Category: Health

In 1882 the French physician Ernest Gaucher identified ‘his’ disease as a typical enlargement of the spleen, easily seen as an epithelioma but not being leukemia or any other kind of cancer. Nowadays we know it comes with an increased risk of hematological malignancies like multiple myeloma and hepatocellular carcinoma. If left untreated, at least.

Lately, in the world of Gaucher Disease (GD), there is a new kid on the block: Gaucheroma. What is it? In this post, I will try to get myself an answer to that.

Lesions

A century later in 1982, the esteemed and beloved pathologist Robert E. Lee published a roundup of 275 cases of GD, with 100 spleens that were removed from them. He described:

“In addition to the fibrosis associated with small or large infarcts there are nodular lesions that are related to vascular malformations of the red pulp. These may measure up to 10.0 cm in diameter and they are dark purple nodules that bulge when sectioned. The parenchyma in these nodules is composed of numerous round spaces that contain Gaucher cells as well as blood cells and fibrous areas usually develop as the vascular areas become organized. … Any of these previously described nodules may be incorrectly considered to be neoplastic when in reality they are the result of distortion of splenic architecture by Gaucher cells.”

Lee continued that liver involvement in GD type 3 is a form of fibrosis that converts the parenchyma into small nodules. In the fibrous areas, there are numerous Gaucher cells. Others have described these cases as cirrhosis. In his view, adenopathy is not a feature of clinical illness. Lee closes his article with

“As we enter the second century of our knowledge of this disease we should keep Dr. Gaucher’s talent of making clinicopathological observations in mind as we search for clues to the better understanding of the various clinical forms of the disease.”

Other publications followed, mentioning these nodular lesions in spleens and livers, increasingly seen with imaging techniques like ultrasound and MRI.

In 2009, Poll and Von Dahl found an extensive accumulation of Gaucher cells within liver sinusoids and labeled it as hepatic Gaucheroma (Gaucher-cell pseudotumor).

Masses and lymphadenopathy

In 2002, Lim et al reported the case of a child with GD type 3 on ERT with a 5 cm mesenteric mass. Surgical biopsy revealed that it was a collection of lymph nodes infiltrated with Gaucher’s cells at the base of the mesentery, also confirmed histologically to be Gaucher’s cell infiltrates.

Fowler et al presented in 2006 two children with persistent abdominal lymphadenopathy whilst receiving ERT. Needle core biopsies showed they contained macrophages that do not form granulomas or classic Gaucher cells on light microscopy. It was assumed to be incomplete clearance, incomplete/partial enzyme replacement, or possibly an unusual response to a relatively small amount of storage material.

Another child with GD (type 3) was reported the following year by Burrow et al, as having developed progressive mesenteric and mediastinal lymphadenopathy. They interpreted it as poorly accessible, differentially responsive compartments in patients with Gaucher disease who are receiving enzyme therapy.

Yağci et al followed in 2009 with a 5-year-old with GD type 3 on ERT. She was initially presented with an ill-defined abdominal mass of 10 cm, palpable in the umbilical area. Ultrasound revealed multiple conglomerating mesenteric lymphadenopathies, some of which contained necrotic areas. Histopathological examination revealed diffuse infiltration of Gaucher cells.

Abdelwahab and SeifEldien reported in 2015 eight cases, some developing lymphadenopathy in association with type 1 GD. Their cohort developed mesenteric and mediastinal lymphadenopathy while on therapy for an average duration of 3 years.

In 2019, Tseng et al. reported from a regular abdominal MRI exam of a 3-year-old a 3.5 × 2.3 cm hypointense under T1 lobulated mass, at S5 and S6 in the liver. Clustered enlarged lymph nodes at the mesenteric and inguinal regions were also discovered during the regular checkup.

Recently, in 2022, Tantawy et al studied fifty children on ERT, of which 26 (60 GD1, 20 GD3) were confirmed to have abdominal lymphadenopathy (ALN). Their size was found to be significantly correlated with the disease severity (SSI) and LysoGB1. Histology was not determined. ALN was found in 80% of splenectomized children. They postulate that ALN can be considered as a marker of GD severity, and regard it as a potential sequel of high disease burden.

So, what is it?

To my understanding, nodular lesions in the spleen and liver are clusters of Gaucher cells, occasionally affecting the surrounding tissues. I wonder if the clusters are formed at sites that normally represent lymph nodes inside an organ. These “pseudotumor” disturbances are thought to increase the occurrence of local neoplasia, but I have not seen statistics of patients on treatment until now.

Gaucheromas outside the spleen and liver are only seen with patients on Gaucher treatment, so far being ERT. In general, these soft-tissue masses are regarded to be lymphadenopathies.

Overlooking gaucheromas inside and outside organs, it is my opinion that they should only be named as such when Gaucher cells are seen in them. Preferably we forget the term gaucheroma, and only use the terms Gaucher cell clusters or masses as Ramaswami et al suggest. The lesions and masses in Gaucher patients can be considered common and understandable, implying no reason for biopsy. Suspicion of neoplasia changes that, of course. Also, as a mass they can cause other serious complications including protein-losing enteropathy.

Their clinical relevance as such lies in their substrate storage, and it seems that only systemic intervention may influence that. (Additional) SRT or a chaperone might be an option, as Yano et al suggest too. I also wonder if these Gaucher cells can be released from the sites by somehow affecting their bonding to others or to the structure. Kim et al seem to support this view.

References

Disclaimer

I am not a clinician nor otherwise medically educated. If you relate this post to your own health, please talk with your clinician about that.

The COVID-19 pandemic has, while continuing surveillance and research, entered a phase of global mass vaccination. Parallel, a morbid growth of boundaries and requirements has emerged to control the entrance of travelers into states all around the world, including a wide variety of analog and digital certificates of vaccination. These control efforts are aimed at protection against the international spread of the disease, as are the certificates. But are these certificates legal? And practical?

The International Health Regulations (IHR) laid down in article 35 that in international traffic no health documents shall be required, other than those provided under the IHR or in recommendations issued by the WHO. According to the next article certificates of vaccination shall conform to certain provisions – when the vaccine is administered pursuant to the IHR or recommendations thereto. In Annex 6 of the IHR, it is stressed: “Persons undergoing vaccination or other prophylaxis under these Regulations shall be provided with an international certificate of vaccination or prophylaxis (hereinafter the “certificate”) in the form specified in this Annex. No departure shall be made from the model of the certificate specified in this Annex.”

The IHR is a treaty, legally binding to all WHO member states. All those certificates of vaccination that do not conform to the IHR provisions are therefore illegal.

With respect to digital certificates, the WHO is momentarily working on guidance documents for the development of Digital Documentation of COVID-19 Certificates (DDCC). Presumably, that process will result in a recommendation. Until then any digital certificate will conflict with the IHR, as will any that does not conform to the provisions of the resulting recommendation.

The only vaccination pursuant to the IHR is vaccination against yellow fever. What about a recommendation for vaccination against COVID-19? Rules on recommendations are laid down in articles 15-18 of the IHR. They are formally issued by the Director-General of the WHO, usually by issuing the advice of the Emergency Committee regarding the coronavirus disease (COVID-19) pandemic as a Temporary Recommendation.

In its April 2021 meeting, that Committee advised as Temporary Recommendation to not require proof of vaccination as a condition of entry, given the limited (although growing) evidence about the performance of vaccines in reducing transmission and the persistent inequity in the global vaccine distribution.

Though many words are spent on vaccination against COVID-19 by the Committee in its advice and by the WHO throughout its website, a formal recommendation to vaccinate is not issued. The entire world is vaccinating against COVID-19, but the WHO apparently does not recommend it. Subsequently, certificates of vaccination have no basis in the IHR and do not have to conform to its provisions.

The Committee motivated its advice by referring to the limited (although growing) evidence about the performance of vaccines in reducing transmission and the persistent inequity in the global vaccine distribution. Both are the consequence of a novel emergency that (presumably) requires a novel intervention, as evidence of its performance in reducing transmission only follows after due time by epidemiological research, and equitable global distribution is hampered by human nature and practicalities.

Many novel emergencies will have these consequences. They will be met only after several months at least, needed to establish the importance or irrelevance of a proven vaccination. Meanwhile, in a pandemic like with COVID-19, the damage by the standstill of international traffic will have accumulated to levels pressing for its swift restoration.

Vaccinations administered until the conclusion that their proof is recommendable as a condition for entry are just as valid as vaccinations administered from then on. After recommendation, they have to be proven at points of entry, whether administered after or before that the recommendation. It is counterproductive to have the ‘new’ vaccinations certified according to specific provisions, and the ‘old’ ones not. Therefore it should be recommended by the WHO that any vaccinations with possible future relevance for international traffic are to be certified the same way. Analog certification may not need the full format prescribed by the IHR. Digital certification will ease formatting.

That being said, it stands to logic that the WHO declared:
“Regardless of any technology implemented in the future, the COVID-19 vaccination status of international travelers should be recorded through the International Certificate for Vaccination and Prophylaxis based on the model presented in Annex 6 of the IHR. The same format could be adapted once WHO pre-qualified COVID-19 vaccines become available universally and relevant recommendations are provided under the IHR.”

The COVID-19 pandemic has, while continuing surveillance and research, entered a phase of global mass vaccination. Parallel, a morbid growth of boundaries and requirements has emerged to control the entrance of travelers into states all around the world, including a wide variety of analog and digital certificates of vaccination. These control efforts are aimed at protection against the international spread of the disease, as are the certificates. But are these certificates legal? And practical?

The International Health Regulations (IHR)[1] laid down in article 35 that in international traffic no health documents shall be required, other than those provided under the IHR or in recommendations issued by the WHO. According to the next article certificates of vaccination shall conform to certain provisions – when the vaccine is administered pursuant to the IHR or recommendations thereto. In Annex 6 of the IHR, it is stressed: “Persons undergoing vaccination or other prophylaxis under these Regulations shall be provided with an international certificate of vaccination or prophylaxis (hereinafter the “certificate”) in the form specified in this Annex. No departure shall be made from the model of the certificate specified in this Annex.”

The IHR is a treaty, legally binding to all WHO member states. All those certificates of vaccination that do not conform to the IHR provisions are therefore illegal.

With respect to digital certificates, the WHO is momentarily working on guidance documents for the development of Digital Documentation of COVID-19 Certificates (DDCC)[2]. Presumably, that process will result in a recommendation. Until then any digital certificate will conflict with the IHR, as will any that does not conform to the provisions of the resulting recommendation.

The only vaccination pursuant to the IHR is vaccination against yellow fever. What about a recommendation for vaccination against COVID-19? Rules on recommendations are laid down in articles 15-18 of the IHR. They are formally issued by the Director-General of the WHO, usually by issuing the advice of the Emergency Committee regarding the coronavirus disease (COVID-19) pandemic as a Temporary Recommendation.

In its April 2021 meeting, that Committee advised as Temporary Recommendation to not require proof of vaccination as a condition of entry, given the limited (although growing) evidence about the performance of vaccines in reducing transmission and the persistent inequity in the global vaccine distribution.[3]

Though many words are spent on vaccination against COVID-19 by the Committee in its advice and by the WHO throughout its website, a formal recommendation to vaccinate is not issued. The entire world is vaccinating against COVID-19, but the WHO apparently does not recommend it. Subsequently, certificates of vaccination have no basis in the IHR and do not have to conform to its provisions.

The Committee motivated its advise by referring to the limited (although growing) evidence about the performance of vaccines in reducing transmission and the persistent inequity in the global vaccine distribution. Both are the consequence of a novel emergency that (presumably) requires a novel intervention, as evidence of its performance in reducing transmission only follows after due time by epidemiological research and equitable global distribution is hampered by human nature and practicalities.

Many novel emergencies will have these consequences. They will be met only after several months at least, needed to establish the importance or irrelevance of a proven vaccination. Meanwhile, in a pandemic like with COVID-19, the damage by the standstill of international traffic will have accumulated to levels pressing for its swift restoration.

Vaccinations administered until the conclusion that their proof is recommendable as a condition for entry are just as valid as vaccinations administered from then on. After recommendation they have to be proven at points of entry, whether administered after or before that the recommendation. It is counterproductive to have the ‘new’ vaccinations certified according to specific provisions, and the ‘old’ ones not. Therefore it should be recommended by the WHO that any vaccinations with possible future relevance for international traffic are to be certified the same way. Analog certification may not need the full format prescribed by the IHR. Digital certification will ease formatting.

That being said, it stands to logic that the WHO declared [4]:
“Regardless of any technology implemented in future, the COVID-19 vaccination status of international travelers should be recorded through the International Certificate for Vaccination and Prophylaxis based on the model presented in Annex 6 of the IHR. The same format could be adapted once WHO pre-qualified COVID-19 vaccines become available universally and relevant recommendations are provided under the IHR.”

[1] World Health Organization, ed., International Health Regulations (2005), 3rd edition (Geneva, Switzerland: World Health Organization, 2016), https://www.who.int/publications/i/item/9789241580496.

[2] “Revised Scope and Direction for the Smart Vaccination Certificate and WHO’s Role in the Global Health Trust Framework,” June 4, 2021, https://www.who.int/news/item/04-06-2021-revised-scope-and-direction-for-the-smart-vaccination-certificate-and-who-s-role-in-the-global-health-trust-framework.

[3] “Statement on the Seventh Meeting of the International Health Regulations (2005) Emergency Committee Regarding the Coronavirus Disease (COVID-19) Pandemic,” April 19, 2021, https://www.who.int/news/item/19-04-2021-statement-on-the-seventh-meeting-of-the-international-health-regulations-(2005)-emergency-committee-regarding-the-coronavirus-disease-(covid-19)-pandemic.

[4] “Interim Position Paper: Considerations Regarding Proof of COVID-19 Vaccination for International Travellers,” February 5, 2021, 19, https://www.who.int/news-room/articles-detail/interim-position-paper-considerations-regarding-proof-of-covid-19-vaccination-for-international-travellers.