosis of sarcoidosis; it can be elevated in the context of Hodgkin’s lymphoma, coccidioidomycosis, and berylliosis, among other conditions. The negative interferon gamma release assay makes tuberculosis less likely, but this assay can be falsely negative in patients with disseminated tuberculosis. Negativity for antinuclear antibody essentially rules out systemic lupus erythematosus. The absence of proteinuria or hematuria rules out glomerulonephritis. Overall, I remain concerned about lymphoma, with sarcoidosis as a likely alternative diagnosis.

Figure 2.

CT and PET Scans of the Chest, Abdomen, and Pelvis.

Chest and abdominal computed tomography (CT) performed after administration of contrast material (Figure 2A through 2D) showed diffuse thoracic and extensive bulky peritoneal and retroperitoneal lymphadenopathy, as well as subcentimeter nodular lower-lobe pulmonary opacities that were consistent with a possible “galaxy sign” (i.e., coalescent pulmonary granulomas that create a mass-like appearance) (Figure 2A). Whole-body positron-emission tomography (PET) showed intensely hypermetabolic lymph nodes in the cervical, retropharyngeal, mediastinal, internal mammary, subcarinal, axillary, abdominopelvic, periaortic, mesenteric, iliac, and inguinal regions. Additional hypermetabolic lesions were noted in areas of bone, lung, and skin (Figure 2E through 2H).

Extensive lymphadenopathy is highly suggestive of a lymphoproliferative disorder, particularly lymphoma, and the hypermetabolism seen in the PET scan further supports this diagnosis. Lymphadenopathy from a metastatic solid tumor, such as breast or lung cancer, is unlikely in this young patient without evidence of a primary tumor. Hypermetabolic lymphadenopathy can also be associated with infectious or inflammatory processes, including disseminated bacterial or fungal infections or autoimmune responses, as in systemic lupus erythematosus. Sarcoidosis remains possible, given the symmetric mediastinal and bilateral hilar lymphadenopathy, and could also explain the skin and bone involvement; sarcoidosis is also a well-recognized cause of a galaxy sign, although this finding can also occur in other conditions, such as tuberculosis. Before a diagnosis of sarcoidosis is made, lymphoma should be ruled out by definitive histologic examination.

Figure 3.

Right Inguinal Lymph-Node Tissue with Diffuse Granulomatous Changes.

The patient underwent excisional biopsy of a right groin lymph node. Flow cytometry of the tissue specimen showed no evidence of a lymphoproliferative disorder. Pathological analysis showed lymph-node effacement by nonnecrotizing granulomatous lymphadenitis without malignant cells (Figure 3). Gram and acid-fast staining was negative, as were bacterial and fungal cultures.

Effacement of lymph-node architecture by granulomas with a nonnecrotizing core is characteristic of, but not specific for, sarcoidosis. Fungal and mycobacterial infections should be ruled out with microbiologic cultures and stains. Multiple biopsy specimens may be needed to identify tuberculosis; however, this patient’s risk of tuberculosis is relatively low, and classically both tuberculosis and fungal infection would appear histologically as necrotizing (caseating) granulomas. Sarcoid-like granulomatous reactions may also be seen in association with Hodgkin’s lymphoma, non-Hodgkin’s lymphomas, seminoma in men, and a variety of carcinomas; clinical correlation is essential to exclude this possibility

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